Repetitive transcranial magnetic stimulation combined with olanzapine and amisulpride for treatment-refractory schizophrenia

BACKGROUND Treatment-refractory schizophrenia(TRS),accounting for approximately 30%of all schizophrenia cases,has poor treatment response and prognosis despite treatment with antipsychotic drugs.AIM To analyze the therapeutic effectiveness of repetitive transcranial magnetic stimulation(rTMS)combined with olanzapine(OLZ)and amisulpride(AMI)for TRS and its influence on the patient’s cognitive function.METHODS This study enrolled 114 TRS patients who received treatment at the First Affiliated Hospital of Zhengzhou University between July 2019 and July 2022.In addition to the basic OLZ+AMI therapy,54 cases of the control group(Con group)received modified electroconvulsive therapy,while 60 cases of the research group(Res group)received rTMS.Data on therapeutic effectiveness,safety(incidence of drowsiness,headache,nausea,vomiting,or memory impairment),Positive and Negative Symptom Scale,Montreal Cognitive Assessment Scale,and Schizophrenia Quality of Life Scale were collected from both cohorts for comparative analyses.RESULTS The Res group elicited a higher overall response rate and better safety profile when compared with the Con group.Additionally,a significant reduction was observed in the post-treatment Positive and Negative Symptom Scale and Schizophrenia Quality of Life Scale scores of the Res group,presenting lower scores than those of the Con group.Furthermore,a significant increase in the Montreal Cognitive Assessment Scale score was reported in the Res group,with higher scores than those of the Con group.CONCLUSION The treatment of TRS with rTMS and OLZ+AMI is effective and safe.Moreover,it can alleviate the patients’mental symptoms,improve their cognitive function and quality of life,and has a high clinical application value.

HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor

Objective Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits.This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet(HFD)and explored the involvement of endoplasmic reticulum(ER)stress.Methods Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine(3 mg/kg/day)and the ER stress inhibitor 4-phenylbutyric acid(4-PBA,1 and 0.5 g/kg/day)for 8 days.Changes in body weight,food intake,and plasma lipids were assessed.Hepatic fat accumulation was evaluated using oil red O staining.Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers,NOD-like receptor pyrin domain-containing protein 3(NLRP3),and proopiomelanocortin(POMC)in the hypothalamus or liver.Results Compared to olanzapine alone,olanzapine+HFD induced greater weight gain,increased hyperlipidemia,and enhanced hepatic fat accumulation(P<0.05).Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects(P<0.05).Further mechanistic investigations revealed that olanzapine alone activated ER stress,upregulated NLRP3 expression in the hypothalamus and liver,and downregulated hypothalamic POMC expression.The HFD exacerbated these effects by 50%–100%.Moreover,co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress,NLRP3,and POMC expression in the hypothalamus and liver(P<0.05).Conclusion HFD worsened olanzapine-induced weight gain and lipid metabolic disorders,possibly through ER stress-POMC and ER stress-NLRP3 signaling.ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

Is Dosage Adjustment for Olanzapine Really Necessary?

Schizophrenia is a prevalent and disabling disorder, commonly treated with medications such as clozapine and olanzapine. However, long-term side effects and limitations of these drugs, coupled with treatment resistance in a significant proportion of patients, necessitate alternative strategies. Furthermore, individuals with schizophrenia are at an increased risk of developing kidney and liver diseases, which may be influenced by cardiovascular comorbidities and shared genetic markers. Considering the use of olanzapine in patients with severe liver or kidney diseases requires careful evaluation. Although these organs play crucial roles in olanzapine excretion and metabolism, current pharmacological research suggests that dosage adjustment may not be necessary even in the presence of severe organ disease. Olanzapine acts on D2 and 5HT2A receptors, alleviating both positive and negative symptoms of schizophrenia. However, the metabolism and clearance of olanzapine exhibit substantial inter-individual variability influenced by factors such as gender, age, ethnicity, smoking habits, and co-medication. Additionally, olanzapine may induce unwanted side effects, including prolactin release, metabolic dysregulation, and liver-related complications. The present study aims to investigate whether dosage adjustment of olanzapine is necessary for individuals with comorbid moderate liver and severe kidney disease. While the study remains ongoing, preliminary findings using a pharmacokinetic model predict that dosage adjustment may not be required in these patients. The expected olanzapine plasma concentration in individuals with both conditions is estimated to be 18.14ng/ml, which is considerably below the identified toxic dosage threshold of 100ng/ml. However, further investigations are warranted to validate the findings and establish definitive guidelines and personalize treatment strategies for individuals with both liver and kidney disease.

Potential Toxic Effects of Olanzapine on Metabolic Parameters in <i>de Novo</i>Paranoid Schizophrenic Patients. The Role of Adjunctive Aripeprazole: Clinical and Experimental Study

Background: Approximately 75% of all deaths in people with schizophrenia are caused by physical illness with cardiovascular disease [CVD] being the commonest cause of death. Factors predisposing people with schizophrenia to CVD include antipsychotic medication. Aim of Work: The aim of this study was to detect metabolic syndrome and its components in de novo paranoid schizophrenics on olanzapine therapy and the metabolic benefits of addition of aripeprazole, clinically and experimentally. Methodology: 1) Clinical study: 200 Outpatients suffered from de novo paranoid schizophrenia according to 10th International Classification of Psychiatric Disorders, Research Criteria [ICD10 RC] were included in the study. None of them had any component of metabolic syndrome. They were maintained on olanzapine [10 - 20 mg]. Patients were assessed clinically, psychometrically using Scale for the Assessment of Negative [SANS] and Positive [SAPS] Symptoms and metabolically at base line and after 6 months. Patients who had metabolic syndrome after 6 month of starting olanzapine therapy, were randomly divided into two groups according to added regime to maintained olanzapine: Group 1: olanzapine [10 mg/day] + placebo [empty hard gelatin capsule]. Group II: olanzapine [10 mg/day] + aripeprazole [10 mg/day]. 2) Experimental study: 40 male albino rats were randomly equally divided into 4 groups: Group 1 [control group]: received a standard diet, Group II [olanzapine treated]: received olanzapine at a dose of 0.5 mg/kg/day, Group III [aripiprazole treatd]: received aripiprazole at a dose of 2 mg/kg/day, Group IV [combined olanzapine and aripiprazole treated]: received olanzapine at a dose of 0.5 mg/kg/day combined with aripiprazole at a dose of 2 mg/kg/day orally. The duration of the study was 16 weeks. All treated rat groups were assessed for metabolic parameters, liver enzymes and histopathology. Results: Clinically, after the 6 months of olanzapine treatment [mean dose 12.75 mg], there was significant increase [p Conclusion and Recommendation: Olanzapine treatment was found to be associated with risk factors of metabolic syndrome clinically and experimentally and its hepatic manifestation of non-alcoholic fatty liver disease in wister rats. Improvements were observed clinically and experimentally in metabolic measures, liver enzymes and liver histopathology by addition of aripeprazole. Patients on olanzapine therapy must be followed regularly regarding metabolic parameters, hepatic, cardiac and cerebrovascular morbidity, with urgent interference with early manifestations. It is recommended to check liver enzymes regularly for those patients kept on atypical antipsychotic drug [olanzapine].

Association between polymorphism of MC4R rs489693 gene and disorder of glucose and lipid metabolism in schizophrenia patients treated with olanzapine

Objective:To investigate the effect of Melanocortin four receptor,MC4R rs489693 polymorphism on glucose and Lipid metabolism in schizophrenia patients treated with Olanzapine for 12 weeks.Methods:171 patients with schizophrenia were divided into AA Group(N=12),AC group(N=59)and CC Group(N=100)according to the polymorphism of MC4R gene at 489693 locus detected by DNA sequencing.Blood Glucose and lipid levels were measured before and 12 weeks after treatment,the differences of variables among the 3 groups were compared,and the incidence of glucose and lipid abnormalities after treatment was statistically analyzed.Results:After 12 weeks of treatment,the net increase of blood glucose in AA group was greater than that in CC group(P<0.05),and the net increase of cholesterol and triglyceride in AA group was greater than that in AC group and CC group(all P<0.05),and the incidence of Blood Glucose and at least one dyslipidemia in AA Group was higher than that in AC and CC group(all P<0.01).Conclusion:The rs489693 gene polymorphism of MC4R gene is related to the disorder of glucose and lipid metabolism in schizophrenia treated with olanzapine.

Olanzapine Induces Inflammation and Immune Response via Activating ER Stress in the Rat Prefrontal Cortex

Objective Antipsychotics,in particular olanzapine,are first-line medications for schizophrenia.The prefrontal cortex(PFC)is an important region for antipsychotics’therapeutic effects.The PFC inflammatory and immune pathways are associated with schizophrenia pathogenesis.However,the effect of antipsychotics on the inflammatory and immune pathways in the PFC remains unclear.We aimed to examined the time-dependent effect of olanzapine on inflammatory and immune markers in the PFC of rats.Since the inflammatory and immune pathways are related to endoplasmic reticulum(ER)stress,we further investigated whether or not olanzapine-induced inflammation and immune responses were related to ER stress.Methods Expression of pro-inflammatory markers including IkappaB kinaseβ(IKKβ),nuclear factor kappa B(NFκB),tumor necrosis factorα(TNF-α),interleukin-6(IL-6)and IL-1β,and immune-related proteins including inducible nitric oxide synthase(iNOS),toll-like receptor 2(TLR2)and cluster of differentiation 14(CD14)were examined by Western blotting.Results Olanzapine treatments for 1,8 and 36 days significantly activated the inflammatory IKKβ/NFκB signaling,and increased the expression of TNF-α,IL-6,IL-1βand immune-related proteins such as iNOS,TLR4 and CD14.Olanzapine treatment for 1 day,8 and 36 days also induced ER stress in the PFC.Co-treatment with an ER stress inhibitor,4-phenylbutyrate,inhibited olanzapine-induced inflammation and the immune response in the PFC.Conclusion These results suggested olanzapine exposure could be a factor that induces central inflammation and immunological abnormities in schizophrenia subjects.Olanzapine induces PFC inflammation and immune response,possibly via activating ER stress signaling.

The Efficacy of Escitalopram Combined with Olanzapine in Depression:A Systematic Review and Meta-analysis

Background:Depression will become the second most common disease after coronary heart disease(CHD).Escitalopram and olanzapine are commonly used to treat depression.Some studies indicated that escitalopram combined with olanzapine is effective in treating depression,however,there is no evidence to support these results.Our objective was to study the efficacy of escitalopram combined with olanzapine on depression by conducting a systematic review and meta analysis,and to provide reference for doctors.Methods:Relevant evidence were searched from PubMed,SinoMed,the Cochrane Library,Web of Science,Embase,China Knowledge Resource Integrated(CNKI),Wanfang Data Knowledge Service Platform databases(WANFANG)and VIP dating from inception to July 2020.The randomized controlled trials(RCTs)of escitalopram and olanzapine for the treatment of depression was obtained.According to inclusion and exclusion criteria,two researches(Sun Wu and Wang Zhe)independently screened the literature,extracted data,and evaluated the quality of included studies.Rev Man 5.3 software was used to conduct statistical analyze.Results:A total of 39 studies involving 3,267 patients were identified.These studies were finally included into the meta-analysis.Pooled results showed that there was a significant difference in efficiency(RR=1.18,95%CI:1.14 to 1.12,P<0.00001),HAMD(MD=-4.54,95%CI:-5.09 to-3.99,P<0.00001),and HAMA(MD=-3.94,95%CI:-5.57 to-2.12,P<0.0001).There was no significant difference in adverse reactions(MD=0.07,95%CI-0.03 to 0.17,P=0.19).Heterogeneity test showed that due to the high heterogeneity of HAMD(P<0.00001,12=86%)and HAMA(P<0.00001,I2=91%),after removing the items with high heterogeneity,there were also statistically significant in HAMD(MD=-5.22,95%CI:-5.53 to-4.91,P<0.00001)and HAMA(MD=-5.46,95%CI:-6.15 to-4.77,P<0.00001).Conclusion:Based on this study,the combination of escitalopram and olanzapine was more effective in treating depression than the control group.It is suggested that clinical and scientific researchers carry out more high-quality,large-sample,multi-center RCTs to provide more evidence-based medical evidence for the future study of escitalopram combined with olanzapine in the treatment of depression.

Novartis公司的抗神经病药物Clozaril（clozapine）和EliLilly的Zyprexa（olanzapine）可能增加糖尿病的危险

在一项有36例非肥胖患者参加的临床研究中，受试者被给予该2种药物和risperidone。患者在用餐后被要求禁止进食12h，然后被进行静脉血糖耐受性试验。Clozaril和Zyprexa组患者的胰岛素耐受性和血糖效价偏差比risperidone组患者要显著大得多。因此Novartis建议服用该2种药物的患者应当被常规性地监督血糖状态，以降低不良作用的危险性和及时采取相应的医疗措施。

Olanzapine-associated hypothermia in an adolescent anorexic girl

This is a 12th case report on olanzapine induced hypothermia and based on the results of literature search, by far is the youngest case ever is reported. The hypothermia occurred during the refeeding phase, despite a weight gain since increasing the dosage from 5 mg to 7.5 mg olanzapine. Our recent literature search found 11 published cases of olanzapine treatment associated with hypothermia. Olanzapine acts on serotonin or dopamin receptors and has antagonistic properties on histaminergic, muscarinic and α-adrenergic receptors. Olanzapine mediates the hypothermic effect through antagonism at receptors other than dopamine.

Case report: Olanzapine-induced acute pancreatitis and new diabetes mellitus

The aim of this case study is to review the literature and report the first published case of olanzapine-induced acute pancreatitis in New Zealand. A case report of acute pancreatitis with new onset diabetes mellitus secondary to olanzapine in a 42-year-old male, in the absence of medical risk factors is reported. Eleven previous case reports of olanzapine induced acute-pancreatitis were identified in the literature. A 42-year-old male was diagnosed with acute pancreatitis and new diabetes mellitus induced by olanzapine. Although rare, pancreatitis is associated with use of some atypical antipsychotic medications. It is important for prescribers to be aware of this potentially fatal side effect. In addition to this, we are highlighting the well documented evidence of metabolic disruption associated with olanzapine.

Effect of aripiprazole and olanzapine on the cognitive function in patients with schizophrenia

Objective:To observe the effect of aripiprazole and olanzapine on the cognitive function in patients with schizophrenia in order to provide a reference evidence for the clinical medication.Methods:A total of 60 patients with schizophrenia who were admitted in our hospital were included in the study and randomized into the treatment 1 group and treatment 2 group.The patients in the two groups were given aripiprazole and olanzapine,respectively.PANSS,WCST,DS,IGT,and EIRT were used to evaluate the disease condition and cognitive function before and after treatment in the two groups.Results:Comparision of PANSS scores and other various scores before treatment between the two groups was not significantly different(P>0.05);however,PANSS scores and other various scores after treatment were significantly reduced(P<0.05).Comparision of PANSS scores and other various scores after treatment between the two groups was not significantly different(P>0.05).DS,WCST,and IGT scores before treatment between the two groups was comparable(P>0.05),and those scores after treatment were significantly elevated(P<0.05).DS score after treatment in the treatment 2 group was significantly higher than that in the treatment 1 group(P<0.05).Comparison of WCST and IGT scores after treatment between the two groups was not significantly different(P>0.05).The four cognition scores of happiness,fear,anger,and disgust after treatment in the treatment 1 group were significantly elevated(P<0.05),while the cognition of happiness and sadness after treatment in the treatment 2 group was significantly elevated when compared with before treatment(P<0.05).The comparison of various scores before and after treatment between the two groups was not significantly different(P>0.05).Conclusions:Aripiprazole and olanzapine can improve the clinical symptoms and partial cognitive function in patients with schizophrenia,while aripiprazole can make a better effect on the work and memory.

Differences in Baseline Characteristics of Patients Treated with Olanzapine or Other Antipsychotics in Japanese Patients with Acute Schizophrenia: A 1-Year Observational Study under Routine Clinical Practice in Japan

Objective: Baseline characteristics of acute schizophrenia patients were analyzed to identify differences in the baseline characteristics of patients treated with olanzapine monotherapy compared with those treated with other antipsychotic monotherapies. Methods: This prospective, naturalistic observational study was designed to evaluate discontinuation rates of olanzapine and non-olanzapine antipsychotic monotherapy in Japanese adult patients with acute schizophrenia. Results: A total of 1089 patients were assessed: 578 patients were treated with olanzapine, 487 with non-olanzapine atypical antipsychotics, and 24 with typical antipsychotics. The mean Clinical Global Impression-Severity (CGI-S) Schizophrenia, Brief Psychiatric Rating Scale (BPRS) total, and BPRS positive scores were higher in patients treated with olanzapine compared with most of the non-olanzapine treated patients. The majority of patients with a CGI-S Schizophrenia score of 7 (29/41 patients) as well as patients with a BPRS total score of 90 or higher (14/18 patients) were treated with olanzapine. On the other hand, physicians tended to prescribe antipsychotics other than olanzapine for patients with heavier body weight or diabetes mellitus. Conclusion: The present study demonstrated that olanzapine was more likely to be prescribed to patients with more severe schizophrenia symptoms. However, further studies are warranted to reach a definite conclusion.

Very-high-dose olanzapine for treatment-resistant schizophrenia

Treatment-resistant schizophrenia has an extremely negative impact on mental health and social life. If clozapine, the gold standard treatment, fails, there are very few options left. The literature suggests that high-dose olanzapine (20 - 60 mg/day) is a possible alternative. We report two cases in which very high doses of olanzapine were administered, with significant clinical improvements above 60 mg/day. Clinical, metabolic and cardiac tolerance was good. This report highlights the usefulness of very-high-dose olanzapine in treatment-resistant schizophrenia. The main hypotheses concerning the psychopharmacological mechanisms of very-high-dose olanzapine are discussed.

Efficacy and adverse effects of olanzapine in the treatment of moderate to severe refractory neuropathic pain

Objective The aim of the study was to investigate the efficacy and adverse effects of olanzapine in the treatment of moderate to severe refractory neuropathic pain.Methods Forty patients with digestive system cancer were enrolled,who had moderate to severe refractory neuropathic pain;the patients were treated with olanzapine for 2 weeks at a daily dosage of 5 mg to 10 mg per night according to patients’response and tolerability,combined with conventional analgesic therapy.Pain intensity was evaluated by using a Numeral Rating Scale(NRS)at baseline,3 days,and 2 weeks after therapy.The Pittsburg Sleep Quality Index(PSQI)was evaluated at baseline and 2 weeks after therapy.Data on adverse events were recorded.The dosage of conventional analgesics was adjusted over time based on the severity of pain.Results The mean pain score decreased by 2.575±1.318(P<0.000)at 3 days and by 3.400±1.614(P<0.000)at 2 weeks;30%of the patients experienced significant pain relief at 3 days and 50%at 2 weeks.The PSQI decreased by 4.725±2.828(P<0.000)at 2 weeks.The adverse events induced by olanzapine included sleepiness,weight gain,dizziness,fatigue,dry mouth,and constipation;all the side effects were mild.Conclusion When combined with conventional analgesic therapy,olanzapine was effective in relieving pain and sleep disturbance,and was well-tolerated among patients with refractory neuropathic pain.

Evaluation of the quality of olanzapine orally disintegrated tablets by multiple dissolution curves

Objective: To investigate the dissolution behavior similarity between Self-made praeparatum and reference praeparatum in different pH menstruum,using the Olanzapine Orally Disintegrating Tablets listed in abroad as the reference praeparatum. Methods: The dissolution curve of olanzapine in Self-made praeparatum and reference praeparatum was measured,the similarity of the dissolution curve was evalued by F2 similar factor. Results: The single-point dissolution of both Self-made praeparatum and reference praeparatum within 15 min was more than 85%. Conclusion: Self-made praeparatum and reference praeparatum were similar in dissolution behavior.

Hyponatremia with olanzapine - A suspected association

低钠血症是一种罕见的具有潜在生命危险的抗精神病药物治疗的不良反应。这里,我们报告一个病例,45岁女性精神分裂症患者在奥氮平治疗后不久出现低钠血症。为此我们评估了低钠血症和奥氮平治疗之间的关系,因为及时的药物监测至关重要。根据Naranjo算法,在奥氮平和低钠血症之间的关联性评价,可评价为"可能"。因此有必要探究低钠血症这一临床上重大、危及生命的不良事件产生的可能原因。我们报告的病例聚焦于奥氮平治疗引起的低钠血症的不良事件。由于精神疾病患者有时无法主诉或主诉不被重视,内科疾病常常被忽视或错过。在处理这种可能的不良反应时,应保持高度警觉性。