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Aging Cell Nov 2023The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for...
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.
Topics: Animals; Humans; Olanzapine; Antipsychotic Agents; Aging; Mitophagy; Mitochondria; Caenorhabditis elegans
PubMed: 37828862
DOI: 10.1111/acel.14003 -
Military Medical Research Jun 2023Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable...
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, R 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), R = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R = 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 ).
Topics: Humans; Antipsychotic Agents; Schizophrenia; Olanzapine; Risperidone; Aripiprazole; Precision Medicine; Multiomics; Benzodiazepines; Randomized Controlled Trials as Topic; Phospholipases
PubMed: 37269009
DOI: 10.1186/s40779-023-00459-7 -
Der Nervenarzt Jan 2020Schizophrenia is a severe psychiatric disorder with variable therapeutic responses, the etiology and pathophysiology of which require further elucidation. (Review)
Review
BACKGROUND
Schizophrenia is a severe psychiatric disorder with variable therapeutic responses, the etiology and pathophysiology of which require further elucidation.
OBJECTIVE
To review which pharmacological options are effective and safe and for which treatment goals in schizophrenia.
MATERIAL AND METHODS
Narrative review of the pharmacological therapy of adults diagnosed with schizophrenia.
RESULTS
Despite heterogeneous therapeutic responses, to date only dopamine antagonists or partial agonists are approved for the treatment of schizophrenia. The efficacy of antipsychotic agents differs only gradually, with the exception of clozapine for treatment-resistant schizophrenia, whereas undesired adverse effects are more variable. Those antipsychotic agents that show gradual efficacy advantages in meta-analyses of acute and maintenance treatment (clozapine, amisulpride, olanzapine, risperidone) are also those where at least one undesired adverse effect is most severely expressed. Antipsychotic adverse effects occur in subgroups of patients and are generally tolerable or treatable, whereas the "side effect" of untreated schizophrenia affects almost all patients, including relapses, psychosocial deterioration, secondary treatment resistance and increased mortality. Therefore, in patients with a confirmed diagnosis of schizophrenia, a lifelong continuous therapy is currently most likely indicated, ideally with antipsychotic agents for which adherence is directly measurable and improved. In the case of treatment resistant clozapine is the agent of choice, followed by electroconvulsive therapy, which also has the best evidence as augmentation treatment in cases of clozapine resistance.
CONCLUSION
New therapeutic agents with improved efficacy and tolerability as well as effectiveness for negative symptoms and cognitive disturbance are needed.
Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Olanzapine; Risperidone; Schizophrenia
PubMed: 31919550
DOI: 10.1007/s00115-019-00858-z -
Clinical Cardiology May 2024Olanzapine, an atypical antipsychotic medication, has gained prominence in the treatment of schizophrenia and related psychotic disorders due to its effectiveness and... (Review)
Review
Olanzapine, an atypical antipsychotic medication, has gained prominence in the treatment of schizophrenia and related psychotic disorders due to its effectiveness and perceived safety profile. However, emerging evidence suggests a potential link between olanzapine use and adverse cardiovascular effects, including cardiomyopathy. This narrative review explores the mechanisms, clinical implications, and management strategies associated with olanzapine-induced cardiomyopathy. A comprehensive review of the literature was conducted to investigate the relationship between olanzapine and cardiomyopathy. The search included epidemiological studies, clinical case reports, and mechanistic research focusing on the pathophysiology of olanzapine-induced cardiomyopathy. The review also examined treatment strategies for managing this potential complication. Olanzapine-induced cardiomyopathy is hypothesized to be associated with metabolic disturbances and receptor antagonism. The metabolic effects of olanzapine, such as weight gain, insulin resistance, and dyslipidemia, share similarities with obesity-related cardiomyopathy. Additionally, olanzapine's antagonism of certain receptors may contribute to cardiovascular stress. The review highlighted that patients with new-onset heart failure and significant weight gain while on olanzapine should be closely monitored for signs of cardiomyopathy. Early detection and prompt withdrawal of olanzapine, along with initiation of goal-directed medical therapy, are crucial for mitigating this potentially life-threatening condition. The relationship between olanzapine and cardiomyopathy is complex and not yet fully understood. However, the potential for significant cardiovascular risk necessitates vigilance among healthcare providers. Early identification and management of olanzapine-induced cardiomyopathy can improve patient outcomes. Further research is needed to elucidate the precise mechanisms behind this adverse effect and to develop optimized treatment strategies for patients requiring antipsychotic therapy.
Topics: Humans; Olanzapine; Antipsychotic Agents; Cardiomyopathies; Obesity; Schizophrenia; Diagnosis, Differential; Risk Factors
PubMed: 38767024
DOI: 10.1002/clc.24278 -
Canadian Journal of Psychiatry. Revue... Apr 2020
Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clozapine; Female; Hospitalization; Humans; Longitudinal Studies; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Outpatients; Program Development; United States
PubMed: 31958979
DOI: 10.1177/0706743719900460 -
The Primary Care Companion For CNS... Feb 2019
Topics: Adult; Antipsychotic Agents; Fever; Humans; Male; Olanzapine; Schizophrenia, Paranoid
PubMed: 30817864
DOI: 10.4088/PCC.18l02332 -
Expert Review of Clinical Pharmacology 2023Olanzapine is widely used for treating schizophrenia and bipolar I disorder. Due to its high pharmacokinetic variability, several population pharmacokinetic studies have... (Review)
Review
INTRODUCTION
Olanzapine is widely used for treating schizophrenia and bipolar I disorder. Due to its high pharmacokinetic variability, several population pharmacokinetic studies have been performed to identify factors contributing to the variability and thus facilitate individualized dosing. This review aims to provide a comprehensive overview of published population pharmacokinetic studies and explore potential covariates.
METHODS
We systematically searched PubMed, Web of Science, and EMBASE databases from their inception to 31 December 2022. Information on the study design, characteristics, and final parameter estimates was summarized and compared. Monte Carlo simulations provided visual predictive distributions to compare eligible studies. Forest plots were constructed to explore the effects of covariates on olanzapine pharmacokinetics.
RESULTS
A total of 10 population pharmacokinetic and three population pharmacokinetic/pharmacodynamic studies involving infants, children, adolescents, and adults were finally included. The median apparent clearance was 0.253 L/h/kg in adults, 27-43% lower than that of infants and children. Men and smokers increased the apparent clearance of olanzapine by 32% and 34%, respectively. The concentration required to achieve half of the maximum effect for the Positive and Negative Syndrome Scale total score was 24.80 ng/mL, comparable with 22.32 ng/mL for dopamine D receptor occupancy.
CONCLUSIONS
A higher dosage may be required for men or heavy smokers than for women or nonsmokers to reach the same exposure. Moreover, further population studies are essential to be conducted to clarify the dose-exposure-response relationship of olanzapine.
PROSPERO REGISTRATION
CRD42022368637.
Topics: Male; Adult; Child; Infant; Adolescent; Humans; Female; Olanzapine; Antipsychotic Agents; Schizophrenia; Research Design; Models, Biological
PubMed: 37231707
DOI: 10.1080/17512433.2023.2219055 -
Current Treatment Options in Oncology Nov 2020Olanzapine has become a major drug in the management of chemotherapy-induced nausea and vomiting as a prophylactic agent. In addition, a recent randomized trial has... (Review)
Review
Olanzapine has become a major drug in the management of chemotherapy-induced nausea and vomiting as a prophylactic agent. In addition, a recent randomized trial has demonstrated its benefits in treating nausea and vomiting associated with advanced cancer. The added benefit to olanzapine is that it also stimulates appetite. As a result, since it treats multiple symptoms associated with advanced cancer, it is likely to become the antiemetic of choice in palliative care at least in the USA. The added benefit of treating insomnia and the avoidance of benzodiazepines should place olanzapine in at the top of the list of drugs to use for patients who do complain of insomnia. There is no good evidence that it potentiates the respiratory depression of opioids unlike benzodiazepines. The evidence is weak that olanzapine in as an adjuvant analgesic. Hopefully, future trials will explore this in greater depth. The benefits of adding olanzapine to potent opioids are that it may reduce craving, drug cues, and opioid misuse. Other symptoms like anxiety and depression may be addressed by the addition of olanzapine to standard antidepressants.
Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Antipsychotic Agents; Drug Monitoring; Humans; Nausea; Neoplasms; Olanzapine; Palliative Care; Postoperative Complications; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Vomiting
PubMed: 33244634
DOI: 10.1007/s11864-020-00804-1 -
The Psychiatric Quarterly Dec 2023Aripiprazole is an atypical antipsychotic medication, and its use in treating borderline personality disorder (BPD) is debatable because it is not FDA-approved for... (Review)
Review
Aripiprazole is an atypical antipsychotic medication, and its use in treating borderline personality disorder (BPD) is debatable because it is not FDA-approved for treating BPD. This study aimed to investigate the efficacy and safety of aripiprazole in patients with BPD. On July 2, 2021, the protocol (CRD42021256647) was registered in PROSPERO. PubMed, Scopus, Web of Science, Ovid-Medline, Embase, PsycINFO, and Cochrane (CENTRAL) were searched without regard for language or publication date. We also searched trial registries on ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Randomized clinical trials with adult patients diagnosed with BPD met the inclusion criteria. The Cochrane risk of bias for randomized trials (RoB-2) method was used to assess the quality of the included studies. We included two previously published randomized clinical trials. There were 76 patients with BPD, with 38, 12, and 26 assigned to the aripiprazole, olanzapine, and placebo groups, respectively. Most patients (88.16%) were females, with ages ranging from 22.1 to 28.14 yr. Aripiprazole has been proven to reduce anxiety, depression, anger, hostility, clinical severity, and obsessive-compulsive behavior, insecurity, melancholy, anxiety, aggressiveness/hostility, phobic anxiety, paranoid thinking, psychoticism, and somatization. The adverse effects were headache, insomnia, restlessness, tremor, and akathisia. The risk of bias was considerable in both trials, which is somewhat problematic considering that prejudice can lead to incorrect outcomes and conclusions. Aripiprazole has demonstrated encouraging outcomes in the treatment of patients with BPD. More randomized controlled studies are needed.
Topics: Adult; Female; Humans; Male; Aripiprazole; Borderline Personality Disorder; Antipsychotic Agents; Olanzapine; Anxiety Disorders
PubMed: 37566261
DOI: 10.1007/s11126-023-10045-8 -
The Journal of Clinical Psychiatry 2017
Topics: Adolescent; Adult; Child; Exercise Therapy; Female; Humans; Male; Marijuana Abuse; Olanzapine; Psychotic Disorders; Young Adult
PubMed: 29099552
DOI: 10.4088/JCP.17f11922