Haloperidol (oral) versus olanzapine (oral) for people with schizophrenia and schizophrenia-spectrum disorders.

BACKGROUND: Schizophrenia is often a severe and disabling psychiatric disorder. Antipsychotics remain the mainstay of psychotropic treatment for people with psychosis. In limited resource and humanitarian contexts, it is key to have several options for beneficial, low-cost antipsychotics, which require minimal monitoring. We wanted to compare oral haloperidol, as one of the most available antipsychotics in these settings, with a second-generation antipsychotic, olanzapine. OBJECTIVES: To assess the clinical benefits and harms of haloperidol compared to olanzapine for people with schizophrenia and schizophrenia-spectrum disorders. SEARCH METHODS: We searched the Cochrane Schizophrenia study-based register of trials, which is based on monthly searches of CENTRAL, CINAHL, ClinicalTrials.gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed and WHO ICTRP. We screened the references of all included studies. We contacted relevant authors of trials for additional information where clarification was required or where data were incomplete. The register was last searched on 14 January 2023. SELECTION CRITERIA: Randomised clinical trials comparing haloperidol with olanzapine for people with schizophrenia and schizophrenia-spectrum disorders. Our main outcomes of interest were clinically important change in global state, relapse, clinically important change in mental state, extrapyramidal side effects, weight increase, clinically important change in quality of life and leaving the study early due to adverse effects. DATA COLLECTION AND ANALYSIS: We independently evaluated and extracted data. For dichotomous outcomes, we calculated risk ratios (RR) and their 95% confidence intervals (CI) and the number needed to treat for an additional beneficial or harmful outcome (NNTB or NNTH) with 95% CI. For continuous data, we estimated mean differences (MD) or standardised mean differences (SMD) with 95% CIs. For all included studies, we assessed risk of bias (RoB 1) and we used the GRADE approach to create a summary of findings table. MAIN RESULTS: We included 68 studies randomising 9132 participants. We are very uncertain whether there is a difference between haloperidol and olanzapine in clinically important change in global state (RR 0.84, 95% CI 0.69 to 1.02; 6 studies, 3078 participants; very low-certainty evidence). We are very uncertain whether there is a difference between haloperidol and olanzapine in relapse (RR 1.42, 95% CI 1.00 to 2.02; 7 studies, 1499 participants; very low-certainty evidence). Haloperidol may reduce the incidence of clinically important change in overall mental state compared to olanzapine (RR 0.70, 95% CI 0.60 to 0.81; 13 studies, 1210 participants; low-certainty evidence). For every eight people treated with haloperidol instead of olanzapine, one fewer person would experience this improvement. The evidence suggests that haloperidol may result in a large increase in extrapyramidal side effects compared to olanzapine (RR 3.38, 95% CI 2.28 to 5.02; 14 studies, 3290 participants; low-certainty evidence). For every three people treated with haloperidol instead of olanzapine, one additional person would experience extrapyramidal side effects. For weight gain, the evidence suggests that there may be a large reduction in the risk with haloperidol compared to olanzapine (RR 0.47, 95% CI 0.35 to 0.61; 18 studies, 4302 participants; low-certainty evidence). For every 10 people treated with haloperidol instead of olanzapine, one fewer person would experience weight increase. A single study suggests that haloperidol may reduce the incidence of clinically important change in quality of life compared to olanzapine (RR 0.72, 95% CI 0.57 to 0.91; 828 participants; low-certainty evidence). For every nine people treated with haloperidol instead of olanzapine, one fewer person would experience clinically important improvement in quality of life. Haloperidol may result in an increase in the incidence of leaving the study early due to adverse effects compared to olanzapine (RR 1.99, 95% CI 1.60 to 2.47; 21 studies, 5047 participants; low-certainty evidence). For every 22 people treated with haloperidol instead of olanzapine, one fewer person would experience this outcome. Thirty otherwise relevant studies and several endpoints from 14 included studies could not be evaluated due to inconsistencies and poor transparency of several parameters. Furthermore, even within studies that were included, it was often not possible to use data for the same reasons. Risk of bias differed substantially for different outcomes and the certainty of the evidence ranged from very low to low. The most common risks of bias leading to downgrading of the evidence were blinding (performance bias) and selective reporting (reporting bias). AUTHORS' CONCLUSIONS: Overall, the certainty of the evidence was low to very low for the main outcomes in this review, making it difficult to draw reliable conclusions. We are very uncertain whether there is a difference between haloperidol and olanzapine in terms of clinically important global state and relapse. Olanzapine may result in a slightly greater overall clinically important change in mental state and in a clinically important change in quality of life. Different side effect profiles were noted: haloperidol may result in a large increase in extrapyramidal side effects and olanzapine in a large increase in weight gain. The drug of choice needs to take into account side effect profiles and the preferences of the individual. These findings and the recent inclusion of olanzapine alongside haloperidol in the WHO Model List of Essential Medicines should increase the likelihood of it becoming more easily available in low- and middle- income countries, thereby improving choice and providing a greater ability to respond to side effects for people with lived experience of schizophrenia. There is a need for additional research using appropriate and equivalent dosages of these drugs. Some of this research needs to be done in low- and middle-income settings and should actively seek to account for factors relevant to these. Research on antipsychotics needs to be person-centred and prioritise factors that are of interest to people with lived experience of schizophrenia.

Comparative efficacy and safety of olanzapine and risperidone in the treatment of psychiatric and behavioral symptoms of Alzheimer's disease: Systematic review and meta-analysis.

OBJECTIVES: Olanzapine and risperidone have emerged as the most widely used drugs as short-term prescription in the treatment of behavioral disturbances in dementia. The present systematic review and meta-analysis was hence performed to investigate the effectiveness and safety profile of olanzapine and risperidone in the treatment of behavioral and psychological symptoms of dementia (BPSD), aiming to provide updated suggestion for clinical physicians and caregivers. DESIGN: Prospective controlled clinical studies were included, of which available data was extracted. Outcomes of BEHAVE-AD scores with the variation of grades, specific behaviors variables, as well as safety signals were pooled for the analysis by odds rates and weighted mean differences, respectively. DATA SOURCES: Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and WanFang. ELIGIBILITY CRITERIA: Prospective, controlled clinical studies, conducted to compare the effectiveness and safety profile of olanzapine and risperidone in the treatment of BPSD. DATA EXTRACTION AND SYNTHESIS: Interested data including baseline characteristics and necessary outcomes from the included studies were extracted independently by 2 investigators. BEHAVE-AD scale was adopted to assess the efficacy in the present study. All behaviors were evaluated at the time of the initiation of the treatment, as well as the completion of drugs courses. Adverse events were assessed with the criteria of Treatment Emergent Symptom Scale, or Coding Symbols for a Thesaurus of Adverse Reaction Terms dictionary. Weighted mean difference was used for the pooled analysis. RESULTS: A total of 2427 participants were included in the present meta-analysis. Comparative OR on response rate, and remarkable response rate between olanzapine and risperidone was 0.65 (95% CI: 0.51-0.84; P = .0008), and 0.62 (95% CI: 0.50-0.78; P < .0001), respectively. There were statistical differences observed by olanzapine on the improvement of variables including delusions (WMD, -1.83, 95% CI, -3.20, -0.47), and nighttime behavior disturbances (WMD, -1.99, 95% CI, -3.60, -0.38) when compared to risperidone. CONCLUSION: Our results suggested that olanzapine might be statistically superior to risperidone on the reduction of BPSD of Alzheimer's disease, especially in the relief of delusions and nighttime behavior disturbances. In addition, olanzapine was shown statistically lower risks of agitation, sleep disturbance, and extrapyramidal signs.

Efficacy, acceptability and tolerability of second-generation antipsychotics for behavioural and psychological symptoms of dementia: a systematic review and network meta-analysis.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are highly prevalent in people living with dementia. Second-generation antipsychotics (SGAs) are commonly used to treat BPSD, but their comparative efficacy and acceptability are unknown. METHODS: The standard mean difference (SMD) was used to pool the fixed effects of continuous outcomes. We calculated ORs with corresponding 95% credible intervals (CI) for the categorical variable. Efficacy was defined as the scores improved on the standardised scales. Acceptability was defined as the all-cause dropout rate. Tolerability was defined as the discontinuation rate due to adverse effects (AEs). The relative treatment rankings were reported with the surface under the cumulative curve. The AE outcomes included mortality, cerebrovascular adverse events (CVAEs), falls, sedation, extrapyramidal symptoms and urinary symptoms. RESULTS: Twenty randomised controlled trials with a total of 6374 individuals containing 5 types of SGAs (quetiapine, olanzapine, risperidone, brexpiprazole and aripiprazole) with intervention lengths ranging from 6 weeks to 36 weeks were included in this network meta-analysis. For the efficacy outcome, compared with the placebo, brexpiprazole (SMD=-1.77, 95% CI -2.80 to -0.74) was more efficacious, and brexpiprazole was better than quetiapine, olanzapine and aripiprazole. Regarding acceptability, only aripiprazole (OR=0.72, 95% CI 0.54 to 0.96) was better than the placebo, and aripiprazole was also better than brexpiprazole (OR=0.61, 95% CI 0.37 to 0.99). In terms of tolerability, olanzapine was worse than placebo (OR=6.02, 95% CI 2.87 to 12.66), risperidone (OR=3.67, 95% CI 1.66 to 8.11) and quetiapine (OR=3.71, 95% CI 1.46 to 9.42), while aripiprazole was better than olanzapine (OR=0.25, 95% CI 0.08 to 0.78). Quetiapine presented good safety in CVAE. Brexpiprazole has better safety in terms of falls and showed related safety in sedation among included SGAs. CONCLUSION: Brexpiprazole showing great efficacy in the treatment of BPSD, with aripiprazole showing the highest acceptability and olanzapine showing the worst tolerability. The results of this study may be used to guide decision-making.

miR-486-5p-rich extracellular vesicles derived from patients with olanzapine-induced insulin resistance negatively affect glucose-regulating function.

A high risk of glucometabolic disorder severely disturbs compliance and limits the clinical application of olanzapine. MicroRNAs (miRNAs) in extracellular vesicles (EVs) have been reported as emerging biomarkers in glucolipid metabolic disorders. A total of 81 individuals with continuous olanzapine treatment over 3 months were recruited in this study, and plasma EVs from these individuals were isolated and injected into rats via the tail vein to investigate the glucose-regulating function in vivo. Moreover, we performed a miRNA profiling assay by high through-put sequencing to clarify the differentiated miRNA profiles between two groups of patients who were either susceptible or not susceptible to olanzapine-induced insulin resistance (IR). Finally, we administered antagomir and cocultured them with adipocytes to explore the mechanism in vitro. The results showed that individual insulin sensitivity varied in those patients and in olanzapine-administered rats. Furthermore, treatment with circulating EVs from patients with olanzapine-induced IR led to the development of metabolic abnormalities in rats and adipocytes in vitro through the AKT-GLUT4 pathway. Deep sequencing illustrated that the miRNAs of plasma EVs from patients showed a clear difference based on susceptibility to olanzapine-induced IR, and miR-486-5p was identified as a notable gene. The adipocyte data indicated that miR-486-5p silencing partially reversed the impaired cellular insulin sensitivity. Collectively, this study confirmed the function of plasma EVs in the interindividual differences in olanzapine-induced insulin sensitivity.

A prospective randomized controlled clinical trial investigating the efficacy of low-dose olanzapine in preventing nausea and vomiting associated with oxaliplatin-based and irinotecan-based chemotherapy.

OBJECTIVE: The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors. METHODS: Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions. RESULTS: 1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05). CONCLUSION: Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020.

Potent synergistic effects of dulaglutide and food restriction in prevention of olanzapine-induced metabolic adverse effects in a rodent model.

BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.

Olanzapine-induced cardiomyopathy: A mimicker of obesity cardiomyopathy?

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.

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

AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Haematological adverse effects associated with olanzapine in adolescents with anorexia nervosa: Three case reports.

OBJECTIVES: To describe haematological adverse effects in adolescents with anorexia nervosa who are taking olanzapine. METHODS: Case series report. CASE REPORT: The reported cases (two female patients and one male) were found to have blood test abnormalities after starting olanzapine and to rapidly recover their platelet and neutrophil values after the drug was discontinued. Low haemoglobin values persisted longer than observed in other series. These abnormalities became more noticeable when the dose of olanzapine was increased to 5 mg/day (initial dose 2.5 mg/day). It should be noted that two of the patients already had values indicative of mild neutropenia before they started the antipsychotic drug, and that these worsened as they continued taking the drug. In one of the patients there was only a decrease in neutrophil values, as well as mild anaemia. CONCLUSIONS: This first case series of haematological abnormalities in adolescents with anorexia nervosa who are taking olanzapine found values corresponding to pancytopenia in two of the three cases reported. It would be worthwhile to consider heightening haematological surveillance in this population when starting treatment with olanzapine and rethinking our knowledge regarding the frequency of these side effects.

B-GOS alleviates olanzapine-induced lipid disturbances in mice by enriching Akkermansia and upregulation of PGRMC1-Wnt signaling.

Although olanzapine (OLZ) remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability issues related to its metabolic profile such as weight gain and dyslipidemia. Our previous studies have demonstrated that progesterone receptor membrane component 1 (PGRMC1) plays a key role in antipsychotic-induced metabolic side effects. Prebiotics showed positive effects on lipid metabolism, however, limited studies focused on their therapeutic potential and mechanisms in treating antipsychotic-induced lipid metabolic disorders. Herein, our study aims to explore the effects of the prebiotic B-GOS on lipid disturbances induced by OLZ and elucidate its underlying mechanisms via PGRMC1 pathway. In an 8-week study, long-term intraperitoneal administration of OLZ at a dosage of 8 mg/kg/day in mice induced lipid disturbances as manifested by significantly increased lipid indexes in plasma and liver. B-GOS effectively alleviated the OLZ-induced abnormal lipid metabolism by enhancing the diversity of the gut microbiota, with a 100-fold increase in Akkermansia abundance and a 10-fold decrease in Faecalibaculum abundance. Followed by the B-GOS related changes of gut microbiota, OLZ-induced substantial hepatic inhibition of PGRMC1, and associated protein factors of Wnt signaling pathway (Wnt3a, ß-catenin, and PPAR-γ) were reversed without affecting plasma levels of short-chain fatty acids. Taken together, prebiotics like B-GOS enriching Akkermansia offer a promising novel approach to alleviate antipsychotic-induced lipid disturbances by modulating the PGRMC1-Wnt signaling pathway.

PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine-induced hepatic steatosis via both receptor-dependent and receptor-independent pathways.

Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine-induced NAFLD. C57BL/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs in vitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor-dependent pathways (impacting NPC1L1) and receptor-independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP-1c, rather than SREBP-2, was identified as a key driver of PCSK9 increase in olanzapine-induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine-induced NAFLD, influencing both receptor-related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.