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American Journal of Physiology.... Dec 2020Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing...
Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach. Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.
Topics: Animals; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Lipolysis; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL; Olanzapine; Selective Serotonin Reuptake Inhibitors; Triglycerides
PubMed: 33017220
DOI: 10.1152/ajpendo.00309.2020 -
European Neuropsychopharmacology : the... Jun 2023The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzapine treatment showing mixed results on treatment efficacy in anorexia...
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.
Topics: Rats; Animals; Olanzapine; Anorexia; Administration, Intranasal; Body Weight; Anorexia Nervosa; Eating; Disease Models, Animal
PubMed: 37031523
DOI: 10.1016/j.euroneuro.2023.03.008 -
Brain Research Bulletin Dec 2022Antipsychotic-induced obesity affects millions of people and is a serious health condition worldwide. Olanzapine is the most widely prescribed antipsychotic agent with...
Antipsychotic-induced obesity affects millions of people and is a serious health condition worldwide. Olanzapine is the most widely prescribed antipsychotic agent with high obesogenic potential. However, the exact mechanism by which it causes its metabolic dysregulation remains poorly understood. In this study, we investigated the effect of agmatine in olanzapine-induced metabolic derangements in Female Sprague-Dawley rats. Repeated olanzapine administration for 28 days increased body weight while treatment with agmatine from days 15 to 28 prevented the body weight gain induced by olanzapine without any alteration in food intake. Repeated agmatine treatment decreased the elevated feeding efficiency and adiposity index, as well as improved dysregulated lipid metabolism induced by olanzapine. Increased activity of fatty acid synthase (FAS) and decreased expression of carnitine palmitoyl transferase-1 (CPT-1) were detected in chronic olanzapine-treated rats. Although agmatine treatment did not alter FAS activity, it increased CPT-1 activity. It is possible that the inhibitory effect of agmatine on weight gain and adiposity might be associated with increased mitochondrial fatty acid oxidation and energy expenditure in olanzapine-treated rats. We suggest that agmatine can be explored for the prevention of obesity complications associated with chronic antipsychotic treatment.
Topics: Rats; Female; Animals; Olanzapine; Antipsychotic Agents; Agmatine; Benzodiazepines; Rats, Sprague-Dawley; Obesity; Weight Gain; Body Weight; Eating
PubMed: 36272666
DOI: 10.1016/j.brainresbull.2022.10.013 -
BMC Psychiatry Jun 2023Antipsychotic treatment may improve clinical insight. However, previous studies have reported inconclusive findings on whether antipsychotics improve insight over and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Antipsychotic treatment may improve clinical insight. However, previous studies have reported inconclusive findings on whether antipsychotics improve insight over and above the reduction in symptoms of psychosis. These studies assessed homogeneous samples in terms of stage of illness. Randomised studies investigating a mixed population of first- and multiepisode schizophrenia spectrum disorders might clarify this disagreement.
METHODS
Our data were derived from a pragmatic, rater-blinded, semi-randomised trial that compared the effectiveness of amisulpride, aripiprazole and olanzapine. A sample of 144 patients with first- or multiepisode schizophrenia spectrum disorders underwent eight assessments during a 1-year follow-up. Clinical insight was assessed by item General 12 from the Positive and Negative Syndrome Scale (PANSS). We analysed latent growth curve models to test if the medications had a direct effect on insight that was over and above the reduction in total psychosis symptoms. Furthermore, we investigated whether there were differences between the study drugs in terms of insight.
RESULTS
Based on allocation analysis, all three drugs were associated with a reduction in total psychosis symptoms in the initial phase (weeks 0-6). Amisulpride and olanzapine were associated with improved insight over and above what was related to the reduction in total psychosis symptoms in the long-term phase (weeks 6-52). However, these differential effects were lost when only including the participants that chose the first drug in the randomisation sequence. We found no differential effect on insight among those who were antipsychotic-naïve and those who were previously medicated with antipsychotics.
CONCLUSIONS
Our results suggest that antipsychotic treatment improves insight, but whether the effect on insight surpasses the effect of reduced total psychosis symptoms is more uncertain.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01446328, 05.10.2011.
Topics: Humans; Schizophrenia; Olanzapine; Aripiprazole; Antipsychotic Agents; Amisulpride
PubMed: 37386462
DOI: 10.1186/s12888-023-04981-9 -
Journal of the American Academy of... Mar 2024To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with...
OBJECTIVE
To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a pre-specified protocol (PROSPERO ID 252336).
METHOD
We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference [medianD], mean difference [MD], standardized mean difference [SMD], odds ratio [OR], risk ratio ([RR]). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence.
RESULTS
A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD [95% CI]: 37 [12.27, 61.74] mg/dL; MD [95% CI]: 38.57 [21.44, 55.77] mg/dL) and quetiapine (medianD [95% CI]: 21.58 [95% CI]: 4.27, 38.31 mg/dL; MD [95% CI]: 34.87 [20.08, 49.67] mg/dL; SMD [95% CI]: 0.37 [0.06, 0.068]), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD [95% CI]: 9.1 [1.73, 16.44] mg/dL), quetiapine (medianD [95% CI]: 15.60 [7.30, 24.05] mg/dL; olanzapine (MD [95% CI] from 3.67 [1.43, 5.92] mg/dL to 20.47 [13.97, 26.94] mg/dL]; and lurasidone (medianD [95% CI]: 8.94 [1.27, 16.90] mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size.
CONCLUSION
By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low.
STUDY REGISTRATION INFORMATION
Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.
Topics: Child; Humans; Adolescent; Antipsychotic Agents; Olanzapine; Quetiapine Fumarate; Lurasidone Hydrochloride; Metabolic Syndrome; Schizophrenia; Triglycerides
PubMed: 37391174
DOI: 10.1016/j.jaac.2023.04.018 -
Scientific Reports Nov 2020Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain...
Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O, mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume.
Topics: Acetylcysteine; Animals; Antioxidants; Antipsychotic Agents; Autophagy; Cell Line; Cell Survival; Hypothalamus; Mice; Mitochondria; Mitophagy; Neurons; Olanzapine; Oxidative Stress; Reactive Oxygen Species
PubMed: 33154380
DOI: 10.1038/s41598-020-75356-3 -
British Journal of Clinical Pharmacology Feb 2023Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called...
Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called post-injection delirium/sedation syndrome (PDSS), characterised by drowsiness, anticholinergic and extrapyramidal symptoms. The objective is to investigate olanzapine PDSS presentations including clinical features and treatment approach. This is a retrospective review of olanzapine PDSS patients from three toxicology units and the NSW Poisons Information Centre between 2017 and 2022. Adult patients were included if they had intramuscular olanzapine then developed PDSS criteria. Clinical symptoms, treatment, timing and length of symptoms were extracted into a preformatted Excel database. There were 18 patients included in the series, with a median age of 49 years (interquartile range [IQR]: 38-58) and male predominance (89%). Median onset time post injection was 30 min (IQR: 11-38). PDSS symptoms predominate with drowsiness, confusion and dysarthria. Median length of symptoms was 24 h (IQR: 20-54). Most common treatment included supportive care without any pharmacological intervention (n = 10), benzodiazepine (n = 4) and benztropine (n = 3). In one case, bromocriptine and physostigmine followed by oral rivastigmine were given to manage antidopaminergic and anticholinergic symptoms respectively. This proposed treatment combination could potentially alleviate some of the symptoms but needs further studies to validate the findings. In conclusion, this case series supports the characterisation of PDSS symptomology predominantly being anticholinergic with similar onset (<1 h) and duration (<72 h). Bromocriptine is proposed to manage PDSS if patients develop severe dopamine blockade and physostigmine followed by rivastigmine for anticholinergic delirium.
Topics: Adult; Humans; Male; Middle Aged; Female; Olanzapine; Antipsychotic Agents; Bromocriptine; Physostigmine; Rivastigmine; Benzodiazepines; Delirium
PubMed: 36349832
DOI: 10.1111/bcp.15588 -
Psychological Medicine Jul 2023Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy.
METHODS
A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events.
RESULTS
Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, = 4375), amisulpride [1.99 (1.55-2.55)], sulpiride [1.50 (1.03-2.17)], and quetiapine [1.48 (1.23-1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, = 8349), ziprasidone [1.80 (1.07-3.04)], risperidone [1.59 (1.19-2.14)], aripiprazole [1.54 (1.35-1.76)], brexpiprazole [1.41 (1.21-1.66)], cariprazine [1.27 (1.07-1.52)], and quetiapine [1.23 (1.08-1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior.
CONCLUSION
Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Risperidone; Depressive Disorder, Major; Amisulpride; Olanzapine; Benzodiazepines; Dibenzothiazepines
PubMed: 35510505
DOI: 10.1017/S0033291722000745 -
Biochimie Jul 2023Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss...
Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28-30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (-13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone.
Topics: Female; Mice; Animals; Olanzapine; Antipsychotic Agents; Housing; Cancellous Bone; Mice, Inbred C57BL
PubMed: 37236340
DOI: 10.1016/j.biochi.2023.05.002 -
Archives of Iranian Medicine Jan 2023Rhabdomyolysis is a rare serious side effect of antipsychotic medication use. There are cases of rhabdomyolysis due to the use of clozapine, risperidone, olanzapine, and...
Rhabdomyolysis is a rare serious side effect of antipsychotic medication use. There are cases of rhabdomyolysis due to the use of clozapine, risperidone, olanzapine, and haloperidol in the literature. In this report, we describe a rhabdomyolysis case developed on the 13th day of using 2.5 mg /day aripiprazole in a 17-year-old male patient with a diagnosis of somatic symptom disorder. This case is one of the youngest in the literature to develop rhabdomyolysis after the use of aripiprazole. Moreover, this case is distinguished from the others with its low-dose, short-term and single antipsychotic use. In the child and adolescent age group, routine blood tests should be done before starting medication. Symptoms that appear to be nonspecific and that may be overlooked or may be thought to be caused by an existing psychiatric complaint should be carefully and thoroughly considered during follow-up.
Topics: Male; Child; Adolescent; Humans; Aripiprazole; Antipsychotic Agents; Olanzapine; Risperidone; Rhabdomyolysis
PubMed: 37543922
DOI: 10.34172/aim.2023.08