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Alzheimer's Research & Therapy Jun 2022The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer's disease (AD) besides age itself, but the mechanisms underlying this risk are...
BACKGROUND
The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer's disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD.
METHODS
Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer's Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication.
RESULTS
Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers.
CONCLUSIONS
The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Catalysis; Cognition; Humans; Imipramine; Olanzapine; Polymerization; Retrospective Studies
PubMed: 35768831
DOI: 10.1186/s13195-022-01020-9 -
BMJ Mental Health Feb 2023Are antipsychotic dose equivalents between acute mania and schizophrenia the same? (Meta-Analysis)
Meta-Analysis
QUESTION
Are antipsychotic dose equivalents between acute mania and schizophrenia the same?
STUDY SELECTION AND ANALYSIS
Six databases were systematically searched (from inception to 17 September 2022) to identify blinded randomised controlled trials (RCTs) that used a flexible-dose oral antipsychotic drug for patients with acute mania. The mean and SD of the effective dose and the pre-post changes in manic symptoms were extracted. A network meta-analysis (NMA) under a frequentist framework was performed to examine the comparative efficacy between the antipsychotics. A classic mean dose method (sample size weighted) was used to calculate each antipsychotic dose equivalent to 1 mg/day olanzapine for acute mania. The antipsychotic dose equivalents of acute mania were compared with published data for schizophrenia.
FINDINGS
We included 42 RCTs which enrolled 11 396 participants with acute mania. The NMA showed that risperidone was superior to olanzapine (reported standardised mean difference: -022, 95% CI -0.41 to -0.02), while brexpiprazole was inferior to olanzapine (standardised mean difference: 0.36, 95% CI 0.08 to 0.64). The dose equivalents to olanzapine (with SD) were 0.68 (0.23) for haloperidol, 0.32 (0.07) for risperidone, 0.60 (0.11) for paliperidone, 8.00 (1.41) for ziprasidone, 41.46 (5.98) for quetiapine, 1.65 (0.32) for aripiprazole, 1.23 (0.20) for asenapine, 0.53 (0.14) for cariprazine and 0.22 (0.03) for brexpiprazole. Compared with the olanzapine dose equivalents for schizophrenia, those of acute mania were higher for quetiapine (p<0.001, 28.5%) and aripiprazole (p<0.001, 17.0%), but lower for haloperidol (p<0.001, -8.1%) and risperidone (p<0.001, -15.8%).
CONCLUSIONS
Antipsychotic drugs have been considered first-line treatment for acute mania, warranting specific dose equivalence for scientific and clinical purposes.
Topics: Humans; Antipsychotic Agents; Olanzapine; Risperidone; Aripiprazole; Quetiapine Fumarate; Haloperidol; Bipolar Disorder; Mania; Schizophrenia; Randomized Controlled Trials as Topic
PubMed: 36789916
DOI: 10.1136/bmjment-2022-300546 -
Scientific Reports Apr 2021This study compared weight and cardiometabolic changes after short-term treatment of olanzapine/samidorphan and olanzapine. Eligible criteria for an included trial... (Comparative Study)
Comparative Study Meta-Analysis
This study compared weight and cardiometabolic changes after short-term treatment of olanzapine/samidorphan and olanzapine. Eligible criteria for an included trial were ≤ 24 weeks, randomized controlled trials (RCTs) that compared olanzapine/samidorphan and olanzapine treatments in patients/healthy volunteers and reported weight or cardiometabolic outcomes. Three databases were searched on October 31, 2020. Primary outcomes included weight changes and all-cause dropout rates. Standardized mean differences (SMDs) and risk ratios (RRs) were computed and pooled using a random-effect model. This meta-analysis included four RCTs (n = 1195). The heterogeneous data revealed that weight changes were not significantly different between olanzapine/samidorphan and olanzapine groups (4 RCTs, SDM = - 0.19, 95% CI - 0.45 to 0.07, I = 75%). The whole-sample, pooled RR of all-cause dropout rates (4 RCTs, RR = 1.02, 95% CI 0.84 to 1.23, I = 0%) was not significant different between olanzapine/samidorphan and olanzapine groups. A lower percentage of males and a lower initial body mass index were associated with the greater effect of samidorphan in preventing olanzapine-induced weight gain. Current evidence is insufficient to support the use of samidorphan to prevent olanzapine-induced weight gain and olanzapine-induced cardiometabolic abnormalities. Samidorphan is well accepted by olanzapine-treated patients.
Topics: Antipsychotic Agents; Cardiometabolic Risk Factors; Drug Therapy, Combination; Female; Humans; Male; Metabolic Syndrome; Naltrexone; Olanzapine; Schizophrenia; Weight Gain
PubMed: 33828206
DOI: 10.1038/s41598-021-87285-w -
Translational Psychiatry Oct 2021Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the... (Meta-Analysis)
Meta-Analysis Review
Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the generalizability of their findings has been questioned. To address this issue, an increasing number of naturalistic studies and real-world database analyses have been conducted. The question of how much information from these two approaches is congruent or discrepant with each other is of great importance for the clinical practice. To answer this question, we focused on data from the antipsychotic (AP) treatment of schizophrenia. Our aim was two-fold: to conduct a meta-analysis of real-world studies (RWS), and to compare the results of RWS meta-analysis with previously published meta-analyses of RCTs. The principal measure of effectiveness was all-cause treatment discontinuation for both RWS and RCTs (when not available, then drop out for RCTs). We included publications for 8 selected APs (oral formulations of amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and long-acting injectable (LAI) risperidone). We identified 11 RWS and 7 RCT meta-analyses for inclusion. Our results indicated that the RWS yielded statistically conclusive and consistent findings across individual investigations. For the overwhelming majority of the comparisons where both RWS and RCT meta-analyses were available, there was good congruency between the RWS and the RCT results. Our results support that RCTs, despite their limitations, provide evidence which is generalizable to real-world settings. This is an important finding for both regulators and clinicians. RWS can provide guidance for situations where no evidence is available from double-blind clinical trials.
Topics: Antipsychotic Agents; Humans; Olanzapine; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia
PubMed: 34615850
DOI: 10.1038/s41398-021-01636-9 -
Molecules (Basel, Switzerland) Apr 2022Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to...
Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.
Topics: Animals; Antipsychotic Agents; Benzodiazepines; Dizocilpine Maleate; Humans; Mice; Olanzapine; Pyrans; Schizophrenia; Weight Gain
PubMed: 35458749
DOI: 10.3390/molecules27082550 -
JAMA Network Open May 2023It is unknown whether olanzapine combined with triplet antemetic therapy is effective for all patients undergoing highly emetogenic chemotherapy. A secondary analysis of... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
It is unknown whether olanzapine combined with triplet antemetic therapy is effective for all patients undergoing highly emetogenic chemotherapy. A secondary analysis of randomized clinical trials using olanzapine may provide insight into the effectiveness of olanzapine for chemotherapy-induced nausea and vomiting (CINV), including cisplatin.
OBJECTIVE
To examine the add-on effect of olanzapine according to risk factors for CINV.
DESIGN, SETTING, AND PARTICIPANTS
This preplanned secondary analysis evaluated results of the J-FORCE trial, a large double-blind, placebo-controlled phase 3 randomized clinical trial conducted in Japan from February 9, 2017, to July 18, 2018. Participants were enrolled from 26 participating hospitals across Japan and included patients aged 20 to 75 years who had a malignant tumor and were cisplatin-naive. The efficacy analysis population of the J-FORCE trial was analyzed according to allocation adjustment factors (sex [male or female], age [≥55 years or <55 years], and cisplatin dose [≥70 mg/m2 or <70 mg/m2]) and patient-related risk factors (history of motion sickness, drinking habit [defined as alcoholic drinks consumption in excess of occasional drinking], and history of morning sickness during pregnancy). Statistical analysis was performed from February 18 to April 18, 2020.
INTERVENTIONS
Patients were randomized 1:1 to receive 5 mg of olanzapine or placebo combined with standard triplet antiemetic therapy.
MAIN OUTCOMES AND MEASURES
The primary end point was complete response (CR, defined as no vomiting and no use of rescue medication) in the delayed phase (24-120 hours after cisplatin-based chemotherapy administration). Secondary end points were CR, complete control, and total control in the acute, delayed, and overall phases for 6 CINV risk factors as well as time to treatment failure. The CR point estimates and 95% CIs of the differences between groups were calculated, and a Mantel-Haenszel test was performed.
RESULTS
Of the 705 patients (mean [SD] age, 63.0 [9.2] years; 471 males [66.8%]) included in the efficacy analysis population; 581 patients (82.4%) were 55 years or older, and 526 (74.6%) were treated with a cisplatin dose of 70 mg/m2 or more. Risk difference (RD) for a CR in the delayed phase was significantly greater in the olanzapine group than the placebo group in males (RD, 12.6% [95% CI, 5.0%-20.1%]; P = .001); in females (RD, 14.5% [95% CI, 2.2%-26.3%]; P = .02); in those 55 years or older (RD, 11.1% [95% CI, 3.9%-18.2%]; P = .003) or younger than 55 years (RD, 23.6% [95% CI, 7.3%-38.3%]; P = .005); for a cisplatin dose of 70 mg/m2 or more (RD, 13.5% [95% CI, 5.9%-21.0%]; P < .001); for those without a history of motion sickness (RD, 13.9% [95% CI, 6.9%-20.6%]; P < .001); for those with a drinking habit (RD, 14.9% [95% CI, 6.1%-23.4%]; P = .001) or without a drinking habit (RD, 12.0% [95% CI, 2.5%-21.3%]; P = .01); and for those with a history of morning sickness during pregnancy (RD, 27.2% [9.7%-42.6%]; P = .002). In other subgroups, a delayed CR was higher in the olanzapine group than the placebo group, although not significantly higher.
CONCLUSIONS AND RELEVANCE
Results of this study suggest a benefit of using 5 mg of olanzapine plus triplet antiemetic therapy to counter CINV regardless of the presence or absence of risk factors.
TRIAL REGISTRATION
University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000024676.
Topics: Humans; Male; Female; Pregnancy; Middle Aged; Antiemetics; Olanzapine; Cisplatin; Vomiting; Nausea; Motion Sickness; Morning Sickness
PubMed: 37129897
DOI: 10.1001/jamanetworkopen.2023.10894 -
Metabolism: Clinical and Experimental Dec 2022Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and...
BACKGROUND
Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity.
METHODS
Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed.
RESULTS
Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain.
CONCLUSION
Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.
Topics: Male; Mice; Animals; Olanzapine; AMP-Activated Protein Kinases; Phosphorylation; Hypothalamus; Thermogenesis; Body Weight; Energy Metabolism; Weight Gain; Adipose Tissue, Brown
PubMed: 36272468
DOI: 10.1016/j.metabol.2022.155335 -
European Journal of Pharmaceutical... Oct 2022Clinical use of the a olanzapine has significantly different individual-to-individual outcomes. Accordingly, this study aimed to develop a means of predicting response...
Clinical use of the a olanzapine has significantly different individual-to-individual outcomes. Accordingly, this study aimed to develop a means of predicting response to olanzapine using a combined approach based on pharmacokinetics, pharmacometabonomics, and genetic polymorphism. The olanzapine pharmacokinetics of 19 healthy volunteers treated with orally disintegrating tablets were determined using high-performance liquid chromatography-tandem mass spectrometry. Metabolic profiling and phenotyping were performed on the blood samples that remained after pharmacokinetic analysis using ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry. Uridine diphosphate-glucuronosyltransferase (UGT), tyrosine hydroxylase (TH), γ-aminobutyric acid transaminase (GABA-T), and succinic semialdehyde dehydrogenase (SSADH) were identified as key genes. The single nucleotide polymorphism genotypes most related to drug metabolism were investigated by polymerase chain reaction and Sanger sequencing. Forty-one metabolites (p < 0.05) are increased or decreased after treatment with olanzapine. Tryptophan metabolism, norepinephrine metabolism, and γ-aminobutyric acid metabolism were identified as being related to the effects of olanzapine. Subjects carrying rs1641031 AC and CC exhibited a 59.2% increase in the mean peak concentration (C) value and a 25.33% decrease in the mean oral clearance rate (CL/F) value, compared to that in subjects with the GABA-T rs1641031 AA genotype (p < 0.05). Moreover, polymorphism of the GABA-T gene has an impact on the metabolism of 5-hydroxytryptamine. Lysophosphatidylethanolamine (0:0/18:3), lysophosphatidylethanolamine (0:0/22:5), and octadecatrienoic acid distinguish subjects with high and low olanzapine drug oral clearance and are thus identified as biomarkers for predicting its efficacy.
Topics: Chromatography, Liquid; Glucuronosyltransferase; Humans; Olanzapine; Polymorphism, Single Nucleotide; gamma-Aminobutyric Acid
PubMed: 35981664
DOI: 10.1016/j.ejps.2022.106277 -
Redox Biology Jul 2023Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we...
Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition.
Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.
Topics: Male; Animals; Mice; Olanzapine; Signal Transduction; Protein Tyrosine Phosphatase, Non-Receptor Type 1; AMP-Activated Protein Kinases; Liver; Fatty Liver; Mice, Knockout; Inflammation; Fatty Acid Synthases; Weight Gain; Hypothalamus; Mice, Inbred C57BL
PubMed: 37230004
DOI: 10.1016/j.redox.2023.102741 -
Journal of Cutaneous Medicine and... 2023The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to... (Review)
Review
BACKGROUND
The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs).
METHODS
The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment.
RESULTS
Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania ( = 12), pathologic skin picking ( = 5), nail biting ( = 2), delusional parasitosis ( = 1), and dermatitis from compulsive hand washing ( = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking.
CONCLUSION
Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.
Topics: Humans; Sertraline; Fluoxetine; Clomipramine; Olanzapine; Antipsychotic Agents; Desipramine; Pimozide; Randomized Controlled Trials as Topic; Acetylcysteine; Dermatitis
PubMed: 36802832
DOI: 10.1177/12034754231155888