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Molecular Psychiatry Jan 2023People with mood disorders have increased risk of comorbid medical diseases versus the general population. It is paramount to identify interventions to improve physical...
The impact of pharmacological and non-pharmacological interventions on physical health outcomes in people with mood disorders across the lifespan: An umbrella review of the evidence from randomised controlled trials.
OBJECTIVE
People with mood disorders have increased risk of comorbid medical diseases versus the general population. It is paramount to identify interventions to improve physical health in this population.
METHODS
Umbrella review of meta-analyses of randomised controlled trials (RCTs) on pharmacological/non-pharmacological interventions for physical health outcomes/intolerability-related discontinuation in mood disorders (any age).
RESULTS
Ninety-seven meta-analyses were included. Among youths, against placebo, in depression, antidepressants/antipsychotics had higher discontinuation rates; in bipolar depression, olanzapine+fluoxetine worsened total cholesterol (TC)/triglycerides/weight gain (WG) (large ES). In adults with bipolar disorder, olanzapine worsened HbA1c/TC/WG (moderate/large ES); asenapine increased fasting glucose (small ES); quetiapine/cariprazine/risperidone induced WG (small/moderate ES). In bipolar depression, lurasidone was metabolically neutral. In depression, psychological interventions improved physical health-related quality of life (PHQoL) (small ES), fasting glucose/HbA1c (medium/large ES); SSRIs improved fasting glucose/HbA1c, readmission for coronary disease, pain (small ES); quetiapine/aripiprazole/olanzapine induced WG (small to large ES). Exercise improved cardiorespiratory fitness (moderate ES). In the elderly, fluoxetine yielded more detrimental cardiovascular effects than sertraline/escitalopram (large ES); antidepressants were neutral on exercise tolerance and PHQoL. In mixed age groups, in bipolar disorder aripiprazole was metabolically neutral; in depression, SSRIs lowered blood pressure versus placebo and serotonin-noradrenaline reuptake inhibitors (small ES); brexpiprazole augmentation caused WG and was less tolerated (small ES); exercise improved PHQoL (moderate ES).
CONCLUSIONS
Some interventions (psychological therapies, exercise and SSRIs) improve certain physical health outcomes in mood disorders, few are neutral, but various pharmacological interventions are associated with negative effects. Evidence from this umbrella review has limitations, should consider evidence from other disorders and should be integrated with recent evidence from individual RCTs, and observational evidence. Effective treatments with either beneficial or physically neutral profiles should be prioritized.
Topics: Adult; Humans; Aged; Adolescent; Fluoxetine; Olanzapine; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Aripiprazole; Longevity; Glycated Hemoglobin; Antipsychotic Agents; Antidepressive Agents; Bipolar Disorder; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic
PubMed: 36138129
DOI: 10.1038/s41380-022-01770-w -
Ugeskrift For Laeger May 2023Treatment with olanzapine depot is associated with a rare but potentially adverse reaction, namely post-injection delirium/sedation syndrome (PDSS), characterized by...
Treatment with olanzapine depot is associated with a rare but potentially adverse reaction, namely post-injection delirium/sedation syndrome (PDSS), characterized by delirium and/or sedation. This is a case report of a 38-year-old male patient who developed symptoms consistent with PDSS shortly after receiving intramuscular injection of olanzapine depot. Clinicians should be aware of PDSS and observe patients for three hours after receiving the injection, measuring vitals and referring to medical care if necessary.
Topics: Male; Humans; Adult; Olanzapine; Antipsychotic Agents; Benzodiazepines; Schizophrenia; Delayed-Action Preparations; Syndrome; Delirium; Injections, Intramuscular
PubMed: 37170738
DOI: No ID Found -
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 -
Current Oncology (Toronto, Ont.) Oct 2022Common treatment methods for malignant tumors include surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy, etc., among which chemotherapy plays an... (Review)
Review
Common treatment methods for malignant tumors include surgery, chemotherapy, radiotherapy, immunotherapy, targeted therapy, etc., among which chemotherapy plays an important role. However, chemotherapy brings corresponding side effects while killing tumor cells, and nausea and vomiting are the most common adverse reactions induced by chemotherapy. It not only affects the patient's appetite, resulting in malnutrition and electrolyte disturbances, but also reduces the patient's compliance with treatment, which further aggravates the disease. Thus, it is important to quickly prevent and cure nausea and vomiting induced by chemotherapy (CINV). In addition, with the continuous development of medicine, more and more antiemetic drugs have been developed. At present, the most common antiemetic agents for chemotherapy-induced nausea and vomiting are NK-1R antagonists, 5-HT3R antagonists, and dexamethasone. Surprisingly, olanzapine, often used as a psychotropic drug, has been found to be an effective antiemetic and is similar to other regimens on the safety of medicine. However, although there are numerous studies on the antiemetic effects of olanzapine, its comprehensive application remains unclear. Therefore, this review will elaborate the antiemetic effect of olanzapine in terms of the antiemetic mechanism and the safety, economic cost, dose, administration time, and drug delivery aspects.
Topics: Humans; Olanzapine; Antiemetics; Pharmaceutical Preparations; Nausea; Vomiting; Antineoplastic Agents
PubMed: 36354710
DOI: 10.3390/curroncol29110650 -
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 -
The Primary Care Companion For CNS... Jul 2019
Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Female; Humans; Lurasidone Hydrochloride; Olanzapine
PubMed: 31298818
DOI: 10.4088/PCC.18l02406 -
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 -
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 -
Journal of Clinical Pharmacology Nov 2021A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I...
A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.
Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Body Weight; Cigarette Smoking; Cytochrome P-450 CYP3A; Drug Combinations; Female; Food-Drug Interactions; Humans; Liver Failure; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Racial Groups; Renal Insufficiency; Rifampin; Schizophrenia; Sex Factors; Young Adult
PubMed: 34018607
DOI: 10.1002/jcph.1911 -
Neuropsychopharmacology : Official... Feb 2022A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or... (Randomized Controlled Trial)
Randomized Controlled Trial
A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine's unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.
Topics: Adult; Antipsychotic Agents; Glucose; Healthy Volunteers; Humans; Insulin; Naltrexone; Narcotic Antagonists; Olanzapine; United States
PubMed: 34887529
DOI: 10.1038/s41386-021-01244-7