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Journal of Pharmaceutical Sciences Dec 2022Co-amorphization is a promising approach to stabilize drugs in the amorphous form. Olanzapine, a poorly water-soluble drug was used in this study. Sulfonic acids...
Co-amorphization is a promising approach to stabilize drugs in the amorphous form. Olanzapine, a poorly water-soluble drug was used in this study. Sulfonic acids (saccharin, cyclamic acid and acesulfame), free and in salt forms, were used as co-formers and compared with carboxylic acids commonly used in the preparation of co-amorphous systems. Several manufacturing techniques were tested, and the co-amorphous systems characterized by differential scanning calorimetry, X-ray powder diffraction, thermogravimetry and Fourier-transform infrared spectroscopy. Free sulfonic acids produced co-amorphous systems with the drug, unlike their salts. Spectroscopy data suggests the formation of salts between olanzapine and the sulfonic acids, used as co-formers. The co-amorphous system produced with saccharin by solvent evaporation, showed the most notable solubility enhancement (145 times). The stability of amorphous and co-amorphous olanzapine systems was assessed upon exposure to stress conditions during storage. Amorphized olanzapine readily reconverted back to the crystalline form while sulfonic acids:olanzapine co-amorphous were stable for up to 24 weeks in low/medium humidity conditions (11-75% RH). Results highlight the potential advantages offered by sulfonic acids as co-formers to produce stable and more soluble co-amorphous olanzapine.
Topics: Solubility; Sulfonic Acids; Saccharin; Olanzapine; Salts
PubMed: 36007560
DOI: 10.1016/j.xphs.2022.08.023 -
Expert Review of Neurotherapeutics May 2022Although olanzapine remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability concerns related... (Review)
Review
INTRODUCTION
Although olanzapine remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability concerns related to its weight and metabolic profile. Olanzapine-samidorphan combination tablets (OLZ/SAM), branded as Lybalvi, is a newly FDA approved formulation aimed at attenuating antipsychotic induced weight gain via modulation of the endogenous opioid system with samidorphan, while retaining the robust antipsychotic efficacy of olanzapine.
AREAS COVERED
We reviewed the published literature of OLZ/SAM for the management of schizophrenia using the US National Library of Medicine's PubMed.gov resource. Topics covered in this narrative review include the pharmacokinetics, pharmacodynamics, efficacy, and tolerability of OLZ/SAM.
EXPERT OPINION
OLZ/SAM is an effective and well-tolerated pharmacologic option in mitigating olanzapine induced weight gain while retaining olanzapine's efficacy. OLZ/SAM cumulatively tends to attenuate weight gain rather than promote weight loss. Effect on metabolic laboratory variables appears limited. Additional research will be needed to determine its effectiveness compared to alternative strategies to attenuate antipsychotic induced weight gain.
Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Humans; Naltrexone; Narcotic Antagonists; Olanzapine; Schizophrenia; Tablets; Weight Gain
PubMed: 35354374
DOI: 10.1080/14737175.2022.2060742 -
Molecular Psychiatry Aug 2023The effect of antipsychotic medication on resting state functional connectivity in major depressive disorder (MDD) is currently unknown. To address this gap, we examined... (Randomized Controlled Trial)
Randomized Controlled Trial
The effect of antipsychotic medication on resting state functional connectivity in major depressive disorder (MDD) is currently unknown. To address this gap, we examined patients with MDD with psychotic features (MDDPsy) participating in the Study of the Pharmacotherapy of Psychotic Depression II. All participants were treated with sertraline plus olanzapine and were subsequently randomized to continue sertraline plus olanzapine or be switched to sertraline plus placebo. Participants completed an MRI at randomization and at study endpoint (study completion at Week 36, relapse, or early termination). The primary outcome was change in functional connectivity measured within and between specified networks and the rest of the brain. The secondary outcome was change in network topology measured by graph metrics. Eighty-eight participants completed a baseline scan; 73 completed a follow-up scan, of which 58 were usable for analyses. There was a significant treatment X time interaction for functional connectivity between the secondary visual network and rest of the brain (t = -3.684; p = 0.0004; pFDR = 0.0111). There was no significant treatment X time interaction for graph metrics. Overall, functional connectivity between the secondary visual network and the rest of the brain did not change in participants who stayed on olanzapine but decreased in those switched to placebo. There were no differences in changes in network topology measures when patients stayed on olanzapine or switched to placebo. This suggests that olanzapine may stabilize functional connectivity, particularly between the secondary visual network and the rest of the brain.
Topics: Humans; Antipsychotic Agents; Depressive Disorder, Major; Olanzapine; Sertraline; Benzodiazepines; Drug Therapy, Combination; Magnetic Resonance Imaging
PubMed: 37258617
DOI: 10.1038/s41380-023-02118-8 -
Pakistan Journal of Pharmaceutical... Sep 2021To investigate the efficacy and safety of olanzapine, aripiprazole, and risperidone in the treatment of mental and behavioral symptoms of Alzheimer's Disease. A... (Comparative Study)
Comparative Study
To investigate the efficacy and safety of olanzapine, aripiprazole, and risperidone in the treatment of mental and behavioral symptoms of Alzheimer's Disease. A retrospective analysis was performed on the clinical data of 126 patients with Alzheimer's Disease from February 2018 to February 2020. The patients were divided into group A (aripiprazole, n=44), group B (olanzapine, n=42) and group C (risperidone, n=40) based on the treatment method. Remarkably differences at different time points among the three groups were observed (P<0.05). Significant differences in the Positive and Negative Syndrome Scale scores of different time points and cross-group comparison among the three groups were detected (P<0.05). The time-point comparison of BEHAVE-AD scores among the three groups indicated a remarkable difference (P<0.05). After 4 weeks of treatment, the Positive and Negative Syndrome Scale and BEHAVE-AD scores of group A were lower than those of groups B and C (P<0.05). The total incidence of adverse reactions in group A was remarkably lower than in groups B and C (P<0.05). Olanzapine, aripiprazole and risperidone are effective in treating Alzheimer's disease and aripiprazole, with a better safety profile and fewer adverse reactions, is more suitable for elderly patients.
Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Aripiprazole; Female; Humans; Male; Olanzapine; Retrospective Studies; Risperidone; Time Factors; Treatment Outcome
PubMed: 34862873
DOI: No ID Found -
FASEB Journal : Official Publication of... Feb 2024Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been...
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.
Topics: Humans; Mice; Animals; Mice, Inbred C57BL; Olanzapine; Proprotein Convertase 9; Non-alcoholic Fatty Liver Disease; Lipid Metabolism; Homeostasis; Triglycerides; Cholesterol; Lipids
PubMed: 38358343
DOI: 10.1096/fj.202301748R -
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 -
Molecular Psychiatry Nov 2022Hypothalamic detection of elevated circulating glucose triggers suppression of endogenous glucose production (EGP) to maintain glucose homeostasis. Antipsychotics...
Hypothalamic detection of elevated circulating glucose triggers suppression of endogenous glucose production (EGP) to maintain glucose homeostasis. Antipsychotics alleviate symptoms associated with schizophrenia but also increase the risk for impaired glucose metabolism. In the current study, we examined whether two acutely administered antipsychotics from different drug classes, haloperidol (first generation antipsychotic) and olanzapine (second generation antipsychotic), affect the ability of intracerebroventricular (ICV) glucose infusion approximating postprandial levels to suppress EGP. The experimental protocol consisted of a pancreatic euglycemic clamp, followed by kinomic and RNA-seq analyses of hypothalamic samples to determine changes in serine/threonine kinase activity and gene expression, respectively. Both antipsychotics inhibited ICV glucose-mediated increases in glucose infusion rate during the clamp, a measure of whole-body glucose metabolism. Similarly, olanzapine and haloperidol blocked central glucose-induced suppression of EGP. ICV glucose stimulated the vascular endothelial growth factor (VEGF) pathway, phosphatidylinositol 3-kinase (PI3K) pathway, and kinases capable of activating K channels in the hypothalamus. These effects were inhibited by both antipsychotics. In conclusion, olanzapine and haloperidol impair central glucose sensing. Although results of hypothalamic analyses in our study do not prove causality, they are novel and provide the basis for a multitude of future studies.
Topics: Antipsychotic Agents; Glucose; Phosphatidylinositol 3-Kinases; Vascular Endothelial Growth Factor A; Olanzapine; Benzodiazepines
PubMed: 36241692
DOI: 10.1038/s41380-022-01798-y -
Psychopharmacology Jan 2021Olanzapine is widely prescribed for patients with mental disorders; however, it may induce metabolic dysfunction. Metformin is an efficient adjuvant for preventing...
OBJECTIVE
Olanzapine is widely prescribed for patients with mental disorders; however, it may induce metabolic dysfunction. Metformin is an efficient adjuvant for preventing olanzapine-induced metabolic dysfunction in clinical practice. Although the mechanism of how metformin prevents this metabolic dysfunction remains unknown, changes in the gut-liver axis are considered a potential explanation.
METHODS
Forty-eight male rats were gavaged with olanzapine and/or metformin for 35 consecutive days. Body weight, food intake, and water intake were measured daily. Histopathological and biochemical tests were performed to evaluate the metabolic dysfunction. The 16S rRNA obtained from fecal bacterial DNA was assessed.
RESULTS
Olanzapine treatment increased the body weight, blood glucose and triglyceride levels, and the number of adipocytes in the liver. While coadministration of metformin, there was a dose-dependent reverse of the abnormal changes induced by olanzapine treatment. Both olanzapine and metformin treatments altered the composition of the gut microbiota. Bacteroides acidifaciens and Lactobacillus gasseri were possibly played a positive role in metformin-mediated olanzapine-induced metabolic dysfunction prevention.
CONCLUSION
Metformin prevented olanzapine-induced metabolic dysfunction and regulated the gut microbiota in a dose-dependent manner.
Topics: Adjuvants, Pharmaceutic; Animals; Bacteroides; Blood Glucose; Body Weight; Dose-Response Relationship, Drug; Feces; Gastrointestinal Microbiome; Humans; Lactobacillus gasseri; Liver; Male; Metabolic Diseases; Metformin; Olanzapine; RNA, Ribosomal, 16S; Rats
PubMed: 33095288
DOI: 10.1007/s00213-020-05677-8 -
Bioscience Reports Oct 2022The addition of olanzapine to fluoxetine produces an antidepressant effect on fluoxetine nonresponders. Promoting hippocampal neurogenesis is associated with the...
The addition of olanzapine to fluoxetine produces an antidepressant effect on fluoxetine nonresponders. Promoting hippocampal neurogenesis is associated with the successful treatment of depression. The present study aimed to investigate the interaction of olanzapine and fluoxetine in regulating neurogenesis. We found that fluoxetine alone does not affect cell proliferation and inhibits the neuronal differentiation of cultured neural stem cells (NSCs), but promotes NSCs proliferation and exerts no effect on neuronal fate when NSCs are cocultured with neurons. In addition, fluoxetine alone also does not alter the neuronal fate of newborn hippocampal cells in vivo. Although fluoxetine treatment elicits different results, our data consistently show that olanzapine alone does not affect the proliferation and neuronal differentiation of NSCs. The combination of olanzapine and fluoxetine has no profound effect on NSCs proliferation compared with fluoxetine alone, but olanzapine add-on treatment produces a greater number and percentage of differentiated neurons from NSCs. Further investigations are needed to explore the underlying mechanisms of the increased neurogenesis caused by the combination of olanzapine with fluoxetine.
Topics: Humans; Infant, Newborn; Fluoxetine; Olanzapine; Cells, Cultured; Neural Stem Cells; Neurogenesis; Cell Differentiation; Cell Proliferation; Antidepressive Agents
PubMed: 36134560
DOI: 10.1042/BSR20220804 -
Journal of Psychopharmacology (Oxford,... Oct 2023Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical...
BACKGROUND
Expert consensus-based clinically equivalent dose estimates and dosing recommendations can provide valuable support for the use of drugs for psychosis in clinical practice and research.
AIMS
This second International Consensus Study of Antipsychotic Dosing provides dosing equivalencies and recommendations for newer drugs for psychosis and previously reported drugs with low consensus.
METHODS
We used a two-step Delphi survey process to establish and update consensus with a broad, international sample of clinical and research experts regarding 26 drug formulations to obtain dosing recommendations (start, target range, and maximum) and estimates of clinically equivalent doses for the treatment of schizophrenia. Reference agents for equivalent dose estimates were oral olanzapine 20 mg/day for 15 oral and 7 long-acting injectable (LAI) agents and intramuscular haloperidol 5 mg for 4 short-acting injectable (SAI) agents. We also provide a contemporary list of equivalency estimates and dosing recommendations for a total of 44 oral, 16 LAI, and 14 SAI drugs for psychosis.
RESULTS
Survey participants ( = 72) from 24 countries provided equivalency estimates and dosing recommendations for oral, LAI, and SAI formulations. Consensus improved from survey stages I to II. The final consensus was highest for LAI formulations, intermediate for oral agents, and lowest for SAI formulations of drugs for psychosis.
CONCLUSIONS
As randomized, controlled, fixed, multiple-dose trials to optimize the dosing of drugs for psychosis remain rare, expert consensus remains a useful alternative for estimating clinical dosing equivalents. The present findings can support clinical practice, guideline development, and research design and interpretation involving drugs for psychosis.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Psychotic Disorders; Haloperidol; Olanzapine; Delayed-Action Preparations
PubMed: 37842908
DOI: 10.1177/02698811231205688