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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 -
Journal of Applied Physiology... Feb 2021Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off-label" conditions. Although effective in reducing psychoses, OLZ causes rapid...
Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off-label" conditions. Although effective in reducing psychoses, OLZ causes rapid impairments in glucose and lipid homeostasis. The purpose of this study was to investigate if voluntary physical activity via wheel running (VWR) would protect against the acute metabolic side effects of OLZ. Male C57BL/6J mice remained sedentary or were provided with running wheels overnight, before treatment with OLZ either at the beginning of the light cycle, or 7 or 24 h following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 h following a bout of overnight wheel running. Protection against, hyperglycemia immediately following VWR was associated with increased insulin tolerance and an attenuated OLZ-induced increase in the serum glucagon:insulin ratio. The protective effect of VWR against OLZ-induced increases in hyperglycemia and glucagon:insulin ratio was maintained in high-fat fed, and AMPK β1-deficient mice, models which display a potentiated OLZ-induced increase in blood glucose. Repeated OLZ treatment did not impair VWR performance and protection against the acute effects of OLZ on blood glucose was present after 1 wk of daily OLZ treatment in mice given access to running wheels. In contrast to the effects on glucose metabolism, VWR, for the most part, did not impact OLZ-induced perturbations in lipolysis, liver triglyceride accumulation, or whole body substrate oxidation. Collectively, our findings demonstrate the efficacy of voluntary physical activity as an approach to protect against OLZ-induced impairments in glucose metabolism. The antipsychotic medication olanzapine causes rapid and large increases in blood glucose. We demonstrate that a prior bout of voluntary overnight wheel running can protect against this harmful side effect and is likely mediated by reductions in olanzapine-induced increases in the circulating glucagon to insulin ratio. This study highlights the powerful effects of voluntary activity in conditions of treatment with antipsychotic medications.
Topics: Animals; Blood Glucose; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Motor Activity; Olanzapine
PubMed: 33382959
DOI: 10.1152/japplphysiol.00876.2020 -
Molecular Psychiatry May 2023Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain... (Review)
Review
Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.
Topics: Animals; Humans; Mice; Agouti-Related Protein; Antipsychotic Agents; Eating; Hyperphagia; Hypothalamus; Olanzapine; Receptors, Cytoplasmic and Nuclear; Weight Gain
PubMed: 36765131
DOI: 10.1038/s41380-023-01981-9 -
General Hospital Psychiatry 2023Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of... (Randomized Controlled Trial)
Randomized Controlled Trial
Does drug use affect the efficacy of amisulpride, aripiprazole and olanzapine in patients with schizophrenia spectrum disorders? Results from a pragmatic, randomised study.
OBJECTIVES
Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use.
METHODS
The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20-29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score.
RESULTS
At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients.
CONCLUSION
The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use.
Topics: Humans; Adolescent; Adult; Olanzapine; Aripiprazole; Antipsychotic Agents; Schizophrenia; Amisulpride; Clozapine; Risperidone; Benzodiazepines; Piperazines; Thiazoles; Treatment Outcome
PubMed: 37269769
DOI: 10.1016/j.genhosppsych.2023.05.003 -
Frontiers in Pharmacology 2022Long-term use of olanzapine can induce various side effects such as lipid metabolic disorders, but the mechanism remains to be elucidated. The gut microbiota-brain axis...
Long-term use of olanzapine can induce various side effects such as lipid metabolic disorders, but the mechanism remains to be elucidated. The gut microbiota-brain axis plays an important role in lipid metabolism, and may be related to the metabolic side effects of olanzapine. Therefore, we explored the mechanism by which olanzapine-induced lipid disturbances through the gut microbiota-brain axis. Sprague Dawley rats were randomly divided into two groups, which underwent subphrenic vagotomy and sham surgery. Then the two groups were further randomly divided into two subgroups, one was administered olanzapine (10 mg/kg/day) by intragastric administration, and the other was administered normal saline by intragastric administration (4 ml/kg/day) for 2 weeks. The final changes in lipid parameters, gut microbes and their metabolites, and orexin-related neuropeptides in the hypothalamus were investigated among the different groups. Olanzapine induced lipid disturbances as indicated by increased weight gain, elevated ratio of white adipose tissue to brown adipose tissue, as well as increased triglyceride and total cholesterol. Olanzapine also increased the Firmicutes/Bacteroides (F/B) ratio in the gut, which was even aggravated by subphrenic vagotomy. In addition, olanzapine reduced the abundance of short-chain fatty acids (SCFAs) metabolism related microbiome and 5-hydroxytryptamine (5-HT) levels in the rat cecum, and increased the gene and protein expression of the appetite-related neuropeptide Y/agouti-related peptide (NPY/AgRP) in the hypothalamus. The abnormal lipid metabolism caused by olanzapine may be closely related to the vagus nerve-mediated gut microbiota-brain axis.
PubMed: 35991866
DOI: 10.3389/fphar.2022.897926 -
Ugeskrift For Laeger Aug 2022Tobacco smoke can cause drug interactions by induction of CYP1A2, which metabolizes drugs like clozapine, olanzapine and theophylline. This means that smokers need...
Tobacco smoke can cause drug interactions by induction of CYP1A2, which metabolizes drugs like clozapine, olanzapine and theophylline. This means that smokers need higher doses to achieve the same plasma concentrations as non-smokers. Furthermore, smoking cessation can cause an increase in plasma concentrations of drugs metabolised by CYP1A2, which in turn may lead to adverse effects. Of the drugs used for smoking cessation only bupropione has clinically relevant interactions. All of these situations may be handled by dose adjustment.
Topics: Clozapine; Cytochrome P-450 CYP1A2; Drug Interactions; Humans; Olanzapine; Smoking Cessation
PubMed: 36065858
DOI: No ID Found -
Psychological Medicine Mar 2022There are significant differences between men and women in the efficacy and tolerability of antipsychotic drugs. Here, we provide a comprehensive overview of what is... (Review)
Review
There are significant differences between men and women in the efficacy and tolerability of antipsychotic drugs. Here, we provide a comprehensive overview of what is currently known about the pharmacokinetics and pharmacodynamics of antipsychotics in women with schizophrenia spectrum disorders (SSDs) and translate these insights into considerations for clinical practice. Slower drug absorption, metabolism and excretion in women all lead to higher plasma levels, which increase the risk for side-effects. Moreover, women reach higher dopamine receptor occupancy compared to men at similar serum levels, since oestrogens increase dopamine sensitivity. As current treatment guidelines are based on studies predominantly conducted in men, women are likely to be overmedicated by default. The risk of overmedicating generally increases when sex hormone levels are high (e.g. during ovulation and gestation), whereas higher doses may be required during low-hormonal phases (e.g. during menstruation and menopause). For premenopausal women, with the exceptions of quetiapine and lurasidone, doses of antipsychotics should be lower with largest adjustments required for olanzapine. Clinicians should be wary of side-effects that are particularly harmful in women, such as hyperprolactinaemia which can cause oestrogen deficiency and metabolic symptoms that may cause cardiovascular diseases. Given the protective effects of oestrogens on the course of SSD, oestrogen replacement therapy should be considered for postmenopausal patients, who are more vulnerable to side-effects and yet require higher dosages of most antipsychotics to reach similar efficacy. In conclusion, there is a need for tailored, female-specific prescription guidelines, which take into account adjustments required across different phases of life.
Topics: Male; Female; Humans; Antipsychotic Agents; Schizophrenia; Olanzapine; Quetiapine Fumarate; Lurasidone Hydrochloride
PubMed: 34763737
DOI: 10.1017/S0033291721004591 -
Pakistan Journal of Medical Sciences 2020To investigate the clinical efficacy of paroxetine combined with olanzapine in the treatment of senile schizophrenia with depression.
OBJECTIVE
To investigate the clinical efficacy of paroxetine combined with olanzapine in the treatment of senile schizophrenia with depression.
METHODS
Eighty-four elderly schizophrenic patients with depression who were admitted to our hospital from August 2016 to February 2018 were selected as research subjects and randomly divided into observation group and control group using random number table, 42 cases in each group. The control group was treated with olanzapine orally, while the observation group was treated with olanzapine and paroxetine orally. The level of homocysteine (Hcy) in the two groups was analyzed before and after treatment. The efficacy was evaluated by the Positive and Negative Symptoms Scale (PANSS) score and Hamilton Depression Scale (HAMD) score. The adverse reactions of the two groups were compared.
RESULTS
After treatment, the level of serum Hcy in the observation group was significantly lower than that in the control group (P<0.05), and it was close to the normal level. There was no significant difference in PANSS score between the two groups before treatment (P>0.05). After treatment, the negative factor score and PANSS score in the observation group were significantly lower than those in the control group, and the differences were statistically significant (P<0.05). The HAMD score of the two groups had no significant difference before treatment (P>0.05). After treatment, the HAMD score of the observation group was significantly lower than that of the control group (P<0.05). The difference of incidence of adverse reactions between the two groups had no statistical significance (P>0.05).
CONCLUSION
Paroxetine combined with olanzapine has a definite clinical effect in the treatment of senile schizophrenia with depression. It can effectively reduce the level of serum Hcy, relieve the symptoms of schizophrenia, and alleviate the depressive symptoms of patients, with high safety. It is worth promoting.
PubMed: 32292463
DOI: 10.12669/pjms.36.3.846 -
Annals of Medicine and Surgery (2012) Jul 2022Schizophrenia is a complex medical illness characterized by hallucinations, delusions, and cognitive issues. Olanzapine, a second-generation antipsychotic widely... (Review)
Review
INTRODUCTION
Schizophrenia is a complex medical illness characterized by hallucinations, delusions, and cognitive issues. Olanzapine, a second-generation antipsychotic widely prescribed for schizophrenia has proven to be efficacious, however, its use is associated with major adverse effects such as weight gain, metabolic syndrome and diabetes mellitus. Recently, FDA approved a combination dose of olanzapine and samidorphan (OLZ/SAM) to mitigate the adverse outcomes associated with olanzapine use for the treatment of Schizophrenia.
OBJECTIVES
The approval of olanzapine/samidorphan combination by FDA in treatment of schizophrenia and bipolar I disorder has been a milestone. This article summarizes the clinical trials reporting the clinical efficacy and adverse effects of olanzapine/samidorphan combination along with their bias assessment.
METHODS
Pubmed, science direct, Ovid SP and Google Scholar were comprehensively searched for data collection. Clinical trials reporting the efficacy and adverse outcomes of the OLZ/SAM regimen were included in the review and the Cochrane risk of bias assessment tool (RoB 2.0, version 2019) was used to assess the risk of bias in each study.
RESULTS
Five trials employed the use of Positive and Negative Syndrome Scales (PANSS) and Clinical Global Impression-Severity (CGI-S) scale to assess the efficacy of OLZ/SAM. Overall, OLZ/SAM showed a significant reduction in PANSS total scores and CGI-S scores and might be a viable option for long-term treatment. The safety of combined therapy is assessed by trials considering the factors of ECG parameters, suicidal events, and movement disorders. Major adverse events included nervous system disorders, changes in blood chemistry, and metabolic or nutritional disorders, with worsening of adverse outcomes observed in a total of nineteen cases in six studies.
CONCLUSION
The FDA-approved drug recombination of OLZ/SAM for the treatment of schizophrenia revealed efficacious outcomes and was generally well tolerated by patients partaking in various trials. The potential of samidorphan in mimicking the efficacy of olanzapine while mitigating olanzapine-induced weight gain makes it a promising regimen for improving symptoms and health outcomes in schizophrenic patients.
PubMed: 35860157
DOI: 10.1016/j.amsu.2022.104115 -
Postgraduate Medicine Jan 2020: Based on a substantial literature, olanzapine appears to be one of the most efficacious antipsychotics marketed in the United States, with only clozapine clearly more... (Review)
Review
: Based on a substantial literature, olanzapine appears to be one of the most efficacious antipsychotics marketed in the United States, with only clozapine clearly more advantageous. However, olanzapine is marred by an equally substantial literature demonstrating a metabolic burden of olanzapine, particularly for weight gain. With the publication of successful strategies to limit olanzapine induced weight gain, a reassessment of the clinical utility of olanzapine appears warranted. The purpose of this paper is to review recent evidence for olanzapine, highlighting use in both schizophrenia and other conditions, safety and supporting the use of olanzapine above 20 mg/day, focusing on studies published since our previous reviews in 2008 and 2009.: The US National Library of Medicine's PubMed resource (https://www.ncbi.nlm.nih.gov/pubmed/) was searched using the text word 'olanzapine' for all English-language articles published between 2008 to July 2019, inclusive with a specific focus on double-blind randomized controlled trials and meta-analyses. In addition, we examined the review articles for other reports of interest that may have been missed by our initial search.: The studies were evaluated based on efficacy and safety data. Use of olanzapine may be decreasing but remains common overall. Evidence continues to support both the relative efficacy advantage and weight gain/metabolic disadvantages of olanzapine in schizophrenia, and recent research supports olanzapine's use in treating anorexia nervosa and chemotherapy-induced nausea. The evidence for high dose olanzapine dosages >20 mg remains limited. Non-pharmacological options, such as dietary counseling and exercise, appear to be efficacious in addressing antipsychotic-induced weight gain. Topiramate, metformin and possibly the olanzapine-samidorphan combination also appear helpful.: Olanzapine remains a useful antipsychotic, but requires with careful monitoring. Further research is needed to compare the different options available to mitigate olanzapine-induced weight gain and to evaluate potential synergism between pharmacological and non-pharmacological treatments.
Topics: Anorexia Nervosa; Antipsychotic Agents; Humans; Nausea; Olanzapine; Schizophrenia
PubMed: 31813311
DOI: 10.1080/00325481.2019.1701823