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International Journal of Psychiatry in... Mar 2024Anhedonia is a common symptom of depression, but is also a negative symptom of schizophrenia. The purpose of this study was to examine the effects of vortioxetine on... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Anhedonia is a common symptom of depression, but is also a negative symptom of schizophrenia. The purpose of this study was to examine the effects of vortioxetine on anhedonia in patients with schizophrenia.
METHODS
A total of 120 patients with schizophrenia in remission who met inclusion criteria were randomized 1:1 by the envelope method into intervention and control groups. All participants in both groups were divided into three subgroups based on the antipsychotic therapy they were receiving (olanzapine, risperidone, or aripiprazole). Vortioxetine was administered to those in the intervention group at a fixed dose of 10 mg per day. The Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), and Chapman Scale for Social and Physical Anhedonia (CSPA) were administered. The study lasted 12 weeks. Participants were assessed twice: At baseline and at the end of the study. Six participants dropped out, with 114 completing the trial.
FINDINGS
Vortioxetine treatment had a significant effect on level of physical anhedonia. The treatment interaction was also statistically significant, but with a relatively small effect (F = 3.17, < .05; η2 = .061). Vortioxetine treatment had a particularly strong effect on the level of social anhedonia. The interaction between the treatment and the type of antipsychotics was also statistically significant with a small effect (F = 5.04, < 0. 01; η2 = .091).
CONCLUSION
The combination of olanzapine and vortioxetine was found to be the best option to reduce symptoms of social and physical anhedonia in these patients with remitted schizophrenia.
Topics: Humans; Schizophrenia; Olanzapine; Anhedonia; Vortioxetine; Antipsychotic Agents; Benzodiazepines
PubMed: 37647498
DOI: 10.1177/00912174231199925 -
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 Child and Adolescent... May 2018To compare the efficacy and safety of olanzapine and risperidone in children and adolescents (aged ≤18 years) with psychosis by conducting a meta-analysis of... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
To compare the efficacy and safety of olanzapine and risperidone in children and adolescents (aged ≤18 years) with psychosis by conducting a meta-analysis of randomized controlled trials (RCTs).
METHODS
Several English and Chinese databases were searched for studies published before February 8th, 2017. Two independent investigators screened the studies according to prespecified criteria and extracted the data. Review Manager 5.3 was used to conduct the data synthesis.
RESULTS
Eight RCTs involving 457 participants (225 participants in the olanzapine group and 232 participants in the risperidone group) were included. No significant differences were observed in the mean scores on the Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale (standard mean difference [SMD] = -0.06, 95% confidence intervals [CI] = [-0.31, 0.19], p = 0.63), the positive symptom scores (SMD = -0.09, 95% CI = [-0.32, 0.15], p = 0.48), or the negative symptom scores (SMD = -0.11 95% CI = [-0.34, 0.13], p = 0.38) between the two groups. Regarding adverse effects, the mean increases in weight (MD = 2.90, 95% CI = [1.41, 4.39], p = 0.0001), body mass index (MD = 0.90, 95% CI = [0.42, 1.38], p = 0.0003), and incidence of hypersomnia (risk ratios [RR] = 1.98, 95% CI = [1.15, 3.43], p = 0.01) were higher in the olanzapine group, while the incidence of insomnia (RR = 0.31, 95% CI = [0.11, 0.85], p = 0.02), prolactin elevation (RR = 0.11, 95% CI = [0.01, 0.85], p = 0.03), myotonia (RR = 0.12, 95% CI = [0.03, 0.49], p = 0.003), tremor (RR = 0.22, 95% CI = [0.08, 0.63], p = 0.005), and akathisia (RR = 0.27, 95% CI = [0.12, 0.57], p = 0.0007) was higher in the risperidone group.
CONCLUSIONS
There is no significant difference in efficacy between olanzapine and risperidone for the treatment of children and adolescents with psychosis, but the side effect profiles of these two medications differ. High-quality RCTs are needed before recommending clinical treatment in children and adolescents.
Topics: Adolescent; Antipsychotic Agents; Child; Humans; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Treatment Outcome
PubMed: 29356569
DOI: 10.1089/cap.2017.0120 -
Journal of Affective Disorders Oct 2023Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess the evidence for the efficacy of atypical antipsychotics in treating unipolar and bipolar depression in adolescents and young adults.
METHOD
We conducted a comprehensive systematic review and meta-analysis of randomized-control-trial studies (RCTs) of antipsychotic medications for 10- to 25-year-olds with unipolar and bipolar depression. The primary outcome of interest was change in depressive symptoms from baseline to trial endpoint.
RESULTS
No studies were identified that evaluated the use of antipsychotics in the treatment of unipolar depression. However, we identified four studies, of quetiapine, lurasidone and olanzapine/fluoxetine combination, comprising a total of 866 randomized patients, that evaluated treatment of bipolar depression. All studies used the Children's Depression Rating Scale-Revised (CDRS-R). Our meta-analysis revealed the weighted mean difference (WMD) was -4.58 (95 % CI, -6.59 to -2.57) between antipsychotic and placebo-treated groups. Response and remission rates were also significantly in favor of antipsychotic treatment.
LIMITATIONS
There were few studies, several did not address risk-of-bias domains and there was a lack of non-industry sponsored studies.
CONCLUSION
There is an absence of evidence for the use of antipsychotic medications in treatment of youth unipolar depression, and no recommendations can be made. There is some evidence for the efficacy of antipsychotics, specifically lurasidone and olanzapine/fluoxetine combination, in the treatment of young people with bipolar depression. However, this evidence is limited and more studies investigating the use of these medications in young people are needed.
Topics: Child; Adolescent; Young Adult; Humans; Antipsychotic Agents; Bipolar Disorder; Fluoxetine; Olanzapine; Lurasidone Hydrochloride
PubMed: 37467794
DOI: 10.1016/j.jad.2023.07.082 -
The Primary Care Companion For CNS... Apr 2018
Topics: Adult; Anemia, Aplastic; Antipsychotic Agents; Cyclosporine; Drug Interactions; Humans; Immunosuppressive Agents; Male; Myelodysplastic Syndromes; Olanzapine; Schizophrenia, Paranoid; Young Adult
PubMed: 29701931
DOI: 10.4088/PCC.17l02124 -
The Australian and New Zealand Journal... Aug 2018
Topics: Adult; Drug Hypersensitivity; Female; Humans; Olanzapine; Photosensitivity Disorders
PubMed: 29600715
DOI: 10.1177/0004867418767558 -
The Journal of Toxicological Sciences 2023Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a...
Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic side effects are known to be more likely to occur in women. In the present study, we investigated and tested the hypothesis that olanzapine induces oxidative stress in the hypothalamus and induces metabolic side effects. We also examined its association with sex differences. Olanzapine was administered intraperitoneally to male and female C57BL/6 mice, and the expression levels of oxidative stress-responsible genes in the hypothalamus and cerebral cortex were measured by qRT-PCR. In addition, olanzapine was administered intraperitoneally to C57BL/6 and Nrf2 KO mice, and the expression level of total glutathione was measured. Gene expressions induced by the Keap1-Nrf2-regulated system showed different responses to olanzapine for each gene. Under the conditions of this experiment, cystine-glutamate transporter was decreased although heme oxygenase-1 and γ-glutamylcysteine synthetase were increased. It was also clear that these responses were not hypothalamus-specific. Long-term feeding with olanzapine suppressed weight gain in males but not females. No glucose intolerance was observed at 13 weeks of administration. Furthermore, deaths occurred only in females. In conclusion, this study failed to provide evidence that olanzapine induces oxidative stress in a hypothalamic-specific manner. Instead, sex differences were observed in response to long-term and high-dose olanzapine administration, suggesting that individual susceptibility to olanzapine toxicity occurred in female mice.
Topics: Female; Male; Mice; Animals; Olanzapine; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Sex Characteristics; Mice, Inbred C57BL; Weight Gain; Antipsychotic Agents
PubMed: 37005277
DOI: 10.2131/jts.48.191 -
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 -
The Journal of Clinical Psychiatry Jul 2023Aiming at revising the therapeutic reference range for olanzapine, the present study highlights the association between blood olanzapine levels, clinical effects, and...
Aiming at revising the therapeutic reference range for olanzapine, the present study highlights the association between blood olanzapine levels, clinical effects, and dopamine D-receptor occupancy for oral and long-acting injectable (LAI) formulations. Databases were systematically searched for randomized controlled trials (RCTs) and uncontrolled trials concerning blood olanzapine levels in relation to clinical outcomes or D-receptor occupancy using MEDLINE (PubMed), Web of Science, PsycINFO, and Cochrane Library (March 2021, updated in December 2021). We excluded articles not written in English or German and non-human data. Search terms included , , , , and . The process of study selection followed a previously published protocol and PRISMA guidelines. A total of 2,824 articles were identified through database search and 1 article via reference list check. Thirty-four studies were suitable for qualitative synthesis, and 13 studies were included in the quantitative analysis. Reviewers performed data extraction and quality assessment of the included studies independently following the review protocol. Evidence for a relationship between blood olanzapine level and efficacy/side effects (constipation) is considered low (Level C). In total, 3 studies of moderate quality consistently showed therapeutic thresholds of around 20 ng/mL for olanzapine 12 hours post-dose. This threshold is in line with findings from positron emission tomography (PET) studies that suggest optimal drug efficacy (65%-80% D-receptor occupancy) between 17 and 44 ng/mL. We suggest a therapeutic reference range of 20-40 ng/mL for olanzapine oral and LAI formulations. In this range, optimal treatment response is expected in patients with schizophrenia and schizophrenia spectrum disorders. Side effects, especially weight gain, may already occur at therapeutic levels. However, higher plasma concentrations are in general well tolerated and should not necessarily require a dose reduction in case of good response and tolerance.
Topics: Humans; Olanzapine; Antipsychotic Agents; Reference Values; Schizophrenia; Receptors, Dopamine D2; Benzodiazepines
PubMed: 37471567
DOI: 10.4088/JCP.22r14626 -
The Primary Care Companion For CNS... Apr 2023
Topics: Humans; Olanzapine; Schizophrenia; Antipsychotic Agents; Psychotic Disorders; Weight Loss; Benzodiazepines
PubMed: 37027805
DOI: 10.4088/PCC.21cr03113