olanzapine and Liver-Diseases

Treatment resistance is frequently encountered during the long-term care of patients with major depression. A number of 'next step' therapeutic options exist in such cases, including switching to an alternative antidepressant, combining antidepressants from different pharmacological classes, adding evidence-supported psychotherapies to ongoing antidepressant treatment and augmentation with a nonantidepressant drug. Augmenting antidepressants with atypical antipsychotic drugs has generated considerable clinical interest. Three atypical antipsychotics (aripiprazole, quetiapine and olanzapine) have received regulatory approval for adjunctive use with antidepressants for treatment-resistant major depression (TRD) in adults. Symbyax (olanzapine-fluoxetine combination or OFC), the combination of olanzapine and the selective serotonin-reuptake inhibitor fluoxetine, is also approved for this indication. The short-term effectiveness of OFC for TRD is supported by results of five published randomized, controlled, acute-phase studies of generally similar design. In each study, OFC was associated with rapid reduction in depressive symptoms. In two studies, significantly greater improvement in depressive symptoms occurred in OFC-treated patients at study end point compared with those who received antidepressant monotherapy. These effects appeared to be strongest in cases where antidepressant failure was established during the current depressive episode. Although OFC was well-tolerated, increases in body weight and prolactin concentration were greater with OFC than antidepressant monotherapy, and were similar to olanzapine monotherapy. Increases in random total cholesterol levels were greatest for OFC, and were significantly greater than those of olanzapine and antidepressant monotherapy. The long-term efficacy and tolerability of OFC for TRD has not been investigated, and the comparative effectiveness of OFC versus other next-step options is unknown. As such, the exact place of OFC among the available therapeutic options for TRD is not fully understood at this time.

Topics: Adult; Age Factors; Antidepressive Agents; Benzodiazepines; Depression; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Fluoxetine; Humans; Kidney Diseases; Liver Diseases; Olanzapine; Randomized Controlled Trials as Topic

A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain.. There was a 1.67-fold increase in area under the plasma concentration-time curve from time 0 to infinity (AUC. OLZ/SAM 5/10 mg was generally well tolerated under the conditions of the studies, with a safety profile consistent with that observed in other clinical studies of OLZ/SAM.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Liver Diseases; Male; Middle Aged; Naltrexone; Olanzapine; Renal Insufficiency; Tablets; Young Adult

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically-based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once-daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady-state total systemic exposures by 1.1-, 1.5-, and 1.6-fold, respectively, for olanzapine, and by 1.2-, 1.9-, and 2.3-fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.

Topics: Aged; Antipsychotic Agents; Drug Combinations; Female; Humans; Liver Diseases; Male; Middle Aged; Models, Biological; Naltrexone; Narcotic Antagonists; Olanzapine; Severity of Illness Index; Tablets

Schizophrenia is a chronic, disabling neurological illness. This study investigated the effect of rosuvastatin (RSU) addition to the antipsychotic drug: olanzapine (OLZ) in treatment of post-weaning isolation rearing (IR) damaging effect and assessed behavioral impairment, metabolic and hepatic abnormalities, oxidative stress, and inflammatory markers.. Treatment with OLZ (6 mg/kg, P.O.) and/or RSU (10 mg/kg, I.P.) have been started 6 weeks after isolation. We assessed behavioral tests, serum cortisol level, and hippocampal content of neurotransmitters. In addition, we assessed histopathology, inflammatory and oxidative stress markers of hippocampus, liver and adipose tissue RESULTS: Treatment of IR animals with OLZ, and/or RSU significantly counteracted the changes in hippocampus, liver and adipose tissue induced by post-weaning IR. Co-treatment of IR rats with both OLZ and RSU showed additive effects in some areas like improving both tumor necrosis factor alpha (TNFα) in both hippocampus and liver, histopathology of liver, oxidative stress markers of adipose tissue, β. post-weaning IR as a model has behavioral, hippocampal, hepatic and marked metabolic changes more relevant to schizophrenia than drug-induced models. These effects were ameliorated by RSU and/or OLZ that are explained by their antioxidant, anti-inflammatory, anti-stress and anti-hyperlipidemic properties. Interestingly, co-treatment with both drugs showed a better effect.

Topics: Animals; Antipsychotic Agents; Cognitive Dysfunction; Disease Models, Animal; Drug Therapy, Combination; Hippocampus; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Liver Diseases; Male; Olanzapine; Oxidative Stress; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium; Schizophrenia; Social Isolation; Tumor Necrosis Factor-alpha

Olanzapine is a widely used second generation antipsychotic drug. Case reports of intoxications have been published, but reports in the literature of non-fatal intoxications of olanzapine containing repeated measurements of serum levels are scarce. Therefore, this case of non-fatal olanzapine intoxication is presented, in which 19 blood samples were drawn during 2 weeks. The highest (initial) measured value was estimated at 800 pg/L. This patient ingested 550 mg of olanzapine resulting in clinical signs of intoxication, including seizures. Because the patient was found the day after the intoxication, the initial concentration had probably been higher. The pharmacokinetics of olanzapine has been described as linear and dose-proportional throughout the therapeutic dosing range. Large overdoses, however, have been described to show non-linear pharmacokinetics. In this study's series of serum concentrations, a two-phase elimination was seen, with an initial elimination half-life of about 24 h during the first 3 days, followed by a second phase with a half-life of about 2.5 days. The patient in this case recovered completely. Because the elimination time after intoxication can be considerably longer than expected, it is recommended that the patient's serum concentrations after intoxication be monitored.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drug Overdose; Half-Life; Humans; Liver Diseases; Liver Function Tests; Male; Olanzapine; Seizures; Suicide, Attempted