Olanzapine is an atypical antipsychotic drug that is primarily used and approved as a treatment for Schizophrenia since 1988. Olanzapine is typically consumed orally or injected to suppress and reduce symptoms of Schizophrenia during its onset or in the course of long term treatment. Like many other drugs, Olanzapine is subjected to pharmacogenetic properties. Hence, it responds differently to different patients. Olanzapine has been known to produce many adverse drug reactions, which can be accounted for by its pharmacodynamic and pharmacokinetic aspects when taken into the body.
The differences observed between oral and Long-Acting Injection application of Olanzapine
The pharmacokinetics of a drug must be carefully considered in order to determine the correct dosage and dose intervals. Oral consumption of Olanzapine has been shown to have a significant difference in half-life and drug clearance rates in comparison to Olanzapine Long-Acting Injection (OLAI) application.1 Therefore, it affects the dosage and dose intervals of the drug. In patients that were treated with a dosage of oral Olanzapine (20mg/day), steady-state conditions were reached after four days, but its half-life was only approximately 30 hours. However, when patients were treated with OLAI of similar Olanzapine dosage (300mg/2weeks), plasma concentration was observed immediately, steady-state was reached after three months of gradual increase in concentration, but therapeutic concentrations were reached within hours of the first injection, and its half-life was estimated to be around 30 days.1 This was due to prolonged intramuscular absorption. Furthermore, within the six years of conducting the study, the steady-state of OLAI remained consistent and showed no sign of continuing accumulation1. Thus therapeutically sufficient. These were the same result observed in another study of OLAI involving 931 schizophrenic patients between the age of 18-76 conducted over the same amount of time.2 Therefore, this revealed that OLAI was an effective alternative that requires less frequent dosing than oral Olanzapine due to its longer half-life and prolonged intramuscular absorption. Despite its long time to reach a steady-state, it is still able to produce the necessary therapeutic effects to successfully treat Schizophrenia.
Metabolic Effects of Olanzapine results in weight-related disorders in Schizophrenic patients.
Olanzapine is metabolized mainly by the liver, a key organ for glucose and lipid homeostasis. Olanzapine causes liver metabolic disturbances when consumed, leading to weight-related disorders such as obesity or diabetes in schizophrenic patients. In two studies conducted one with schizophrenic patients and the other with rats, it was found that administration of Olanzapine significantly increased body mass index, total cholesterol, BGL, LDL and HDL without an increase in food consumption.3, 4 Fernandez-Egea et al3 found that Olanzapine caused increase blood levels of interleukin 6 (IL-6), a diabetes proinflammatory marker which suggests a modification in lipid and carbohydrate metabolism has taken place. This is further supported by Schmidt et al4, which showed olanzapine administration downregulated gene expression of genes involved in lipid biosynthesis and upregulated Gsk3b, which suppresses glycogen storage.4 It was also discovered that increase in protein kinase AMPK and mTOR activation due to Olanzapine was directly linked to change in carbohydrate and lipid metabolism, whereby AMPK is involved in a catabolic pathway which enhances glycolysis via lipid oxidation rather than glucose, this explains the significant increase in glucose intolerance and unfastened plasma glucose, but at the same time, also inhibits ATP-consuming processes. mTOR, on the other hand, promotes protein and lipid synthesis (ATP-consuming processes).4 These changes collectively would, therefore, result in increased BGL, cholesterol, LDL, and HDL and contribute to significant weight gains. Thus, the two studies examined both suggested consumption of Olanzapine altered lipid and carbohydrate regulations altogether contributed to unhealthy body indexes, which resulted in weight-related disorders such as diabetes and obesity.
Individual factors that affect Olanzapine’s variable responses
Some key individual factors that influence the responses of Olanzapine in the body are smoking and sexual orientation. A 24 weeks study conducted upon schizophrenic smokers and non-smokers found that there was an increase in the clearance of Olanzapine in smokers compared to non-smokers, this resulted in a lower average steady-state plasma concentration.1 Having a lower average steady-state plasma concentration meant that Olanzapine is less effective as a treatment in smoking patients compare to non-smoking patients as they would require a higher dose or more frequent dose interval to produce the necessary responses. Zabala et al5 also found supporting evidence of higher olanzapine clearance in smoking schizophrenic patients. It was determined that the induction of isoenzyme CYP1A2 by polycyclic aromatic hydrocarbons components in tobacco resulted in increased olanzapine clearance and reduced plasma concentration.5 Together these two studies suggest that tobacco smokes contains chemicals that induced the body’s enzymatic activities that would not otherwise occur in non-smokers, leading to a faster clearance of Olanzapine in smoking patients. Olanzapine was found to show a 30-38% faster clearance rate in males in comparison to females in a number of researches.1, 6, 7 Jönsson et al6 suggested that the significant difference observed was due to female’s smaller liver size and different expression of CYP450 in different genders, which was consistent with Lobo et al7. Smaller liver size meant slower activity of hepatic clearance and lower expression of metabolic enzymes; hence, higher steady-state Olanzapine plasma concentration. However, this finding was inconsistent with Li et al10 that saw insignificant gender effect on Olanzapine clearance. This, however, was likely due to the asymmetric distribution of gender in Li et al8 cohort A and B, whereby A were all male subjects. Thus, the different physical and chemical aspects of male compared to female leads to their difference in Olanzapine clearance which precedes to different drug response as male are less exposed to the effects of Olanzapine when it is metabolised at normal rate.
Olanzapine is currently a primarily used drug to treat patients with Schizophrenia with two ways of administrations. Although it may be effective, side effects such as significant weight gain and onsetting of weight-related problems are tenable. Individual factors such as sex and smoking status must also be considered carefully in order to produce therapeutic effects on patients
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