Article: Olanzapine

Olanzapine
Systematic (IUPAC) name
2-methyl-4-(4-methyl-1-piperazinyl)- 10H-thieno[2,3-b][1,5]benzodiazepine
Identifiers
CAS number	132539-06-1
ATC code	N05AH03
PubChem	4585
DrugBank	132539-06-1
Chemical data
Formula	C17H20N4S
Mol. weight	312.439
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Half life	21-54 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	C
Legal status	Rx only
Routes	oral

Olanzapine (oh-LAN-za-peen, sold as Zyprexa®, Zydis®, or in combination with fluoxetine, as Symbyax®) was the second atypical antipsychotic to gain approval by the Food and Drug Administration (FDA) and has become one of the most commonly used atypical antipsychotics. Olanzapine has been approved by the FDA for the treatment of schizophrenia, acute mania in bipolar disorder, agitation associated with schizophrenia and bipolar disorder, and as maintenance treatment in bipolar disorder. It has also been established in treating depression off-label because of its mood-stabilizing properties and its ability to increase the efficacy of antidepressants. Olanzapine is manufactured and marketed by the pharmaceutical company Eli Lilly and Company. It is available as a pill that comes in the strengths of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg and as as Zydis orally disintegrating tablets in the strengths of 5 mg, 10 mg, 15 mg, and 20 mg. It is also available as a rapid-acting intramuscular injection for short term acute use.

Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. general anxiety disorder, panic disorder, post-traumatic stress disorder); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa) and as an adjunctive treatment for major depressive disorder with psychotic features.

Pharmacology

Olanzapine is structurally similar to clozapine, and is classified as a thienobenzodiazepine. Olanzapine has a high affinity for dopamine and serotonin receptors. Like most atypical antipsychotics compared to the older typical ones, Olanzapine has a lower affinity for histamine, cholinergic muscarinic and alpha adrenergic receptors. The mechanism of action of olanzapine is unknown, however it is theorized that olanzapine's antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of olanzapine, but the significance of 5-HT2A antagonism is debated among researchers. Antagonism at muscarinic, histaminic and alpha adrenergic receptors likely explains some of the side effects of olanzapine, such as anticholinergic effects, weight gain, sedation and orthostatic hypotension.

Pharmacokinetics

Olanzapine displays linear kinetics. Its elimination half-life ranges from 21 to 54 hours. Steady state plasma concentrations are achieved in about a week. Olanzapine undergoes extensive first pass metabolism and bioavailability is not affected by food.

Metabolism

Olanzapine is metabolized by the Cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be increased or decreased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamine or ciprofloxacin) CYP1A2 activity respectively.

Adverse events

Adverse events reported in the package insert for olanzapine include dry mouth, dizziness, sedation, insomnia, orthostatic hypotension, akathisia, and weight gain. Olanzapine is reported to cause extrapyramidal symptoms, tardive dyskinesia and neuroleptic malignant syndrome, although at a much reduced rate when compared to the classical anti-psychotics.

Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics. Additionally there are some case reports of olanzapine-induced diabetic ketoacidosis. There is data showing that olanzapine can decrease insulin sensitivity. In addition, increased triglyceride levels may also be an issue with olanzapine. Impaired glucose metabolism, high triglycerides, and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggests that olanzapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.

Citing an increased risk of stroke, in 2004 the Committee for the Safety of Medicines (CSM) in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia.

The results of a large, random-design study funded by NIH's National Institute of Mental Health (NIMH) were published in September 2005. The 18-month study, which involved 1,400 participants at 57 sites around the country, found that "patients on olanzapine also experienced substantially more weight gain and metabolic changes associated with an increased risk of diabetes than those participants taking the other drugs." [1]

There has been a study which seems to indicate that taking Zyprexa Zydis, a wafer that dissolves in the mouth, does not promote weight gain. The study was published in Psychopharmacology (Berl). 2004 Sep;175(3):389-90. "Weight loss after switching from conventional olanzapine tablets to orally disintegrating olanzapine tablets" by de Haan L, van Amelsvoort T, Rosien K, Linszen D.

Overdose

Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness and coma. Death has been reported after an acute overdose of 450mg, but also survival after an acute overdose of 1500mg.