Olanzapine: Uses and Pharmacology

Introduction

Olanzapine （Figure 1） is an effective antipsychotic drug used in psychiatry to treat psychoses, especially schizophrenia and schizoaffective disorders. This compound belongs to the class of organic compounds known as benzodiazepines. These are organic compounds containing a benzene ring fused to either isomers of diazepine(unsaturated seven-member heterocycle with two nitrogen atoms replacing two carbon atoms). Olanzapine very closely resembles clozapine and only differs by two additional methyl groups and the absence of a chloride moiety.[1] It was discovered by scientists at Eli Lilly and approved to be marketed in the US in 1996.[2]

Olanzapine belongs to the 2nd generation antipsychotics, its mechanism of action ranks among multireceptor antagonists (MARTA); it affects the dopamine, serotonin, adrenaline, histamine, and muscarinic systems. The broad pharmacodynamic profile of olanzapine provides for a broad indication spectrum with a better adverse effect profile compared to conventional antipsychotics. It can be used in a number of situations to benefit cancer patients in palliative care as well as in the terminal stages of the disease. Purpose: The review article presents possible indications for olanzapine in oncological palliative care. Apart from dealing with delirium and anxiety, indications for the use of antipsychotics in palliative medicine include the management of nausea, vomiting and loss of appetite. Olanzapine is an effective antiemetic in cancer patients with tumor-induced nausea and in antiemetic regimens for chemotherapy-induced nausea and vomiting. Olanzapine is an effective treatment for delirium, as effective as haloperidol, but with a lower toxicity profile. It increases appetite and can be used with advantage in patients with anorexia and weight loss.It is possible to use its anxiolytic and mood-stabilizing effects; in many situations, it can serve well as a co-analgesic, especially in the so-called total pain. It is proven to increase the quality of life of patients with advanced cancer. Conclusion: Due to its effect, simple dosage and a good safety profile, olanzapine is a useful drug for the routine clinical practice of an oncologist –a non-psychiatrist.[3]

Pharmacology

Pharmacodynamics

The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention.[4] Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects.[1]

Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents.[5]

The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase.

Mechanism of action

The activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor D1, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergic receptor, the histamine receptor H1 and multiple muscarinic receptors.[6]

As above mentioned, olanzapine presents a wide profile of targets, however, its antagonistic effect towards the dopamine D2 receptor in the mesolimbic pathway is key as it blocks dopamine from having a potential action at the post-synaptic receptor. The binding of olanzapine to the dopamine D2 receptors is easily dissociable and hence, it allows for a certain degree of dopamine neurotransmission.[4] On the other hand, olanzapine acts in the serotonin 5HT2A receptors in the frontal cortex in a similar manner than the reported on dopamine D2 receptors. This determined effect allows for a decrease in adverse effects.[4]

Absorption

Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week.6 Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours after oral administration.[6]

Metabolism

Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system. From the CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6. As part of the phase I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2. On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine. On the phase II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine.[6]

Toxicity

The toxicity symptoms of olanzapine are known to include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, extrapyramidal symptoms and anticholinergic effects. The overdosage effects in children are generally associated with more significant side effects.

The maximum registered dosage of olanzapine in clinical trials was of 300 mg and it was reported to present drowsiness and slurred speech. However, on post-marketing surveillance, a wide range of symptoms have been presented including agitation, dysarthria, tachycardia, extrapyramidal symptoms, and reduced consciousness. One case of overdosage-driven death was reported after ingestion of 450 mg of olanzapine. In the cases of acute overdosage, the establishment of adequate oxygenation and ventilation, gastric lavage and administration of activated charcoal with a laxative is recommended.

In carcinogenesis studies, olanzapine was showed to present an increase in the incidence of liver hemangiomas and hemangiosarcomas as well as mammary gland adenomas, and adenocarcinomas. On fertility studies, there was solely found impairment in male mating performance and delays in ovulation. There is no evidence of mutagenic, genotoxic potential not adverse events on fertility.[6-7]

References

[1]Schatzberg A. and Nemeroff C. The american psychiatric association publishing textbook of psychopharmacology (5th ed.). American Psychiatric Association Publishing. 2017;[ISBN:978-161-5371-228]

[2]Green W. Child & adolescent clinical psychopharmacology (3rd ed.). Lippincott Williams & Wilkins.2001; [ISBN:0-7817-5950-1]

[3]?oukalová Z. Olanzapine in oncology palliative care. Olanzapin v onkologické paliativní pé?i. Klin Onkol. 2022;35(4):276-283. doi:10.48095/ccko2022276

[4]Thomas K, Saadabadi A. Olanzapine. 2023 Aug 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan; PMID: 30422498.

[5]Brunner E, Falk DM, Jones M, Dey DK, Shatapathy CC: Olanzapine in pregnancy and breastfeeding: a review of data from global safety surveillance. BMC Pharmacol Toxicol. 2013 Aug 1;14:38. doi: 10.1186/2050-6511-14-38.

[6]Olanzapine. DrugBank Online  https://go.drugbank.com/drugs/DB00334

[7]Chue P, Singer P: A review of olanzapine-associated toxicity and fatality in overdose. J Psychiatry Neurosci. 2003 Jul;28(4):253-261.