Olanzapine


Article Author:
Kristina Thomas


Article Editor:
Abdolreza Saadabadi


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Updated:
9/15/2019 7:03:27 PM

Indications

Olanzapine is a second-generation (atypical) antipsychotic medication. The FDA has approved this medication for the following conditions:

  • Schizophrenia if the patient is over the age of 13
  • Bipolar disorder including mixed or manic episodes

Olanzapine also has approval for use with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), in patients with episodes of depression associated with bipolar disorder type 1 and treatment-resistant depression.

It is important to note that olanzapine is not FDA approved for patients under the age of 13, and the combination of olanzapine with fluoxetine is not approved for patients under the age of 10.

Mechanism of Action

Olanzapine is an atypical (second-generation) antipsychotic which exerts its action primarily on dopamine and serotonin receptors. It works on dopamine D2 receptors in the mesolimbic pathway as an antagonist, blocking dopamine from having a potential action at the post-synaptic receptor. Olanzapine binds loosely to the receptor and dissociates easily, allowing for normal dopamine neurotransmission. The effect on the D2 receptors leads to a decrease in positive symptoms in patients, including hallucinations, delusions, and disorganized speech, thought, and behavior. Olanzapine works similarly on serotonin 5HT2A receptors in the frontal cortex as an antagonist. Its effects on serotonin lead to a decrease in negative symptoms, including anhedonia, flat affect, alogia, avolition, and poor attention.[1]

Olanzapine has a half-life of 21 to 54 hours, with an average of 30 hours. Daily administration of olanzapine leads to reaching the steady-state plasma concentration in about one week. Olanzapine has linear pharmacokinetics when dosed within the FDA-approval range. The volume of distribution is approximately 1000 liters, and the medication is distributed widely throughout the body. It is 93% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein.

Olanzapine is highly metabolized by the liver extensively via direct glucuronidation and the cytochrome P450 system. The enzymes from this system that metabolize olanzapine are primarily 1A2 and minorly 2D6. CYP1A2 genes are poly-morphic; however, a study showed that there were no reported associations between various polymorphisms and pharmacokinetics of the medication.[2] Patients with hepatic impairment do not require a dosage adjustment. Patients with Child-Pugh Classification A and B cirrhosis did not majorly influence the metabolism of this medication. Because of this extensive metabolism of olanzapine, only 7% of the drug remains unchanged upon excretion. Olanzapine excretion is primarily in the urine (53%) and the feces (30%). Patients with renal impairment do not require special dosing for this medication because of its metabolism.[3]

Administration

A major benefit to olanzapine is its multiple routes of administration, giving it potential use in many patients. It is available in a tablet form, which is beneficial in the compliant patient who can take medications orally. The tablet form is available in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg dosages. Olanzapine is also available in a disintegrating tablet form. This form is especially beneficial for the patient who cannot swallow pills but wishes to take an oral form, patients who have a high propensity to avert taking medications by not swallowing the pill or those who are agitated. There is no difference in bioavailability between the tablet and the orally disintegrating tablet form.

Olanzapine can also be offered in an injectable form, dosage at 5 mg/mL. This form may be best for the agitated patient who is not medication compliant and refuses or cannot to swallow the oral form of the drug. The injectable form is not a long-acting injection as it has the same half-life as the tablet forms, and should not act as replacement therapy for long-acting injectable antipsychotic medications.

There is also a long-acting form that could cause post-injection delirium/sedation syndrome.

Adverse Effects

One of the most common adverse effects on olanzapine is the potential for gaining weight. Olanzapine causes an increase in appetite leading to hyperphagia with a consequence of weight gain.[4] Therefore, it should be used cautiously in patients who are obese, have little control over their food intake, and do not exercise regularly to combat weight gain.[5] Another adverse effect of olanzapine is the increased risk of metabolic effects. Olanzapine has a high potential to cause reduced insulin sensitivity, leading to impaired glucose tolerance, especially in a younger population.[6] While an exact mechanism for these adverse effects is still under debate, there is evidence suggesting that the WNT signaling pathway effector TCF7L2 plays a vital role with glucose homeostasis.[7] Olanzapine-induced weight gain and decreased insulin sensitivity lead to increased expression of TCF7L2 in the liver and skeletal muscle. Elevated insulin levels lead to increased expression of TCF7L2 in adipose tissue. This heightened expression of TCF7L2 in multiple body tissues which all play a role of glucose metabolism suggests the mechanism for metabolic dysfunction caused by Olanzapine.[7] This finding also contributes to a possible therapeutic target to prevent or treat the adverse metabolic effects of olanzapine.

Olanzapine's mechanism of action also lends itself to directly causing adverse reactions associated with the dopaminergic blockade. Patients taking Olanzapine have a risk of developing akathisia, extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome. However, the risk of developing these side effects is lesser than first-generation antipsychotics due to the loose association and quick dissociation of olanzapine with the D2 receptors.[1]

Contraindications

There is a black box warning for olanzapine regarding dementia-related psychosis. Elderly patients with dementia who present with symptoms of psychosis should not be prescribed olanzapine due to an increased risk of mortality.[8]

Olanzapine is contraindicated in patients with a known hypersensitivity to this medication or medications in its class. Additionally, due to the adverse effects of weight gain and metabolic dysfunction, this medication should be used with caution in patients who are obese or have diabetes mellitus; however, olanzapine is not absolutely contraindicated in these patients.[4] Frequently monitoring of blood glucose levels and patient education on exercise and diet should follow a prescription for olanzapine.

Monitoring

The optimal therapeutic window for olanzapine is 20 ng/mL to 40 ng/mL. A serum concentration of 80 ng/mL is the threshold for adverse reactions to olanzapine. Toxicology studies identified that postmortem serum levels of olanzapine were higher than antemortem levels, and high dosages olanzapine was only lethal when combined with another drug.[9][10]

Toxicity

Olanzapine has a low potential for toxicity when prescribed alone.[11] However, there are case reports which found olanzapine toxicity caused by high doses of the medication when taken in conjunction with other medications. For example, a case report of a patient overdosed by taking 560 milligrams of olanzapine in addition to 6.4 grams of propranolol and 280 milligrams of amlodipine was found to have extreme hypotension, circulatory collapse, respiratory depression, and coma.[12] However, when taken alone following FDA-approved dosages, the risk of toxicity is low.

Enhancing Healthcare Team Outcomes

Ethics plays a significant role when discussing the chosen route of administration for olanzapine. Olanzapine is the most commonly used medication in episodes for psychosis.[13] The half-life of olanzapine is the same among all three forms of administration as mentioned above, and thus, should not influence the decision of which route of administration to choose. From a clinical standpoint, the injection form may be the preferred route when dealing with an agitated patient who does not wish or cannot swallow a pill; however, a provider should not subject a patient to injection if they do not need it. Strong interpersonal communication skills are necessary when working with an uncooperative or agitated patient. If the patient can consume the dissolving form of olanzapine, this route of administration should be considered over the injectable form.

The prescribing clinician should work closely with specialists, pharmacy, and the nursing staff in patients receiving olanzapine. Nursing will administer the medication in most controlled circumstances; they should be alert to patients refusing to take the drug, as well as watching for adverse effects from the medication. This is where a psychiatric health specialty-trained nurse can be of great benefit because they are more familiar with what to monitor. Pharmacists should carefully vet the patient's medication regimen, looking for red flags for drug interactions, and a board-certified psychiatric pharmacist can participate with the clinicians in agent selection and dosing. All these different areas must coordinate their efforts and communicate with each other so that the patient on olanzapine receives maximum benefit with minimal adverse effects, resulting in successful therapy. [Level V]


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Olanzapine - Questions

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A patient with schizophrenia has failed to respond to the typical antipsychotic agents. He is started on an atypical antipsychotic with less extrapyramidal side effects. The atypical antipsychotic agent appears to have a low potential for drug interactions or bone marrow suppression. What is this drug?



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What is the most common reason a patient would be on olanzapine?



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Which of the following antipsychotic medication is most likely to cause transaminase elevation?



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A family brings in their 70-year old mother because she has been confused, irritable, angry, and is not aware of reality. She is always wandering off and getting lost in the neighborhood. She started to develop memory problems a few years ago but now she is unable to perform the daily living activities. After examining her, you decide to start the patient on olanzapine because of behavior problems. What is the one-parameter you will closely monitor in this patient after starting this medication?



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The generic drug olanzapine is branded under which trademarked name?



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A 29-year-old woman with a known diagnosis of schizophrenia is brought to the emergency department by her friend due to an acute psychotic episode, where she was hearing voices telling her to jump off a bridge. She has not been taking any medications and her friend is not aware of what medications she has taken in the past. She is admitted to the hospital and started on olanzapine. Her condition stabilizes after 3 days and she is discharged. At the time of discharge, her friend asks for information about olanzapine. Which of the following side effect is commonly associated with olanzapine use?



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Which of the following is the generic for the brand medication Zyprexa?



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The psychiatrist is seeing a newly admitted patient. He starts the patient on the drug olanzapine. This drug is FDA-approved to treat patients with which of the following conditions? Select all that apply.



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Olanzapine - References

References

Tollens F,Gass N,Becker R,Schwarz AJ,Risterucci C,Künnecke B,Lebhardt P,Reinwald J,Sack M,Weber-Fahr W,Meyer-Lindenberg A,Sartorius A, The affinity of antipsychotic drugs to dopamine and serotonin 5-HT{sub}2{/sub} receptors determines their effects on prefrontal-striatal functional connectivity. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2018 Jul 10     [PubMed]
Huang M,Yu L,Pan F,Lu S,Hu S,Hu J,Chen J,Jin P,Qi H,Xu Y, A randomized, 13-week study assessing the efficacy and metabolic effects of paliperidone palmitate injection and olanzapine in first-episode schizophrenia patients. Progress in neuro-psychopharmacology     [PubMed]
Hou PH,Chang GR,Chen CP,Lin YL,Chao IS,Shen TT,Mao FC, Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice. Iranian journal of basic medical sciences. 2018 May     [PubMed]
Nicol GE,Yingling MD,Flavin KS,Schweiger JA,Patterson BW,Schechtman KB,Newcomer JW, Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths: A Randomized Clinical Trial. JAMA psychiatry. 2018 Aug 1     [PubMed]
Li R,Ou J,Li L,Yang Y,Zhao J,Wu R, The Wnt Signaling Pathway Effector TCF7L2 Mediates Olanzapine-Induced Weight Gain and Insulin Resistance. Frontiers in pharmacology. 2018     [PubMed]
Kim HM,Chiang C,Kales HC, After the black box warning: predictors of psychotropic treatment choices for older patients with dementia. Psychiatric services (Washington, D.C.). 2011 Oct     [PubMed]
Polasek TM,Tucker GT,Sorich MJ,Wiese MD,Mohan T,Rostami-Hodjegan A,Korprasertthaworn P,Perera V,Rowland A, Prediction of olanzapine exposure in individual patients using physiologically based pharmacokinetic modelling and simulation. British journal of clinical pharmacology. 2018 Mar     [PubMed]
Urban AE,Cubała WJ, Therapeutic drug monitoring of atypical antipsychotics. Psychiatria polska. 2017 Dec 30     [PubMed]
Pourahmad J,Salimi A,Razian M, Analysis of Toxicity Effects of Buspirone, Cetirizine and Olanzapine on Human Blood Lymphocytes: in Vitro Model. Current clinical pharmacology. 2018 May 15     [PubMed]
Hopkins LE,Sunkersing J,Jacques A, Too many pills to swallow: A case of a mixed overdose. Journal of the Intensive Care Society. 2017 Aug     [PubMed]
Yeisen RA,Joa I,Johannessen JO,Opjordsmoen S, Use of medication algorithms in first episode psychosis: a naturalistic observational study. Early intervention in psychiatry. 2016 Dec     [PubMed]
Mauri MC,Paletta S,Di Pace C,Reggiori A,Cirnigliaro G,Valli I,Altamura AC, Clinical Pharmacokinetics of Atypical Antipsychotics: An Update. Clinical pharmacokinetics. 2018 Jun 19     [PubMed]
Na Takuathung M,Hanprasertpong N,Teekachunhatean S,Koonrungsesomboon N, Impact of CYP1A2 genetic polymorphisms on pharmacokinetics of antipsychotic drugs: a systematic review and meta-analysis. Acta psychiatrica Scandinavica. 2018 Aug 15     [PubMed]

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