Chemistry:Olanzapine

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Short description: Atypical antipsychotic medication
Olanzapine
Olanzapine.svg
Olanzapine-from-xtal-3D-balls.png
Clinical data
Trade namesZyprexa, Zypine, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa601213
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular injection
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)
  • CA: ℞-only
  • NZ: Prescription only
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetic data
Bioavailability60-65%[2][3][4]
Protein binding93%[5]
MetabolismLiver (direct glucuronidation and CYP1A2 mediated oxidation)
Elimination half-life33 hours, 51.8 hours (elderly)[5]
ExcretionUrine (57%; 7% as unchanged drug), faeces (30%)[5][6]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H20N4S
Molar mass312.44 g·mol−1
3D model (JSmol)
Melting point195 °C (383 °F)
Solubility in waterPractically insoluble in water mg/mL (20 °C)
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Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder.[7] For schizophrenia, it can be used for both new-onset disease and long-term maintenance.[7] It is taken by mouth or by injection into a muscle.[7]

Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth.[7] Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, and tardive dyskinesia.[7] In older people with dementia, its use increases the risk of death.[7] Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth.[7] Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.[7]

Olanzapine was patented in 1991 and approved for medical use in the United States in 1996.[7][8] It is available as a generic medication.[7] In 2020, it was the 164th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[9][10] Eli Lilly also markets olanzapine in a fixed-dose combination with fluoxetine as olanzapine/fluoxetine (Symbyax).[11] It is on the World Health Organization's List of Essential Medicines.[12]


Medical uses

It is approved by FDA for the following indications:

  • schizophrenia.
  • acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder.
  • adjunct to valproate, carbamazepine or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder.
  • combination olanzapine/fluoxetine for the treatment of depressive episodes associated with bipolar I disorder.[13][14][15]

In United Kingdom and Australia it is approved for schizophrenia, moderate to severe manic episodes, alone, or in combination with lithium or valproate and the short-term treatment of acute manic episodes associated with Bipolar I Disorder.[16][17]

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication.[18] Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia.[19][20][21][22] The usefulness of maintenance therapy, however, is difficult to determine, as more than half of people in trials quit before the 6-week completion date.[23] Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia.[20][24]

Bipolar disorder

Olanzapine is recommended by the National Institute for Health and Care Excellence as a first-line therapy for the treatment of acute mania in bipolar disorder.[25] Other recommended first-line treatments are aripiprazole, haloperidol, quetiapine, and risperidone.[26] It is recommended in combination with fluoxetine as a first-line therapy for acute bipolar depression, and as a second-line treatment by itself for the maintenance treatment of bipolar disorder.[25]

The Network for Mood and Anxiety Treatments recommends olanzapine as a first-line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second-line treatment for bipolar depression.[27]

A review on the efficacy of olanzapine as maintenance therapy in patients with bipolar disorder was published by Dando & Tohen in 2006.[28] A 2014 meta-analysis concluded that olanzapine with fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.[29]

Other uses

Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement of psychological symptoms was noted.[30]

Olanzapine has been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders.[31] Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder.[32] It has also been used for Tourette syndrome and stuttering.[33]

Olanzapine has been studied for the treatment of hyperactivity, aggressive behavior, and repetitive behaviors in autism.[34]

Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficulty falling asleep and staying asleep, even though such use is not recommended.[35] The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. Some evidence of efficacy for treating insomnia is seen; however, side effects such as dyslipidemia and neutropenia, which may possibly be observed even at low doses, outweigh any potential benefits for insomnia that is not due to an underlying mental health condition.[36][37][38][39]

Olanzapine has been recommended to be used in antiemetic regimens in people receiving chemotherapy that has a high risk for vomiting.[40]

Specific populations

Pregnancy and lactation

Olanzapine is associated with the highest placental exposure of any atypical antipsychotic.[41] Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence.[41] Olanzapine is associated with weight gain, which according to recent studies, may put olanzapine-treated patients' offspring at a heightened risk for neural tube defects (e.g. spina bifida).[42][43] Breastfeeding in women taking olanzapine is advised against because olanzapine is secreted in breast milk, with one study finding that the exposure to the infant is about 1.8% that of the mother.[5]

Elderly

Citing an increased risk of stroke, in 2004, the Committee on the Safety of Medicines in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis.[44] A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.[45] Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone.[46]

Adverse effects

The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74.[19] Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine,[47] but may include tremors and muscle rigidity.

Aripiprazole, asenapine, clozapine, quetiapine and olanzapine, in comparison to other antipsychotic drugs, are less frequently associated with hyperprolactinaemia. Although these drugs can cause transient or sustained hyperprolactinaemia, the risk is much lower. Owing to its partial dopaminergic agonist effect, aripiprazole is likely to reduce prolactin levels and, in some patients, can cause hypoprolactinaemia.[48] Although olanzapine causes an early dose-related rise in prolactin, this is less frequent and less marked than that seen with haloperidol, and is usually transient. A rise in prolactin is seen in about half of patients on olanzapine compared to over 90% of those taking risperidone, and enduring increases were less frequent in those taking olanzapine.[49]

It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe hypotension, sick sinus syndrome, and unstable angina.[50]

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce nontrivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the body's natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.[5][6][51][52][53]

Other side effects include galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction (impotence).[54]

Drug-induced OCD

Many different types of medication can create or induce pure obsessive-compulsive disorder (OCD) in patients who have never had symptoms before. A new chapter about OCD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) now specifically includes drug-induced OCD.

Metabolic effects

The US Food and Drug Administration (FDA) requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs' ability to induce weight gain, although some reports have been made of metabolic changes in the absence of weight gain.[55][56] Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures.[57][58][59][60][61] The effect is dose dependent in humans[62] and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis.[63] Olanzapine may decrease insulin sensitivity,[64][65] though one 3-week study seems to refute this.[66] It may also increase triglyceride levels.[58]

Despite weight gain, a large multicenter, randomized National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs.[67] One small, open-label, nonrandomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain,[68] but this has not been substantiated in a blinded experimental setting.

Post-injection delirium/sedation syndrome

Postinjection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate.[69] The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which do not appear to carry the same risk.[69] PDSS is characterized by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation.[69] Most people with PDSS exhibit both delirium and sedation (83%).[69] Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort.[69] PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue.[69] Using the proper, intramuscular-injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate it entirely.[69] This is why the FDA advises that people who are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs.[69]

Animal toxicology

Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumors found were in either the liver or mammary glands of the animals.[70]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[71] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[72] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[72] Less commonly, vertigo, numbness, or muscle pains may occur.[72] Symptoms generally resolve after a short time.[72]

Tentative evidence indicates that discontinuation of antipsychotics can result in psychosis, as a temporary withdrawal symptom.[73] It may also result in reoccurrence of the condition that is being treated.[74] Rarely, tardive dyskinesia can occur when the medication is stopped.[72]

Overdose

Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg.[75] Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death).[76] No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.[75] Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants.[41]

Interactions

Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance.[77] Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone.[76] Another enzyme inducer, ritonavir, has also been shown to decrease the body's exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5'-diphospho-glucuronosyltransferase (UGT).[76] Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine.[76] Although olanzapine's metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapine's clearance.[76]

Pharmacology

Pharmacodynamics

See also: Atypical antipsychotic#Pharmacodynamics and Antipsychotic#Comparison of medicationsOlanzapine was first discovered while searching for a chemical analog of clozapine that would not require hematological monitoring. Investigation on a series of thiophene isosteres on 1 of the phenyl rings in clozapine, a thienobenzodiazepine analog (olanzapine) was discovered.[78]
Site Ki (nM) Action Ref
SERT ≥3,676 ND [79][80]
NET >10,000 ND [79]
DAT >10,000 ND [79]
5-HT1A 2,063–2,720 Antagonist [81][82]
5-HT1B 509–660 ND [79][82]
5-HT1D 540–1,582 ND [79][82]
5-HT1E 2,010–2,408 ND [79][82]
5-HT1F 310 ND [82]
5-HT2A 1.32–24.2 Inverse agonist [83][84]
5-HT2B 11.8–12.0 Inverse agonist [85][86]
5-HT2C 6.4–29 Inverse agonist [84][86]
5-HT3 202 Antagonist [79]
5-HT5A 1,212 Full Agonist [79]
5-HT6 6.0–42 Antagonist [79][87]
5-HT7 105–365 Antagonist [79][88]
α1A 109–115 Antagonist [79][81]
α1B 263 Antagonist [79]
α2A 192–470 Antagonist [82][88]
α2B 82–180 Antagonist [81][82]
α2C 29–210 Antagonist [81][82]
β1 >10,000 ND [79][82]
β2 >10,000 ND [79][82]
D1 35–118 Antagonist [84][88]
D2 3.00–106 Antagonist [89][90]
D2L 31–38 Antagonist [82][84]
D2S 21–52 Antagonist [82][91]
D3 7.8–91 Antagonist [89][90]
D4 1.6–50 Antagonist [89][80]
D4.2 17–102 Antagonist [92][93]
D4.4 21–60 Antagonist [91]
D5 74–90 Antagonist [79][84]
H1 0.65–4.9 Inverse agonist [79][82]
H2 44 Antagonist [79]
H3 3,713 Antagonist [79]
H4 >10,000 Antagonist [79]
M1 2.5–73 Antagonist [94][95]
M2 48–622 Antagonist [87]
M3 13–126 Antagonist [86][87]
M4 10–350 Antagonist [87][94]
M5 6.0–82 Antagonist [87][94]
σ1 >5,000 ND [82]
σ2 ND ND ND
Opioid >10,000 ND [82]
nACh >10,000 ND [79]
NMDA
(PCP)		 >10,000 ND [79]
VDCC >10,000 ND [79][82]
VGSC >5,000 ND [82]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H3 (guinea pig), σ1 (guinea pig), opioid (rodent), NMDA/PCP (rat), VDCC, and VGSC.[79]

Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone.

In one study D2 receptor occupancy was 60% with low-dose olanzapine (5 mg/day) and occupancy with high dose at 83% (20 mg/day).[96] In the usual clinical dose range of 10–20 mg/day, D2 receptor occupancy varied from 71% to 80%.[97][98]

Olanzapine occupancy at 5-HT2A receptor are high at all doses (5 mg to 20 mg). It is reported that 5 mg dose of olanzapine produced a mean occupancy of 85% at 5 mg, 88% at 10 mg, and 93% at 20 mg dose .[99]

Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study.[100] P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood–brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein.[101] A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood–brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug that interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.[102]

Olanzapine is a potent antagonist of the muscarinic M3 receptor,[103] which may underlie its diabetogenic side effects.[104][105] Additionally, it also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, β-adrenergic receptors, and benzodiazepine binding sites.[47][106]

Although antagonistic effects of olanzapine at 5-HT2C alone is not associated with weight gain, olanzapine antagonism at histaminergic H1, and muscarinic M3 receptors have been implicated in weight gain.[78][107][108]

The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation; in addition, it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, but it offers no protection against the development of TD. In common with other second-generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.[109]

Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation.[110]

Pharmacokinetics

Metabolism

Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms, more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect.[47] Clearance of olanzapine appears to vary by sex; women have roughly 25% lower clearance than men.[76] Clearance of olanzapine also varies by race; in self-identified African Americans or Blacks, olanzapine's clearance was 26% higher.[76] A difference in the clearance is not apparent between individuals identifying as Caucasian, Chinese, or Japanese.[76] Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug–drug interactions) or a desire to determine if patients are taking their medicine may prompt its use.[76]

Chemistry

Olanzapine is unusual in having four well-characterised crystalline polymorphs and many hydrated forms.[111]

Chemical synthesis

The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug.[112]

Olanzapine synthesis.svg

Society and culture

Zyprexa (olanzapine) 10 mg tablets (AU)

Regulatory status

Olanzapine is approved by the US FDA for:

  • Treatment—in combination with fluoxetine—of depressive episodes associated with bipolar disorder (December 2003).[113]
  • Long-term treatment of bipolar I disorder (January 2004).[114][115]
  • Long-term treatment—in combination with fluoxetine—of resistant depression (March 2009)[116]
  • Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate)
  • Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults
  • Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults[117]
  • Treatment of the manifestations of psychotic disorders (September 1996[118] – March 2000).[119]
  • Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000)[119]
  • Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000)[119]
  • Maintaining treatment response in schizophrenic patients who had been stable for about eight weeks and were then followed for a period of up to eight months (November 2000)[119]

The drug became generic in 2011. Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide.[120]

Controversy and litigation

Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.[121]

In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits,[122] and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.[123][124]

A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapine's side effects.[123][125] The company denied these allegations and stated that the article had been based on cherry-picked documents.[123][124] The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case.[121] After the documents were leaked to online peer-to-peer, file-sharing networks by Will Hall and others in the psychiatric survivors movement, who obtained copies,[126] in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling.[121] The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales.[124] On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."[124]

Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the company's agreement to drop the threat of charges.[127]

In September 2008, Judge Weinstein issued an order to make public Lilly's internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.[121]

In March 2008, Lilly settled a suit with the state of Alaska,[128] and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.[127]

In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated "Eli Lilly admits that between September 1999 and March 31, 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer's dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets."[129][130]

The outcomes described here, and their legal ramifications, were fueled by motions and appeals that were not resolved until 2010.[131] In 2021, Gottstein summarized this tangle of legal activities, and their impact on the political landscape of psychiatry and antipsychiatry in the US, in The Zyprexa Papers.[132]

Trade names

Olanzapine is generic and available under many trade names worldwide.[1]

List of trade names for olanzapine[1]
A Aedon, Alonzap, Amulsin, Anzap, Anzatric, Anzorin, Apisco, Apo-Olanzapine, Apo-Olanzapine ODT, Apsico, Arenbil, Arkolamyl
B Benexafrina, Bloonis
C Caprilon, Cap-Tiva, Clingozan
D Deprex, Domus, Dopin
E Egolanza, Elynza, Emzypine, Epilanz-10, Exzapine
F Fontanivio, Fordep
G
H
I Irropia
J Jolyon-MD
K Kozylex
L Lanopin, Lanzapine, Lanzep, Lapenza, Lapozan, Lazap, Lazapir, Lazapix, Lezapin-MD, Lopez
M Meflax, Midax, Medizapin
N Niolib, Norpen Oro, Nykob, Nyzol
O Oferta, Oferta-Sanovel, Olace, Oladay, Oladay-F, Olaffar, Olan, Olanap, Olancell, Olandix, Olandoz, Olandus, Olankline, Olanpax, Olanstad, Olanza, Olanza Actavis, Olanza Actavis ODT, Olanzalet, Olanzalux, Olanzamed, Olanzapin 1A Pharma, Olanzapin AbZ, Olanzapin Accord, Olanzapin Actavis, Olanzapin AL, Olanzapin Apotex, Olanzapin Aristo, Olanzapin axcount, Olanzapin beta, Olanzapin Bluefish, Olanzapin Cipla, Olanzapin easypharm, Olanzapin Egis, Olanzapin G.L., Olanzapin Genera, Olanzapin Genericon, Olanzapin Helvepharm, Olanzapin Hennig, Olanzapin Heumann, Olanzapin HEXAL, Olanzapin Krka, Olanzapin Lilly, Olanzapin Mylan, Olanzapin Niolib, Olanzapin Orion, Olanzapin PCD, Olanzapin PharmaS, Olanzapin Ranbaxy, Olanzapin ratiopharm, Olanzapin ReplekFarm, Olanzapin Rth, Olanzapin Sandoz, Olanzapin Spirig HC, Olanzapin Stada, Olanzapin SUN, Olanzapin Teva, Olanzapin Viketo, Olanzapin Zentiva, Olanzapina Accord, Olanzapina Actavis, Olanzapina Actavis PTC, Olanzapina Aldal, Olanzapina Almus, Olanzapina Alter, Olanzapina Angenerico, Olanzapina Anipaz, Olanzapina Apotex, Olanzapina APS, Olanzapina Arrowblue, Olanzapina Aspen, Olanzapina Aurobindo, Olanzapina Basi, Olanzapina Bexalabs, Olanzapina Blixie, Olanzapina Bluefish, Olanzapina Bluepharma, Olanzapina Cantabria, Olanzapina Ceapharma, Olanzapina Ciclum, Olanzapina Cinfa, Olanzapina Cipla, Olanzapina Combix, Olanzapina Doc Generici, Olanzapina Dr. Reddy's, Olanzapina Eulex, Olanzapina Eurogenerici, Olanzapina Fantex, Olanzapina Farmoz, Olanzapina Flas Pharma Combix, Olanzapina Genedec, Olanzapina Generis, Olanzapina Germed, Olanzapina Glenmark, Olanzapina Green Avet, Olanzapina Helm, Olanzapina Kern Pharma, Olanzapina Krka, Olanzapina La Santé, Olanzapina Labesfal, Olanzapina Leugim, Olanzapina Lilly, Olanzapina LPH, Olanzapina Mabo, Olanzapina Medana, Olanzapina Medis, Olanzapina Medley, Olanzapina Mylan, Olanzapina Nakozap, Olanzapina Nolian, Olanzapina Normon, Olanzapina Ozilormar, Olanzapina Parke-Davis, Olanzapina Pensa, Olanzapina Pensa Pharma, Olanzapina Pharmakern, Olanzapina Polipharma, Olanzapina Polpharma, Olanzapina Qualigen, Olanzapina Ranbaxy, Olanzapina Ratio, Olanzapina Ratiopharm, Olanzapina Reconir, Olanzapina Reddy, Olanzapina Rospaw, Olanzapina Sabacur, Olanzapina Sandoz, Olanzapina Sarb, Olanzapina Stada, Olanzapina Sun, Olanzapina TAD, Olanzapina Technigen, Olanzapina Terapia, Olanzapina Teva, Olanzapina Tevagen, Olanzapina tolife, Olanzapina Torrent, Olanzapina Vegal, Olanzapina Vida, Olanzapina Winthrop, Olanzapina Wynn, Olanzapina Kraz, Olanzapina Zentiva, Olanzapina Zerpi, Olanzapina Zonapir, Olanzapin-Actavis, Olanzapin-CT, Olanzapine 1A Pharma, Olanzapine Accord, Olanzapine Actavis, Olanzapine Adamed, Olanzapine Alter, Olanzapine Alvogen, Olanzapine Apotex, Olanzapine Arrow Génériques, Olanzapine Auro, Olanzapine Aurobindo, Olanzapine Biogaran, Olanzapine Bluefish, Olanzapine CF, Olanzapine Clonmel, Olanzapine Cristers, Olanzapine Dexcel, Olanzapine EG, Olanzapine Egis, Olanzapine Evolugen, Olanzapine Galenicum, Olanzapine Generichealth, Olanzapine Glenmark, Olanzapine GSK, Olanzapine Isomed, Olanzapine Jacobsen, Olanzapine Jubilant, Olanzapine Lekam, Olanzapine Lesvi, Olanzapine Medana, Olanzapine Mylan, Olanzapine Neopharma, Olanzapine Niolib, Olanzapine Nyzol, Olanzapine Odis Mylan, Olanzapine ODT Generichealth, Olanzapine ODT Sanis Health, Olanzapine ODT Teva, Olanzapine ODT-DRLA, Olanzapine Orion, Olanzapine Polpharma, Olanzapine Prasco, Olanzapine Ranbaxy, Olanzapine Ratiopharm, Olanzapine Sandoz, Olanzapine Sanis Health, Olanzapine Sanovel, Olanzapine Stada, Olanzapine Sun, Olanzapine Synthon, Olanzapine Teva, Olanzapine Torrent, Olanzapine Zentiva, Olanzapine Zentiva Lab, Olanzapine Zydus, Olanzapine-DRLA, Olzapine, Olanzia
P Pinaz
Q
R
S
T
U
V
W
X
Y
Z Zyprexa, Zolafren, Zalasta, Zypine

Dosage forms

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 mg. Zyprexa (and generic olanzapine) is available as an orally disintegrating "wafer", which rapidly dissolves in saliva. It is also available in 10-mg vials for intramuscular injection.[77]

Research

Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).[133]

In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though some concerns remain for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms. Otherwise, olanzapine appears to be fairly well tolerated for this indication, with somnolence being the most common side effect.[134]

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo.[135] In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis (16.1% vs 37.9%). Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.[136]

References

  1. ↑ 1.0 1.1 1.2 "Drugs.com international listings for Olanzapine". Drugs.com. https://www.drugs.com/international/olanzapine.html. 
  2. ↑ "Disposition and biotransformation of the antipsychotic agent olanzapine in humans". Drug Metabolism and Disposition 25 (1): 81–93. January 1997. PMID 9010634. http://dmd.aspetjournals.org/content/25/1/81.long. 
  3. ↑ "Olanzapine. Pharmacokinetic and pharmacodynamic profile". Clinical Pharmacokinetics 37 (3): 177–193. September 1999. doi:10.2165/00003088-199937030-00001. PMID 10511917. 
  4. ↑ "Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response". Clinical Pharmacokinetics 46 (5): 359–388. 2007. doi:10.2165/00003088-200746050-00001. PMID 17465637. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "PRODUCT INFORMATION OLANZAPINE SANDOZ® 2.5mg/5mg/7.5mg/10mg/15mg/20mg FILM-COATED TABLETS" (PDF). TGA eBusiness Services. Sandoz Pty Ltd. 8 June 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02375-3. 
  6. ↑ 6.0 6.1 "Zyprexa, Zyprexa Relprevv (olanzapine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/zyprexa-relprevv-olanzapine-342979#showall. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 "Olanzapine, Olanzapine Pamoate Monograph for Professionals" (in en). AHFS. https://www.drugs.com/monograph/olanzapine-olanzapine-pamoate.html. 
  8. ↑ The Maudsley Prescribing Guidelines in Psychiatry (12th ed.). London, U K: Wiley-Blackwell. 2015. p. 16. ISBN 978-1-118-75460-3. https://books.google.com/books?id=XvOyBwAAQBAJ&pg=PA16. 
  9. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Olanzapine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Olanzapine. 
  11. ↑ "FDA Approves Symbyax(R) as First Medication for Treatment-Resistant Depression". Eli Lilly. https://investor.lilly.com/news-releases/news-release-details/fda-approves-symbyaxr-first-medication-treatment-resistant. 
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  15. ↑ "FDA-Approved Drugs HIGHLIGHTS OF PRESCRIBING INFORMATION" (in en). https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020592s074,021086s048,021253s061lbl.pdf.  This article incorporates text from this source, which is in the public domain.
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  21. ↑ "Acute Antipsychotic Treatment of Children and Adolescents With Schizophrenia-Spectrum Disorders: A Systematic Review and Network Meta-Analysis". Journal of the American Academy of Child and Adolescent Psychiatry 56 (3): 191–202. March 2017. doi:10.1016/j.jaac.2016.12.013. PMID 28219485. 
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  25. ↑ 25.0 25.1 "Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care | 1-recommendations | Guidance and guidelines | NICE". 24 September 2014. http://www.nice.org.uk/guidance/cg185/chapter/1-recommendations. 
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  27. ↑ "Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007". Bipolar Disorders 8 (6): 721–739. December 2006. doi:10.1111/j.1399-5618.2006.00432.x. PMID 17156158. 
  28. ↑ "Olanzapine - relapse prevention following mania". Journal of Psychopharmacology 20 (2 Suppl): 31–38. March 2006. doi:10.1177/1359786806063076. PMID 16551670. 
  29. ↑ "Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics". Pharmacopsychiatry 47 (2): 43–52. March 2014. doi:10.1055/s-0033-1363258. PMID 24549862. 
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  55. ↑ "Olanzapine-induced destabilization of diabetes in the absence of weight gain". Acta Psychiatrica Scandinavica 105 (3): 235–6; discussion 236–7. March 2002. doi:10.1034/j.1600-0447.2002.2c257a.x. PMID 11939979. 
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  57. ↑ "CAFE Study Shows Varying Benefits Among Atypical Antipsychotics". Medscape Medical News (WebMD). Oct 25, 2005. http://www.medscape.com/viewarticle/515435. 
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  63. ↑ "Complete Resolution of Olanzapine-Induced Diabetic Ketoacidosis". Journal of Pharmacy Practice 19 (4): 255–8. 2006. doi:10.1177/0897190006294180. 
  64. ↑ "The time-dependent change of insulin secretion in schizophrenic patients treated with olanzapine". Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (6): 866–870. August 2010. doi:10.1016/j.pnpbp.2010.04.003. PMID 20394794. 
  65. ↑ "Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers". Neuropsychopharmacology 33 (7): 1633–1641. June 2008. doi:10.1038/sj.npp.1301541. PMID 17712347. 
  66. ↑ "Evaluation of insulin sensitivity in healthy volunteers treated with olanzapine, risperidone, or placebo: a prospective, randomized study using the two-step hyperinsulinemic, euglycemic clamp". The Journal of Clinical Endocrinology and Metabolism 88 (12): 5875–5880. December 2003. doi:10.1210/jc.2002-021884. PMID 14671184. 
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  72. ↑ 72.0 72.1 72.2 72.3 72.4 (in en) Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. 2004. pp. 207–216. ISBN 9780198527480. https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207. 
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  74. ↑ (in en) Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. 2013. p. 85. ISBN 9788847026797. https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85. 
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  76. ↑ 76.0 76.1 76.2 76.3 76.4 76.5 76.6 76.7 76.8 "Does olanzapine warrant clinical pharmacokinetic monitoring in schizophrenia?". Clinical Pharmacokinetics 50 (7): 415–428. July 2011. doi:10.2165/11587240-000000000-00000. PMID 21651311. 
  77. ↑ 77.0 77.1 "Olanzapine Prescribing Information". Eli Lilly and Company. 2009-03-19. http://pi.lilly.com/us/zyprexa-pi.pdf. 
  78. ↑ 78.0 78.1 "A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future". Neuropsychiatric Disease and Treatment 15: 2559–2569. September 2019. doi:10.2147/NDT.S209284. PMID 31564881. 
  79. ↑ 79.00 79.01 79.02 79.03 79.04 79.05 79.06 79.07 79.08 79.09 79.10 79.11 79.12 79.13 79.14 79.15 79.16 79.17 79.18 79.19 79.20 79.21 79.22 Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  80. ↑ 80.0 80.1 "Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl-1-(4-fluorophenyl)butan-1-one"]. Bioorganic & Medicinal Chemistry 16 (15): 7291–7301. August 2008. doi:10.1016/j.bmc.2008.06.030. PMID 18595716. 
  81. ↑ 81.0 81.1 81.2 81.3 "H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs". Neuropsychopharmacology 28 (3): 519–526. March 2003. doi:10.1038/sj.npp.1300027. PMID 12629531. 
  82. ↑ 82.00 82.01 82.02 82.03 82.04 82.05 82.06 82.07 82.08 82.09 82.10 82.11 82.12 82.13 82.14 82.15 82.16 "Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding". Psychopharmacology 124 (1–2): 57–73. March 1996. doi:10.1007/bf02245606. PMID 8935801. 
  83. ↑ "Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies". The Pharmacogenomics Journal 6 (1): 42–51. 2006. doi:10.1038/sj.tpj.6500342. PMID 16314884. 
  84. ↑ 84.0 84.1 84.2 84.3 84.4 "Iloperidone binding to human and rat dopamine and 5-HT receptors". European Journal of Pharmacology 317 (2–3): 417–423. December 1996. doi:10.1016/s0014-2999(96)00840-0. PMID 8997630. 
  85. ↑ "Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences". The Journal of Pharmacology and Experimental Therapeutics 276 (2): 720–727. February 1996. PMID 8632342. 
  86. ↑ 86.0 86.1 86.2 "Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro". Schizophrenia Research 37 (1): 107–122. May 1999. doi:10.1016/s0920-9964(98)00146-7. PMID 10227113. 
  87. ↑ 87.0 87.1 87.2 87.3 87.4 "Muscarinic mechanisms of antipsychotic atypicality". Progress in Neuro-Psychopharmacology & Biological Psychiatry 27 (7): 1125–1143. October 2003. doi:10.1016/j.pnpbp.2003.09.008. PMID 14642972. 
  88. ↑ 88.0 88.1 88.2 "Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents". Journal of Medicinal Chemistry 48 (6): 1709–1712. March 2005. doi:10.1021/jm049632c. PMID 15771415. 
  89. ↑ 89.0 89.1 89.2 "Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors". Molecular Psychiatry 3 (2): 123–134. March 1998. doi:10.1038/sj.mp.4000336. PMID 9577836. 
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  94. ↑ 94.0 94.1 94.2 "Radioreceptor binding profile of the atypical antipsychotic olanzapine". Neuropsychopharmacology 14 (2): 87–96. February 1996. doi:10.1016/0893-133X(94)00129-N. PMID 8822531. 
  95. ↑ "Decreased binding affinity of olanzapine and clozapine for human muscarinic receptors in intact clonal cells in physiological medium". European Journal of Pharmacology 390 (3): 245–248. March 2000. doi:10.1016/s0014-2999(00)00037-6. PMID 10708730. 
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  97. ↑ "5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation". The American Journal of Psychiatry 155 (7): 921–928. July 1998. doi:10.1176/ajp.155.7.921. PMID 9659858. 
  98. ↑ "5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation". The American Journal of Psychiatry 155 (7): 921–928. July 1998. doi:10.1176/ajp.155.7.921. PMID 9659858. 
  99. ↑ "Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol". Neuropsychopharmacology 30 (12): 2283–2289. December 2005. doi:10.1038/sj.npp.1300836. PMID 16123775. 
  100. ↑ "Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein". Psychopharmacology 187 (4): 415–423. September 2006. doi:10.1007/s00213-006-0437-9. PMID 16810505. 
  101. ↑ "Relationship between P-glycoprotein and second-generation antipsychotics". Pharmacogenomics 12 (8): 1193–1211. August 2011. doi:10.2217/pgs.11.55. PMID 21843066. 
  102. ↑ "Drug Transporters: The Final Frontier for Drug Interactions". Pharmacy Times. December 1, 2008. http://www.pharmacytimes.com/publications/issue/2008/2008-12/2008-12-8474. Retrieved 9 February 2017. 
  103. ↑ "Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets: role of muscarinic antagonism in antipsychotic-induced diabetes and hyperglycemia". Diabetes 54 (5): 1552–1558. May 2005. doi:10.2337/diabetes.54.5.1552. PMID 15855345. 
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  105. ↑ "Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes". Methods and Findings in Experimental and Clinical Pharmacology 27 (5): 289–304. June 2005. doi:10.1358/mf.2005.27.5.908643. PMID 16082416. 
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  107. ↑ "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sciences 72 (22): 2429–2449. April 2003. doi:10.1016/s0024-3205(03)00141-3. PMID 12650852. 
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  109. ↑ Foye's Medicinal Chemistry (6th ed.). New Delhi: Wolters Kluwer. 2009. ISBN 978-81-89960-30-8. 
  110. ↑ "Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain". Pharmacogenomics and Personalized Medicine 4: 83–93. 2011-08-18. doi:10.2147/PGPM.S11866. PMID 23226055. 
  111. ↑ "Crystal forms in pharmaceutical applications: olanzapine, a gift to crystal chemistry that keeps on giving". IUCrJ 7 (Pt 6): 955–964. November 2020. doi:10.1107/S2052252520012683. PMID 33209310. 
  112. ↑ Chakrabarti JK, Hotten TM, Tupper DE, "Methods of treatment using a thieno-benzodiazepine", US patent 5817655, issued 1998-10-06, assigned to Eli Lilly and Co Ltd.
  113. ↑ "NDA 21-520". Food and Drug Administration. 2003-12-24. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/21520ltr.pdf. 
  114. ↑ "NDA 20-592 / S-019". Food and Drug Administration. 2004-01-14. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/20592se1-019ltr.pdf. 
  115. ↑ "Trends in use of second-generation antipsychotics for treatment of bipolar disorder in the United States, 1998-2009". Psychiatric Services 63 (1): 83–86. January 2012. doi:10.1176/appi.ps.201100092. PMID 22227765. 
  116. ↑ "Olanzapine and fluoxetine combination therapy for treatment-resistant depression: review of efficacy, safety, and study design issues". Neuropsychiatric Disease and Treatment 5: 369–383. 2009. doi:10.2147/NDT.S5819. PMID 19590732. 
  117. ↑ treatment resistant depression defined as major depressive disorder in adult patients who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode
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  119. ↑ 119.0 119.1 119.2 119.3 "Eli Lilly and Company Agrees to Pay $1.415 Billion to Resolve Allegations of Off-label Promotion of Zyprexa". U.S. Justice Department. 2009-01-15. http://www.justice.gov/opa/pr/2009/January/09-civ-038.html. 
  120. ↑ "Lilly 2008 Annual Report". Lilly. 2009. http://files.shareholder.com/downloads/LLY/696621960x0x296463/611E167A-61C9-4C03-8866-ACF5FA7C8953/English.PDF. 
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  122. ↑ "Mother Wonders if Psychosis Drug Helped Kill Son". The New York Times. January 4, 2007. https://www.nytimes.com/2007/01/04/business/04drug.html. 
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  126. ↑ "Activist Gagged for Drug Fact Leak in Lily Case". Hampshire Daily Gazette. 16 January 2007. http://www.freedom-center.org/pdf/1-16-07ActivistGaggedLillyWillHallGazetteSCANNED.pdf. 
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  128. ↑ "Lilly Settles Alaska Suit Over Zyprexa". The New York Times. 26 March 2008. https://www.nytimes.com/2008/03/26/business/26cnd-zyprexa.html. 
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  133. ↑ "Olanzapine for the prevention and treatment of cancer-related nausea and vomiting in adults". The Cochrane Database of Systematic Reviews 2018 (9): CD012555. September 2018. doi:10.1002/14651858.CD012555.pub2. PMID 30246876. 
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