Olanzapine

From Wikipedia, the free encyclopedia
Olanzapine
Olanzapine.svg
Olanzapine-from-xtal-3D-balls.png
Clinical data
Trade names Zyprexa, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a601213
License data
  • EU EMAby INN
  • US FDAOlanzapine
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration
By mouth, intramuscular injection
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • NZ: Prescription medicine
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability 87%[2]
Protein binding 93%[3]
Metabolism Hepatic (direct glucuronidation and CYP1A2 mediated oxidation)
Biological half-life 33 hours, 51.8 hours (elderly)[3]
Excretion Urine (57%; 7% as unchanged drug), faeces (30%)[3][4]
Identifiers
CAS Number
  • 132539-06-1 YesY
PubChem CID
  • 4585
IUPHAR/BPS
  • 47
DrugBank
  • DB00334 YesY
ChemSpider
  • 10442212 YesY
UNII
  • N7U69T4SZR
KEGG
  • D00454 YesY
ChEBI
  • CHEBI:7735 N
ChEMBL
  • CHEMBL715 YesY
ECHA InfoCard 100.125.320
Chemical and physical data
Formula C17H20N4S
Molar mass 312.439
3D model (JSmol)
  • Interactive image
Melting point 195 °C (383 °F)
Solubility in water Practically insoluble in water mg/mL (20 °C)
 NYesY (what is this?)  (verify)

Olanzapine (originally branded Zyprexa) is an antipsychotic medication used to treat schizophrenia and bipolar disorder. It is usually classed with the atypical antipsychotics, the newer generation of antipsychotics.[5] It appears to have slightly greater effectiveness in treating schizophrenia (especially the negative symptoms) and a lower risk of causing movement disorders than typical antipsychotics.[6] Olanzapine, however, has a higher risk of causing metabolic side effects like weight gain and type 2 diabetes than the typical antipsychotics.[5][6]

Olanzapine is believed to work by blocking, or antagonizing, the dopamine D2 receptor which is an action it shares with most antipsychotics.[7] Like most other atypical antipsychotics olanzapine also strongly antagonizes the 5-HT2A receptor, which may partially underpin its reduced propensity for causing movement disorders.[7] Despite its close structural relation to traditional benzodiazepine anxiety-relieving medications, it possesses no affinity for the GABAA receptor, its anxiety-relieving effect is mediated through its effect on dopamine and 5-HT receptors.

Olanzapine was first patented in 1971.[8] The drug became generic in 2011. Sales of Zyprexa in 2008 were $2.2 billion in the US, and $4.7 billion worldwide.[9]

Medical uses

Schizophrenia

The first-line psychiatric treatment for schizophrenia is antipsychotic medication which includes olanzapine.[10] Olanzapine appears effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia.[6][11][12][13] The usefulness of maintenance therapy, however, is difficult to determine as more than half of people in trials quit before the six-week completion date.[14] Olanzapine treatment 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, other than clozapine.[15][11]

Comparison

National Institute for Health and Care Excellence, the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that there is little difference in effectiveness between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on persons preference and side effect profile.[16][17][18] The U.S. Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms. When trials enrolling only treatment-resistant patients were excluded from the analysis, olanzapine was superior for overall assessment.[19]

In a 2013 comparison of 15 antipsychotic drugs in schizophrenia, olanzapine was ranked third. It was 5% more effective than risperidone (4th), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (1st).[6] A 2013 review of first episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the Clinical Global Impressions score. In contrast, pooled second generation antipsychotics showed superiority to first generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects, less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.[20] A 2012 review concluded that among 10 atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first generation antipsychotics.[21] A 2011 review concluded that neither first- nor second generation antipsychotics produce clinically meaningful changes in Clinical Global Impression scores but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second generation antipsychotics or pooled first generation antipsychotics.[22] A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone and ziprasidone.[15] No differences in effectiveness was detected when comparing olanzapine to amisulpride and clozapine.[15]

A 2014 meta analysis of 9 published trials having minimum duration 6 months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol.[23]

Bipolar disorder

Olanzapine is recommended by the National Institute of Health and Care Excellence as a first line therapy for the treatment of acute mania in bipolar disorder.[24] Other recommended first lines are haloperidol, quetiapine and risperidone.[24] 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.[24]

The Network for Mood and Anxiety Treatments (CANMAT) 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.[25]

A 2014 meta analysis concluded that olanzapine plus fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis.[26]

Other

Evidence does not support the use of atypical antipsychotics including olanzapine in eating disorders.[27]

Olanzapine has not been rigorously evaluated in generalized anxiety disorder, panic disorder, delusional parasitosis or post-traumatic stress disorder. Olanzapine is no less effective than lithium or valproate, and more effective than placebo in treating bipolar disorder.[28] It has also been used for Tourette syndrome and stuttering.[29]

Elderly

Citing an increased risk of stroke, in 2004 the Committee on 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. 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.[30] However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.[31]

Adverse effects

The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in the blood lipid and blood sugar profiles (see section metabolic effects). A recent 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 APD compared with a SMD of 0.74[6] Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine[32] but may include tremors and muscle rigidity.

Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce non-trivial 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.[3][33][34][35][4]

Other side effects include galactorrhea, amenorrhea, gynecomastia, impotence.[36]

Paradoxical effects

Olanzapine is used therapeutically to treat serious mental illness. Occasionally it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts or behavior; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use.[37]

Metabolic effects

Direct glucuronidation and cytochrome P450 mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo. The U.S. Food and Drug Administration 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 there are some reports of metabolic changes in the absence of weight gain.[38][39] 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.[40][41][42][43][44] The effect is dose dependent in humans[45] and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis.[46] Olanzapine may decrease insulin sensitivity,[47][48] though one 3-week study seems to refute this.[49] It may also increase triglyceride levels.[41]

Despite weight gain, a large multi-center 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.[50] One small, open-label, non-randomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain,[51] but this has not been substantiated in a blinded experimental setting.

Pregnancy and lactation

Olanzapine is associated with the highest placental exposure of any atypical antipsychotic.[52] 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.[52] 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).[53][54] Breastfeeding in women taking olanzapine is advised against due to the fact that olanzapine is secreted in breast milk with one study finding that the exposure to the infant (in mg per kg of body weight, that is) is about 1.8% that to the mother.[3]

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.[55]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[56] Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. However, despite increasing demand for safe and effective antipsychotic withdrawal protocols or dose-reduction schedules, no specific guidelines with proven safety and efficacy are currently available. Support groups such as the Icarus Project, and other online forums provide resources and social support for those attempting to discontinue antipsychotics and other psychiatric medications.[57] Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, vomiting, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety.[58][59] Some have argued additional somatic and psychiatric symptoms associated with dopaminergic hypersensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics.[60][61][62][63] Thus, some suggest the withdrawal process itself may be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients.[64]

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.[65] There is no known specific antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case.[65] Olanzapine is considered moderately toxic in overdose; more toxic than quetiapine, aripiprazole and the SSRIs and less toxic than the MAOIs and TCAs.[52]

Pharmacology

Pharmacodynamics

Olanzapine[66]
Site Ki (nM) Action Ref
5-HT1A 2,063–2,720 Antagonist [67][68]
5-HT1B 509–660 ND [66][68]
5-HT1D 540–1,582 ND [66][68]
5-HT1E 2,010–2,408 ND [66][68]
5-HT1F 310 ND [68]
5-HT2A 1.32–24.2 Inverse agonist [69][70]
5-HT2B 11.8–12.0 Inverse agonist [71][72]
5-HT2C 6.4–29 Inverse agonist [70][72]
5-HT3 202 Antagonist [66]
5-HT5A 1,212 ND [66]
5-HT6 6.0–42 Antagonist [66][73]
5-HT7 105–365 Antagonist [66][74]
α1A 109–115 Antagonist [66][67]
α1B 263 Antagonist [66]
α2A 192–470 Antagonist [74][68]
α2B 82–180 Antagonist [67][68]
α2C 29–210 Antagonist [67][68]
β1 >10,000 ND [66][68]
β2 >10,000 ND [66][68]
D1 35–118 Antagonist [70][74]
D2 3.00–106 Antagonist [75][76]
D2L 31–38 Antagonist [68][70]
D2S 21–52 Antagonist [68][77]
D3 7.8–91 Antagonist [75][76]
D4 1.6–50 Antagonist [75][78]
D4.2 17–102 Antagonist [79][80]
D4.4 21–60 Antagonist [77]
D5 74–90 Antagonist [70][66]
H1 0.65–4.9 Inverse agonist [68][66]
H2 44 Antagonist [66]
H3 3,713 Antagonist [66]
H4 >10,000 Antagonist [66]
M1 2.5–73 Antagonist [81][82]
M2 48–622 Antagonist [73]
M3 13–126 Antagonist [72][73]
M4 10–350 Antagonist [81][73]
M5 6.0–82 Antagonist [81][73]
σ1 >5,000 ND [68]
σ2 ND ND ND
Opioid >10,000 ND [68]
nACh >10,000 ND [66]
NMDA
(PCP)
>10,000 ND [66]
SERT ≥3,676 ND [66][78]
NET >10,000 ND [66]
DAT >10,000 ND [66]
VDCC >10,000 ND [66][68]
VGSC >5,000 ND [68]
hERG 6,013 Blocker [83]
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.[66]

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 non-benzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone and perospirone. Olanzapine also had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study.[84] P-glycoprotein transports a myriad of drugs across a numerous of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semi-permeable membrane which 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.[85] A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and it is fairly common for pharmaceuticals to be either substrates of P-GP, or to 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 which interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.[86]

Olanzapine is a potent antagonist of the muscarinic M3 receptor,[87] which may underlie its diabetogenic side effects.[88][89] Additionally, olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.[32][90]

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, however it offers no protection against the development of tardive dyskinesia. In common with other second generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its high affinity for the D1 receptor over the D2 receptor.[91]

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.[92]

Pharmacokinetics

Metabolism

Olanzapine is metabolized by the cytochrome P450 system; principally by isozyme 1A2 and to a lesser extent by 2D6. By these mechanisms more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect.[32] Drugs or agents that increase the activity of CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of Olanzapine; conversely, drugs which inhibit 1A2 activity (examples: Ciprofloxacin, Fluvoxamine) may reduce Olanzapine clearance.[5]

Society and culture

Zyprexa (olanzapine) 10 mg tablets (AU)

Regulatory status

Olanzapine is approved in the U.S.A. by the Food and Drug Administration (FDA) for:

  • Long-term treatment—in combination with fluoxetine—of resistant depression (March 2009).[96]
  • 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[97]
  • Treatment of the manifestations of psychotic disorders (September 1996[98] – March 2000).[99]
  • Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000).[99]
  • Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000).[99]
  • Maintaining treatment response in schizophrenic patients who had been stable for approximately eight weeks and were then followed for a period of up to eight months (November 2000).[99]

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.[100]

In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits,[101] 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.[102][103]

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.[102][104] The company denied these allegations and stated that the article had been based on cherry picked documents.[102][103] 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.[100] 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, and criticized the New York Times reporter, Gottstein, and Egilman in the ruling.[100] 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.[103] On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board he belonged to was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."[103]

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.[105]

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.[100]

In March 2008 Lilly settled a suit with the state of Alaska[106] 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.[105]

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.[107][108]

Trade names

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

Dosage forms

Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 milligrams. Zyprexa (and generic olanzapine) is available as an orally-disintegrating "wafer" which rapidly dissolves in saliva. It is also available in 10 milligram vials for intramuscular injection.[5]

Research

Olanzapine has been investigated for use as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV). A 2007 study demonstrated its successful potential for this use, achieving a complete response in the acute prevention of nausea and vomiting in 100% of patients treated with moderately and highly-emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone.[109]

Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education (PRIME) 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.[110] In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain.[111]

References

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External links

  • Zyprexa.com - official Zyprexa brand website from Eli Lilly and Company
  • Zyprexa package insert
  • Berenson, Alex (December 17, 2006). "Lilly Settles With 18,000 Over Zyprexa". The New York Times. 
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