Olanzapine
Encyclopedia
Olanzapine is an atypical antipsychotic
, approved by the FDA
for the treatment of schizophrenia
and bipolar disorder
. Olanzapine is structurally similar to clozapine
, but is classified as a thienobenzodiazepine
.
The olanzapine formulations are manufactured and marketed by the pharmaceutical company
Eli Lilly and Company
, whose patent for olanzapine proper expires in 2011 (in October 2009 a Canadian judge ruled that the 1991 patent was invalid). Sales of Zyprexa in 2008 were $2.2B in the US alone, and $4.7B in total.
Known FDA approvals are as follows:
, delusional parasitosis
, post-traumatic stress disorder
); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa
) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette syndrome
and stuttering
. Olanzapine is also used in many addiction clinics as a sleep aid (usually 2.5–5 mg) due to its low abuse profile and zero addictive properties.
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
. 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.
, 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. However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.
, 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
.
a rare, but life-threatening, neuroleptic malignant syndrome
. Some also associate all antipsychotics with permanent brain damage.
Other recognised side effects may include:
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. 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. The effect is not dose dependent. Olanzapine may directly affect adipocyte
function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis
. Olanzapine may decrease insulin sensitivity. though one 3-week study seems to refute this. It may also increase triglyceride
levels.
Recent studies have established :
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. One small, open-label, non-randomized study suggest that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.
monkeys receiving olanzapine between 17 and 27 months, a significant brain volume and weight decreases (8-11%) were detected. In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss, with the neurons spared but positioned more closely compared to the controls.
However according to this study the neurons do not seem to be completely spared. The gray matter shrinking found was 14.6%, but the neuron density increase was only 10.2% which corresponds to approximately a loss of 5% of the neurons.
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.
recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. 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. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis
, dyskinesia
, orthostasis, tachycardia
, nervousness, dizziness, headache, excessive non-stop crying, and anxiety
. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can occur after withdrawing from antipsychotics.
, 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 1500 mg. 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.
Prescription should be kept in small quantity to reduce risk overdose as acute bipolar disorder and schizophrenic patients can be at a high risk of suicide(Eli Lilly 2010)
receptors. Affinities are (Ki, nM). Olanzapine binds as an antagonist
/inverse agonist
at the following receptors:
Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.
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
, 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
. 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.
Olanzapine may display an antiemetic
effect due to it's blockade of several receptors (specifically acetylcholine, dopamine, histamine, and serotonin 5-HT3) within the chemoreceptor trigger zone
.
or ciprofloxacin
) CYP1A2 activity, respectively.
. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.
The documents, given to The New York Times by Jim Gottstein
, show that Lilly executives kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes. The Times of London also obtained copies of the documents and reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. In another document, dated 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."
Lilly’s own published data, which it told its sales representatives to play down in conversations with doctors, has shown that 30 percent of patients taking Zyprexa gain 22 pounds or more after a year on the drug, another study showed 16% of Zyprexa patients gained at least 30 kg (66 pounds) in one year, and some patients have reported gaining 100 pounds or more. But Lilly was concerned that Zyprexa’s sales would be hurt if the company was more forthright about the fact that the drug might cause unmanageable weight gain or diabetes, according to the documents, which cover the period 1995 to 2004. In 2006, Lilly paid $700 million to settle 18,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending.
In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings.
Eli Lilly agreed on January 4, 2007 to pay up to $500 million to settle 18,000 lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa. Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who claim they were injured by the drug. At least 1,200 suits are still pending, the company said. About 20 million people worldwide have taken Zyprexa since its introduction in 1996. On January 8, 2007, Judge Jack B. Weinstein
refused the Electronic Frontier Foundation
's motion to stay his order.
On January 15, 2009 Eli Lilly pled guilty to a misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion. Although Lilly had evidence that it is not effective for dementia
, Zyprexa was marketed for elderly Alzheimer's
patients. The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.
In order to make up for the costs for settling the lawsuits and shrinking sales figures for Zyprexa in the U.S.A. the company increased the prices for this medication in Germany in May 2007 by 18 percent.
,In Canada a class action lawsuit was settled in Ontario, Quebec and British Columbia.
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
, approved by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for the treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. Olanzapine is structurally similar to clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
, but is classified as a thienobenzodiazepine
Thienobenzodiazepine
A thienobenzodiazepine is a heterocyclic compound containing a diazepine ring fused to a thiophene ring and a benzene ring....
.
The olanzapine formulations are manufactured and marketed by the pharmaceutical company
Pharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
, whose patent for olanzapine proper expires in 2011 (in October 2009 a Canadian judge ruled that the 1991 patent was invalid). Sales of Zyprexa in 2008 were $2.2B in the US alone, and $4.7B in total.
Medical uses
- 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 lithiumLithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
or valproate) - intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults
- oral formulation combined with fluoxetineFluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults
Known FDA approvals are as follows:
- approved for the treatment of the manifestations of psychotic disorders on September 6, 1996
- approved in combination with fluoxetine for the treatment of depressive episodes associated with Bipolar disorder on December 24, 2003
- approved for the long-term treatment of bipolar I disorder on January 14, 2004
- approved in combination with fluoxetine for treatment of resistant depression on March 19, 2009.
Off-label uses
Case-reports, open-label, and small pilot studies suggest efficacy of olanzapine for the treatment of some anxiety spectrum disorders (e.g. generalized anxiety disorder, panic disorderPanic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
, delusional parasitosis
Delusional parasitosis
Delusional parasitosis is a form of psychosis whose victims acquire a strong delusional belief that they are infested with parasites, whereas in reality no such parasites are present...
, post-traumatic stress disorder
Post-traumatic stress disorder
Posttraumaticstress disorder is a severe anxiety disorder that can develop after exposure to any event that results in psychological trauma. This event may involve the threat of death to oneself or to someone else, or to one's own or someone else's physical, sexual, or psychological integrity,...
); however, olanzapine has not been rigorously evaluated in randomized, placebo-controlled trials for this use and is not FDA approved for these indications. Other common off-label uses of olanzapine include the treatment of eating disorders (e.g. anorexia nervosa
Anorexia nervosa
Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
) and as an adjunctive treatment for major depressive disorder without psychotic features. It has also been used for Tourette syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
and stuttering
Stuttering
Stuttering , also known as stammering , is a speech disorder in which the flow of speech is disrupted by involuntary repetitions and prolongations of sounds, syllables, words or phrases, and involuntary silent pauses or blocks in which the stutterer is unable to produce sounds...
. Olanzapine is also used in many addiction clinics as a sleep aid (usually 2.5–5 mg) due to its low abuse profile and zero addictive properties.
Prevention of psychosis
Olanzapine has been considered as part of an early psychosisEarly intervention in psychosis
Early intervention in psychosis is a clinical approach to those experiencing symptoms of psychosis for the first time. It forms part of a new prevention paradigm for psychiatry and is leading to reform of mental health services, especially in the United Kingdom....
approach for schizophrenia. The Prevention through Risk Identification, Management, and Education (PRIME) study, funded by the National Institute of Mental Health
National Institute of Mental Health
The National Institute of Mental Health is one of 27 institutes and centers that make up the National Institutes of Health...
and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. The study examined 60 patients with prodromal
Prodrome
In medicine, a prodrome is an early symptom that might indicate the start of a disease before specific symptoms occur. It is derived from the Greek word prodromos or precursor...
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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. 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.
Use in elderly
Citing an increased risk of strokeStroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, in 2004 the Committee on the Safety of Medicines
Committee on the Safety of Medicines
The Committee on the Safety of Medicines was an independent advisory committee that for 40 years advised the UK Licensing Authority on the quality, efficacy and safety of medicines....
(CSM) in the UK issued a warning that olanzapine and risperidone
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
, both atypical antipsychotic medications, should not be given to elderly patients with dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. In the U.S., olanzapine comes with a black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. However, a BBC investigation in June 2008 found that this advice was being widely ignored by British doctors.
Investigatory Uses
Olanzapine has has been investigated for use as an antiemeticAntiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
, 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
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, when used in combination with palonosetron
Palonosetron
Palonosetron is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting...
and dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
.
Adverse effects
As with all neuroleptic drugs, olanzapine can cause tardive dyskinesiaTardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
a rare, but life-threatening, neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
. Some also associate all antipsychotics with permanent brain damage.
Other recognised side effects may include:
- akathisiaAkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
; inability to remain still (restlessness) - dry mouth
- dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
- irritabilityIrritabilityIrritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
- sedationSedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
- insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
- constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
- urinary retentionUrinary retentionUrinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
- orthostatic hypotensionOrthostatic hypotensionOrthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
- weight gain
- increased appetite
- runny nose
- impaired judgment, thinking, and motor skills
- impaired spatial orientation
- impaired responses to senses
- seizures
- trouble swallowing
- dental problems and discoloration of teeth
- missed periods
- problems with keeping body temperature regulated
- apathyApathyApathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
, lack of emotion - Endocrine side effects have included hyperprolactinemia, hyperglycemiaHyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
, and diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced... - Brain Zaps
- Auditory Hallucinations
Metabolic effects
The Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
and diabetes, both of which are factors in the metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
. 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. 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. The effect is not dose dependent. Olanzapine may directly affect adipocyte
Adipocyte
However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...
function, promoting fat deposition. There are some case reports of olanzapine-induced diabetic ketoacidosis
Diabetic ketoacidosis
Diabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...
. Olanzapine may decrease insulin sensitivity. though one 3-week study seems to refute this. It may also increase triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels.
Recent studies have established :
- that Olanzapine and Clozapine disturb the metabolism by making the body take preferentially its energy from fat (instead of privileging carbohydrates). Thus, levels of carbohydrates remaining high, the body would develop insulin resistance (reduction of insulin sensitivity).
- that Olanzapine promotes fat accumulation : due to disturbances in fat metabolism, rodents become fatter (but don't have their weight increasing at first). Being fatter, they do less exercise, burning less fat and gaining weight.
Despite weight gain, a large multi-center randomized National Institute of Mental Health
National Institute of Mental Health
The National Institute of Mental Health is one of 27 institutes and centers that make up the National Institutes of Health...
study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, non-randomized study suggest that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting.
Animal toxicology
In a placebo-compared study of six MacaqueMacaque
The macaques constitute a genus of Old World monkeys of the subfamily Cercopithecinae. - Description :Aside from humans , the macaques are the most widespread primate genus, ranging from Japan to Afghanistan and, in the case of the barbary macaque, to North Africa...
monkeys receiving olanzapine between 17 and 27 months, a significant brain volume and weight decreases (8-11%) were detected. In latter studies of the stored samples, the changes were attributed to astrocyte and oligodendrocyte loss, with the neurons spared but positioned more closely compared to the controls.
However according to this study the neurons do not seem to be completely spared. The gray matter shrinking found was 14.6%, but the neuron density increase was only 10.2% which corresponds to approximately a loss of 5% of the neurons.
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.
Discontinuation
The British National FormularyBritish National Formulary
The British National Formulary is a medical and pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about all medicines available on the National Health Service , including indication,...
recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. 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. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis
Diaphoresis
Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions.Diaphoretic is the state of perspiring profusely, or something that has the power to cause increased perspiration....
, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
, orthostasis, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, nervousness, dizziness, headache, excessive non-stop crying, and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can occur after withdrawing from antipsychotics.
Overdose
Symptoms of an overdose include tachycardiaTachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
, decreased consciousness and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 1500 mg. There is no known specific antidote for olanzapine overdose, and even physicians are recommended to call a certified poison control center
Poison control center
A poison control center is a medical facility that is able to provide immediate, free, and expert treatment advice and assistance over the telephone in case of exposure to poisonous or hazardous substances...
for information on the treatment of such a case.
Prescription should be kept in small quantity to reduce risk overdose as acute bipolar disorder and schizophrenic patients can be at a high risk of suicide(Eli Lilly 2010)
Pharmacology
Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamineDopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
receptors. Affinities are (Ki, nM). Olanzapine binds as an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
/inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
at the following receptors:
- dopamine D1: 31
- dopamine D2: 11
- dopamine D4: 27
- serotonin 5-HT2A: 4
- serotonin 5-HT2C: 11
- serotonin 5-HT3: 57
- muscarinic M1: 26
- adrenergic alpha1: 19
- histamine H1: 7
Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.
The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
, and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
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
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
. 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.
Olanzapine may display an antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
effect due to it's blockade of several receptors (specifically acetylcholine, dopamine, histamine, and serotonin 5-HT3) within the chemoreceptor trigger zone
Chemoreceptor trigger zone
The chemoreceptor trigger zone , is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center, to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood-brain barrier...
.
Metabolism
Olanzapine is metabolized by the cytochrome P450 system isoenzymes 1A2 and 2D6 (minor pathway). Drug metabolism may be increased or decreased by agents that induce (e.g. cigarette smoke) or inhibit (e.g. fluvoxamineFluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
or ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
) CYP1A2 activity, respectively.
Controversy, lawsuits and settlements
According to a New York Times article published on December 17, 2006, "Eli Lilly has engaged in a decade-long effort to play down the health risks of Zyprexa, its best-selling medication for schizophrenia, according to hundreds of internal Lilly documents and e-mail messages among top company managers", most of which had been disclosed as the result of lawsuits by individuals who had taken the drug, though other documents had been stolen. These had been sent to a number of journalists by a lawyer advocate for individuals with a psychiatric diagnosis opposed to forced psychiatric treatment. Eli Lilly filed a protection order to stop the dissemination of certain Eli Lilly documents about Zyprexa which they, and the judge, believed to be confidential and "not generally appropriate for public consumption". Temporary injunctions required those who had received the documents to return them and that the documents be removed from websites which had posted them. In his final judgement, Judge Weinstein issued a permanent judgement against further dissemination of the documents and requiring their return by a number of parties named by Lilly. These health risks include an increased risk for diabetes through Zyprexa's links to obesity and its tendency to raise blood sugarBlood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
. Zyprexa is Lilly’s top-selling drug, with sales of $4.2 billion last year.
The documents, given to The New York Times by Jim Gottstein
James Gottstein
James B. "Jim" Gottstein, JD, is an Alaska based lawyer who specializes in business matters and public land law, and is well known as an attorney advocate for people diagnosed with serious mental illness...
, show that Lilly executives kept important information from doctors about Zyprexa’s links to obesity and its tendency to raise blood sugar — both known risk factors for diabetes. The Times of London also obtained copies of the documents and reported that as early as October 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. In another document, dated 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."
Lilly’s own published data, which it told its sales representatives to play down in conversations with doctors, has shown that 30 percent of patients taking Zyprexa gain 22 pounds or more after a year on the drug, another study showed 16% of Zyprexa patients gained at least 30 kg (66 pounds) in one year, and some patients have reported gaining 100 pounds or more. But Lilly was concerned that Zyprexa’s sales would be hurt if the company was more forthright about the fact that the drug might cause unmanageable weight gain or diabetes, according to the documents, which cover the period 1995 to 2004. In 2006, Lilly paid $700 million to settle 18,000 lawsuits from people who said they had developed diabetes or other diseases after taking Zyprexa. Thousands more suits are still pending.
In 2002, British and Japanese regulatory agencies warned that Zyprexa may be linked to diabetes, but even after the FDA issued a similar warning in 2003, Lilly did not publicly disclose their own findings.
Eli Lilly agreed on January 4, 2007 to pay up to $500 million to settle 18,000 lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa. Including earlier settlements over Zyprexa, Lilly has now agreed to pay at least $1.2 billion to 28,500 people who claim they were injured by the drug. At least 1,200 suits are still pending, the company said. About 20 million people worldwide have taken Zyprexa since its introduction in 1996. On January 8, 2007, Judge Jack B. Weinstein
Jack B. Weinstein
Jack Bertrand Weinstein is a United States federal judge in the Eastern District of New York. Judge Weinstein was appointed in 1967 by President Lyndon Johnson. From 1980 to 1988, he served as chief judge of the district. On March 1, 1993, he took senior status; however, unlike some senior...
refused the Electronic Frontier Foundation
Electronic Frontier Foundation
The Electronic Frontier Foundation is an international non-profit digital rights advocacy and legal organization based in the United States...
's motion to stay his order.
On January 15, 2009 Eli Lilly pled guilty to a misdemeanor charge of illegally marketing Zyprexa for off-label use, and agreed to pay $1.4 billion. Although Lilly had evidence that it is not effective for dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, Zyprexa was marketed for elderly Alzheimer's
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
patients. The drug carries an F.D.A. warning that it increases the risk of death in older patients with dementia-related psychosis.
In order to make up for the costs for settling the lawsuits and shrinking sales figures for Zyprexa in the U.S.A. the company increased the prices for this medication in Germany in May 2007 by 18 percent.
,In Canada a class action lawsuit was settled in Ontario, Quebec and British Columbia.
Chemistry
http://www.google.com/patents/about?id=ZGYeAAAAEBAJ&dq=US+5229382Manufacturer site
- Zyprexa.com - official Zyprexa brand website from Eli Lilly and CompanyEli Lilly and CompanyEli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
- Zyprexa package insert
Consumer information
- MedLibrary.org - 'Information on Zyprexa and How to Use It, Precautions and Other Medications to Avoid While Taking, MedLibrary
- NIH.gov - 'Olanzapine (Systemic)' Drug Information, MedlinePlusMedlinePlusMedlinePlus is a free Web site that provides consumer health information for patients, families, and Health care providers. The site brings together information from the United States National Library of Medicine, the National Institutes of Health , other U.S. government agencies, and...
Controversy
- nytyimes.com - Lilly Settles With 18,000 Over Zyprexa, Alex Berenson, New York Times (December 17, 2006)