5-HT_2A Receptor ( Ki = 4 nM ); 5-HT₁ Receptor ( Ki = 7 nM ); 5-HT₆ Receptor ( Ki = 5 nM ); 5-HT_2C Receptor ( Ki = 11 nM ); 5-HT₃ Receptor ( Ki = 57 nM ); Adrenergic α1 Receptor ( Ki = 19 nM ); Muscarinic M1-5 Receptor ( Ki = 1.9-25 nM ); Dopamine Receptor; Mitophagy; Apoptosis

In vitro activity: Olanzapine has a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors, which allows it to interact with important receptors implicated in schizophrenia. Similar to clozapine, olanzapine exhibits a receptor profile that is largely nonselective at dopamine receptor subtypes, with selectivity for mesolimbic and mesocortical dopamine tracts over striatal dopamine tracts (electrophysiology; Fos). [1]

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Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos).
Conclusion: The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug [1].

Olanzapine is a weaker antagonist at alpha-adrenergic and muscarinic receptors, but a strong antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone).[1] In the rat prefrontal cortex, Olanzapine plus fluoxetine together result in strong, prolonged increases in extracellular levels of norepinephrine ([NE](ex)) and dopamine ([DA](ex)) up to 361% and 272% of the baseline, respectively. These increases are noticeably higher than those caused by either medication alone.[2] In rat prefrontal cortex, nucleus accumbens, and striatum, olanzapine at 0.5 mg/kg, 3 mg/kg, and 10 mg/kg (s.c.) dose-dependently raises the extracellular dopamine (DA) and norepinephrine (NE) levels. Olanzapine also raises the concentrations of 3-methoxytyramine, a released DA metabolite, in tissues and extracellular levels of DOPAC, another DA metabolite.[3] Fresh brain weights on average and left cerebrum volumes and fresh weights in macaque monkeys are reduced by 8–11% when olanzapine is administered. [4] Obesity is significantly elevated when taking olanzapine; elevated visceral and subcutaneous adipose stores are reflected in elevated total body fat. Hepatic insulin resistance is brought on by olanzapine.[5]

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In vivo Olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors.[1]

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To understand the mechanism of the clinical efficacy of Olanzapine and fluoxetine combination therapy for treatment-resistant depression (TRD), we studied the effects of olanzapine and other antipsychotics in combination with the selective serotonin uptake inhibitors fluoxetine or sertraline on neurotransmitter release in rat prefrontal cortex (PFC) using microdialysis. The combination of olanzapine and fluoxetine produced robust, sustained increases of extracellular levels of dopamine ([DA](ex)) and norepinephrine ([NE](ex)) up to 361 +/- 28% and 272 +/- 16% of the baseline, respectively, which were significantly greater than either drug alone. This combination produced a slightly smaller increase of serotonin ([5-HT](ex)) than fluoxetine alone. The combination of clozapine or risperidone with fluoxetine produced less robust and persistent increases of [DA](ex) and [NE](ex). The combination of haloperidol or MDL 100907 with fluoxetine did not increase the monoamines more than fluoxetine alone. Olanzapine plus sertraline combination increased only [DA](ex). Therefore, the large, sustained increase of [DA](ex), [NE](ex), and [5-HT](ex) in PFC after olanzapine-fluoxetine treatment was unique and may contribute to the profound antidepressive effect of the olanzapine and fluoxetine therapy in TRD. [3]

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It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, Olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of approximately 20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.[4]

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Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics Olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S(I)), and pancreatic beta-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n = 10), RIS (5 mg/day; n = 10), or gelatin capsules (n = 6) for 4-6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (+91 +/- 20%; P = 0.000001) reflecting marked increases in subcutaneous (+106 +/- 24%; P = 0.0001) and visceral (+84 +/- 22%; P = 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group (P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S(I) [pre- versus postdrug]: 6.05 +/- 0.98 vs. 1.53 +/- 0.93 dl . min(-1) . kg(-1)/[microU/ml], respectively; P = 0.009). beta-Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 +/- 0.15, post-drug: 1.07 +/- 0.25 microU . ml(-1)/[mg/dl]; P = 0.6). OLZ-induced beta-cell dysfunction was further demonstrated when beta-cell compensation was compared with a group of animals with adiposity and insulin resistance induced by moderate fat feeding alone (+8% of calories from fat; n = 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that beta-cell compensation is under neural control [5].

Method: We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays.
Results: Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors [1].

For determination of plasma and brain levels of Olanzapine, fluoxetine, and norfluoxetine, male Sprague-Dawley (n = 3 per group) weighing about 250–300 g were administered 3 mg/kg (s.c.) olanzapine and 10 mg/kg (s.c.) fluoxetine 2 and 1.5 hours prior to euthanasia with carbon dioxide, respectively. The combination group received olanzapine and fluoxetine 2 and 1.5 hours prior to sample collection, respectively. Following anesthesia with carbon dioxide, blood samples were collected by cardiac puncture in heparinized tubes, and plasma was collected by centrifugation. Subsequently, the brain was perfused with normal saline, excised and weighed. Four milliliters of distilled water/g brain was added and the tissue was homogenized. Brain homogenates and plasma samples were then frozen in dry ice and stored at approximately −70°C until analysis. [2]

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Olanzapine was dissolved in 0.01 N HCl at a concentration of 10 mg/ml and diluted with distilled water to 3 mg/ml and then 0.5 mg/ml. Clozapine (RBI) and haloperidol (RBI) were dissolved in 0.01 N HCl containing 5% hydroxypropyl-b-cyclodextrin as a solubilizing agent at a concentration of 10 mg/ml and 2 mg/ml and then diluted with distilled water to 3 mg/ml and 0.5 mg/ml, respectively. The drugs were administered through an implanted SC tube to avoid handling the rats during the experiments. All drugs were injected in a volume of 1 ml/kg. Since our previous data has demonstrated that vehicle alone did not produce signiÞcant inßuence on monoamine baseline values under the same experimental conditions (Perry and Fuller 1992), vehicle control was not included in the present study. [3]

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All animals were trained to self-administer fruit punch-flavored sucrose pellets. Self-administration of the pellets was reinforced with raisins and was followed by drinking 60 ml of orange drink from a syringe. The orange drink was administrated in order to have an alternate vehicle for drug administration, should an animal become unreliable in ingesting the pellets. When animals achieved 100% compliance, sucrose pellets containing drug were introduced to the haloperidol group. Owing to delays in obtaining Olanzapine, the animals in this group received sham pellets for the first ∼10 months. Two monkeys initially allocated to the sham group were switched with two initially allocated to the olanzapine group immediately before the initiation of the olanzapine treatment (see Animal Health section below).
Drug Preparation and Administration: Sucrose pellets (190 mg) containing haloperidol sulfate, Olanzapine, or no drug (sham pellets) were custom made. Two dosage levels per pellet were ordered for each drug. Quality control assays determined the content of haloperidol to be 1.0 or 2.0 mg/pellet and the content of olanzapine to be 0.55 or 1.1 mg/pellet. Methods for quality control were identical to those used for drug plasma level analysis (see Blood Sampling section below).[4]

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The study was divided into three phases: 1) baseline testing (pre-drug), 2) drug treatment period, and 3) post-drug period. Before study entry, dogs were randomly assigned to one of three treatment arms: OLZ, RIS, or placebo. Predrug testing was performed in all dogs to quantify insulin sensitivity (SI), trunk adiposity, and pancreatic β-cell function (see below for details). The order of experiments was randomized and performed in each animal over a 10-day period, with ≥2 days between experiments. After pre-drug testing, dogs were placed on the drug (or placebo) regimen for 4–6 weeks, after which all procedures performed during pre-drug phase were repeated (post-drug) under conditions identical to pre-drug testing. Drug (or placebo) treatment was continued during the entire post-drug testing period. Dogs were assigned to receive either Olanzapine, RIS (Risperdal; Janssen Pharmaceuticals, Titusville, NY; n = 10), or placebo (gelatin capsules). Drugs were administered orally once per day, 6–8 h after daily presentation of food (∼2:00 p.m.). Doses were based on those used in typical treatment of patients, as well as on reported dopamine D2 receptor binding in the caudate nucleus. The RIS dose was chosen as the midpoint between zero and the dose associated with moderate toxicity. The OLZ/Olanzapine dose was subsequently chosen to parallel the approximate 3:1 (OLZ-to-RIS) ratio used in clinical applications. Doses of each drug were stepped up to the target dose by day 4 of treatment. The target dose for OLZ/Olanzapine was 15 mg/day and the target dose for RIS was 5 mg/day. All dogs (including placebo-treated animals) were videotaped for ∼2–5 min before and 1–3 h and 24 h after first dosing at initial and target doses to facilitate monitoring of behavioral changes and possible movement disorders.[5]

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0.5 mg/kg, 3 mg/kg and 10 mg/kg (s.c.)

Macaque monkeys

Absorption, Distribution and Excretion
Olanzapine presents a linear pharmacokinetic profile and, after daily administration, it reaches steady-state in about a week. Under the administration of a normal dosage of olanzapine, the steady-state plasma concentration does not seem to exceed 150 ng/ml with an AUC of 333 ng/h/ml. The absorption of olanzapine is not affected by the concomitant administration of food. The pharmacokinetic profile of olanzapine is characterized by reaching peak plasma concentration of 156.9 ng/ml approximately 6 hours after oral administration.
Olanzapine is mainly eliminated through metabolism and hence, only 7% of the eliminated drug can be found as the unchanged form. It is mainly excreted in the urine which represents around 53% of the excreted dose followed by the feces that represent about 30%.
The volume of distribution of olanzapine is reported to be of 1000 liters which indicate a large distribution throughout the body.
The mean clearance rate of olanzapine is of 29.4 L/hour however, some studies have reported an apparent clearance of 25 L/h.
The excretion of olanzapine into the breast milk of five lactating women with postpartum psychosis was examined in this study. Nine pairs of plasma and breast-milk samples were collected and the concentration of olanzapine determined by high-performance liquid chromatography. Single-point milk-to-plasma ratios were calculated and ranged from 0.2 to 0.84 with a mean of 0.46. The median relative infant dose was 1.6% (range 0-2.5%) of the weight-adjusted maternal dose. During the study period, there were no apparent ill effects on the infant as a consequence of exposure to these doses of olanzapine. As with other antipsychotic drugs this study demonstrates that olanzapine passes into breast milk. ...
Olanzapine is distributed into milk. The manufacturer states that in a study in lactating, healthy women, the average infant dose of olanzapine at steady-state was estimated to be approximately 1.8% of the maternal olanzapine dose. In a separate study that evaluated the extent of infant exposure to olanzapine in 7 breastfeeding women who had been receiving 5-20 mg of olanzapine daily for periods ranging from 19-395 days, median and maximum relative infant doses of 1 and 1.2%, respectively, were observed. Olanzapine was not detected in the plasma of the breast-fed infants, and adverse effects possibly related to olanzapine exposure were not reported in the infants in this study. In addition, peak milk concentrations were achieved a median of 5.2 hours later than the corresponding maximal maternal plasma concentrations. In a case report, a relative infant dose of approximately 4% was estimated in one woman after 4 and 10 days (estimated to be at steady state) of olanzapine therapy at a dosage of 20 mg daily based on measurements of drug concentration in serum and in expressed breast milk.
Intramuscular olanzapine for injection results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a 5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma concentration approximately 5 times higher than the maximum plasma concentration produced by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is similar to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range.
Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and alpha1-acid glycoprotein.
Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that olanzapine tablets and olanzapine orally disintegrating tablets dosage forms of olanzapine are bioequivalent.

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Metabolism / Metabolites
Olanzapine is greatly metabolized in the liver, which represents around 40% of the administered dose, mainly by the activity of glucuronide enzymes and by the cytochrome P450 system. From the CYP system, the main metabolic enzymes are CYP1A2 and CYP2D6. As part of the phase I metabolism, the major circulating metabolites of olanzapine, accounting for approximate 50-60% of this phase, are the 10-N-glucuronide and the 4'-N-desmethyl olanzapine which are clinically inactive and formed by the activity of CYP1A2. On the other hand, CYP2D6 catalyzes the formation of 2-OH olanzapine and the flavin-containing monooxygenase (FMO3) is responsible for N-oxide olanzapine. On the phase II metabolism of olanzapine, UGT1A4 is the key player by generating direct conjugation forms of olanzapine.
Metabolic profiles after intramuscular administration are qualitatively similar to metabolic profiles after oral administration.
Direct glucuronidation and cytochrome P450 (CYP) 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, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.
Following a single oral dose of (14)C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4'-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.
Olanzapine has known human metabolites that include Olanzapine N-Oxide, 2-Hydroxymethyl Olanzapine, N-Desmethylolanzapine, and 7-Hydroxyolanzapine.

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Biological Half-Life
Olanzapine presents a half-life ranging between 21 to 54 hours with an average half-life of 30 hours.
Half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr)

Toxicity Summary
Olanzapine has a low potential for toxicity when prescribed alone. However, there are case reports which found olanzapine toxicity caused by high doses of the medication when taken in conjunction with other medicines. For example, a case report of a patient who overdosed by taking 560 milligrams of olanzapine in addition to 6.4 grams of propranolol and 280 milligrams of amlodipine had extreme hypotension, circulatory collapse, respiratory depression, and coma.
According to the product labeling and postmarketing reports, the following are the features of olanzapine toxicity.
Serum concentration of olanzapine >0.1 mg/L is toxic and serum concentration>1 mg/L can be fatal.
Clinical Features
* Agitation
* Dysarthria
* Tachycardia and hypotension
* Extrapyramidal symptoms
* Sedation
* Miosis
* Aspiration
* Delirium
* Respiratory depression
* Coma
* Convulsions
* Ventricular dysrhythmia

Management
* There is no specific antidote to olanzapine. In acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, including intubation. In addition, clinicians should consider the possibility of multiple drug involvement.

* In addition, gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal with a laxative should be considered. The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a valuable treatment for olanzapine overdose.

* The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Therefore, cardiovascular monitoring should commence immediately and include continuous electrocardiographic monitoring to detect possible arrhythmias.

* Hypotension and circulatory collapse should be treated with appropriate measures; intravenous fluids and sympathomimetic agents. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen hypotension in the setting of the olanzapine-induced alpha blockade.

* Close medical supervision and monitoring should continue until the patient recovers.

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Olanzapine's antipsychotic activity is likely due to a combination of antagonism at D2 receptors in the mesolimbic pathway and 5HT2A receptors in the frontal cortex. Antagonism at D2 receptors relieves positive symptoms while antagonism at 5HT2A receptors relieves negative symptoms of schizophrenia. Olanzapine is an antagonist at types 1, 2, and 4 dopamine receptors, 5-HT receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Olanzapine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Olanzapine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone. Antagonism at muscarinic receptors, H1-receptors, and alpha(1)-receptors also occurs with olanzapine.

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Hepatotoxicity Liver test abnormalities have been reported to occur in 10% to 50% of patients on long term therapy with olanzapine. These abnormalities are usually mild, asymptomatic and transient, and can reverse even with continuation of medication. In addition, instances of more marked elevations in serum aminotransferase levels and clinically apparent hepatitis with jaundice have been reported in patients taking olanzapine. Among atypical antipsychotic agents, olanzapine has most often been linked to cases of clinically apparent liver injury, the incidence being estimated to be 1:1200 treated patients. The time to onset of liver injury with olanzapine therapy in generally within 1 to 4 weeks of starting therapy or achieving optimal daily dose. However, cases with onset a year after starting have also been reported. The pattern of serum enzyme elevations is most often mixed (Case) but can range from hepatocellular to cholestatic. Fatal cases of olanzapine induced liver injury have been reported, but most cases resolve rapidly once olanzapine is stopped. Allergic manifestations (rash, fever, eosinophilia) and autoimmune markers are uncommon. Cases with a long latency and accompanied by significant weight gain may represent nonalcoholic fatty liver disease, rather than olanzapine hepatotoxicity.

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Interactions
The manufacturer states that the clearance of olanzapine in smokers is approximately 40% higher than in nonsmokers. Therefore, plasma olanzapine concentrations generally are lower in smokers than in nonsmokers receiving the drug. Adverse extrapyramidal effects have been reported in one olanzapine-treated patient after a reduction in cigarette smoking, while worsened delusions, hostility, and aggressive behavior have been reported in another olanzapine-treated patient following a marked increase in smoking (i.e., an increase from 12 up to 80 cigarettes per day). Although the precise mechanism(s) for this interaction has not been clearly established, it has been suggested that induction of the CYP isoenzymes, particularly 1A2, by smoke constituents may be responsible at least in part for the reduced plasma olanzapine concentrations observed in smokers compared with nonsmokers. Although the manufacturer states that routine dosage adjustment is not recommended in patients who smoke while receiving olanzapine, some clinicians recommend that patients treated with olanzapine should be monitored with regard to their smoking consumption and that dosage adjustment be considered in patients who have reduced or increased their smoking and/or who are not responding adequately or who are experiencing dose-related adverse reactions to the drug. In addition, monitoring of plasma olanzapine concentrations may be helpful in patients who smoke and have other factors associated with substantial alterations in metabolism of olanzapine (e.g., geriatric patients, women, concurrent fluvoxamine administration).
Concurrent administration of activated charcoal (1 g) reduced peak plasma concentrations and the AUC of a single, 7.5-mg dose of olanzapine by approximately 60%. Since peak plasma concentrations are not usually obtained until about 6 hours after oral administration, activated charcoal may be useful in the management of olanzapine intoxication.
Olanzapine therapy potentially may enhance the effects of certain hypotensive agents during concurrent use. In addition, the administration of dopamine, epinephrine, and/or other sympathomimetic agents with beta-agonist activity should be avoided in the treatment of olanzapine-induced hypotension, since such stimulation may worsen hypotension in the presence of olanzapine-induced alpha-blockade.
In a pharmacokinetic study, concomitant administration of a single dose of alcohol did not substantially alter the steady-state pharmacokinetics of olanzapine (given in dosages of up to 10 mg daily). However, concomitant use of olanzapine with alcohol potentiated the orthostatic hypotension associated with olanzapine. The manufacturer therefore states that alcohol should be avoided during olanzapine therapy.
For more Interactions (Complete) data for Olanzapine (11 total), please visit the HSDB record page.

[1]. J Clin Psychiatry. 1997:58 Suppl 10:28-36.

[2]. Neuropsychopharmacology. 2000 Sep;23(3):250-62

[3]. Psychopharmacology (Berl). 1998 Mar;136(2):153-61.

[4]. Neuropsychopharmacology. 2005 Sep;30(9):1649-61.

[5]. Diabetes. 2005 Mar;54(3):862-71.

Therapeutic Uses
Antiemetic, Antipsychotic Agent, Serotonin Uptake Inhibitor
Oral olanzapine is indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial. /Included in US product label/
Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies in adult patients. /Included in US product label/
Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials. /Included in US product label/
For more Therapeutic Uses (Complete) data for Olanzapine (7 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Olanzapine is not approved for the treatment of patients with dementia-related psychosis.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
The possibility of a suicide attempt is inherent in schizophrenia and in bipolar I disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Like other atypical antipsychotic agents, olanzapine has a low potential for causing certain adverse extrapyramidal effects (e.g., dystonias). Results from controlled clinical trials suggest that extrapyramidal reactions associated with olanzapine therapy are dose related. Tremor was reported in about 4% of patients receiving oral olanzapine and in about 1% of patients receiving IM olanzapine in controlled clinical trials; the incidence of tremor appears to be dose related. In addition, akathisia occurred in about 3% of patients receiving oral olanzapine and in less than 1% of patients receiving IM olanzapine; hypertonia occurred in about 3% of patients receiving oral olanzapine in short-term controlled clinical trials.
For more Drug Warnings (Complete) data for Olanzapine (45 total), please visit the HSDB record page.

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Pharmacodynamics
The effect of olanzapine in the D2 receptor is reported to produce the positive effects of this drug such as a decrease in hallucinations, delusions, disorganized speech, disorganized thought, and disorganized behavior. On the other hand, its effect on the serotonin 5HT2A receptor prevents the onset of anhedonia, flat affect, alogia, avolition and poor attention. Based on the specific mechanism of action, olanzapine presents a higher affinity for the dopamine D2 receptor when compared to the rest of the dopamine receptor isotypes. This characteristic significantly reduces the presence of side effects. Clinical trials for the original use of olanzapine demonstrated significant effectiveness in the treatment of schizophrenia and bipolar disorder in adults and acute manic or mixed episodes associated with bipolar disorder in adolescents. The effect of olanzapine on dopamine and serotonin receptors has been suggested to reduce chemotherapy-induced nausea and vomiting as those receptors are suggested to be involved in this process. For this effect, several clinical trials have been conducted and it has been shown that olanzapine can produce a significant increase in total control of nausea and vomiting. In a high-level study of the effect of olanzapine for this condition, a complete response on the delay phase was observed in 84% of the individual and control of emesis of over 80% despite the phase.

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Background: Classical (typical) antipsychotic drugs are in wide use clinically, but some patients do not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail to respond. Also, these drugs often cause serious motor disturbances. Clozapine, an atypical antipsychotic, appears to correct many of these deficiencies, but has a significant incidence of potentially fatal agranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychotics that is both more efficacious and safe. Our strategy was to create a compound that is not only active in behavioral tests that predict antipsychotic action but also shares the rich, multifaceted receptor pharmacology of clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. In this article we characterize the in vitro and in vivo receptor pharmacology of olanzapine. Method: We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays. Results: Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos). Conclusion: The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.[1]

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In conclusion, this study is the first demonstration of the intrinsic effects of the most widely prescribed atypical antipsychotics on weight, adiposity, insulin sensitivity of the liver and peripheral tissues, and pancreatic β-cell function. There were clear differences in the effects of OLZ and RIS. OLZ caused significant weight gain and marked increases in total trunk adiposity, reflecting marked expansion of both visceral and subcutaneous adipose depots and severe hepatic insulin resistance. RIS had modest effects on adiposity that did not differ from the effects of placebo. Most importantly, the present studies reveal a significant effect of OLZ to impair β-cell compensation for insulin resistance. OLZ completely blocked the compensatory response with obesity and resistance seen with fat feeding, whereas β-cell function during RIS appears intact. The mechanisms by which these actions of antipsychotics occur are not known, but these data suggest that drugs may impede possible neural regulation of β-cell compensation. Failure of β-cell compensation to atypical antipsychotics provides a mechanistic basis by which diabetes may develop in the vulnerable psychiatric population treated with these therapeutic agents. These results underscore the importance of examining drug effects in the absence of risk factors common among psychiatric patients. Further studies are needed to determine the mechanisms underlying differential metabolic sequelae of these agents, and the processes which may lead to development of diabetes in this population.[5]

C17H20N4S

312.44

312.14

C, 65.35; H, 6.45; N, 17.93; S, 10.26

132539-06-1

Olanzapine-d3; 786686-79-1; 132539-06-1; 783334-36-1 (HCl)

135398745

Yellow crystalline solid
Crystals from acetonitrile

1.3±0.1 g/cm3

476.0±55.0 °C at 760 mmHg

195°C

241.7±31.5 °C

0.0±1.2 mmHg at 25°C

1.709

2.18

1

4

1

22

432

0

S1C(C([H])([H])[H])=C([H])C2=C1N([H])C1=C([H])C([H])=C([H])C([H])=C1N=C2N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H]

KVWDHTXUZHCGIO-UHFFFAOYSA-N

InChI=1S/C17H20N4S/c1-12-11-13-16(21-9-7-20(2)8-10-21)18-14-5-3-4-6-15(14)19-17(13)22-12/h3-6,11,19H,7-10H2,1-2H3

2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (6.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)