olanzapine and Agranulocytosis

Drug-induced agranulocytosis is believed to be an extremely rare adverse drug reaction. It can be caused by various drugs, but it is mostly described in patients taking antithyroid drugs, antipsychotics and antibiotics. Four cases of patients treated for drug-induced agranulocytosis from January 2006 to March 2007 were described. In two cases agranulocytosis appeared in the course of therapy with methimazole. In one patient agranulocytosis was caused by perazine and by promazine or olanzapine in the last one. In all of the cases the leading symptom was fever, three of our patients had changes of mouth mucosa. All patients were treated with betalactam antibiotics. Granulocyte colony-stimulating factor (G-CSF) was not used in anyone. The recovery of white blood cell count and granulocyte count in all of the patients was detected in the first ten days of hospitalization.

Topics: Aged; Agranulocytosis; Anti-Bacterial Agents; Antipsychotic Agents; Antithyroid Agents; Benzodiazepines; beta-Lactams; Female; Humans; Male; Methimazole; Middle Aged; Olanzapine; Perazine; Promazine

The novel antipsychotic olanzapine has structural and pharmacological properties similar to clozapine. Until recently, no haematological toxicity has been reported with olanzapine use and it was expected to be a safer alternative. The authors report a case of agranulocytosis induced by olanzapine and reviewed the 11 cases reported in the literature.

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Humans; Male; Middle Aged; Olanzapine; Pirenzepine

Four new antipsychotic medications--clozapine, risperidone, olanzapine, and quetiapine--have been introduced in the United States during the past decade. These new medications now account for the majority of antipsychotic prescriptions. The author reviews specific issues related to the use of traditional antipsychotic medications and then highlights the emerging clinical research data regarding the new medications, which have all been shown to be efficacious in the treatment of schizophrenia. Clinical research data indicate that they are also more useful for a broader array of symptoms associated with schizophrenia than traditional compounds. Furthermore, movement disorder side effects are substantially decreased--a property that leads to higher acceptability. Surprisingly, there has been little relationship between the pivotal trials designed for FDA approval and current dosing strategies in broader clinical settings. These dosing issues are described. New uses, including treatment of mood disorders and conduct disorder, are also discussed. These medicines offer substantial hope for improved treatment of schizophrenia.

Topics: Agranulocytosis; Akathisia, Drug-Induced; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Humans; Olanzapine; Pirenzepine; Prolactin; Quetiapine Fumarate; Risperidone; Schizophrenia

Adverse effects of antipsychotics often lead to noncompliance. Thus, clinicians should address patients' concerns about adverse effects and attempt to choose medications that will improve their patients' quality of life as well as overall health. The side effect profiles of the atypical antipsychotics are more advantageous than those of the conventional neuroleptics. Conventional agents are associated with unwanted central nervous system effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, sedation, and possible impairment of some cognitive measures, as well as cardiac effects, orthostatic hypotension, hepatic changes, anticholinergic side effects, sexual dysfunction, and weight gain. The newer atypical agents have a lower risk of EPS, but are associated in varying degrees with sedation, cardiovascular effects, anticholinergic effects, weight gain, sexual dysfunction, hepatic effects, lowered seizure threshold (primarily clozapine), and agranulocytosis (clozapine only). Since the incidence and severity of specific adverse effects differ among the various atypicals, the clinician should carefully consider which side effects are most likely to lead to the individual's dissatisfaction and noncompliance before choosing an antipsychotic for a particular patient.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Central Nervous System Diseases; Clozapine; Dibenzothiazepines; Drug Interactions; Dyskinesia, Drug-Induced; Health Status; Humans; Hypotension, Orthostatic; Olanzapine; Pirenzepine; Quality of Life; Quetiapine Fumarate; Receptors, Cholinergic; Risperidone; Schizophrenia; Sexual Dysfunctions, Psychological; Sleep Wake Disorders; Treatment Refusal; Weight Gain

When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation.. Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]).. Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation.. For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cross-Over Studies; Dibenzothiazepines; Drug Monitoring; Drug Resistance; Eosinophilia; Female; Follow-Up Studies; Humans; Male; Olanzapine; Piperazines; Prospective Studies; Psychiatric Status Rating Scales; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Treatment Outcome

Although clozapine-induced granulocytopenia (CIG) is less severe than clozapine-induced agranulocytosis (CIA), and some patients with CIG may not go on to develop serious complications, clozapine is discontinued in cases of both CIA and CIG. Understanding the pathogenic mechanisms of CIA/CIG could provide better management of clozapine therapy. Recently, as a mechanistic insight into adaptive immune systems, European groups reported clozapine-specific proliferative responses and clozapine-specific T cells using blood taken from patients with CIA and/or CIG.. The aims of our study are to support this mechanistic evidence and to investigate the difference in the lymphocyte response to clozapine between patients with CIG and those with CIA.. Lymphocyte stimulation tests (LSTs) were conducted using CD25-positive cell-depleted peripheral blood-derived mononuclear cells (PBMCs) isolated from blood of four Japanese patients with CIA, four patients with CIG, and nine clozapine-tolerant subjects.. Three of four patients with CIA and one of four patients with CIG showed proliferative responses to clozapine with a stimulation index of greater than 2. In contrast, none of the nine clozapine-tolerant subjects showed any response to clozapine. Olanzapine did not stimulate PBMCs of patients with CIA, patients with CIG, or clozapine-tolerant subjects.. Clozapine- and CIA-specific lymphocyte reactions in a Japanese population provided supportive evidence that the pathogenesis of CIA is based on adaptive immune reactions. In addition, patients with CIG who show a positive response to an LST may at the very least not be chosen for clozapine-rechallenge and further prospective studies are desirable to verify this hypothesis.

Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Japan; Olanzapine; Prospective Studies

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clopenthixol; Clozapine; Drug Resistance; Drug Substitution; Drug Synergism; Drug Therapy, Combination; Humans; Male; Olanzapine; Schizophrenia, Paranoid; Valproic Acid

Clozapine is effective in the treatment of schizophrenia; however, its use is limited by a relatively high incidence of idiosyncratic agranulocytosis. The mechanism of clozapine-induced idiosyncratic agranulocytosis is unknown. Although most patients treated with clozapine do not develop agranulocytosis, most do have an immune response with an increase in inflammatory cytokines such as IL-6 and a release of immature neutrophils with neutrophilia rather than agranulocytosis. We have previously shown that treatment of rabbits with clozapine also causes an early release of neutrophils. Clozapine is oxidized to a reactive nitrenium ion that covalently binds to neutrophils, and this reactive metabolite may be responsible for the observed effects. Olanzapine and clozapine have very similar structures, and olanzapine is also oxidized to a reactive nitrenium ion; however, if it ever causes agranulocytosis, the incidence is much lower than that of clozapine. One possible basis for the difference in incidence of agranulocytosis between clozapine and olanzapine is that the therapeutic dose of olanzapine is much lower than that of clozapine. In this study, we compared the effects of clozapine and olanzapine in Sprague-Dawley rats at an equimolar dose and found that only clozapine had a significant effect on neutrophil kinetics. This suggests that the immune response and effects on neutrophil kinetics induced by clozapine are related to its ability to cause agranulocytosis.

Topics: Agranulocytosis; Animals; Antipsychotic Agents; Benzodiazepines; Bone Marrow; Clozapine; Female; Femur; Kinetics; Leukocyte Count; Neutrophils; Olanzapine; Rats, Sprague-Dawley; Tibia

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.

Topics: Agranulocytosis; Benzodiazepines; Biomarkers; Cell Line, Tumor; Clozapine; Computational Biology; Drug-Related Side Effects and Adverse Reactions; GABA Antagonists; HSP70 Heat-Shock Proteins; Humans; Olanzapine; Protein Interaction Mapping; Proteomics; Reactive Oxygen Species; Retrospective Studies; Risk Factors

Topics: Adolescent; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Humans; Male; Olanzapine; Psychotic Disorders

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Follow-Up Studies; Granulocytes; Humans; Leukocyte Count; Male; Olanzapine; Schizophrenia; Time Factors; Treatment Outcome

Neutropenia and agranulocytosis are risks known to occur with phenothiazines and clozapine. The mechanisms responsible for these conditions currently remain unclear. To our knowledge, no case of fatal agranulocytosis as a result of olanzapine treatment was reported in the literature. Thus any case of severe neutropenia occurring in a patient receiving olanzapine is alarming to clinicians. First, a review of the literature produced 41 anecdotic cases of neutropenia or agranulocytosis during treatment with olanzapine (Zyprexa) reported in a total of 24 publications. Second, we report a case of neutropenia, which proved to be fatal in a schizophrenia patient receiving olanzapine and thiazide. The cause of the death was Myelodysplastic syndrome. There is not enough evidence to prove the involvement of either olanzapine or hydrochlorothiazide or the interaction between them in this patient's myelodysplasia. Bone marrow cytogenetic study confirmed the deletion of the long arm of chromosome 11, as reported in myeloid leukemia. If this patient would have died suddenly without the laboratory investigations that lead to the diagnosis of myeloblastic leukemia, the cause would have been probably and wrongfully allotted to treatment with olanzapine.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Blood Cell Count; Bone Marrow Cells; Fatal Outcome; Humans; Male; Myelodysplastic Syndromes; Neutropenia; Olanzapine; Schizophrenia, Paranoid

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Monitoring; Humans; Leukocyte Count; Male; Neutropenia; Neutrophils; Olanzapine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

DMP 406 is a clozapine analogue developed by Dupont-Pharma for the treatment of schizophrenia. Unfortunately it caused agranulocytosis in dogs during preclinical studies. Clozapine also causes agranulocytosis and this is believed to be due to a reactive nitrenium ion metabolite produced by neutrophils. We studied the oxidation of DMP 406 by activated neutrophils and found that the major reactive species that is produced is not a nitrenium ion but rather an imine. This metabolite is similar to the reactive metabolite that has been proposed to be responsible for mianserin-induced agranulocytosis. Therefore we also studied the oxidation of mianserin by activated neutrophils and found that, although the major species is an iminium ion, it also bears a lactam moiety in the piperazine ring resulting from further oxidation. We usually find that HOCl is a good model system for the production of reactive metabolites of drugs that are formed by activated neutrophils, but in the case of both DMP 406 and mianserin, the products produced were significantly different than those formed by activated neutrophils. In contrast, the combination of horseradish peroxidase and hydrogen peroxide (HRP/H(2)O(2)) formed a very similar pattern of products, and this system was used to produce sufficient quantities of metabolites to allow for identification. The reactive metabolites of both DMP 406 and mianserin reacted with a range of nucleophiles, but in many cases the reaction was reversible. The best nucleophile for trapping these reactive metabolites was cyanide. It has been demonstrated that the products of clozapine oxidation by HRP/H(2)O(2), presumably the nitrenium ion, induced apoptosis in neutrophils at therapeutic concentrations of clozapine. It has been suggested that this process is involved in the mechanism of clozapine-induced agranulocytosis. We tested DMP 406 and mianserin in this system to see if the ability of a reactive metabolite of a drug to cause apoptosis could predict the ability of that drug to cause agranulocytosis. We used clozapine as a positive control and we also tested olanzapine, a drug that forms a reactive metabolite similar to that of clozapine but is given at a lower dose and does not cause agranulocytosis. We found that DMP 406 did not increase apoptosis at concentrations below 50 microM, and although mianserin did increase apoptosis at 10 microM this is above the therapeutic concentration. Olanzapine caused an increase in apoptosis at the same c

Topics: Agranulocytosis; Antipsychotic Agents; Apoptosis; Benzodiazepines; Chromatography, High Pressure Liquid; Chromatography, Liquid; Clozapine; Cyanides; Horseradish Peroxidase; Humans; Hydrogen Peroxide; Hypochlorous Acid; Mass Spectrometry; Mianserin; Neutrophils; Nuclear Medicine; Olanzapine; Pirenzepine

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Leukocyte Count; Neutropenia; Olanzapine; Perphenazine; Pirenzepine; Risperidone; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Patient Compliance; Pirenzepine; Practice Patterns, Physicians'; Quality of Life; Quetiapine Fumarate; Risperidone

Recent case studies suggest that impaired granulopoiesis, well-known to occur during clozapine treatment, may also be observed when olanzapine is administered. The underlying mechanisms are unknown, but haematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) are likely to be involved.. We measured the plasma levels of G-CSF and of other cytokines longitudinally in a female patient who developed granulocytopenia twice, first during clozapine treatment and again when olanzapine was administered.. G-CSF levels, but not those of other cytokines, closely paralleled granulocyte counts, yielding a significant positive correlation. G-CSF was not detectable in plasma when granulocytopenia occurred. Granulocytopenia resolved spontaneously despite continuing treatment with olanzapine.. The present case suggests that clozapine and olanzapine both are able to induce transient granulocytopenia through a similar or common mechanism that does not involve a compensatory increase in G-CSF levels.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Cytokines; Female; Granulocyte Colony-Stimulating Factor; Granulocytes; Hospitalization; Humans; Leukocyte Count; Olanzapine; Pirenzepine; Remission, Spontaneous; Schizophrenia

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; HLA-A2 Antigen; Humans; Olanzapine; Pirenzepine; Racial Groups

Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Dibenzothiazepines; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Olanzapine; Pirenzepine; Schizophrenia

How to best treat psychotic patients who have had past clozapine-induced agranulocytosis or granulocytopenia remains a problem.. We report 3 patients with chronic schizophrenia who had previously stopped clozapine due to hematologic side effects. The patients evidenced improvement with olanzapine that equated to 16- to 31-point decreases in rating scale scores during 1-year follow-up without any hematologic abnormalities.. The results suggest that olanzapine may be useful in treating patients with clozapine-induced granulocytopenia without the risk of recurrence of hematologic side effects.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Follow-Up Studies; Humans; Leukocyte Count; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Interactions; Humans; Olanzapine; Pirenzepine

Whether or not olanzapine causes bone marrow toxicity is still a matter of debate. In spite of pre-marketing and post-marketing clinical trials, and although there have been no cases in animals of olanzapine-induced neutropenia or agranulocytosis, the risk of bone marrow toxicity cannot be excluded. The present paper addresses the following questions: what is the potential background of drug-induced agranulocytosis? Are there any case reports supporting the view that olanzapine has relevant bone marrow toxicity? What strategies might be helpful in identifying the pathological mechanisms underlying this side effect?

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Female; Genetic Predisposition to Disease; Haplotypes; HLA Antigens; Humans; Olanzapine; Pirenzepine

The antipsychotic drug olanzapine was developed to reduce the risk of haematotoxicity. We report a case of agranulocytosis induced by olanzapine.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Humans; Male; Olanzapine; Pirenzepine; Schizophrenia

Olanzapine was shown to be oxidized to a reactive intermediate by HOCl, which is the major oxidant produced by activated neutrophils. A mass spectrum obtained using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a mass spectrometer revealed a reactive intermediate at m/z 311. This is 2 mass units less than the protonated molecular ion of parent olanzapine and suggests that the reactive intermediate is a nitrenium ion. The reactive intermediate could be trapped with glutathione or N-acetylcysteine to produce two conjugates. These data are analogous to results we reported previously with the structurally related atypical antipsychotic agent clozapine. However, the clozapine and olanzapine reactive metabolites showed differences in their ability to cause toxicity to human neutrophils. Toxicity to neutrophils was observed only at high concentrations of clozapine (>50 microM) when HOCl was used to generate reactive metabolite. In contrast, concentration-dependent toxicity (p < 0.05) was observed when neutrophils were incubated with clozapine (0-20 microM) and H2O2 to generate clozapine reactive metabolite. No toxicity was observed with clozapine alone (at concentrations of > 50 microM). Similar results were observed in monocytes and HL-60 cells. Olanzapine reactive metabolite only seemed to cause slight toxicity at the highest concentrations tested (20 microM), even when the reactive metabolite was generated using H2O2. Neutrophils from two patients with a history of clozapine-induced agranulocytosis seemed to be more sensitive to the toxic effects of the clozapine reactive metabolite; however, the numbers are too small to draw any definite conclusions.

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; HL-60 Cells; Humans; Hypochlorous Acid; Neutrophils; Olanzapine; Oxidation-Reduction; Pirenzepine

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Risk Factors; Schizophrenia; Treatment Outcome

Topics: Adult; Aged; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Female; Humans; Male; Olanzapine; Pirenzepine

Two cases are reported of patients who developed agranulocytosis after treatment with typical and atypical antipsychotics. The patients were successfully treated with olanzapine. We suggest the consideration of olanzapine as a safer treatment in patients who require immediate continuation of antipsychotic medication and have a prior history of classic and atypical neuroleptic-induced agranulocytosis.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clopenthixol; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leukocyte Count; Male; Olanzapine; Pirenzepine; Risperidone; Schizophrenia, Paranoid

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Administration Schedule; Humans; Olanzapine; Pirenzepine; Time Factors

Clozapine is associated with a high incidence of agranulocytosis. We had previously found that it is oxidized by granulocytes, or simply HOCl, to a reactive metabolite that irreversibly binds to the cells, and we proposed that this reactive metabolite is responsible for clozapine-induced agranulocytosis. The reactive metabolite appeared to be a nitrenium ion formed by chlorination of the nitrogen bridge between the two aromatic rings. If this is correct, analogs that contain this structural feature should also be oxidized to a reactive intermediate while those not possessing this feature would, at least, not form the same type of reactive intermediate and, therefore, may not induce agranulocytosis. We tested the first part of this hypothesis with three clozapine analogs that do contain a nitrogen bridge and three that do not. Consistent with the hypothesis, the three analogs that do contain the nitrogen bridge formed reactive intermediates that could be trapped with glutathione when oxidized by HOCl, myeloperoxidase or activated neutrophils. In contrast, we found no evidence of a reactive intermediate on oxidation of analogs that contained an oxygen or sulfur bridge rather than a nitrogen bridge. If such reactive metabolites are responsible for drug-induced agranulocytosis, it should be possible to use such a simple screening method to test drugs at an early stage in their development for the potential to induce agranulocytosis.

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Binding Sites; Chromatography, High Pressure Liquid; Chromatography, Liquid; Clozapine; Dibenzazepines; Glutathione; Granulocytes; Humans; Hydrogen Peroxide; Hypochlorous Acid; Lymphocyte Activation; Mass Spectrometry; Neutrophils; Nitrogen; Olanzapine; Oxidation-Reduction; Peroxidase; Pirenzepine; Structure-Activity Relationship

Topics: Agranulocytosis; Antipsychotic Agents; Benzodiazepines; Clozapine; Drug Interactions; Humans; Olanzapine; Pirenzepine; Schizophrenia