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Background: Metabolic side effects have been increasingly noted during therapy with novel antipsychotics, but there is a dearth of comprehensive comparative data in this area. The goal of this retrospective study was to examine the changes in weight parameters, fasting glucose, and fasting lipids in long-term inpatients treated with either risperidone or olanzapine., Method: A retrospective study was performed by reviewing charts of patients at Oregon State Hospital, Salem, who were treated during July and August 1999, comparing metabolic outcomes during the first year of therapy with either risperidone or olanzapine. Data were analyzed also by age, sex, and concurrent use of lithium or valproate. Included for analysis were patients at least 18 years old with baseline weights obtained within 3 weeks of drug initiation, and baseline fasting triglycerides, cholesterol, and glucose obtained within 3 months prior to drug initiation and at 1 year of treatment (+/- 4 weeks). The patients meeting these criteria in each drug cohort (risperidone, N = 47; olanzapine, N = 47) included 1 patient with diagnosed diabetes mellitus prior to onset of treatment., Results: Among those patients under 60 years old, olanzapine patients (N = 37) experienced significantly greater increases at 1 year in all metabolic parameters than the risperidone group (N = 39), except for weight variables: triglycerides +104.8 mg/dL (olanzapine) versus +31.7 mg/dL (risperidone) (p = .037); cholesterol +30.7 mg/dL (olanzapine) versus +7.2 mg/dL (risperidone) (p = .004); glucose +10.8 mg/dL (olanzapine) versus +0.74 mg/dL (risperidone) (p = .030). Patients under 60 years of age with concurrent use of lithium or valproate were associated with greater weight gain in both drug groups, but this difference was statistically significant only for the olanzapine cohort. Neither weight change nor use of lithium or valproate was associated with increases in glucose or lipids among those under 60 years old for either drug., Conclusion: Olanzapine therapy is associated with significantly greater increases in fasting glucose and lipid levels for nongeriatric adult patients than risperidone, and the increases are not correlated with changes in weight parameters. Appropriate monitoring of fasting glucose and serum lipid levels should be considered during extended treatment with atypical antipsychotics.

This double-blind study investigated the efficacy and safety of rapid-acting intramuscular olanzapine in treating agitation associated with Alzheimer's disease and/or vascular dementia. At 2 h, olanzapine (5.0 mg, 2.5 mg) and lorazepam (1.0 mg) showed significant improvement over placebo on the PANSS Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES), and both 5.0 mg olanzapine and lorazepam showed superiority to placebo on the Cohen-Mansfield Agitation Inventory. At 24 h, both olanzapine groups maintained superiority over placebo on the PANSS-EC; lorazepam did not. Olanzapine (5.0 mg) and lorazepam improved ACES scores more than placebo. Simpson-Angus and Mini-Mental State Examination scores did not change significantly from baseline. Sedation (ACES > or =8), adverse events, and laboratory analytes were not significantly different from placebo for any treatment. No significant differences among treatment groups were seen in extrapyramidal symptoms or in corrected QT interval at either 2 h or 24 h, and no significant differences among treatment groups were seen in vital signs, including orthostasis. Intramuscular injection of olanzapine may therefore provide substantial benefit in rapidly treating inpatients with acute dementia-related agitation.

We describe here a case of olanzapine associated weight gain, hyperglycemia and neuroleptic malignant syndrome in a 64 year-old woman with a significant medical history. Eighteen weeks after initiating olanzapine, Mrs X lost glycemic control, exhibited signs and symptoms consistent with neuroleptic malignant syndrome and gained 8.9 kg. We suggest that utilization of olanzapine in the less medically stable geriatric patient be implemented with vigilant monitoring for such complications mentioned above., (Copyright 2002 John Wiley & Sons, Ltd.)

In cancer patients, cognitive impairment, psychological distress, and anxiety may accompany and aggravate pain. Neuroleptics are frequently used to control these symptoms and may be used to treat pain that has been unresponsive to more conventional approaches. Because of prominent side effects of traditional neuroleptics and conflicting data regarding their analgesic efficacy, their use in the treatment of pain remains controversial. Olanzapine, an atypical neuroleptic, might offer advantages because of its safer side effect profile. It has also been shown to have an independent antinociceptive activity in animals. The use of olanzapine in the management of cancer pain has not been previously described. We prospectively collected the data on 8 cancer patients with severe pain, uncontrolled in spite of aggressive opioid titration, who received olanzapine to treat severe anxiety and mild cognitive impairment. Patients did not meet criteria for delirium and their cognitive impairment was defined as cognitive disorder not otherwise specified (NOS) according to DSM-IV. Patients received 2.5 to 7.5 mg of olanzapine daily. In all patients, opioid requirements had escalated rapidly prior to starting olanzapine. Levels of pain, sedation, and opioid use were measured 2 days before and 2 days after olanzapine was started. Cognitive state was assessed daily. All 8 patients had marked reduction of the daily pain scores. The average daily opioid use decreased significantly in all patients. Cognitive impairment and anxiety resolved within 24 hours of initiating olanzapine. In these 8 patients, decreased pain scores and opioid requirements may have resulted from improvement in cognitive function and the known anxiolytic effect of olanzapine. Other mechanisms may include independent or adjuvant analgesic effects of olanzapine. We conclude that olanzapine may be useful in the treatment of patients with uncontrolled cancer pain associated with cognitive impairment or anxiety. Further studies to evaluate possible analgesic effect of olanzapine are needed.

The treatment of severe depression represents a difficult task in the daily psychiatric practice. In certain cases, augmentation therapies in order to improve the efficacy of SSRIs can be useful. Recently, it has become possible to use atypical antipsychotics for SSRI augmentation. This option adds to the existing strategies in the treatment of depression and primary systematic studies show encouraging results. In this review, the possibility of a SSRI augmentation by additionally administering risperidone or olanzapine is critically discussed.

Objective: The development of both type I and type II diabetes after initiation of some atypical neuroleptics has been reported, primarily in studies involving small series of patients. This study used administrative data from a large national sample of patients with a diagnosis of schizophrenia to compare the prevalence of diabetes mellitus in patients receiving prescriptions for atypical and typical neuroleptics., Method: All outpatients with schizophrenia treated with typical and atypical neuroleptics over 4 months in 1999 in the Veterans Health Administration of the Department of Veterans Affairs (VA) were included in this study. Patients treated with atypical neuroleptics were those who received prescriptions for clozapine, olanzapine, risperidone, or quetiapine. Patients with a diagnosis of diabetes were also identified by using ICD-9 codes in VA administrative databases. The prevalence of diabetes mellitus across age groups and among patients receiving prescriptions for different atypical neuroleptics was examined with multiple logistic regression., Results: A total of 38,632 patients were included in the study: 15,984 (41.4%) received typical neuroleptics and 22,648 (58.6%) received any atypical neuroleptic (1,207 [5.3%] received clozapine; 10,970 [48.4%], olanzapine; 955 [4.2%], quetiapine; and 9,903 [43.7%], risperidone; 387 patients received prescriptions for more than one atypical neuroleptic). When the effects of age were controlled, patients who received atypical neuroleptics were 9% more likely to have diabetes than those who received typical neuroleptics, and the prevalence of diabetes was significantly increased for patients who received clozapine, olanzapine, and quetiapine, but not risperidone. However, for patients less than 40 years old, all of the atypical neuroleptics were associated with a significantly increased prevalence of diabetes., Conclusions: In this large group of patients with schizophrenia, receipt of a prescription for atypical neuroleptics was significantly associated with diabetes mellitus.

Background: Recent evidence suggests that effects upon glutamatergic transmission may contribute to the therapeutic action of certain atypical antipsychotic agents., Methods: Glutamate concentrations were measured in serum and were estimated (Glx/Cr) in cingulate cortex by proton magnetic resonance spectroscopy (MRS) in schizophrenia patients while they were being treated with conventional neuroleptics and then 8 weeks after switching to olanzapine. Serum glutamate concentrations were obtained from 11 subjects, and MRS estimates of Glx/Cr were available from 10 subjects at both time points., Results: Serum glutamate concentrations significantly increased after the switch from conventional agents to olanzapine; brain glutamate (Glx/Cr) did not change significantly; however, brain glutamate (Glx/Cr) concentrations increased significantly in patients who exhibited an improvement in negative symptoms with olanzapine compared with patients with no change or worsening of negative symptoms., Conclusions: Comparisons performed following the switch from conventional agents to olanzapine are consistent with previous studies of clozapine and provide additional preliminary evidence supporting the hypothesis that effects on excitatory amino acid activity may contribute to olanzapine's efficacy for treating negative symptoms.

This case report describes an 18-year-old African American male who presented to a state psychiatric facility with symptoms of bizarre behavior, delusions and auditory hallucination. He was diagnosed with schizophrenia and treated with eight days of risperidone followed by five days of olanzapine. During this two-week period, this patient began to develop signs and symptoms of neuroleptic malignant syndrome (NMS). Two weeks after all neuroleptic medications were discontinued, all his vital signs and labs returned to baseline. This case report and others from literature suggest that risperidone and olanzapine may induce NMS in some patients.

Objective: To provide evidence that olanzapine can cause glucose dysregulation by a mechanism other than weight gain., Method: I report a case of a diabetic patient who developed glucose dysregulation soon after initiation of olanzapine treatment, occurring in the absence of weight gain. I compare this case to previous case reports., Results: Our patient developed persistent hyperglycaemia within 3 weeks of initiating treatment with olanzapine. Weight recorded just prior to commencement and soon after discontinuation of olanzapine were not significantly different., Conclusion: Controlled studies are necessary to elucidate the mechanism by which olanzapine can cause dysregulation of glucose homeostasis, and to develop guidelines for the use of olanzapine in patients with known diabetes as well as in patients with risk factors for diabetes.

Objective: To report a case involving a witnessed seizure in a patient receiving concurrent olanzapine and quetiapine., Case Summary: A 27-year-old white woman was observed to have a seizure while receiving a stable dosage of olanzapine 15 mg/d, with the addition of quetiapine 100 mg in the evening 1 day before the occurrence of the seizure. There were no known risk factors for epilepsy., Discussion: This case reports a new-onset seizure in the context of concurrent olanzapine and quetiapine use. Interpretation is complicated by recent discontinuation of low-dose clonazepam., Conclusions: While uncommon, seizures can occur with non-clozapine atypical antipsychotics. Caution is indicated when using these drugs with other agents that may lower the seizure threshold.

Objective: To determine whether severity of obsessive-compulsive symptoms (OCS) differs during treatment with olanzapine or risperidone and to establish whether duration of antipsychotic treatment is related to severity of OCS., Method: We conducted a prospective study of consecutively hospitalized young patients (mean age = 22.4 years) with DSM-IV schizophrenia or related disorders (N = 113) who were treated with olanzapine or risperidone. Olanzapine or risperidone was randomly prescribed for patients who were drug-naive or were treated with typical antipsychotics before admission (N = 36). Patients who had started olanzapine (N = 39) or risperidone treatment (N = 23) prior to admission continued with that medication if they showed initial clinical response. Patients who prior to admission started olanzapine (N = 6) or risperidone (N = 9) but showed no response or suffered from adverse effects switched at admission to risperidone or olanzapine, respectively. Medical records, parents, and patients revealed information on duration of treatment and compliance with olanzapine or risperidone prior to admission. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was administered at admission and 6 weeks thereafter., Results: At baseline and 6-week assessments, OCS were found in about 30% of 106 evaluable cases and 15% met DSM-IV criteria for obsessive-compulsive disorder. No differences in OCS were found in the patients randomly assigned to olanzapine or risperidone. The 35 subjects treated with olanzapine at both assessments had significantly (p = .01) more severe OCS at week 6 than the 20 subjects treated with risperidone at both assessments. Duration of treatment with olanzapine was significantly (p < .01) related to severity of OCS., Conclusion: There are no differences in the short-term propensity of olanzapine or risperidone to induce or exacerbate OCS. However, severity of OCS was associated with duration of treatment with olanzapine.

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.

Objective: The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder., Method: In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period)., Results: Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain., Conclusions: The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small.

Akathisia (restlessness and characteristic movements of the legs) is one of the most disagreeable extrapyramidal side effects and often causes non-compliance. Dopamine blocking agents such as antipsychotics and antiemetics, may induce akathisia. Particular care must be taken to distinguish akathisia from psychotic agitation and restless legs. The prevalence of akathisia in patients using classical antipsychotics is 20-30% and for users of clozapine, olanzapine and quetiapine (atypical antipsychotics) it is lower. Risk factors are a high dosage of antipsychotics, akathisia in a previous treatment, and diabetes mellitus. The treatment of akathisia starts, if possible, with the antipsychotic being withdrawn or the dose administered being lowered. Another treatment possibility is switching to clozapine, olanzapine or quetiapine, or adding a beta-blocking agent, an anticholinergic or mianserin.

Conventional antidepressant treatment fails for up to 30% of patients with major depression. When there are concomitant psychotic symptoms, response rates are even worse. Thus, subsequent treatment often includes combinations of antidepressants or augmentation with antipsychotic agents. Atypical antipsychotic agents such as olanzapine cause fewer extrapyramidal adverse effects than conventional antipsychotics; for that reason, they are an advantageous augmentation strategy for treatment-resistant and psychotic depression. The purpose of this study was to assess the potential for pharmacokinetic interaction between olanzapine and fluoxetine, a popular antidepressant that is a selective serotonin reuptake inhibitor. The pharmacokinetics of 3 identical single therapeutic doses of olanzapine (5 mg) were determined in 15 healthy nonsmoking volunteers. The first dose of olanzapine was taken alone, the second given after a single oral dose of fluoxetine (60 mg), and the third given after 8 days of treatment with fluoxetine 60 mg, qd. Olanzapine mean Cmax was slightly higher (by about 18%) and mean CL/F was slightly lower (by about 15%) when olanzapine was coadministered with fluoxetine in single or multiple doses. Olanzapine mean t((1/2)) and median t(max) did not change. Although the pharmacokinetic effects of fluoxetine on olanzapine were statistically significant, the effects were small and are unlikely to modify olanzapine's safety profile. The mechanism of influence is consistent with an inhibition of CYP2D6, which is known to control a minor pathway of olanzapine metabolism.

Background: A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes., Methods: The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer)., Results: Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech., Conclusion: Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes.

Data from clinical trials reviewed in this article fulfill predictions based on preclinical findings that atypical antipsychotic drugs are associated with a reduced potential for inducing extrapyramidal symptoms (EPS) and other movement disorders. Atypical drugs have been shown to reduce all subtypes of acute EPS, the frequency of EPS-related patient dropouts, and the need for concomitant antiparkinsonian drug use. Clozapine remains superior to other atypicals in treating psychosis without worsening motor symptoms in patients with Parkinson's disease. Atypicals may be selectively advantageous in treating schizophrenic patients with a predisposition to catatonia. Although the risk of developing lethal neuroleptic malignant syndrome may be diminished with atypical drugs, clinicians must remain alert to the signs of this disorder. Atypicals have reduced liability for inducing tardive dyskinesia (TD) and show antidyskinetic properties in patients with preexisting TD. Passive resolution of TD may be facilitated in some patients by the use of these agents. Thus, the risk of movement disorders has become only one of several considerations in choosing among antipsychotic drugs.

Olanzapine is an atypical antipsychotic medication indicated for the treatment of schizophrenia and other manifestations of psychotic illness. Common side effects include somnolence, constipation, weight gain, and postural hypotension. The authors report a case of hypotension accompanied by bradycardia in a normal, healthy volunteer participating in an olanzapine pharmacokinetic study following a single 5 mg dose. A venous catheter allowed for serial blood sampling of olanzapine concentrations before, during, and after the adverse event. The subject experienced a rapid absorption of the drug and higher than anticipated maximum plasma concentrations. This case suggests that atypical antipsychotics, although generally better tolerated than conventional agents, may still result in untoward reactions that may be partially due to individual differences in drug absorption and metabolism.

Study Design: The metabolic pathways of most xenobiotics and endogenous compounds can be divided into phase 1 (oxidative, reductive, and hydrolytic) and phase 2 (glucuronidation, sulfate conjugation, glycine and glutathione conjugation, and acetylation and methylation) processes. Oxidative metabolism by the cytochrome P450 system has been intensively investigated compared with glucuronidation and other conjugation pathways. The primary aim of this study was to evaluate the disposition of olanzapine or risperidone in healthy volunteers with and without coadministration of the uridine diphosphoglucuronate-glucuronosyltransferase inhibitor probenecid. We hypothesized that olanzapine disposition would be altered as a result of decreased glucuronidation, whereas risperidone disposition would be relatively unaffected., Methods: Our objective was to investigate whether this interaction would occur in 12 healthy volunteers, aged 22 to 42 years, who participated in a single-dose, randomized, 4-period, double-blind, crossover study receiving a single dose of either 5 mg olanzapine or 1 mg risperidone with and without 500 mg probenecid (8 doses over 4 days). Multiple blood samples were analyzed by means of liquid chromatography-tandem mass spectrometry or HPLC to assess the 48-hour time course of risperidone and olanzapine. Urine was assayed for free and glucuronidated drugs., Results: When olanzapine was administered with probenecid, statistically significant differences were observed between plasma pharmacokinetic parameters compared with olanzapine administered alone (maximum concentration, P <.05; area under the plasma concentration-time curve from time zero to 24 hours, P <.01). Clearance was not significantly different between the treatment phases. Risperidone pharmacokinetic parameters were not significantly different (all parameters, P >.05)., Conclusion: Inhibition of uridine diphosphoglucuronate-glucuronosyltransferase appeared to influence the disposition of olanzapine but not risperidone. Phase 2 metabolism may significantly influence the disposition of antipsychotic drugs and may be an important aspect of the variability in metabolism, participation in drug-drug interactions, and clinical response to some antipsychotic agents.

Objective: Atypical antipsychotics are thought not to elevate prolactin levels. The authors examined data suggesting that atypical antipsychotics do elevate prolactin levels but more transiently than typical antipsychotics., Method: Prolactin levels in 18 male patients with schizophrenia who were receiving atypical antipsychotics were monitored over the 24-hour period following administration of their daily oral dose of risperidone, olanzapine, or clozapine., Results: The baseline prolactin levels in patients receiving risperidone (mean=27 ng/ml, SD=14) were abnormally high, but baseline prolactin levels in patients receiving olanzapine (mean=9 ng/ml, SD=5) and clozapine (mean=9 ng/ml, SD=5) were not high. All three atypical antipsychotics caused a doubling of prolactin levels over baseline levels 6 hours after medication administration., Conclusions: These data suggest that these atypical antipsychotics raise prolactin levels, although the increases with olanzapine did not reach statistical significance. This suggests that the differences in the effects on prolactin levels of atypical and typical antipsychotics are not categorical but lie in the degree and duration of dose-induced prolactin elevation, attributable to the differential binding properties of each drug on pituitary dopamine D(2) receptors.

Objective: This study sought to determine whether patients with dementia with Lewy bodies (DLB) and psychosis responded to treatment with olanzapine., Methods: This was a post hoc analysis of a subgroup of patients with DLB included in a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of psychosis in patients with Alzheimer's disease. Patients meeting the consensus criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Psychosis was assessed with the Neuropsychiatric Inventory/Nursing Home (NPI-NH) version and the Brief Psychiatric Rating Scale (BPRS). Extrapyramidal symptoms were evaluated with the Simpson-Angus scale., Results: Twenty-nine patients met the criteria for DLB; 10 were randomized to placebo, 5 received 5 mg of olanzapine, 7 received 10 mg of olanzapine and 7 received 15 mg of olanzapine. Patients with DLB treated with 5 mg of olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg showed a significant reduction in the NPI-NH delusion subscale score. No significant differences were found between the 15-mg group and the placebo group. Confirmatory findings emerged from an analysis of the BPRS. Caregivers reported decreased disruptions in their occupational routines for the group receiving 5 or 10 mg of olanzapine. There was no significant exacerbation of parkinsonian symptoms in any study group, no decrement in Mini-Mental State Examination scores in any of the treatment groups, and symptoms suggestive of anticholinergic toxicity did not differ among treatment groups., Conclusions: This preliminary analysis suggests that olanzapine (5 or 10 mg) reduces psychosis in patients with DLB without worsening parkinsonism., (Copyright 2002 S. Karger AG, Basel)

Background: Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance., Objective: To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs., Methods: All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed., Results: Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20-12.73), an increase in weight (OR 2.36, 95% CI 1.76-3.17), male gender (OR 1.27, 95% CI 1.11-1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61-2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33-1.99) or buspirone (OR 2.24, 95% CI 1.33-3.77)., Conclusion: Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.

During 20th century serious mental disorders were divided into two groups according symptomatology and course of disorder. Individuals with dominating disturbance of perception, thinking and cognition were basically diagnosed having schizophrenic. Individuals with mood disturbance were basically diagnosed having affective disorders. However, there were patients who did not fit neatly into either category. In 1933 Jocob Kasanin introduced the term "schizoaffective psychosis". Scientific discussions involved the possibility that schizoaffective disorder was conceptualized most accurately as following: a type of schizophrenia, a type of affective disorder, a unique disorder that was separate from both schizophrenia and bipolar disorder, an arbitrary categorization of clinical symptoms that marked a continuum between schizophrenia and affective illness, a heterogeneous collection of "interforms" between schizophrenia and affective disorders. However, diagnosis of schizoaffective disorder is included both in DSM-IV-TR and ICD-10. Schizoaffective disorder is listed in the category "schizophrenia and other psychotic disorders". The differential diagnosis includes basically either schizophrenia or affective disorder. The epidemiological status of schizoaffective disorder is somewhat uncertain compared with schizophrenia because of dilemmas related to diagnosis and classification of the disorder. Treatment of schizoaffective disorder comprises psychotropic medication, supportive psychotherapy, social care, rehabilitation. The most important groups of psychotropic medications are: antipsychotics, antidepressants and mood stabilizers. Atypical antipsychotics are the first-line medication for schizoaffective disorder due to their pharmacological properties. In the case of schizoaffective disorders combination of atypical antipsychotics with antidepressants seems to be useful. Novel antidepressants have priority for the combination mentioned above. Peculiarities of mechanism of action of antidepressant are important for combinations. Mood stabilizers seem to be useful for treatment of certain type of schizoaffective disorder as well.

Increasing numbers of articles on adverse drug reactions are published in a wide range of medical journals. To help keep you up-to-date with the latest advances worldwide on all aspects of adverse drug reactions, this section of the journal brings you information selected from the drug safety alerting service Reactions Weekly. The following reports are selected from the latest issues, summarizing the most important clinical studies, adverse reaction news, and expert opinion pieces published across a broad range of literature sources.

Psychopharmacology research aims to expand the therapeutic ratio between efficacy, on the one hand, and adverse events and safety, on the other. The novel antipsychotics are now the antipsychotics of choice in the treatment of bipolar disorders. They have the advantages of potential antidepressant properties and low risks of extrapyramidal side effects and, especially, of tardive dyskinesia. However, novel antipsychotics may also have varying propensities to cause side effects, such as somnolence, hyperprolactinemia, weight gain (sometimes significant), and possibly diabetes mellitus. The increasing use of these novel agents requires careful assessment and monitoring of emergent side effects and diligent consideration of associated medical complications. Two new anticonvulsants, lamotrigine and topiramate, have recently shown promise in the treatment of bipolar disorders. Most of their adverse effects can be avoided by slow titration toward the recommended doses. In contrast to carbamazepine and valproic acid, topiramate may be associated with weight loss.

Study Objectives: To compare the effects of risperidone and olanzapine on cognition in elderly patients with dementia and psychosis, and to compare the side effects of these drugs., Design: Single-blind, multicenter, observational study., Setting: Four rural nursing care facilities., Patients: Nineteen elderly patients with dementia and psychosis., Intervention: Eleven patients were treated with risperidone, eight with olanzapine., Measurements and Main Results: Rating assessments were completed at baseline, 1 month, and 2 months. Simple paired and unpaired t tests determined between- and within-group differences. Social functioning, including activities of daily living, improved over baseline in both groups (p=0.03). Cognition declined significantly (p<0.05) in the risperidone group; comparatively more side effects occurred and blood pressure decreased (p<0.05) in the olanzapine group. When compared with each group cross-sectionally at baseline and end point, however, the two groups did not differ significantly., Conclusion: Improvements in social functioning in all 19 patients suggest that both risperidone and olanzapine may help improve functioning in elderly patients with dementia and psychosis. Cognitive and side effect profiles of these drugs may differ substantially. Further study is needed to determine patient subpopulations who may be able to tolerate one drug over another.

Most research literature concerning pharmacological treatments reports results from controlled clinical trials, which provide data critical to assess the efficacy of new treatments in research populations. Fewer studies examine how treatments are adopted in everyday practice settings, where comorbid disorders and environmental issues typically complicate patients' situations. In this study, we examine the evolution of antipsychotic prescribing practices in the New York region of the Veterans Healthcare Administration (VHA) from 1998 to 2000 using administrative data. Second generation antipsychotic medications are now prescribed more frequently than the older antipsychotic medications, with a concomitant increase in cost. Data show low rates of clozapine use, relatively high rates of polypharmacy, and intersite variation in prescribing practices. Additional research in everyday practice settings is needed to address clinical questions unlikely to be answered through traditional efficacy research and to examine reasons for intersite differences in prescribing patterns.

Selective dopamine D(2) antogonists increase meal size and decrease the rate of feeding within a meal. Three experiments investigated the extent to which the atypical antipsychotics, clozapine and olanzapine, and the prototypical antipsychotic, haloperidol, affected meal size and feeding rate. Microstructural analyses of meal patterning were made over a range of drug doses administered to free feeding male Lister hooded rats. Haloperidol and clozapine produced a short-term increase in food intake. Haloperidol (0.05-0.2 mg/kg) enhanced meal size (maximal at 0.1 mg/kg) and reduced feeding rate (monotonic decrease with increasing dose). Neither clozapine (1-10 mg/kg) nor olanzapine (0.3-3 mg/kg) enhanced meal size, although both drugs produced similar reductions in feeding rate to haloperidol. These data suggest that enhancement of meal size may be correlated with a high level of extrapyramidal side effects in an antipsychotic drug. The absence of an increase in meal size by two atypical compounds suggests that the increase in body weight associated with clinical treatment with these drugs cannot be modelled by acute stimulation of meal size in the rat.

Background: Antipsychotic medication causes a wide range of predictable adverse effects, and has long been associated with sudden unexplained and unexpected death in psychiatric patients, despite controversies surrounding the issue. In light of the evidence that sudden cardiovascular-related death is associated with neuroleptic medication, we are especially interested in examining whether measurements of the power spectral analysis (PSA) of heart rate variability (HRV) are differentially affected by various antipsychotic medications. We will also examine the cases in which PAS provides information regarding the relative safety of the various groups of drugs under investigation, in terms of their influence on the sympathetic-parasympathetic balance., Aim: The primary aim of this study is to utilize spectral analysis of heart rate variability as a tool to examine the differential arythmogenic effects of antipsychotic medications. The secondary aim was to examine the QT interval in schizophrenic patients receiving this treatment., Method: Standardized heart rate analysis was carried out in twenty-one schizophrenic patients receiving monotherapy with the following medications: treatment with 300-700 mg/day of clozapine, eighteen schizophrenic patients treated with 5-10 mg/day haloperidol, seventeen schizophrenic patients treated with 5-20 mg/day Olanzapine, and 53 healthy subjects., Results: Our results show that schizophrenic patients treated with clozapine had significantly higher HR, lower HRV, lower high frequency (HF) and higher low frequency (LF) components compared to the patients treated with haloperidol, olanzapine, and the matched control subjects. Prolonged QTc intervals were more common in patients receiving treatment than in the control group, although the PR and QRS intervals did not differ significantly., Conclusions: The overall results showed that, patients treated with neuroleptic medication, especially clozapine, presented autonomic dysregulation and cardiac repolarization changes. Care should be taken in prescribing clozapine to patients prone to cardiovascular side effects.

Objective: The objective of this analysis was to compare the treatment-emergent central anticholinergic-like adverse events experienced during treatment with olanzapine versus placebo in patients with psychosis and/or agitation due to Alzheimer's disease (AD). In addition, changes in cognition were assessed in a subgroup of patients with mild to moderate cognitive impairment., Methods: Double-blind data were compared for placebo and three fixed olanzapine dosages (5 mg/day, 10 mg/day, and 15 mg/day) in 206 nursing home-residing patients with AD for five a priori selected central nervous system anticholinergic-like adverse events: confusion, delirium, delusions, hallucinations, abnormal thinking. Mean change from baseline to endpoint on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) was measured for a subgroup of 43 patients who had mild to moderate cognitive impairment at baseline., Results: There were no significant differences in central anticholinergic-like adverse events at any olanzapine dose compared to placebo. Additionally, in the 43-patient subgroup, there were no significant differences in mean change in ADAS-Cog scores between placebo and the three olanzapine dose subgroups., Conclusion: Olanzapine did not differ significantly from placebo for any of the five central nervous system anticholinergic events nor on the ADAS-Cog. Olanzapine's initially reported potent in vitro muscarinic receptor affinity is not consistent with this clinical study of central nervous system anticholinergic-like adverse events in patients with AD., (Copyright 2001 John Wiley & Sons, Ltd.)

The number of elderly persons with psychosis will increase with the increasing geriatric population. Olanzapine is one of the newer atypical antipsychotics with efficacy for positive and negative symptoms and safer side effect profile compared to conventional antipsychotics. The manuscript describes the pharmacology, efficacy and tolerability studies, adverse effects and dosing considerations in the elderly. Further studies are needed to fully assess the efficacy and safety of olanzapine in the elderly. Current research supports a role for olanzapine in treating elderly patients with schizophrenia, schizoaffective disorder and behavioral and psychological symptoms of dementia.

Olanzapine is an 'atypical' antipsychotic indicated for the treatment of schizophrenia. We analysed adverse events (AEs) reported in primary practice in England. Dispensed prescriptions issued between December 1996 and May 1998 provided exposure data. Questionnaires sent to general practitioners provided outcomes. Frequently reported AEs were: drowsiness/sedation (n = 19), extrapyramidal disorder (n = 13) and unspecified side-effects (n = 33). Events with highest incidence density in first month and reason for stopping were: drowsiness/sedation [n = 153, incidence density (ID)1 18.9], weight gain (n = 117, ID1 8.9) and malaise/lassitude (n = 65, ID1 5.2). Extrapyramidal disorders were more common in elderly population (> 70 years, ID1 3.6, risk 26.0 per 1,000 patients) compared to < 70 years (ID1 1.1, risk 8.4 per 1,000 patients). Serious suspected adverse reactions were neuroleptic malignant syndrome (n = 1) and angioneurotic ooedema (n = 2). There were eight reports of diabetes mellitus assessed as possibly due to olanzapine. Diabetes mellitus was an unlabelled AE and possible signal generated by prescription-event monitoring.

Background: Psychotic symptoms and behavioral disturbances are a leading cause of institutionalization in elderly patients with Alzheimer's disease (AD)., Objectives: Elderly nursing home patients (n=105) with possible or probable AD were entered into a multicenter study to determine the long-term efficacy and safety of olanzapine in treatment of psychotic symptoms and behavioral disturbances due to AD., Methods: Following a double-blind, 6-week exposure to fixed-dose olanzapine (5, 10, or 15 mg/d), patients entered an additional 18-week, open-label, flexible-dose treatment. Baseline was defined from the start of the extension phase., Results: Patients improved significantly on the primary efficacy measure, defined a priori, which consisted of the sum of the Agitation/Aggression, Delusions, and Hallucinations items ('Core':) of the NPI/NH. Olanzapine also significantly improved scores for the NPI/NH total and the Core item-associated Occupational Disruptiveness of the NPI/NH, as well as the BPRS total and CGI Severity-of-Alzheimer's scores. Barnes Akathasia scores improved significantly from baseline, while Simpson-Angus and AIMS scores were not significantly changed. Treatment-emergent symptoms included somnolence, accidental injury, and rash. No significant changes were seen in ECGs, including QT(c) interval, nor in weight or vital signs, including orthostasis., Conclusions: Low-dose olanzapine appears to be effective and well tolerated for treatment of behavioral disturbances and psychotic symptoms due to AD in elderly patients., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: To report the case of a patient taking olanzapine who developed diabetic ketoacidosis (DKA)., Case Summary: A 46-year-old African American woman with no previous history of diabetes mellitus was admitted to the hospital and subsequently diagnosed with DKA and acute pancreatitis. The patient had been taking olanzapine, valproic acid, carbamazepine, hydrochlorothiazide/triamterene, and conjugated estrogens prior to admission. Olanzapine was the last medication added to the regimen. In addition to clinicians treating the DKA with appropriate interventions, olanzapine (due to possible association with hyperglycemia and DKA) as well as valproic acid (due to possible association with pancreatitis) were discontinued from the medication regimen. The patient was discharged home and her most recent glycosylated hemoglobin and fasting glucose concentrations have been within the normal range., Discussion: Atypical antipsychotics, such as olanzapine, have been associated with hyperglycemia and possibly DKA. We believe that this occurred in our patient who had no previous history of diabetes mellitus. Possible mechanisms of action and potential confounding variables are discussed., Conclusions: Clinicians should monitor blood glucose concentrations periodically in patients taking olanzapine, especially in those patients with risk factors for diabetes mellitus.

Objective: To compare the risk of extrapyramidal syndrome (EPS) between risperidone, olanzapine, and haloperidol, taking into account patients' past antipsychotic drug use and past EPS., Methods: Data were obtained from the PHARMO-database, containing filled prescriptions of 450,000 community-dwelling people in the Netherlands from 1986 through 1999. We defined cohorts of first-time users of haloperidol, risperidone, or olanzapine aged 15 to 54 years. In the first 90 days of treatment, we assessed the occurrence of EPS, defined as first use of any antiparkinsonian agent. We estimated relative risks of EPS for risperidone and olanzapine versus haloperidol using a Cox proportional hazards model. Patients were subdivided according to prior use of antipsychotic and antiparkinsonian drugs., Results: We identified 424 patients starting treatment with haloperidol, 243 with risperidone, and 181 with olanzapine. Prior use of antipsychotic plus antiparkinsonian medication was significantly more frequent among users of risperidone and olanzapine than in those using haloperidol (36.2%, 40.3%, and 4.5%, respectively; p < 0.001). Within most subgroups of comparable treatment history, patients using risperidone and olanzapine showed reduced risks of EPS compared with haloperidol, although some of these findings did not reach statistical significance (RR 0.03-0.22). However, this was not observed for patients using risperidone who had experienced EPS in the past (RR 1.30; 95% CI 0.24 to 7.18)., Conclusions: In general, we observed reduced risks of EPS for risperidone and olanzapine compared with haloperidol within subgroups of patients with a similar treatment history. However, the added value of risperidone in patients who have experienced EPS in the past needs further study.

Background: Alzheimer's disease (AD) is associated with both cognitive and behavioral symptoms. Agitation, hallucinations, delusions, aggression, irritability, and anxiety are observed in up to 90% of patients with dementia. Although new information has emerged in recent years on the treatment of psychosis and agitation in dementia, very little information is available about the treatment of anxiety symptoms in this population., Objectives: To assess the efficacy and tolerability of olanzapine in the treatment of significant anxiety symptoms in patients with AD., Methods: A post hoc analysis of a previously published study was performed. Those post hoc analysis evaluated the response to treatment with olanzapine of a subgroup of AD patients presenting with significant symptoms of anxiety. Patients were considered to have significant symptoms of anxiety if their baseline in the Nursing home version of the Neuropsychiatric Instrument NPI/NH anxiety scores were > or = 2. The analysis included 120 patients., Results: Patients receiving olanzapine 5 mg/d were statistically significantly improved on the NPI/NH Anxiety item compared to those receiving placebo (olanzapine, 5 mg/d: -3.72; placebo: -1.67; p = 0.034). In the group of patients with clinically significant anxiety, somnolence was the only treatment-emergent event that was statistically different in any olanzapine treatment group compared with placebo (olanzapine 5 mg/d: 9 patients [25%], p = 0.034; 10 mg/d: 7 [23%], p = 0.054; 15 mg/d: 7 [26%], p = 0.050; placebo: 1 [3.7%]). When controlling for treatment-emergent somnolence, the improvement in anxiety in the olanzapine 5 mg/d group remained statistically significant (p = 0.049)., Conclusions: These findings suggest that olanzapine could be a safe and effective treatment for anxiety in Alzheimer's disease., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapine's mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available., Method: Preclinical and clinical studies of OLZ are reviewed, with emphasis on its possible effects on the cholinergic system and the histamine H(1) receptor. Weight change and related metabolic considerations, cardiac and cardiovascular safety, and motor function during treatment with OLZ are also reviewed., Results and Conclusion: In vitro receptor characterization methods, when done using physiologically relevant conditions allow accurate prediction of the relatively low rate of anticholinergic-like adverse events, extrapyramidal symptoms, and cardiovascular adverse events during treatment with OLZ. Currently available clinical data suggest olanzapine is predictably safe in treating adult patients of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some types of neurodegenerative disorders., (Copyright 2001 John Wiley & Sons, Ltd.)

Background: Typical antipsychotics are commonly used in combination with mood stabilizers for acute mania. Although typical antipsychotics are effective, they have undesirable side effects such as induction of depressive symptoms and tardive dyskinesia. Atypical antipsychotics have more favorable side effect profiles, and recent evidence shows their efficacy in treating mania. Apart from a previous small study that compared risperidone with typical neuroleptics as add-on therapy to mood stabilizers, no studies to date have directly compared atypical antipsychotics with typical antipsychotics as add-on therapy to mood stabilizers in a clinically relevant, naturalistic setting., Method: This study is a chart review of all patients with DSM-IV-defined bipolar disorder, current episode mania (N = 204), admitted to the University of British Columbia Hospital during a 30-month period. Patients were separated into 3 groups according to the medications used: (1) mood stabilizer and typical antipsychotic, (2) mood stabilizer and atypical antipsychotic, and (3) combination: mood stabilizer plus a typical antipsychotic, then switched to mood stabilizer plus risperidone or olanzapine within I week. The atypical group was further subdivided into risperidone and olanzapine subgroups. Outcome was measured using Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) ratings generated by review of clinical information in the chart., Results: Patients treated with typical antipsychotics were more severely ill at admission and at discharge than those treated with atypical antipsychotics. Patients in the atypical (p < .005) and combination (p < .05) groups showed significantly greater clinical improvement at discharge than patients treated with typical antipsychotics. This difference was also significant in the subset of patients with psychotic features (p < .03). Risperidone and olanzapine were associated with fewer extrapyramidal side effects than were typical antipsychotics (risperidone vs. typical antipsychotics, chi2 = 8.72, p < .01; olanzapine vs. typical antipsychotics, chi2 = 16.9, p < .001)., Conclusion: Due to their superior effectiveness and side effect profile when compared with typical antipsychotics. atypical antipsychotics are an excellent choice as add-on therapy to mood stabilizers for the treatment of patients with mania.