olanzapine and Drug-Related-Side-Effects-and-Adverse-Reactions

Bipolar depression constitutes a major public health problem due to its substantial burden of disease. Although pharmacological interventions are available, guidelines required updated evidence synthesis to improve their current recommendations. In order to inform evidence-based prescribing, we investigated the comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression.. We conducted a systematic review and network meta-analysis. We searched for randomised controlled trials comparing pharmacological interventions with each other or placebo in adults with acute bipolar depression (type I, type II, or not otherwise specified), excluding those with substance misuse, unipolar depression, or schizophrenia, in MEDLINE, Embase, PsycINFO, Google Scholar, Cochrane Library, Web of Knowledge, CINAHL, and LILACS from database inception up to April 13, 2023. Criteria for eligibility were a duration of 2-16 weeks with masked outcome assessments, and we included combination, add-on design, and monotherapy studies. The co-primary outcomes were depressive symptoms, examined with standardised mean differences (SMDs), and manic switch, examined with odds ratios (ORs). We also investigated dropouts due to any reason, inefficacy, adverse events, and important side-effects as secondary outcomes. The confidence in the evidence was evaluated using Confidence-In-Network-Meta-Analysis (CINeMA). The study was registered with PROSPERO, CRD42020171726.. We analysed data from 101 randomised controlled trials covering 20 081 participants, 8063 men (41·7%) and 11 263 women (58·3%; sex not available in four studies), mean age 41·0 years (range of means 28·7-53·6 years), and 68 medications and placebo. Ethnicity data were not available. With moderate confidence in the evidence, olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were more efficacious than placebo in reducing depressive symptoms, with SMDs ranging from 0·41 (95% CI 0·19-0·64) for olanzapine plus fluoxetine to 0·16 (0·03-0·29) for lamotrigine. Several other drugs might also be efficacious, but the confidence in the evidence was very low to low. Antidepressants as a class seem to be efficacious, but had a higher risk for manic switch compared to antipsychotics. Medications differed in their side-effect profiles.. This is, to our knowledge, the largest network meta-analysis of pharmacotherapy for bipolar depression to date. Olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were found to be more efficacious than placebo in adults with acute bipolar depression, with good confidence in the evidence, and to differ in their side-effect profiles. These findings can inform evidence-based care and the development of treatment guidelines internationally.. None.

Topics: Adult; Bipolar Disorder; Depression; Drug-Related Side Effects and Adverse Reactions; Female; Fluoxetine; Humans; Lamotrigine; Lurasidone Hydrochloride; Male; Middle Aged; Network Meta-Analysis; Olanzapine; Quetiapine Fumarate

A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions.. A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression.. Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences.. The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported.

Topics: Adult; Aged; Antipsychotic Agents; Body Mass Index; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Observational Studies as Topic; Olanzapine; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Weight Gain

Switching between different antipsychotic therapies is a frequent occurrence in the management of patients with schizophrenia and other psychotic disorders. This paper provides a review of the principles of antipsychotic switching and discusses pharmacological principles underlying adverse events that occur while switching olanzapine to another antipsychotic medication. It offers suggestions for management of switch-associated adverse events in clinical settings.. Few publications explore olanzapine switch-related adverse events, the underlying pharmacological principles and appropriate switching strategies to minimise the risk of adverse events. There is still a need for further studies to verify existing knowledge and assist in the development of 'gold standard' guidelines that outline appropriate switching strategies and duration of the switching process to reduce and avoid adverse events.

Topics: Antipsychotic Agents; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Humans; Olanzapine; Psychotic Disorders; Schizophrenia

The aim of the present study was to evaluate the efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV).. The literature was searched for randomized controlled trials (RCTs) evaluating the efficacy of olanzapine for the prophylaxis of CINV using PubMed, Embase, Central, as well as clinicaltrials.gov for unpublished studies. The endpoints of the study were the number of patients who achieved a complete response (CR; no emesis and no rescue) and no nausea in the acute, delayed and overall phases. Two authors independently selected studies, assessed the risk of bias and extracted data. The included RCTs were analysed using RevMan 5.3 provided by the Cochrane Collaboration.. Ten RCTs were identified for the meta-analysis. Compared with other antiemetic agents, olanzapine significantly improved the CR in the delayed and overall phases, but did not enhance the CR in the acute phase. For the control of CINV, olanzapine was better than and comparable with aprepitant in the acute phase and delayed phase, respectively. Compared with placebo, treatment with 5 mg and 10 mg olanzapine exhibited similar efficacy in terms of the CR in the delayed and overall phases.. Olanzapine is an excellent alternative for the prophylaxis of CINV. Olanzapine 5 mg per day should be recommended as the initial dose because of equivalent efficacy to a 10 mg dose but a lower potential risk of side effects. Further studies are needed to explore the optimal combination of medicines.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Benzodiazepines; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Morpholines; Nausea; Neoplasms; Olanzapine; Randomized Controlled Trials as Topic; Treatment Outcome; Vomiting

Patients exposed to second-generation antipsychotics (SGAs) have approximately 10 times increased risk of diabetic ketoacidosis (DKA) compared with the general population. However, as DKA is a rare complication of type 2 diabetes mellitus, and susceptible patients exposed to antipsychotics may rapidly develop DKA independently of treatment duration and weight gain, this is rather suggestive of type 1 diabetes mellitus (T1DM) or latent autoimmune diabetes in adults.. We performed a systematic review of current studies regarding antipsychotic-associated DKA with type 1 etiology and analyzed Danish adverse drug event (ADE) reports (previously unpublished cases).. PubMed, Embase, and the Cochrane Library were searched for all relevant studies, and the Danish Medicines Agency retrieved ADE reports using the Danish ADE database (up to date as of June 28, 2016). Diagnosis of antipsychotic-associated DKA with type 1 etiology was either considered confirmed or possible depending on authors' conclusions in the studies and/or clinical aspects. In addition, clinico-demographic risk factors were extracted.. A total of 655 records and 11 ADE reports were identified, and after screening for eligibility, we included 21 case reports/series and two ADE reports (n = 24). No relevant clinical studies were included. Although fatal cases were identified, these were excluded because of diagnostic uncertainties (n = 15). DKA occurred in 15 males (62.5 %) and nine females (37.5 %), with a mean age ± standard deviation of 34.8 ± 12.4 years. Median time to DKA was 5 months (interquartile range: 1.4-11 months). Associated antipsychotics were olanzapine (n = 9, 36 %), aripiprazole (n = 6, 24 %), risperidone (n = 6, 24 %), clozapine (n = 3, 12 %), and quetiapine (n = 1, 4 %). Nine patients (37.5 %) were confirmedly diagnosed with T1DM following DKA resolution, whereas 15 patients (62.5 %) had possible T1DM. In 22 patients (91.7 %), ongoing insulin treatment was required for glycemic control.. Increased awareness of the potential risk of antipsychotic-associated DKA and subsequent T1DM diagnosis, with insulin requirements for glycemic control, is warranted. The underlying mechanisms are poorly understood but most probably multifactorial. Certainly, further studies are warranted. Clinicians must utilize appropriate monitoring in susceptible patients and consider the possibility of continuing antipsychotic treatment with appropriate diabetic care.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Denmark; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Olanzapine; Risk Factors; Risperidone; Young Adult

Olanzapine is an atypical antipsychotic agent of the thiobenzodiazepine class. It blocks multiple neurotransmitter receptors including dopaminergic at D1, D2, D3, D4 brain receptors, serotonergic at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors. Olanzapine has five times the affinity for 5-HT2 receptors than D2 receptors and has been used to treat schizophrenia and delirium. Olanzapine's activity at multiple receptors, particularly at the D2, 5-HT2c, and 5-HT3 receptors which appear to be involved in nausea and emesis, has prompted its use in the treatment of nausea and vomiting refractory to standard antiemetics. Case reports and formal clinical trials have demonstrated its efficacy in the treatment of chronic nausea, the prevention of chemotherapy-induced nausea and emesis, and the treatment of breakthrough chemotherapy-induced nausea and emesis. Phase II and phase III clinical trials have demonstrated that there is a significant improvement in nausea when olanzapine is added to guideline directed prophylactic antiemetic agents 5-HT3 receptor antagonists and tachykinin NK1 receptor antagonists in patients receiving moderately or highly emetogenic chemotherapy Common side effects of olanzapine when used over a period of months include weight gain as well as an association with the onset of diabetes mellitus, but these effects have not been seen with short term use of daily doses of less than one week.

Topics: Animals; Benzodiazepines; Chronic Disease; Drug-Related Side Effects and Adverse Reactions; Humans; Nausea; Olanzapine; Vomiting

The anticonvulsant valproic acid and the atypical antipsychotics olanzapine and quetiapine provide synergistic mood-stabilising, antidepressant and antipsychotic activities in the treatment of bipolar and schizoaffective disorders. Existing literature shows that pharmacokinetic and pharmacodynamics drug-drug interactions (DDIs) possibly occur with the use of such a combination. Clinical reports of a possible interaction between the drugs leading to an increased risk of adverse drug reactions have also emerged. The main objective of this paper is to review the incidence of DDIs between the anticonvulsant and the antipsychotics, to postulate the possible mechanisms of the interaction and to establish whether certain target populations are at an increased susceptibility to such interactions. The usefulness of therapeutic drug monitoring (TDM) of the antipsychotics to monitor for an interaction was also assessed. A systematic database search was carried out using the search engine provided by PubMed using the following key words: olanzapine, quetiapine, valproic acid, pharmacokinetic drug-drug interaction, bipolar disorder, therapeutic drug monitoring.. Evidence of a possible clinically relevant DDI between valproic acid and both antipsychotics has been uncovered. A possible mechanism for the interactions has been postulated, and the importance of TDM has been discussed.. Further research is required to determine whether DDIs occur with the concurrent use of valproic acid and olanzapine or quetiapine, and to investigate the potential of TDM as a clinical tool in improving pharmacotherapy and preventing toxicity.

Topics: Anticonvulsants; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dibenzothiazepines; Drug Interactions; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Olanzapine; Quetiapine Fumarate; Valproic Acid

Treatment resistance is frequently encountered during the long-term care of patients with major depression. A number of 'next step' therapeutic options exist in such cases, including switching to an alternative antidepressant, combining antidepressants from different pharmacological classes, adding evidence-supported psychotherapies to ongoing antidepressant treatment and augmentation with a nonantidepressant drug. Augmenting antidepressants with atypical antipsychotic drugs has generated considerable clinical interest. Three atypical antipsychotics (aripiprazole, quetiapine and olanzapine) have received regulatory approval for adjunctive use with antidepressants for treatment-resistant major depression (TRD) in adults. Symbyax (olanzapine-fluoxetine combination or OFC), the combination of olanzapine and the selective serotonin-reuptake inhibitor fluoxetine, is also approved for this indication. The short-term effectiveness of OFC for TRD is supported by results of five published randomized, controlled, acute-phase studies of generally similar design. In each study, OFC was associated with rapid reduction in depressive symptoms. In two studies, significantly greater improvement in depressive symptoms occurred in OFC-treated patients at study end point compared with those who received antidepressant monotherapy. These effects appeared to be strongest in cases where antidepressant failure was established during the current depressive episode. Although OFC was well-tolerated, increases in body weight and prolactin concentration were greater with OFC than antidepressant monotherapy, and were similar to olanzapine monotherapy. Increases in random total cholesterol levels were greatest for OFC, and were significantly greater than those of olanzapine and antidepressant monotherapy. The long-term efficacy and tolerability of OFC for TRD has not been investigated, and the comparative effectiveness of OFC versus other next-step options is unknown. As such, the exact place of OFC among the available therapeutic options for TRD is not fully understood at this time.

Topics: Adult; Age Factors; Antidepressive Agents; Benzodiazepines; Depression; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Fluoxetine; Humans; Kidney Diseases; Liver Diseases; Olanzapine; Randomized Controlled Trials as Topic

An advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI.. Safety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors.. Based on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified.. Post-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period.. ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Cognition Disorders; Delayed-Action Preparations; Delirium; Drug Administration Schedule; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Injections, Intramuscular; Olanzapine; Risk Factors; Schizophrenia; Sleep; Syndrome; Treatment Outcome

To examine potential differences in efficacy and safety of treatment with olanzapine in patients with schizophrenia of white and black descent.. A post-hoc, pooled analysis of 6 randomized, double-blind trials in the treatment of schizophrenia, schizophreniform disorder, or schizoaffective disorder compared white (N = 605) and black (N = 375) patients treated with olanzapine (5 to 20 mg/day) for 24 to 28 weeks. Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) total score; and positive, negative, and general psychopathology scores; and the Clinical Global Impression of Severity (CGI-S) scores at 6 months. Safety measures included differences in the frequencies of adverse events along with measures of extrapyramidal symptoms, weight, glucose, and lipid changes over time.. 51% of black patients and 45% of white patients experienced early study discontinuation (P = .133). Of those who discontinued, significantly more white patients experienced psychiatric worsening (P = .002) while significantly more black patients discontinued for reasons other than efficacy or tolerability (P = .014). Discontinuation for intolerability was not different between groups (P = .320). For the estimated change in PANSS total score over 6 months, there was no significant difference in efficacy between white and black patients (P = .928), nor on the estimated PANSS positive (P = .435), negative (P = .756) or general psychopathology (P = .165) scores. Overall, there was no significant difference in the change in CGI-S score between groups from baseline to endpoint (P = .979). Weight change was not significantly different in white and black patients over 6 months (P = .127). However, mean weight change was significantly greater in black versus white patients at Weeks 12 and 20 only (P = .028 and P = .026, respectively). Additionally, a significantly greater percentage of black patients experienced clinically significant weight gain (≥ 7%) at anytime compared to white patients (36.1% vs. 30.4%, P = .021). Changes across metabolic parameters (combined fasting and random lipids and glucose) were also not significantly different between groups, with the exception of a greater categorical change in total cholesterol from borderline to high among white subjects and a categorical change from normal to low in high density lipoprotein (HDL) cholesterol among white males.. The findings did not demonstrate overall substantive differences in efficacy or safety between white and black patients diagnosed with schizophrenia or related disorders treated with olanzapine. However, a significantly greater percentage of black patients (36.1%) experienced clinically significant weight gain compared to white patients (30.4%).

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Black or African American; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Obesity; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; Weight Gain; White People

To explore efficacy of short-course olanzapine with or without low-dose dexamethasone for prevention of delayed emesis in gynecologic cancer patients receiving carboplatin/paclitaxel.. This was a prospective study in 81 chemo-naive patients receiving 0.25 mg intravenous palonosetron, 16 mg dexamethasone, and 10 mg oral olanzapine before chemotherapy. On days 2 and 3, patients randomly received 10 mg olanzapine (arm A; n=27), 10 mg olanzapine plus 4 mg dexamethasone (arm B; n=27), or 8 mg dexamethasone (reference arm C; n=27). The primary endpoint was total control (TC; no vomiting, no rescue antiemetics, and no nausea) on days 2-5, using a diary. Secondary endpoints included proportion of patients with no emesis impact on daily life using the Functional Living Index-Emesis (FLIE) questionnaire, and patient's satisfaction with antiemetic coverage.. Fifty-two percent of patients in arm A (. In this exploratory study with a small sample size, we did not find any clue about better control of delayed emesis with either olanzapine regimen in gynecologic cancer patients treated with carboplatin/paclitaxel and receiving the same prophylaxis for acute emesis.

Topics: Adult; Aged; Carboplatin; Dexamethasone; Drug-Related Side Effects and Adverse Reactions; Female; Genital Neoplasms, Female; Humans; Italy; Middle Aged; Nausea; Olanzapine; Paclitaxel; Palonosetron; Surveys and Questionnaires; Vomiting

Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths.. To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity.. This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017.. Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49).. Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers.. The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments.. Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths.. ClinicalTrials.gov identifier: NCT00205699.

Topics: Abdominal Fat; Absorptiometry, Photon; Adolescent; Antipsychotic Agents; Aripiprazole; Child; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Insulin Resistance; Intention to Treat Analysis; Male; Mental Disorders; Olanzapine; Problem Behavior; Risperidone; Treatment Outcome

The primary aim of this study was to compare the effectiveness of olanzapine, palonosetron and ondansetron infusion (standard of care) for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients undergoing hematopoietic stem cell transplantation (HSCT).. It was a randomized open-label prospective study. Sixty-two patients were randomized to receive either ondansetron 32-mg infusion over 24 h, or olanzapine wafer 10 mg once daily in addition to ondansetron 8 mg IV three times a day or a single dose of palonosetron 0.25 mg IV instead of ondansetron. All groups were allowed rescue antiemetics. The primary endpoint was a composite outcome of no emesis, no use of rescue medication, and nausea score reduction of ≥50 %. The secondary endpoint was nausea score reduction of ≥50 %. Both endpoints were measured at 24 and 48 h after initiation of the study treatment. Statistical analysis was conducted using a double-sided Fisher's exact test.. The primary endpoint was achieved in 6, 45, and 18 %, and 6, 64, and 18 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. The secondary outcome was observed in 17, 60, and 62 %, and 35, 71, and 43 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. Serious adverse drug reactions were not reported in any arms. Time to engraftment was not significantly different between the arms.. Olanzapine was an effective treatment of breakthrough CINV. A single dose of palonosetron significantly reduced nausea up to 24 h.

Topics: Adolescent; Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Hematopoietic Stem Cell Transplantation; Humans; Isoquinolines; Male; Middle Aged; Nausea; Olanzapine; Ondansetron; Palonosetron; Prospective Studies; Quinuclidines; Transplantation Conditioning; Treatment Outcome; Vomiting; Young Adult

Clinical trials with healthy volunteers are a useful model for evaluating safety and tolerability, without the interference of concomitant diseases and drugs. The present study aims to improve our understanding of antipsychotic-related adverse reactions (ARs) and their possible association with common genetic variants of pharmacodynamic proteins such as neurotransmitter receptors/transporters.. A total of eight polymorphisms located in seven pharmacodynamic-related genes (SCL6A4, MDR1, 5HT2A, DRD2, DRD3, COMT and GRIN2B) were genotyped in a cohort of 211 healthy volunteers who received a single dose of risperidone (1 mg), olanzapine (5 mg) or quetiapine (25 mg).. Interestingly, a significant association was found between the incidence of neurological ARs and specific polymorphisms in key genes (DRD2 and SCL6A4).. Genetic variants in pharmacodynamic genes could represent valuable markers of AR risk and antipsychotic safety. Original submitted 7 February 2013; Revision submitted 3 June 2013.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers, Pharmacological; Dibenzothiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Healthy Volunteers; Humans; Huntingtin Protein; Male; Nerve Tissue Proteins; Olanzapine; Quetiapine Fumarate; Receptors, Dopamine D2; Risperidone

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60.

Topics: Antipsychotic Agents; Bayes Theorem; Benzodiazepines; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Dystonia; Haloperidol; Humans; Monte Carlo Method; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Research Design; Retrospective Studies; Sample Size; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Treatment Outcome

Topics: Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Italy; Olanzapine; Pharmacovigilance

Atypical neuroleptics such as olanzapine are indicated for the treatment of various psychiatric disorders and have been used in the palliative care setting also for several clinical indications. Peripheral and facial edema are a rare side effect of the treatment with olanzapine. We report a case of an advanced cancer patient cared receiving palliative care who developed severe facial edema after initiating a low dose of olanzapine in monotherapy.. A patient with advanced cancer who presented with severe facial edema after initiating olanzapine for the treatment of her opioid use disorder.. After excluding other differential diagnosis for facial edema, olanzapine was discontinued with complete resolution of the edema.. To the best of our knowledge, this is the first case reporting facial edema due to olanzapine treatment in a patient with advanced cancer. Our report will help clinicians recognize the possible role of olanzapine in cases of rapid onset of facial edema, allowing its rapid resolution.

Topics: Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Edema; Female; Humans; Neoplasms; Olanzapine; Palliative Care

Retrospective studies using spontaneous reporting system databases have provided a great understanding of adverse drug reactions (ADRs) in the real world, complementing the data obtained from randomized controlled trials. However, there have been few reports on large-scale epidemiological studies on the adverse effects of antipsychotics in Asia.. This study aimed to investigate the characteristics of antipsychotic ADRs using a nationwide pharmacovigilance database.. Data were collected from the Korea Adverse Event Reporting System database between 2010 and 2019. The study subjects were selected using the International Classification of Disease codes for diseases related to psychosis and Electronic Data Interchange codes for amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. The causality assessment of "possible," "probable," or "certain" by the World Health Organization-Uppsala Monitoring Center System causality category was selected. All data were descriptively analyzed.. In total, 5067 adverse events associated with antipsychotic drugs were reported. The antipsychotics that commonly resulted in ADRs were quetiapine (47.7%), olanzapine (11.3%), and clozapine (10.7%). Serious ADRs were most commonly observed with clozapine. Gastrointestinal and central nervous system problems occurred within a month when ADRs were classified according to the time of onset. In contrast, metabolic and bone marrow-related symptoms occurred after long-term use. Sedation and nausea were the most common ADRs in children and adolescents, whereas constipation and dizziness were common in adults and the elderly.. This study extends our knowledge of antipsychotic ADRs in the Asian population.

Topics: Adolescent; Adult; Aged; Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Clozapine; Drug-Related Side Effects and Adverse Reactions; Haloperidol; Humans; Olanzapine; Paliperidone Palmitate; Quetiapine Fumarate; Retrospective Studies; Risperidone; Schizophrenia

Polypharmacy increases the risk of potential drug-drug interactions (pDDIs). This retrospective analysis was conducted to detect pDDIs and adverse drug reactions (ADRs) among older adults with psychiatric disorder, and identify pDDIs with clinical significance.. A retrospective analysis was carried out based on the medical records of older adults with psychiatric disorders. Data on demographic characteristics, substance abuse, medical history, and medications were extracted. The Lexi-Interact online database was used to detect pDDIs. The minimal clinically important difference (MCID) was set as the change in the Treatment Emergent Symptom Scale (TESS) score between admission and discharge. The median and interquartile ranges were used for continuous variables, and frequencies were calculated for dichotomous variables. Poisson regression was implemented to determine the factors influencing the number of ADR types. The influencing factors of each ADR and the clinical significance of the severity of the ADR were analysed using binary logistic regression. P < 0.05 was considered statistically significant.. A total of 308 older adults were enrolled, 171 (55.52%) of whom had at least 1 pDDI. Thirty-six types of pDDIs that should be avoided were found, and the most frequent pDDI was the coadministration of lorazepam and olanzapine (55.5%). A total of 26 ADRs induced by pDDIs were identified, and the most common ADR was constipation (26.05%). There was a 9.4 and 10.3% increase in the number of ADR types for each extra medical diagnosis and for each extra drug, respectively. There was a 120% increase in the number of ADR types for older adults hospitalized for 18-28 days compared with those hospitalized for 3-17 days. There was an 11.1% decrease in the number of ADR types for each extra readmission. The length of hospitalization was a risk factor for abnormal liver function (P < 0.05). The use of a large number of drugs was a risk factor for gastric distress (P < 0.05) and dizziness and fainting (P < 0.05). None of the four pDDIs, including coadministrations of olanzapine and lorazepam, quetiapine and potassium chloride, quetiapine and escitalopram, and olanzapine and clonazepam, showed clinical significance of ADR severity (P > 0.05).. pDDIs are prevalent in older adults, and the rate is increasing. However, many pDDIs may have no clinical significance in terms of ADR severity. Further research on assessing pDDIs, and possible measures to prevent serious ADRs induced by DDIs is needed to reduce the clinical significance of pDDIs.

Topics: Aged; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Lorazepam; Mental Disorders; Olanzapine; Quetiapine Fumarate; Retrospective Studies

The aim of the present study was to survey adverse drug events (ADEs) in patients with bipolar disorders and identify risk factors using the Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system. Data on patients with bipolar disorders were extracted from the JADER database. The Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PT) and standardized MedDRA queries (SMQ) were used to define ADEs. A multiple logistic regression analysis was performed to identify risk factors for ADEs. A total of 8653 reports of 1108 types of ADEs (PT) were registered in data collected on 3521 patients with bipolar disorders. Rash (PT) was the most frequently reported in 549 patients, followed by drug eruption (PT) in 387, fever (PT) in 364, toxicity to various agents (PT) in 291, and Stevens-Johnson syndrome (PT) in 261. Among 24 ADEs (PT) that were reported in more than 50 patients, lamotrigine was associated with increased risks of 13 ADEs (PT), followed by carbamazepine with increased risks of 8 ADEs (PT). The majority of these ADEs belonged to hypersensitivity (SMQ) or hepatic disorder (SMQ). Lithium carbonate was associated with increased risks of rash (PT), drug interaction (PT), and tubulointerstitial diseases (SMQ). All antipsychotics increased the adjusted odds ratio for neuroleptic malignant syndrome (PT). The risk of hyperglycemia/new onset diabetes mellitus (SMQ) was increased by olanzapine, quetiapine fumarate, and risperidone. We are presenting the profiles of ADEs in patients with bipolar disorders using the JADER database, and propose risk factors for 19 ADEs (PT) and 4 ADEs (SMQ).

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Bipolar Disorder; Carbamazepine; Drug-Related Side Effects and Adverse Reactions; Exanthema; Humans; Japan; Lamotrigine; Lithium Carbonate; Olanzapine; Quetiapine Fumarate; Risperidone

An association between antipsychotic drugs and pneumonia has been demonstrated in several studies; however, the risk for pneumonia caused by specific antipsychotics has not been extensively studied. The underlying mechanism is still unknown, and several receptor mechanisms have been proposed. Therefore, using a combined pharmacovigilance-pharmacodynamic approach, we aimed to investigate safety signals of US Food and Drug Administration (FDA)-approved antipsychotics for reporting pneumonia and the potential receptor mechanisms involved. A disproportionality analysis was performed to detect a signal for reporting "infective-pneumonia" and "pneumonia-aspiration" and antipsychotics using reports submitted between 2004 and 2019 to the FDA adverse events spontaneous reporting system (FAERS) database. Disproportionality was estimated using the crude and the adjusted reporting odds ratio (aROR) and its 95% confidence interval (CI) in a multivariable logistic regression. Linear regressions investigated the relationship between aROR and receptor occupancy, which was estimated using in vitro receptor-binding profiles. Safety signals for reporting infective-pneumonia were identified for clozapine (LL = 95% 3.4, n = 546 [aROR: 4.8]) as well as olanzapine (LL = 95% 1.5, n = 250 [aROR: 2.1]) compared with haloperidol, while aRORs were associated with higher occupancies of muscarinic receptors (beta = .125, P-value = .016), yet other anti-muscarinic drugs were not included as potential confounders. No safety signals for reporting pneumonia-aspiration were detected for individual antipsychotics. Multiple antipsychotic use was associated with both reporting infective-pneumonia (LL 95%: 1.1, n = 369 [aROR:1.2]) and pneumonia-aspiration (LL 95%: 1.7, n = 194 [aROR: 2.0]). Considering the limitations of disproportionality analysis, further pharmacovigilance data and clinical causality assessment are needed to validate this safety signal.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Antipsychotic Agents; Clozapine; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Pharmacovigilance; Pneumonia; Pneumonia, Aspiration; Receptors, Muscarinic; United States; United States Food and Drug Administration; Young Adult

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Intellectual Disability; Male; Olanzapine; Stress Disorders, Post-Traumatic; Vitamin E

Some medications are more rapidly metabolized by smokers; upon smoking cessation, medication metabolism may be significantly reduced, resulting in medication-related adverse events. Clozapine, olanzapine and theophylline have been deemed to have potentially highly significant interactions with smoking cessation, which could lead to seizures, extrapyramidal effects and tachycardia, respectively. This study examined the period prevalence and characteristics of patients at risk of highly significant medication-smoking cessation interactions when admitted to a smoke-free hospital.. A retrospective cross-sectional study was undertaken in an Australian tertiary-referral hospital with a well-established electronic prescribing system. Smokers prescribed clozapine, olanzapine or theophylline prior to and during a hospital admission in 2015 were included. Length of hospital stay, daily doses, and recognition of the potential interaction by treating clinicians were determined from medical records.. The period prevalence of patients at risk of a potentially highly significant medication-smoking cessation interaction was 23/48 (48%), 66/256 (26%) and 1/16 (6%) amongst smokers prescribed clozapine, olanzapine or theophylline, respectively. These interactions were poorly recognized by healthcare professionals during the admission.. Up to one in two patients receiving medications that have potentially highly significant interactions with smoking cessation may be experiencing clinically significant potential interactions. Such interactions, however, were commonly overlooked by hospital staff. Interventions to improve awareness of this issue are warranted.

Topics: Adult; Aged; Australia; Clozapine; Cross-Sectional Studies; Delivery of Health Care; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Olanzapine; Prevalence; Retrospective Studies; Smokers; Smoking Cessation; Theophylline

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Topics: Adolescent; Aripiprazole; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Child; Child, Preschool; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Humans; Male; Neoplasm Proteins; Olanzapine; Pediatrics; Polymorphism, Genetic; Quetiapine Fumarate; Risperidone; Schizophrenia; Young Adult

Chemotherapy-induced nausea and vomiting (CINV) is a distressing adverse effect. Neurokinin-1 receptor antagonist (NK1RA)-containing regimens are the standard regimens for CINV prophylaxis in patients with cancer receiving highly or moderately emetogenic chemotherapy (HEC or MEC). NK1RA agents are expensive and were not registered in Sudan. Recently, regimens containing olanzapine, the available and affordable medication in Sudan, were introduced as another option. This study aimed to compare the efficacy of an olanzapine-containing regimen with the antiemetic regimen that was currently used in our institute for CINV prophylaxis in HEC/MEC settings.. The study prospectively compared an olanzapine-containing regimen (acute phase: olanzapine, ondansetron, dexamethasone; delayed phase: olanzapine, ondansetron) with an ondansetron/dexamethasone regimen (acute phase: ondansetron, dexamethasone; delayed phase: ondansetron) in adult patients with cancer receiving HEC or MEC. The study outcomes were complete response (CR; no emesis and no rescue medications) and nausea control (no nausea), which were assessed in the acute (0 to 24 hours), delayed (24 to 120 hours), and overall (0 to 120 hours) phases.. The study included 131 patients (olanzapine-containing: 50 patients; ondansetron/dexamethasone: 81 patients). CR and nausea control were higher in the olanzapine-containing than in the ondansetron/dexamethasone regimen (CR: acute phase, 86% v 71.6%; P = .086; delayed phase, 72% v 30.9%; P < .001; overall phase, 66% v 25.9%; P < .001; nausea control: acute phase, 86% v 74.1%; P = .127; delayed phase, 76% v 34.6%; P < .001; overall phase, 72% v 29.6%; P < .001). The major toxicity of olanzapine was grade 1 and 2 sedation or drowsiness (25 patients).. An olanzapine-containing regimen has better efficacy for prevention of CINV in the HEC/MEC setting. Oncologists working in a limited-resource setting should be familiar with olanzapine-containing regimens, because NK1RA agents are not affordable and not easily available.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Middle Aged; Nausea; Neoplasms; Olanzapine; Ondansetron; Receptors, Neurokinin-1; Sudan; Vomiting; Young Adult

Parkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs.. A retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs.. Forty-five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs.. This study was limited by its retrospective study design and small sample size and with likely selection bias.. The prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Olanzapine; Outcome and Process Assessment, Health Care; Parkinson Disease; Piperidines; Psychological Techniques; Psychotic Disorders; Quality of Life; Retrospective Studies; Urea

This cross-sectional study compared quality of life and side effects in 108 users of olanzapine or risperidone suffering schizophrenia and being attended at psychiatric ambulatory services in Rio Grande do Norte, Brazil. Economic, socio-demographic, anthropometric, biochemical, and hormonal variables were compared. The EuroQoL Five-Dimension Scale (EQ-5D) was used to evaluate quality of life, and side effects were assessed using the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale and the Simpson-Angus Scale. Data were analysed using the χ(2) test and Student's t test, with a significance level of 5 %.The household incomes of approximately 80 % of patients were <2.0 minimum wages ($678). Anthropometric variables (waist circumference, hip circumference, weight, waist-to-hip ratio) and systolic and diastolic blood pressure were noted among male olanzapine users (all p < 0.05). EQ-5D scores showed that olanzapine use significantly impacted self-help ability (p < 0.001). Risperidone users had a mean quality-adjusted life year value of 1. Mean total Simpson-Angus Scale scores was 0.38 for olanzapine users and 0.11 for risperidone users (p < 0.02). Significant differences in UKU were observed for the following items: asthenia/lassitude/fatigue (higher among olanzapine users, p = 0.02), dystonia (higher among olanzapine users, p = 0.01), tremors (higher among olanzapine users, p = 0.03), gynecomastia (higher among risperidone users, p < 0.02), and ejaculatory dysfunction (higher among risperidone users, p < 0.02). Olanzapine users had impaired quality of life, which can be explained in part by adverse motor, biochemical, and hormonal effects characteristic of metabolic syndrome.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Pressure; Body Weights and Measures; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Olanzapine; Quality of Life; Risperidone; Schizophrenia

Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations.. The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57.. The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-α at any time-point of the study.. This study provides data suggesting early alteration in adipose tissue endocrine function as a factor involved in mechanisms underlying metabolic adverse effects of antipsychotics.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Leptin; Olanzapine; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain

The aim of this study was to evaluate demographic, clinical, and treatment factors that may impact on neurological adverse effects in naive and quasi-naive children and adolescents treated with antipsychotics.. This was a 1-year, multicenter, observational study of a naive and quasi-naive pediatric population receiving antipsychotic treatment. Two subanalyses were run using the subsample of subjects taking the 3 most used antipsychotics and the subsample of antipsychotic-naive subjects. Total dyskinesia score (DyskinesiaS) and total Parkinson score (ParkinsonS) were calculated from the Maryland Psychiatric Research Center Involuntary Movement Scale, total UKU-Cognition score was calculated from the UKU Side Effect Rating Scale. Risk factors for tardive dyskinesias (TDs) defined after Schooler-Kaine criteria were studied using a logistic regression.. Two hundred sixty-five subjects (mean age, 14.4 [SD, 2.9] years) with different Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders were recruited. DyskinesiaS (P < 0.001) and ParkinsonS (P < 0.001) increased at 1-year follow-up. Risperidone was associated with higher increases in DyskinesiaS compared with quetiapine (P < 0.001). Higher increases in ParkinsonS were found with risperidone (P < 0.001) and olanzapine (P = 0.02) compared with quetiapine. Total UKU-Cognition Score decreased at follow-up. Findings were also significant when analyzing antipsychotic-naive subjects. Fifteen subjects (5.8%) fulfilled Schooler-Kane criteria for TD at follow-up. Younger age, history of psychotic symptoms, and higher cumulative exposure time were associated with TD at follow-up.. Antipsychotics increased neurological adverse effects in a naive and quasi-naive pediatric population and should be carefully monitored. Risperidone presented higher scores in symptoms of dyskinesia and parkinsonism. Quetiapine was the antipsychotic with less neurological adverse effects. Younger subjects, psychosis, and treatment factors predicted an increased risk of TD.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Olanzapine; Parkinson Disease, Secondary; Quetiapine Fumarate; Risperidone

The PDSS is a potential side-effect of the intramuscular injection of olanzapine pamoate. We saw the typical symptoms develop in a 46-year-old man 4 hours after the injection. The syndrome is caused by a toxic concentration of olanzapine, and is possibly the result of the direct injection of the substance in the bloodstream. The most important measures that can be taken to prevent such an emergency are: a careful injection procedure, a 3-hour observation period following the injection and good counselling of the patient and his family. The treatment is conservative.

Topics: Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Delirium; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Humans; Injections, Intramuscular; Male; Middle Aged; Olanzapine; Schizophrenia; Syndrome; Treatment Outcome

We sought to evaluate the within-drug benefit-risk of olanzapine long-acting injection (LAI) using both quantitative and qualitative methods. Subjects included 1192 adult patients with schizophrenia or schizoaffective disorder who participated in clinical trials with the opportunity for at least two years of continuous treatment with olanzapine LAI (45-405 mg every two to four weeks). Using the Benefit Risk Action Team (BRAT) framework, we evaluated frequency versus duration of benefits and risks commonly observed with atypical antipsychotics. We then used the Transparent Uniform Risk/Benefit Overview (TURBO) method, which weighs the drug's two most medically serious and/or frequent adverse events versus its primary benefit (effectiveness) and an ancillary benefit. The most frequent events among all patients were remaining free of relapse (91.4% for an average of 306 days at one year, 88.4% for 546 days at two years) and symptomatic remission (81.7% for an average of 239 days at one year, 84.1% for 438 days at two years). One- and two-year incidence of ≥7% weight gain was 33.3% and 41.7%. Incidences for sexual dysfunction, hyperprolactinemia, and post-injection delirium/sedation syndrome (PDSS) were <2%. TURBO ratings unanimously selected PDSS and weight gain as key risks and resulted in an average score in the acceptable benefit-risk balance range.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Risk Assessment; Schizophrenia; Time Factors; Treatment Outcome

Olanzapine pamoate injection is an anti-psychotic depot to be administered intramuscularly once every 2-4 weeks. A post-injection syndrome may occur shortly after administration, resulting in an acute intoxication with olanzapine.. A 42-year-old patient with a schizophrenic disorder lost consciousness 30 min after administration of olanzapine pamoate. He was admitted to a nearby hospital with tachycardia, hypotension, pin-point pupils and respiratory distress leading to reduced oxygen saturation. He was ventilated during one night and recovered within 2 days.. A post-injection syndrome may develop after administration of olanzapine pamoate when the entire dose olanzapine is released at once from the muscle. Therefore, the patient should be observed for at least 3 hours after every injection. The risk of a post-injection syndrome and the necessary observation period should to be taken into account when deciding to start treatment with olanzapine pamoate depot.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Humans; Injections, Intramuscular; Male; Olanzapine; Schizophrenia; Syndrome

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

The frequency of severe adverse drug reactions (ADRs) from psychotropic drugs was investigated in hospitalised psychiatric patients in relation to their age. Specifically, the incidence of ADRs in patients up to 60 years was compared to that of patients older than 60 years.. Prescription rates of psychotropic drugs and reports of severe ADRs were collected in psychiatric hospitals in Switzerland between 2001 and 2010. The data stem from the drug surveillance programme AMSP.. A total of 699 patients exhibited severe ADRs: 517 out of 28,282 patients up to 60 years (1.8%); 182 out of 11,446 elderly patients (1.6%, ns). Logistic regression analyses showed a significantly negative relationship between the incidence of ADRs and patients' age in general and in particular for weight gain, extrapyramidal motor system (EPMS) symptoms, increased liver enzymes and galactorrhoea. A significantly negative relationship was observed for age and the dosages of olanzapine, quetiapine, risperidone, valproic acid and lamotrigine. When comparing age groups, frequency of ADRs was lower in general for antipsychotic drugs and anticonvulsants, in particular for valproic acid in the elderly. Weight gain was found to be lower in the elderly for antipsychotic drugs, in particular for olanzapine. For the group of mood-stabilising anticonvulsants (carbamazepine, lamotrigine and valproic acid) the elderly exhibited a lower incidence of reported allergic skin reactions.. The results suggest that for psychiatric inpatients the incidence of common severe ADRs (e.g., weight gain or EPMS symptoms) arising from psychotropic medication decreases with the age of patients.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Aged, 80 and over; Antimanic Agents; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Carbamazepine; Causality; Dibenzothiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Galactorrhea; Humans; Lamotrigine; Logistic Models; Male; Middle Aged; Neuroleptic Malignant Syndrome; Olanzapine; Quetiapine Fumarate; Risperidone; Severity of Illness Index; Switzerland; Triazines; Valproic Acid; Weight Gain; Young Adult

This cross-sectional study aimed to compare the effects of treatment with an atypical antipsychotic drug (olanzapine or risperidone) on quality of life (QoL) and to document adverse effects in 115 patients diagnosed with schizophrenia who attended the ambulatory service of Hospital Dr. João Machado, Natal, Rio Grande do Norte, Brazil. Socioeconomic, sociodemographic, and clinical variables were compared. The QoL Scale validated for Brazil (QLS-BR) was used to evaluate QoL, and adverse effects were assessed using the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale. Data were analyzed using the χ(2) test and Student's t test, with a significance level of 5 %. Patients in both drug groups showed severe impairment in the occupational domain of the QLS-BR. Global QLS-BR scores indicated impairment among risperidone users and severe impairment among olanzapine users. The most significant side effects were associated with risperidone, including asthenia/lassitude/fatigue, somnolence/sedation, paresthesia, change in visual accommodation, increased salivation, diarrhea, orthostatic posture, palpitations/tachycardia, erythema, photosensitivity, weight loss, galactorrhea, decreased sexual desire, erectile/orgasmic dysfunction, vaginal dryness, headache, and physical dependence. QoL was impaired in patients using olanzapine and in those using risperidone. Risperidone use was associated with psychic, neurological, and autonomous adverse effects and other side effects.

Topics: Activities of Daily Living; Adult; Ambulatory Care; Antipsychotic Agents; Benzodiazepines; Brazil; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Employment; Female; Humans; Interpersonal Relations; Male; Olanzapine; Quality of Life; Risperidone; Schizophrenia; Social Participation

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Topics: Angioedema; Antipsychotic Agents; Benzodiazepines; Diagnosis, Differential; Drug-Related Side Effects and Adverse Reactions; Edema; Eosinophilia; Female; Humans; Leg; Middle Aged; Olanzapine

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

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: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Conflict of Interest; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Ethics, Pharmacy; Evidence-Based Medicine; Fraud; Germany; Humans; Information Dissemination; Marketing; Olanzapine; Publication Bias; Research Support as Topic; Risperidone

Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur.. Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media.. Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue.. Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS.. ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Delayed-Action Preparations; Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Humans; Injections, Intramuscular; Olanzapine; Schizophrenia; Syndrome; Treatment Outcome

To describe the safety of olanzapine treatment in adolescents (aged 13-17 years) with schizophrenia or bipolar I disorder, and to compare these data with those of olanzapine-treated adults.. Placebo-controlled database, adolescents: acute phase of 2 double-blind, placebo-controlled trials (3-6 weeks; olanzapine, N = 179, mean age = 15.5 years; placebo, N = 89, mean age = 15.7 years); overall adolescent olanzapine exposure database, adolescents: 4 trials (e.g., the 2 aforementioned studies, each with a 26-week open-label extension phase, and 2 open-label, 4.5- and 24-week trials; N = 454, mean age = 15.9 years); and adult database: 84 clinical trials of up to 32 weeks.. The mean daily dosage of olanzapine was 10.6 mg/day (exposure = 48,946 patient days). In the overall adolescent olanzapine exposure database, the most common adverse events included increased weight (31.7%), somnolence (19.8%), and increased appetite (17.4%). In up to 32 weeks of treatment, when compared with adults, adolescents from the overall adolescent olanzapine exposure database gained statistically significantly more weight (7.4 kg vs. 3.2 kg, p < .001); statistically significantly more adolescents gained > or = 7% of their baseline weight (65.1% vs. 35.6%, p < .001). Adolescents experienced statistically significant within-group baseline-to-endpoint changes in fasting glucose (p < .001), total cholesterol (p = .002), triglycerides (p = .007), and alanine aminotransferase (p < .001). Two patients from the overall adolescent olanzapine exposure database (0.4%) attempted suicide; 13 (2.9%) had suicidal ideation. In the placebo-controlled database, adolescents had statistically significant baseline-to-endpoint increases in prolactin (11.4 micrograms/L, p < .001); 47.4% had high prolactin levels.. The types of adverse events in olanzapine-treated adolescents appear to be similar to those of adults. The magnitude and incidence of weight and prolactin changes were greater in adolescents.. clinicaltrials.gov Identifiers: NCT00051298, NCT00050206, and NCT00113594.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Meta-Analysis as Topic; Olanzapine; Randomized Controlled Trials as Topic; Schizophrenia

A formalized policy was developed to warn of the potential for adverse events associated with the use of intramuscular olanzapine in combination with injectable benzodiazepines.. Administrators in the psychiatry department at Lutheran Hospital proposed that concomitantly active orders for both intramuscular olanzapine and parenteral benzodiazepines be prohibited as a matter of policy; this decision was supported by the institution's pharmacy and therapeutics and medical executive committees. The pharmacy department subsequently examined its processes as they related to the two medications, and changes were implemented in the areas of order processing and floor-stock provision. Before policy implementation, injectable olanzapine was stored as floor stock in several automated medication cabinets for use in urgent situations. Injectable lorazepam was also included in the stock inventory for most patient care areas. After policy implementation, intramuscular olanzapine was removed from the general floor stock on all hospital units. The drug is now only available after a pharmacist's review and approval of each individual order. Upon receipt of an order for intramuscular olanzapine, the pharmacist is required to conduct a prospective review of the individual patient's medication profile to determine if an active order for an injectable benzodiazepine exists. In the event that the prescriber cannot be reached in a timely fashion, the new order is held until a physician's clarification can be obtained.. Implementation of a policy that increased pharmacist surveillance and regulation of the use of intramuscular olanzapine reduced the potential for coadministration of the agent with parenteral benzodiazepines in a community hospital.

Topics: Antipsychotic Agents; Benzodiazepines; Contraindications; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Infusions, Parenteral; Injections, Intramuscular; Medication Errors; Ohio; Olanzapine; Organizational Case Studies; Pharmacy Service, Hospital; Safety Management

The behavioral and psychological symptoms of dementia present a major challenge in the management of these patients. There is no Food and Drug Administration-indicated medication for the management of these symptoms. Even though atypical antipsychotics are considered safer than conventional antipsychotics, safety concerns have emerged.. The FDA has issued warnings regarding the cardiac and metabolic side effects, cerebrovascular events, and, most recently, mortality risk. This study was conducted in 2003 when physicians were notified of the cerebrovascular risks of risperidone. Since then, similar warnings have been issued for olanzapine and aripiprazole.. The medical records of 58 elderly dementia patients who were taking risperidone and were abruptly switched to olanzapine were reviewed. Clinical Global Impressions scale at assigned retrospectively at switch, and weeks 4-6 assessed treatment.. Baseline and follow-up Clinical Global Impressions scale scores were essentially unchanged. Adverse events were mild to moderate in severity. Mean risperidone dose at switch was 1.54 mg/day (range: 0.25-6 mg/day). Mean olanzapine dose after the switch was 5.69 mg/day (range: 2.52-27.5 mg/day).. Most of the 58 patients were switched from risperidone to olanzapine without any deterioration in their clinical status. Even though it is generally not recommended in elderly patients, abrupt switching did not have any negative consequences in this group of patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Benzodiazepines; Comorbidity; Dementia, Vascular; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Homes for the Aged; Humans; Male; Nursing Homes; Olanzapine; Psychotic Disorders; Retrospective Studies; Risk Factors; Risperidone; Schizophrenia; Treatment Outcome

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration