146 results on '"Charles M. Beasley"'
Search Results
2. Reference Limits for Outlier Analyses in Randomized Clinical Trials
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Brenda J. Crowe, Paul S. Horn, Charles M. Beasley, Rebeka Tabbey, Robert A. Dean, Lieling Wu, Mary E. Nilsson, and Ryan T. Hietpas
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Percentile ,Public Health, Environmental and Occupational Health ,Healthy subjects ,Interval (mathematics) ,01 natural sciences ,law.invention ,Clinical trial ,010104 statistics & probability ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Reference values ,Statistics ,Outlier ,Pharmacology (medical) ,030212 general & internal medicine ,Limit (mathematics) ,0101 mathematics ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Mathematics - Abstract
Reference limits used in clinical medicine to screen and manage patients are typically developed nonparametrically using reference values from a limited number of healthy subjects using a 95th percentile reference interval. We have evaluated alternative methods of computation and the resulting limits for use in the analyses of treatment-emergent outliers in clinical trials. We developed a set of alternative reference limits for 38 laboratory analytes based on alternative statistical methods and assessed their relative performance in clinical trial analysis. Performance assessment was based on the clinical credibility of the limits, inferential statistical performance, consideration of incidences for the test drug and control (placebo) in cases where the drug was reasonably believed to be associated with a change in an analyte (positive cases), and in cases where prior analyses failed to demonstrate a change associated with the drug (negative cases). Based on consideration of these cases, no single method resulted in optimal limits for all cases considered. However, with the limits developed using clinical trial subjects’ values at baseline as reference values, excluding outliers, the robust method and the 98th percentile interval appeared to produce optimal limits across the greatest number of cases considered. Although no single method of limit computation will result in optimal limits for all outlier analyses for all analytes across all clinical trials, the 98th percentile reference interval robust limits based on clinical trial reference values appeared superior to multiple alternatives considered for such analyses.
- Published
- 2017
3. Twenty-Four-Hour Measures of Heart Rate-Corrected QT Interval, Peak-to-End of the T-Wave, and Peak-to-End of the T-Wave/Corrected QT Interval Ratio During Antipsychotic Treatment
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Mustafa M. Tümüklü, Mevhibe N. Tümüklü, Herbert Y. Meltzer, Charles M. Beasley, Vladislav Nesterenko, and Karu Jayathilake
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,medicine.medical_treatment ,Pilot Projects ,QT interval ,Piperazines ,Sudden cardiac death ,03 medical and health sciences ,Electrocardiography ,0302 clinical medicine ,Heart Rate ,Torsades de Pointes ,Internal medicine ,Heart rate ,Medicine ,Repolarization ,Humans ,Pharmacology (medical) ,Ziprasidone ,cardiovascular diseases ,Antipsychotic ,medicine.diagnostic_test ,business.industry ,Case-control study ,Middle Aged ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Thiazoles ,Case-Control Studies ,cardiovascular system ,Cardiology ,Female ,business ,030217 neurology & neurosurgery ,circulatory and respiratory physiology ,medicine.drug ,Antipsychotic Agents - Abstract
PURPOSE/BACKGROUND Prolonged ventricular repolarization, measured by heart rate-corrected QT interval (QTc) prolongation, might be a biomarker for risk of torsade de pointes (TdP) and sudden cardiac death. However, the predictive value of QTc has been challenged, and a component of QTc, peak-to-end of the T-wave (Tpe), and a high Tpe/QT ratio might be superior biomarkers because they better reflect increased transmural dispersion of ventricular myocyte repolarization, which can lead to TDP. The purpose of this pilot study was to provide the first measurements of heart rate, QTc, Tpe, Tpe/QTc, and their variability over 24 hours in medication-free patients with schizophrenia, during treatment with ziprasidone or other antipsychotic drugs, and healthy controls. METHODS Subjects included 12 patients treated with ziprasidone, 30 treated with other antipsychotic drugs, 3 unmedicated patients, and 15 normal controls. Subjects underwent 24-hour analog Holter recording, and the recordings were digitized. A cardiologist blind to treatment selected multiple 10-cycle segments throughout each recording and measured the electrocardiogram metrics. RESULTS Variability in QTc, Tpe, and Tpe/QTc over the 24 hours was present in all groups; 91.1% of patients and 100% of controls had 1 or more QTc values of 450 milliseconds or greater. Mean QTc length was significantly greater in the ziprasidone-treated than the non-ziprasidone-treated patients (P = 0.02). Mean Tpe was not elevated in the ziprasidone patients, whereas mean Tpe/QTc was lower (P < 0.01). CONCLUSIONS The large variability in QTc, Tpe, and Tpe/QTc observed supports the need for 24-hour electrocardiogram recordings to provide an accurate assessment of risk of TdP. Heart rate-corrected QT interval alone does not capture the risk of TdP.
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- 2019
4. Adaptation of the robust method to large distributions of reference values: program modifications and comparison of alternative computational methods
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Lieling Wu, Brenda J. Crowe, Rebeka Tabbey, Robert A. Dean, Paul S. Horn, Ryan T. Hietpas, Mary E. Nilsson, and Charles M. Beasley
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Statistics and Probability ,Databases, Factual ,Computation ,Adaptation (eye) ,Interval (mathematics) ,01 natural sciences ,Statistics, Nonparametric ,010104 statistics & probability ,03 medical and health sciences ,0302 clinical medicine ,Reference Values ,Statistics ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Limit (mathematics) ,0101 mathematics ,Mathematics ,Randomized Controlled Trials as Topic ,Pharmacology ,Clinical Laboratory Techniques ,Nonparametric statistics ,Reference intervals ,Research Design ,Reference values ,Data Interpretation, Statistical ,Outlier ,Algorithms - Abstract
The objective of this research was to compute reference limits using reference values from patients entering pharmaceutical development clinical trials by the nonparametric method and the robust method of Horn and Pesce, with and without outlier exclusion, and compare the methods with respect to influence on the limits. Reference limits were computed for 38 analytes with over 130,000 subjects contributing reference values. Subjects were partitioned into 10 demographic strata for limit computation. Limits were computed for both 95- and 98-percentile reference intervals by both methods. For each reference interval and method, the limits were calculated with and without outliers. Outliers were excluded by the Horn algorithm. Irrespective of method, reference limits were expanded with the 98-percentile interval, but some expansions were small. Outlier exclusion contracted limits with more influence on the upper limit. The robust method contracted the upper limit to a meaningful degree and slightly expanded the lower limit for many analytes. Outlier exclusion and computation by the robust method have an increasing influence on analytes with right-skewed distributions of reference values from large populations not screened to exclude common, stable diseases and environmental factors that might affect analyte variability. The method has advantages for computation of reference limits used in clinical trial analyses.
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- 2019
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5. Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers
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Malcolm I. Mitchell, John H. April, Prajakti A. Kothare, Charles M. Beasley, Ling Jin, Harry Haber, Lynnette Kauffman, Corina Loghin, and Albert J. Allen
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Pharmacology ,CYP2D6 ,medicine.medical_specialty ,Chemistry ,Atomoxetine ,Placebo ,QT interval ,Gastroenterology ,Crossover study ,Moxifloxacin ,Internal medicine ,Anesthesia ,Heart rate ,medicine ,Pharmacology (medical) ,Atomoxetine hydrochloride ,medicine.drug - Abstract
Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared.
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- 2013
6. Systematic Decrements in QTc between the First and Second Day of Contiguous Daily ECG Recordings under Controlled Conditions
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S. Stanley Young, Charles M. Beasley, Jessie Q. Xia, Charles Benson, Harry Haber, Corina Loghin, and Malcolm I. Mitchell
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medicine.medical_specialty ,business.industry ,Diurnal temperature variation ,Group behavior ,General Medicine ,Replicate ,QT interval ,Drug treatment ,Normal volunteers ,Internal medicine ,Cardiology ,medicine ,Inpatient status ,Cardiology and Cardiovascular Medicine ,business ,Inpatient environment - Abstract
Background: Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment. Methods: Two separate crossover TQT studies included 2 days of no treatment lead-in days with ECG collection preceding periods of drug treatment. In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead-in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within-patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated. Results: Modest (4.2 ms [range 1.9–6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10−16). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days. Conclusions: Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation. (PACE 2011; 34:1116–1127)
- Published
- 2011
7. Suicidality and Risk of Suicide—Definition, Drug Safety Concerns, and a Necessary Target for Drug Development
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Sharon-Lise T. Normand, Herbert Y. Meltzer, Roger E. Meyer, David Shaffer, Madhukar H. Trivedi, Gregory K. Brown, Neal D. Ryan, Carl Salzman, Karl Broich, J. John Mann, Kelly Posner, Maria A. Oquendo, Frederick K. Goodwin, Gustavo Turecki, Charles M. Beasley, Annette L. Beautrais, Jeffrey A. Bridge, Larry Alphs, Wayne K. Goodman, David V. Sheehan, Dennis A. Revicki, Barbara Stanley, Eric A. Youngstrom, John F. Greden, and Paula J. Clayton
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Adult ,Suicide Prevention ,medicine.medical_specialty ,Adolescent ,Drug-Related Side Effects and Adverse Reactions ,Consensus Development Conferences as Topic ,Postmarketing surveillance ,Poison control ,Suicide prevention ,Meta-Analysis as Topic ,Risk Factors ,Cause of Death ,Terminology as Topic ,Drug Discovery ,Nominal group technique ,medicine ,Humans ,Child ,Psychiatry ,Suicidal ideation ,Medical education ,United States Food and Drug Administration ,Mental Disorders ,Clinical study design ,Middle Aged ,Antidepressive Agents ,United States ,Clinical trial ,Suicide ,Psychiatry and Mental health ,medicine.symptom ,Psychology ,Selective Serotonin Reuptake Inhibitors - Abstract
OBJECTIVE: To address issues concerning potential treatment-emergent "suicidality," a consensus conference was convened March 23-24, 2009. PARTICIPANTS: This gathering of participants from academia, government, and industry brought together experts in suicide prevention, clinical trial design, psychometrics, pharmacoepidemiology, and genetics, as well as research psychiatrists involved in studies in studies of psychiatric disorders associated with elevated suicide risk across the life cycle. The process involved reviews of the relevant literature, and a series of 6 breakout sessions focused on specific questions of interest. EVIDENCE: Each of the participants at the meeting received references relevant to the formal presentations (as well as the slides for the presentations) for their review prior to the meeting. In addition, the assessment instruments of suicidal ideation/behavior were reviewed in relationship to standard measures of validity, reliability, and clinical utility, and these findings were discussed at length in relevant breakout groups, in the final plenary session, and in the preparation of the article. Consensus and dissenting views were noted. CONSENSUS PROCESS: Discussion and questions followed each formal presentation during the plenary sessions. Approximately 6 questions per breakout group were prepared in advance by members of the Steering Committee and each breakout group chair. Consensus in the breakout groups was achieved by nominal group process. Consensus recommendations and any dissent were reviewed for each breakout group at the final plenary session. All plenary sessions were recorded and transcribed by a court stenographer. Following the transcript, with input by each of the authors, the final paper went through 14 drafts. The output of the meeting was organized into this brief report and the accompanying full article from which it is distilled. The full article was developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement at the conference have been noted in the text. CONCLUSIONS: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's encouragement of standard definitions and definable expectations for investigators and industry sponsors. Further research of available assessment instruments is needed to verify their utility, reliability, and validity in identifying suicide-associated treatment-emergent adverse effects and/or a signal of efficacy in suicide prevention trials. The FDA needs to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the requirement that all central nervous system clinical drug trials must include a Columbia Classification Algorithm of Suicide Assessment (C-CASA)-compatible screening instrument for assessing and documenting the occurrence of treatment-emergent suicidal ideation and behavior. Finally, patients at high risk for suicide can safely be included in clinical trials, if proper precautions are followed. Language: en
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- 2010
8. Evaluating suicide-related adverse events in clinical trials of fluoxetine treatment in adults for indications other than major depressive disorder
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Damon Disch, Charles M. Beasley, John Plewes, Sitra Tauscher-Wisniewski, and Susan Ball
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medicine.medical_specialty ,Poison control ,Risk Assessment ,Age Distribution ,Double-Blind Method ,Fluoxetine ,medicine ,Humans ,Adverse effect ,Psychiatry ,Suicidal ideation ,Applied Psychology ,Randomized Controlled Trials as Topic ,Psychopathology ,Incidence ,Mental Disorders ,Absolute risk reduction ,medicine.disease ,Suicide ,Psychiatry and Mental health ,Relative risk ,Major depressive disorder ,medicine.symptom ,Risk assessment ,Psychology ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
BackgroundThe association between treatment-emergent suicidality as an adverse event and fluoxetine treatment was examined using a fluoxetine double-blind placebo-controlled database of clinical trials for indications other than major depressive disorder.MethodThe database consisted of 53 trials for 16 different indications (14 psychiatric, two non-psychiatric). Within each study, patient adverse event reports and narratives were searched extensively for treatment-emergent thoughts and behaviors associated with suicide. The incidence of adverse events was classified using Food and Drug Administration (FDA) codes for completed suicide, preparatory acts, suicidal ideation and the summary category of ‘all suicidality.’ The risk difference and risk ratios between fluoxetine and placebo treatment arms were compared using Mantel–Haenszel methods.ResultsWithin this large database, patients were randomly assigned to receive treatment with either fluoxetine (n=7066) or placebo (n=4382). Treatment groups did not differ in their risk for the emergence of suicidality for any FDA code; the risk ratio for ‘all suicidality’ was 0·82 (p=0·406), and there were no completed suicides in either group. Analyses based on treatment indication (bulimia, obsessive-compulsive disorder, other psychiatric and non-psychiatric illness) also showed no significant difference in risk between treatment groups. When examined by age categories (18–24, 25–30, 31–65, and ⩾65 years), fluoxetine and placebo treatments did not result in significant risk difference for the emergence of suicidality.ConclusionsThe risk of treatment-emergent suicidality does not appear to be associated with fluoxetine treatment for adults with various non-MDD conditions.
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- 2007
9. Early Symptomatic Worsening During Treatment With Fluoxetine in Major Depressive Disorder
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Jay D. Amsterdam, Roy H. Perlis, Maurizio Fava, Frederic M. Quitkin, Jerrold F. Rosenbaum, Cristina Cusin, Frederick W. Reimherr, and Charles M. Beasley
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Adult ,Male ,medicine.medical_specialty ,Fluoxetine ,Internal medicine ,Post-hoc analysis ,Prevalence ,medicine ,Humans ,Major depressive episode ,Psychiatry ,Depression (differential diagnoses) ,Retrospective Studies ,Clinical Trials as Topic ,Depressive Disorder, Major ,Hamilton Rating Scale for Depression ,Retrospective cohort study ,Middle Aged ,Prognosis ,medicine.disease ,Discontinuation ,Psychiatry and Mental health ,Disease Progression ,Major depressive disorder ,Female ,medicine.symptom ,Psychology ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Background A subset of patients experience worsening of depressed mood after beginning antidepressant treatment, which could represent the natural history of the illness or a treatment-related effect. While patterns of response have been examined as possible predictors of outcome, the clinical correlates and implications of early worsening per se have not been investigated. Method In a post hoc analysis, we studied the clinical correlates of early worsening in a large sample of outpatients (N = 694) diagnosed with a DSM-III-R-defined major depressive episode and treated with fluoxetine (20 mg/day) for up to 12 weeks. We defined early worsening as an increase of at least 5 points on a modified 17-item Hamilton Rating Scale for Depression (mHAM-D, including reverse vegetative symptoms) compared to the previous visit, and occurring during the acute phase of treatment. The primary analysis compared remission and response at week 12 between those patients with and without worsening. Results In our sample, 211 patients (30.4%) experienced early worsening of depression. An increase in mHAM-D score at week 2, 3, 4, or 6 was associated with a significantly lower probability of remission and response at both week 8 and week 12, while no significant difference was observed in study discontinuation. Baseline features, including gender, age, mHAM-D score at entry, number of previous depressive episodes, and duration of illness were not associated with the development of early worsening during fluoxetine treatment. Conclusion Early clinical worsening is common and associated with a decreased likelihood of achieving remission.
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- 2007
10. Treatment-Associated Suicidal Ideation and Adverse Effects in an Open, Multicenter Trial of Fluoxetine for Major Depressive Episodes
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Roy H. Perlis, Frederick M. Quitkin, Deborah L. Shear, Jerrold F. Rosenbaum, Charles M. Beasley, Roy N. Tamura, James D. Wines, Cristina Cusin, Maurizio Fava, Robert E. Strong, and Jay D. Amsterdam
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Poison control ,Suicide, Attempted ,Severity of Illness Index ,Drug Administration Schedule ,law.invention ,Drug Therapy ,Randomized controlled trial ,law ,Fluoxetine ,Surveys and Questionnaires ,Multicenter trial ,Severity of illness ,Ambulatory Care ,medicine ,Humans ,Risk factor ,Adverse effect ,Psychiatry ,Suicidal ideation ,Applied Psychology ,Aged ,Depressive Disorder, Major ,Incidence ,General Medicine ,Middle Aged ,Psychiatry and Mental health ,Clinical Psychology ,Female ,medicine.symptom ,Psychology ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Background: Some reports suggest that a subset of depressed patients may experience suicidality – that is increase or emergence of suicidal ideation (SI) or behavior – after initiation of an antidepressant. The time course and clinical correlates of this phenomenon have not been characterized in detail. Method: We conducted a secondary analysis of a multicenter, prospective, open, 12-week trial of fluoxetine 20 mg in outpatients with nonpsychotic major depressive episodes. Adverse effects and other clinical features associated with the emergence of suicidality, defined using item 3 of the Hamilton Depression Rating Scale, were examined using Cox regression models. Results: Among 414 subjects without SI at baseline, 59 (14.3%) reported SI on at least 1 postbaseline visit. In a Cox regression, emergence of activation and worsening of depression severity were independently associated with emergence of SI, along with female gender, younger age and having thoughts that life was not worth living prior to treatment. Treatment response and remission were significantly less likely among subjects who developed SI. Conclusions: New SI was relatively common in this trial of fluoxetine and associated with the emergence of activation and overall symptomatic worsening. Whether prophylaxis against or aggressive treatment of adverse events can decrease emergence of SI merits further study.
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- 2006
11. Effects of Antipsychotic Drugs on Ito, INa, Isus, IK1, and hERG: QT Prolongation, Structure Activity Relationship, and Network Analysis
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Charles M. Beasley, Steven A. Wrighton, James H. Wikel, William J. Crumb, Christopher Carlson, Sean Ekins, and R. Dustan Sarazan
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Drug ,congenital, hereditary, and neonatal diseases and abnormalities ,Indoles ,media_common.quotation_subject ,medicine.medical_treatment ,hERG ,Action Potentials ,Pharmaceutical Science ,In Vitro Techniques ,Pharmacology ,Transfection ,QT interval ,Ion Channels ,Sodium Channels ,Cell Line ,Benzodiazepines ,Electrocardiography ,Structure-Activity Relationship ,Potassium Channel Blockers ,medicine ,Humans ,Myocytes, Cardiac ,Pharmacology (medical) ,Patch clamp ,Potassium Channels, Inwardly Rectifying ,Antipsychotic ,Ion channel ,Aged ,media_common ,Molecular Structure ,biology ,Thioridazine ,Chemistry ,Organic Chemistry ,Imidazoles ,Middle Aged ,Ligand (biochemistry) ,Ether-A-Go-Go Potassium Channels ,Potassium channel ,Olanzapine ,biology.protein ,Molecular Medicine ,Neural Networks, Computer ,Antipsychotic Agents ,Biotechnology - Abstract
To evaluate in vitro and computationally model the effects of selected antipsychotic drugs on several ionic currents that contribute to changes in the action potential in cardiac tissue.Fourteen antipsychotic drugs or metabolites were examined to determine whether QT interval prolongation could be accounted for by an effect on one or more myocardial ion channels [I(to), I(Na), I(sus), I(K1), and human ether-a-go-go related gene (hERG)]. Using the patch clamp technique, drug effects on these human cardiac currents were tested.All molecules had little inhibitory effect on ion channels (blocking at concentrations5 microM) other than hERG. A significant correlation was observed between the estimated hERG blockade and the increase in corrected QT for five of the antipsychotics. Molecular modeling identified hydrophobic features related to the interaction with hERG and correctly rank-ordered the test set molecules olanzapine and its metabolites. A network analysis of ligand and protein interactions around hERG using MetaCore (GeneGo Inc., St. Joseph, MI, USA) was used to visualize antipsychotics with affinity for this channel and their interactions with other proteins in this database.The antipsychotics do not inhibit the ion channels I(to), I(Na), I(sus), I(K1) to any appreciable extent; however, blockade of hERG is a likely mechanism for the prolongation of the QT interval.
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- 2006
12. Is Quality of Life Among Minimally Symptomatic Patients With Schizophrenia Better Following Withdrawal or Continuation of Antipsychotic Treatment?
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Gopalan Sethuraman, Virginia K. Sutton, Dieter Naber, Cindy C. Taylor, Charles M. Beasley, and Martin Dossenbach
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Adult ,Male ,Olanzapine ,medicine.medical_specialty ,Psychosis ,Adolescent ,medicine.medical_treatment ,Antipsychotic treatment ,Relapse prevention ,Placebo ,Drug Administration Schedule ,Benzodiazepines ,Internal medicine ,Secondary Prevention ,medicine ,Humans ,Pharmacology (medical) ,Psychiatry ,Antipsychotic ,Aged ,Psychiatric Status Rating Scales ,Chemotherapy ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Quality of Life ,Schizophrenia ,Female ,Psychology ,Antipsychotic Agents ,Psychopathology ,medicine.drug - Abstract
This secondary report from our 52-week, double-blind, relapse prevention trial tested whether stable patients with schizophrenia who were taken off active drug treatment would experience greater improvements in long-term quality of life than those who were continued on antipsychotic treatment. On average, Heinrichs-Carpenter Quality-of-Life Scale total scores improved by 4.3 +/- 10.6 points during treatment with olanzapine (10-20 mg/d; n = 212), but decreased by 7.1 +/- 14.6 points during treatment with placebo (n = 92; P < 0.001). Mean Quality-of-Life Scale total scores worsened in both treatment groups for the relapsing patient subgroup, whereas for nonrelapsing patients, those treated with olanzapine had significantly improved mean Quality-of-Life Scale total scores compared with those given placebo. For a subset of nonrelapsing patients who were considered "nonexacerbating" on the basis of minimal non-clinically relevant increases in psychopathology, Quality-of-Life Scale total mean change was no better (P = 0.066) for those given placebo (2.7 +/- 11.0; n = 40) than those treated with olanzapine (5.7 +/- 8.9; n = 174). Path analysis indicated a direct effect of treatment (approximately 29%) on quality of life that was not accounted for by differential changes in psychopathology. In conclusion, stable patients with schizophrenia who were taken off active drug treatment experienced no greater improvements in long-term quality of life than those who were continued on antipsychotic treatment, even in the absence of psychotic symptoms.
- Published
- 2006
13. The Combined Use of Ibutilide as an Active Control With Intensive Electrocardiographic Sampling and Signal Averaging as a Sensitive Method to Assess the Effects of Tadalafil on the Human QT Interval
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Margaret R. Warner, Charles M. Beasley, Alex Dmitrienko, Arash Bakhtyari, Robert A. Kloner, Jeremy N. Ruskin, Malcolm I. Mitchell, Michael Turik, Wei Shen, Louis R. Cantilena, Alun Bedding, Timothy M. Costigan, and Jeffrey T. Emmick
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Adult ,Male ,Time Factors ,Adolescent ,Phosphodiesterase Inhibitors ,Long QT syndrome ,Ibutilide ,Placebo ,QT interval ,Tadalafil ,law.invention ,Placebos ,Electrocardiography ,Erectile Dysfunction ,Randomized controlled trial ,law ,medicine ,Humans ,Ventricular Function ,Sulfonamides ,business.industry ,Middle Aged ,medicine.disease ,Confidence interval ,Electrophysiology ,Long QT Syndrome ,Erectile dysfunction ,Case-Control Studies ,Anesthesia ,Cardiology and Cardiovascular Medicine ,business ,Anti-Arrhythmia Agents ,Carbolines ,medicine.drug - Abstract
ObjectivesThis study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval.BackgroundCardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve.MethodsEffects of tadalafil (100 mg by mouth), ibutilide (0.002 mg/kg intravenously), and placebo on the QT interval in healthy men were compared (placebo and tadalafil [n = 90], with a subset [n = 61] receiving all treatments; mean age 30 years, range 18 to 53 years). Electrocardiographic sampling was done for two days before treatment and on treatment days. The QT was corrected for RR interval with five correction methods, including an individual correction (QTcI). Plasma concentrations of tadalafil were measured to evaluate concentration-QT effect relationships.ResultsAt the time corresponding to maximum plasma concentration of tadalafil, the mean difference in the change in QTcI between tadalafil and placebo was 2.8 ms; tadalafil was equivalent to placebo (a priori, upper limit of 90% confidence interval
- Published
- 2005
14. Tadalafil Improved Erectile Function at Twenty-Four and Thirty-Six Hours After Dosing in Men With Erectile Dysfunction: US Trial
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Wei Shen, Stephen M. Auerbach, Sanjeev Ahuja, Jay M. Young, Charles M. Beasley, Jayne A. Hague, Aileen Murphy, Carmen S. Garcia, Robert A. Feldman, and Joel M. Kaufman
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Phosphodiesterase Inhibitors ,Urology ,Endocrinology, Diabetes and Metabolism ,Placebo ,Tadalafil ,law.invention ,Endocrinology ,Erectile Dysfunction ,Randomized controlled trial ,3',5'-Cyclic-GMP Phosphodiesterases ,law ,medicine ,Back pain ,Humans ,Dosing ,Adverse effect ,Aged ,Aged, 80 and over ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,business.industry ,Coitus ,Middle Aged ,medicine.disease ,Surgery ,Clinical trial ,Erectile dysfunction ,Reproductive Medicine ,Anesthesia ,medicine.symptom ,business ,Carbolines ,medicine.drug - Abstract
In a previous study assessing tadalafil for the treatment of erectile dysfunction (ED), tadalafil 20 mg was shown to improve erectile function for up to 36 hours vs placebo. This study sought to demonstrate the effectiveness of both 10- and 20-mg tadalafil vs placebo at 2 prespecified assigned times of 24 and 36 hours postdosing. This double-blind, placebo-controlled, parallel-group study randomized 483 men with ED into 6 groups according to a combination of treatment (placebo, tadalafil 10 or 20 mg) and assigned time (24 or 36 hours) for intercourse attempts. Patients were stratified by baseline ED severity based on Erectile Function Domain scores. The study had 4 phases: a 4-week run-in (no ED medication taken); a 2- to 4-week equilibration (dosing as needed); a 4- to 6-week assessment; and a 6-month open-label extension. During the assessment phase, men took a total of 4 doses of study medication, each dose separated by more than or equal to 7 days. Efficacy was measured as the mean per-patient percentage of successful intercourse attempts (Sexual Encounter Profile Diary Question 3: SEP3) during the assessment phase. Men taking either 10- or 20-mg tadalafil had a significant increase in SEP3 from baseline scores vs placebo at both 24 hours (P = .038 and
- Published
- 2005
15. Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5—sildenafil, tadalafil, and vardenafil
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Jeffrey T. Emmick, R. Dustan Sarazan, Peter J. Sausen, Kenneth Michael Ferguson, William J. Crumb, Christine A. Strnat, and Charles M. Beasley
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Phosphodiesterase Inhibitors ,Sildenafil ,hERG ,Pharmacology ,QT interval ,Piperazines ,Sildenafil Citrate ,Cell Line ,Tadalafil ,chemistry.chemical_compound ,Vardenafil Dihydrochloride ,3',5'-Cyclic-GMP Phosphodiesterases ,Heart Rate ,Internal medicine ,medicine ,Humans ,Repolarization ,Sulfones ,cardiovascular diseases ,Cation Transport Proteins ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Dose-Response Relationship, Drug ,biology ,Phosphoric Diester Hydrolases ,Triazines ,Chemistry ,Imidazoles ,Ether-A-Go-Go Potassium Channels ,Potassium channel ,Endocrinology ,Potassium Channels, Voltage-Gated ,Purines ,Vardenafil ,cGMP-specific phosphodiesterase type 5 ,Ventricular Fibrillation ,Tachycardia, Ventricular ,biology.protein ,Carbolines ,medicine.drug - Abstract
Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, tadalafil, and vardenafil--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for vardenafil and 33.3 microM for sildenafil. Because the maximum soluble concentration of tadalafil (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for tadalafil could not be determined with the Hill equation. Tadalafil had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for vardenafil (100 microM) and 75.2% for sildenafil (100 microM). In conclusion, the concentrations of the PDE5 inhibitors required to evoke a 50% inhibition of the HERG current were well above reported therapeutic plasma concentrations of free and total compound. None of the three compounds was a potent blocker of the HERG channel.
- Published
- 2004
16. A Multicenter, Randomized, Double-Blind, Crossover Study to Evaluate Patient Preference between Tadalafil and Sildenafil
- Author
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Alexander von Keitz, Scott Segal, Jonathan Denne, Jeffrey T. Emmick, Daniel C. Lockhart, Charles M. Beasley, Aileen Murphy, Timothy M. Costigan, and Jacob Rajfer
- Subjects
Adult ,Male ,Phosphodiesterase Inhibitors ,Sildenafil ,Urology ,Placebo ,Piperazines ,Sildenafil Citrate ,Tadalafil ,law.invention ,chemistry.chemical_compound ,Double-Blind Method ,Erectile Dysfunction ,Randomized controlled trial ,law ,medicine ,Humans ,Sulfones ,Dosing ,Aged ,Cross-Over Studies ,business.industry ,Middle Aged ,medicine.disease ,Crossover study ,respiratory tract diseases ,Clinical trial ,Erectile dysfunction ,chemistry ,Patient Satisfaction ,Purines ,Anesthesia ,cardiovascular system ,business ,Carbolines ,medicine.drug - Abstract
To assess patient preference for erectile dysfunction treatment between either sildenafil or tadalafil, each administered with their respective dosing instructions, and to evaluate preference for either sildenafil or tadalafil dosing instructions during tadalafil therapy.We conducted a randomized, double-blind, crossover study consisting of four treatment arms. Because the dosing instructions for sildenafil and tadalafil are different, a unique methodology using sham placebo arms was employed to maintain the blind. To assess drug preference, 219 patients were randomized to either sildenafil 50 mg or tadalafil 20 mg, with dosing instructions reflecting their respective product profiles. To assess dosing instruction preference during tadalafil therapy, 46 patients were randomized to tadalafil 20 mg with either tadalafil or sildenafil dosing instructions. After 12 weeks, patients were crossed-over. After 4 weeks of each treatment, all patients following sildenafil dosing instructions were offered the opportunity for an upward dose titration. In a double-blind fashion, all patients who requested an upward titration received additional capsules. To mimic the pattern of dose usage observed in clinical practice, the number of patients who received additional double-blind active medication was limited to 35% of patients taking sildenafil in each treatment period in each country. Following the crossover treatment period, patients chose their preferred double-blind treatment with dosing instructions to receive in the 12-week extension period.In the drug preference assessment, 132 of 181 (73%) evaluable patients chose to receive tadalafil (p0.001) during the extension period. In the dosing instruction preference assessment, 24 of 36 (67%) evaluable patients preferred tadalafil with tadalafil dosing instructions (p = 0.046). Sildenafil and tadalafil were well tolerated.In the doses utilized in this study, 73% of patients preferred tadalafil with tadalafil dosing instructions for the treatment of their erectile dysfunction over sildenafil with sildenafil dosing instructions. During tadalafil therapy, 67% of patients preferred tadalafil dosing instructions over sildenafil dosing instructions.
- Published
- 2004
17. A Double-Blind, Randomized, Placebo-Controlled Trial of Olanzapine in the Prevention of Psychotic Relapse
- Author
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Charles M. Beasley, S.H. Hamilton, Martin Dossenbach, Gary D. Tollefson, Deborah Bykowski, Karla Alaka, Virginia K. Sutton, Daniel J. Walker, and Cindy C. Taylor
- Subjects
Adult ,Male ,Olanzapine ,medicine.medical_specialty ,Time Factors ,Adolescent ,medicine.medical_treatment ,Placebo-controlled study ,Schizoaffective disorder ,Relapse prevention ,Placebo ,law.invention ,Benzodiazepines ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Brief Psychiatric Rating Scale ,Secondary Prevention ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,Psychiatry ,Antipsychotic ,Aged ,Psychiatric Status Rating Scales ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Treatment Outcome ,Psychotic Disorders ,Schizophrenia ,Female ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Sustained response to antipsychotic therapy is an important outcome measure for patients with psychotic disorders. Placebo control in studies of relapse prevention contributes valuable information yet provokes much debate. This study, using placebo as a control, evaluated olanzapine's efficacy in preventing a psychotic relapse. Participants were stable minimally symptomatic outpatients with schizophrenia or schizoaffective disorder. The study included 4 phases: (1) 4-day to 9-day screening/evaluation (N = 583), (2) 6-week conversion to open-label olanzapine (N = 493; 10-20 mg/d), (3) 8-week stabilization on olanzapine (N = 458; 10-20 mg/d), and (4) 52-week randomized (2:1), double-blind maintenance with olanzapine (N = 224; 10-20 mg/d) or placebo (N = 102). Primary relapse criteria were clinically significant changes in the Brief Psychiatric Rating Scale (BPRS) positive item cluster or rehospitalization due to positive symptoms. Statistical methodology allowed sequential real-time estimation of efficacy across blinded treatment groups and multiple interim analyses, which permitted study termination when efficacy was significantly different between treatments. A significant between-treatment difference emerged 210 days after first patient randomization to double-blind treatment. Thus, 151 (46.3%) of the randomized patients were discontinued early and 34 (10.4%) of the planned patient enrollment were not required. The olanzapine group had a significantly longer time to relapse (P < 0.0001) than the placebo group. The 6-month cumulative estimated relapse rate (Kaplan-Meier) was 5.5% for olanzapine-treated patients versus 55.2% for placebo-treated patients. The design of this study enabled appropriate statistical testing of the primary hypothesis while minimizing exposure of patients to a less effective treatment than olanzapine. In remitted stabilized patients with schizophrenia or schizoaffective disorder, olanzapine demonstrated a positive benefit-to-risk profile in relapse prevention.
- Published
- 2003
18. Tadalafil has No Detrimental Effect on Human Spermatogenesis or Reproductive Hormones
- Author
-
James W. Overstreet, Khalil Saikali, Wei Shen, Wayne J.G. Hellstrom, Vish Watkins, Charles M. Beasley, and Albert Yu
- Subjects
Male ,medicine.medical_specialty ,Phosphodiesterase Inhibitors ,Urology ,Placebo ,Tadalafil ,3',5'-Cyclic-GMP Phosphodiesterases ,Semen ,Internal medicine ,medicine ,Humans ,Testosterone ,Gonadal Steroid Hormones ,Spermatogenesis ,Cyclic Nucleotide Phosphodiesterases, Type 5 ,Phosphoric Diester Hydrolases ,business.industry ,Luteinizing Hormone ,Middle Aged ,medicine.disease ,Sperm ,Endocrinology ,Erectile dysfunction ,Sperm Motility ,Follicle Stimulating Hormone ,Luteinizing hormone ,business ,Carbolines ,medicine.drug ,Hormone - Abstract
We assessed the effects on spermatogenesis of placebo vs 10 or 20 mg tadalafil administered daily for 6 months to healthy men and men with mild erectile dysfunction.In 2 studies 421 healthy men or men with mild erectile dysfunction who were 45 years or older and met semen criteria derived from WHO reference values were randomized to 6 months of treatment with placebo (101) or 10 mg tadalafil (103), or to placebo (106) or 20 mg tadalafil (111). Semen samples and serum for reproductive hormones (testosterone, luteinizing hormone and follicle-stimulating hormone) were collected at baseline, after 3 months and at the end of treatment.Tadalafil had no adverse effects on spermatogenesis, as assessed by sperm concentration, sperm count per ejaculate, percent sperm motility, normal morphology or serum reproductive hormones. Tadalafil was well tolerated. Common adverse events were headache, dyspepsia and back pain.Chronic daily administration of tadalafil at doses of 10 and 20 mg for 6 months had no adverse effects on spermatogenesis or on reproductive hormones in men older than 45 years.
- Published
- 2003
19. An Integrated Analysis of Acute Treatment-Emergent Extrapyramidal Syndrome in Patients With Schizophrenia During Olanzapine Clinical Trials
- Author
-
Hank Wei, Charles M. Beasley, P. Cavazzoni, Paul Berg, Christopher Carlson, and John M. Kane
- Subjects
Adult ,Male ,Olanzapine ,medicine.medical_specialty ,Akathisia ,Placebo ,Gastroenterology ,Cholinergic Antagonists ,Placebos ,Benzodiazepines ,Basal Ganglia Diseases ,Double-Blind Method ,Internal medicine ,medicine ,Haloperidol ,Humans ,Clozapine ,Randomized Controlled Trials as Topic ,Retrospective Studies ,Risperidone ,Dopamine antagonist ,Pirenzepine ,Barnes Akathisia Scale ,Psychiatry and Mental health ,Anesthesia ,Acute Disease ,Schizophrenia ,Female ,medicine.symptom ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Background: The frequency and severity of extrapyramidal syndrome (EPS) were evaluated in patients with DSM-III or DSM-IV schizophrenia in the acute phase (≤ 8 weeks) of randomized, double-blind, controlled trials from the integrated olanzapine clinical trial database. Method: This retrospective analysis included 23 clinical trials and 4611 patients from November 11, 1991, through July 31, 2001. Incidences of dystonic, parkinsonian, and akathisia events were compared using treatment-emergent adverse-event data. Categorical analyses of Simpson-Angus Scale and Barnes Akathisia Scale (BAS) scores, use of anticholinergic medications, and baseline-to-endpoint changes in Simpson-Angus Scale and BAS scores were compared. Results: A significantly smaller percentage of olanzapine-treated patients experienced dystonic events than did haloperidol- (p
- Published
- 2003
20. Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients
- Author
-
Charles M. Beasley, Stacy R. Lindborg, Karla Alaka, and Cindy C. Taylor
- Subjects
Olanzapine ,Bipolar Disorder ,Psychomotor agitation ,medicine.medical_treatment ,Placebo ,Injections, Intramuscular ,QT interval ,Benzodiazepines ,Electrocardiography ,Double-Blind Method ,mental disorders ,Haloperidol ,medicine ,Humans ,Antipsychotic ,Psychomotor Agitation ,Biological Psychiatry ,Dose-Response Relationship, Drug ,Dopamine antagonist ,Long QT Syndrome ,Psychiatry and Mental health ,Anesthesia ,Schizophrenia ,Dementia ,medicine.symptom ,Psychology ,Mania ,Antipsychotic Agents ,medicine.drug - Abstract
Prolongation of the QTc interval has been reported during treatment with oral antipsychotic agents and may be more pronounced during parenteral administration. Pooled QTc interval data from acutely agitated patients across four double-blind trials were compared. Databases included: placebo-controlled [two schizophrenia, one bipolar mania trials (n=565)]; haloperidol-controlled [two schizophrenia trials (n=482)]; geriatric placebo-controlled [1 dementia trial (n=204)]. Patients received 1-3 injections of intramuscular (IM) olanzapine (2.5-10 mg/injection), IM haloperidol (7.5 mg/injection), or IM placebo. At 2 and 24 h after IM olanzapine treatment, the mean QTc interval decreased approximately 3 ms from baseline in the placebo- and haloperidol-controlled databases. When there was a statistically significant difference between IM olanzapine and IM placebo, QTc intervals decreased during treatment with IM olanzapine and increased with IM placebo. The incidences of prolonged (endpoint >/=99th percentile of healthy adults or >/=500 ms) or lengthened (increase >/=60 ms) QTc intervals during treatment with IM olanzapine (
- Published
- 2003
21. Extrapyramidal symptom profiles assessed with the Drug-Induced Extrapyramidal Symptom Scale: comparison with Western scales in the clinical double-blind studies of schizophrenic patients treated with either olanzapine or haloperidol
- Author
-
Charles M. Beasley, Yoko Tanaka, Daniel J. Walker, and Toshiya Inada
- Subjects
Adult ,Male ,Olanzapine ,medicine.medical_specialty ,medicine.medical_treatment ,Akathisia ,Diagnosis, Differential ,Benzodiazepines ,Basal Ganglia Diseases ,Extrapyramidal symptoms ,Internal medicine ,Odds Ratio ,Prevalence ,medicine ,Haloperidol ,Humans ,Pharmacology (medical) ,Antipsychotic ,Retrospective Studies ,Psychiatric Status Rating Scales ,Incidence ,Incidence (epidemiology) ,Pirenzepine ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Dyskinesia ,Schizophrenia ,Anesthesia ,Female ,medicine.symptom ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
The superiority of olanzapine to haloperidol with respect to a decreased incidence of treatment-emergent extrapyramidal syndromes (EPS) in patients with schizophrenia was demonstrated in studies conducted in both Japan and Western countries. EPS measurements used in Western countries included the Simpson-Angus, Barnes akathisia and the Abnormal Involuntary Movement Scale, while the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) was used in Japan. The aim of this study was to clarify how the DIEPSS captures EPS profiles. The baseline prevalence and treatment-emergent incidence of EPS in Japanese schizophrenic patients treated with olanzapine or haloperidol were retrospectively compared as assessed by the DIEPSS to the prevalence and incidence of EPS in primarily Caucasian schizophrenic patients who were treated with olanzapine or haloperidol. Specifically, the prevalence and incidence of dyskinesia, akathisia and parkinsonism were compared between the Japanese trial and an international trial to examine if appropriate definitions using the DIEPSS can be derived assuming that a comparable prevalence and incidence of the syndromes would be observed when any differences in residual antipsychotic exposure at the initiation of study treatment were accounted for. For the incidence of all EPS syndromes, odds ratios were observed to be similar between the two studies, indicating that appropriate criteria for the clinical diagnosis of the EPS syndromes could be established based on the DIEPSS. This preliminary and retrospective work suggests that the DIEPSS can be used to operationally define the presence or absence, and make the clinical diagnosis, of specific EPS syndromes.
- Published
- 2003
22. Fluoxetine and norfluoxetine plasma concentrations during relapse-prevention treatment
- Author
-
Jay D. Amsterdam, Jerrold F. Rosenbaum, Jan Fawcett, Charles M. Beasley, Frederic M. Quitkin, David J. Brunswick, and Frederick W. Reimherr
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Relapse prevention ,Placebo ,Gastroenterology ,Drug Administration Schedule ,law.invention ,Double-Blind Method ,Maintenance therapy ,Randomized controlled trial ,Recurrence ,law ,Fluoxetine ,Internal medicine ,medicine ,Humans ,Aged ,Depressive Disorder, Major ,Chemotherapy ,Middle Aged ,Long-Term Care ,Psychiatry and Mental health ,Clinical Psychology ,Treatment Outcome ,Endocrinology ,Antidepressant ,Female ,Reuptake inhibitor ,Psychology ,medicine.drug - Abstract
Background: Virtually no attention has been given to the relationship between antidepressant plasma drug concentrations and relapse-prevention during maintenance therapy. The purpose of this study was to investigate the relationship between steady-state plasma drug concentrations and outcome during relapse-prevention therapy with fluoxetine. Methods: The patients studied had responded to acute fluoxetine treatment for major depression (defined by DSM-III-R). Patients who met criteria for remission after 10–12 weeks of open-label acute fluoxetine therapy (N=395 of 839 patients), were randomly assigned to one of four treatment arms (50 weeks of fluoxetine, 38 weeks of fluoxetine followed by 12 weeks of placebo, 14 weeks of fluoxetine followed by 36 weeks of placebo and 50 weeks of placebo). Plasma fluoxetine and norfluoxetine concentrations were measured (1) after 4 and 8 weeks of open-label treatment and (2) at the beginning and after 14 weeks of double-blind, relapse-prevention therapy. Results: Mean drug plasma levels were stable throughout the study. There was no significant difference in steady state plasma levels for the patients who relapsed compared to those who completed fluoxetine therapy without relapsing after 14, 38 or 50 weeks of fluoxetine relapse-prevention treatment. In addition, time-to-relapse was not related to steady-state drug plasma levels. Finally, after dividing patients into two groups based on their drug plasma levels, no significant differences were seen in the cumulative proportions of patients staying well during relapse-prevention therapy. Discussion: Plasma concentrations of fluoxetine and/or its metabolite norfluoxetine, are not correlated with relapse in patients treated with a fixed dose of 20 mg/day fluoxetine. Fluoxetine plasma levels cannot be used to guide relapse-prevention treatment.
- Published
- 2002
23. Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings
- Author
-
Malcolm I. Mitchell, Charles M. Beasley, and Alex Dmitrienko
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Ventricular Repolarization ,medicine.medical_specialty ,business.industry ,RR interval ,12 lead ecg ,General Medicine ,QT interval ,Internal medicine ,Heart rate ,cardiovascular system ,medicine ,Cardiology ,Pharmacology (medical) ,cardiovascular diseases ,General Pharmacology, Toxicology and Pharmaceutics ,Degree of certainty ,business - Abstract
The QT interval from the ECG cannot be measured precisely. The relationship of the QT interval to the RR interval within individuals across time and different RR values, and across individuals eludes complete understanding. Intrinsic beat-to-beat variability in QT interval corrected for heart rate (QTc interval) is not trivial. Therefore, it is difficult to determine a valid and reliable estimate of the time for ventricular repolarization based on the QTc interval. Yet, it must be demonstrated that a drug does not result in an increase in the QTc interval that exceeds 5 ms with some reasonable degree of certainty to be quite confident that the drug does not convey some risk of ventricular tachydysrhythmia due to delayed ventricular repolarization. This demonstration can be a Herculean task due to the magnitude of variability in the QTc interval. Design features and analytical methods that might be used in the thorough QT study to improve the chances of demonstrating the true relationship between a drug and QTc interval are reviewed.
- Published
- 2014
24. Analysis of the QTc Interval During Olanzapine Treatment of Patients With Schizophrenia and Related Psychosis
- Author
-
Joerg Czekalla, Mary Anne Dellva, Charles M. Beasley, Paul Berg, and S. L. Grundy
- Subjects
Adult ,Male ,Olanzapine ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Ventricular tachycardia ,QT interval ,Sudden death ,Sudden cardiac death ,Placebos ,Benzodiazepines ,Electrocardiography ,Heart rate ,medicine ,Haloperidol ,Adverse Drug Reaction Reporting Systems ,Humans ,cardiovascular diseases ,Aged ,business.industry ,Incidence ,Dopamine antagonist ,Arrhythmias, Cardiac ,Pirenzepine ,Middle Aged ,Risperidone ,medicine.disease ,Long QT Syndrome ,Psychiatry and Mental health ,Anesthesia ,Acute Disease ,Schizophrenia ,cardiovascular system ,Female ,business ,Antipsychotic Agents ,circulatory and respiratory physiology ,medicine.drug - Abstract
Background: There may be a temporal association between some antipsychotics and prolongation of the heart-rate-corrected QT interval (QTc) representing a delay in ventricular repolarization. QTc prolongation significantly exceeding normal intra-individual and interindividual variation may increase the risk of ventricular tachydysrhythmias, especially torsade de pointes, and therefore, sudden cardiac death. Method: Electrocardiogram recordings obtained as part of the safety assessment of olanzapine in 4 controlled, randomized clinical trials (N = 2700) were analyzed. These analyses were conducted to characterize any change in QTc temporally associated with olanzapine, compared with placebo, haloperidol, and risperidone, in acutely psychotic patients (DSM-III-R and DSM-IV) and to characterize variability and temporal course of the QTc in this patient population. Changes from baseline to minimum and maximum QTc were tested for significance, and baseline to acute-phase endpoint change in mean QTc was tested for significance within treatments and for differences between olanzapine and comparators. The possibility of a linear relationship between dose of olanzapine and mean change in QTc, as well as incidence of treatment-emergent prolongation of QTc (change from < 430 msec at baseline to ≥ 430 msec at endpoint), was tested. Results: The incidence of maximum QTc ≥ 450 msec during treatment was approximately equal to the incidence of QTc ≥ 450 msec at baseline. Conclusion: Results of these analyses suggest that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute to QTc prolongation resulting in potentially fatal ventricular arrhythmias.
- Published
- 2001
25. A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data
- Author
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Donald P. Hay, Christian C. Felder, David O. Calligaro, Alan Breier, Martin Dossenbach, Mark Bernauer, John H. Holcombe, Christopher Kaiser, Bruce J. Kinon, John S. Kennedy, Mark B. Effron, Charles M. Beasley, Robert W. Baker, H. John Roth, George G. Nomikos, Leslie M. Schuh, and Frank P. Bymaster
- Subjects
Olanzapine ,medicine.medical_specialty ,Psychosis ,medicine.medical_treatment ,Weight change ,medicine.disease ,Symptomatic relief ,Psychiatry and Mental health ,Extrapyramidal symptoms ,Internal medicine ,medicine ,Bipolar disorder ,Geriatrics and Gerontology ,medicine.symptom ,Psychiatry ,Antipsychotic ,Psychology ,Mania ,medicine.drug - Abstract
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 11, 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 patterns of any age with schizophrenia and acute bipolar mania, as well as in treatment of patients with some type, of neurodegenerative disorders. Copyright (C) 2001 John Wiley Sons, Ltd.
- Published
- 2001
26. Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: An updated meta-analysis
- Author
-
Stephanie C. Koke, Charles M. Beasley, Jill S. Gonzales, and Mary E. Nilsson
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Population ,Antidepressive Agents, Tricyclic ,Placebo ,Double-Blind Method ,Fluoxetine ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Child ,education ,Adverse effect ,Aged ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,Pharmacology ,Depressive Disorder, Major ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,Discontinuation ,Clinical trial ,Anesthesia ,Antidepressive Agents, Second-Generation ,Major depressive disorder ,Female ,business ,Reuptake inhibitor ,medicine.drug - Abstract
A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agent's more favorable adverse-event profile compared with tricyclic antidepressants (TCAs).The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted.Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups.The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P0.001). The most common events (or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients.Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.
- Published
- 2000
27. Efficacy, Adverse Events, and Treatment Discontinuations in Fluoxetine Clinical Studies of Major Depression
- Author
-
Jill S. Gonzales, Stephanie C. Koke, Charles M. Beasley, and Mary E. Nilsson
- Subjects
Adult ,Male ,Nausea ,Sedation ,Placebo ,Severity of Illness Index ,Drug Administration Schedule ,Placebos ,Double-Blind Method ,Fluoxetine ,Sleep Initiation and Maintenance Disorders ,medicine ,Humans ,Adverse effect ,Rhinitis ,Depressive Disorder ,business.industry ,Headache ,Hamilton Rating Scale for Depression ,Discontinuation ,Psychiatry and Mental health ,Treatment Outcome ,Anesthesia ,Female ,Chills ,medicine.symptom ,business ,medicine.drug - Abstract
BACKGROUND: The efficacy and safety of fluoxetine in adults with moderate-to-severe major depression are well established. However, most analyses combined dosages (20-80 mg/day) of the compound. We hypothesized that in patients taking 20 mg/day, efficacy would be maintained but the incidence of adverse events would be lower. We present a meta-analysis of efficacy and safety data for fluoxetine, 20 mg/day. METHOD: Data were from 3 double-blind studies (N = 417) that included patients with moderate-to-severe major depression (DSM-III or DSM-III-R criteria) who received placebo or fixed-dose 20-mg/day treatment with fluoxetine. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D; HAM-D-17 total score and anxiety/somatization, retardation, sleep disturbance, and cognitive disturbance factors) and response and remission rates. Safety assessments included treatment-emergent adverse events, reasons for discontinuation, and adverse events leading to discontinuation. Adverse events were evaluated to determine the emergence of activation and/or sedation. RESULTS: At 20 mg/day, fluoxetine-treated patients demonstrated significantly greater remission and response rates and mean changes on HAM-D-17 total score and anxiety/somatization, retardation, and cognitive disturbance factor scores than placebo-treated patients (p < .001). The incidence of specific adverse events leading to discontinuation and the frequency of study discontinuations due to adverse events were similar among fluoxetine-treated and placebo-treated patients (6.1% vs. 5.8%, p = .879). Several adverse events (insomnia, asthenia, somnolence, gastroenteritis, decreased libido, chills, and confusion) occurred significantly more frequently among fluoxetine-treated patients. A significant change in sedation, but not activation, occurred in patients in the fluoxetine 20-mg/day group compared with the placebo group. CONCLUSION: These data affirm that fluoxetine at 20 mg/day is efficacious, safe, and of similar activation potential when compared with placebo in patients with major depression.
- Published
- 2000
28. Fluoxetine efficacy in menopausal women with and without estrogen replacement
- Author
-
Felipe Garcia-Espana, Jay D. Amsterdam, Charles M. Beasley, Jan Fawcett, Fredrick W. Reimherr, Jerrold F. Rosenbaum, and Frederic M. Quitkin
- Subjects
Male ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Fluoxetine ,Internal medicine ,medicine ,Humans ,Depression (differential diagnoses) ,Climacteric ,Retrospective Studies ,Depressive Disorder, Major ,Chemotherapy ,Estrogen Replacement Therapy ,Middle Aged ,medicine.disease ,Menopause ,Psychiatry and Mental health ,Clinical Psychology ,Treatment Outcome ,Endocrinology ,Estrogen ,Antidepressive Agents, Second-Generation ,Antidepressant ,Drug Therapy, Combination ,Female ,Age of onset ,Reuptake inhibitor ,Psychology ,medicine.drug - Abstract
A gradual decline in estrogen levels after the age of 40 may contribute to a higher rate of depression in women over 45 years of age. Estrogen replacement therapy (ERT) has been shown to produce cognitive and mood-enhancing effects in women and may facilitate antidepressant activity.We examined the efficacy rates in women on ERTor = 45 years (n = 40) compared to womenor = 45 years not on ERT (n = 132) and to women45 years (n = 396) and to men (n = 262) with major depression during fluoxetine 20 mg daily up to 8 weeks. Remitters with a HAM-D17 scoreor = 7 from week 9 to 12 were then treated up to 1-year in a placebo-controlled, relapse-prevention trial.Efficacy rates were similar in womenor = 45 years on ERT when compared to womenor = 45 years taking fluoxetine alone, and when compared to women45 years and men taking fluoxetine. A Kaplan-Meier survival analysis in fluoxetine responders treated up to 26 weeks showed a somewhat greater relapse rate in womenor = 45 years taking ERT compared to other treatment groups (P0.06).This study was retrospective nature and ERT was given in an uncontrolled fashion: 63% of women received estrogen alone while 37% also took intermittent progesterone. Other variables include the absence of hormonal documentation of menopausal status, no direct assessment of ERT compliance and the use of fixed-dose fluoxetine 20 mg daily.In contrast to prior reports suggesting that ERT may facilitate antidepressant activity, we observed similar efficacy in depressed womenor = 45 years taking fluoxetine plus ERT compared to those taking fluoxetine alone.
- Published
- 1999
29. Changes in Adverse Events Reported by Patients During 6 Months of Fluoxetine Therapy
- Author
-
David Michelson, Jay D. Amsterdam, Jerrold F. Rosenbaum, Roy N. Tamura, Karen Sundell, Frederic M. Quitkin, John Zajecka, Charles M. Beasley, and Frederick W. Reimherr
- Subjects
medicine.medical_specialty ,Nausea ,medicine.medical_treatment ,Anxiety ,Drug Administration Schedule ,law.invention ,Placebos ,Double-Blind Method ,Randomized controlled trial ,law ,Fluoxetine ,Sleep Initiation and Maintenance Disorders ,Surveys and Questionnaires ,Internal medicine ,Secondary Prevention ,medicine ,Humans ,Psychiatry ,Adverse effect ,Depression (differential diagnoses) ,Depressive Disorder ,Chemotherapy ,business.industry ,Headache ,Clinical trial ,Psychiatry and Mental health ,Treatment Outcome ,Sleep Stages ,medicine.symptom ,business ,Selective Serotonin Reuptake Inhibitors ,Somnolence ,Follow-Up Studies ,medicine.drug - Abstract
Background: Although a period of 6 to 12 months of antidepressant therapy is recommended for most patients with depression, systematic examinations of the course of adverse events over time, the resolution of early-onset events, and the possible emergence of later-onset events are limited. We examined the safety of fluoxetine, 20 mg/day, in a large, prospective, long-term treatment trial, and we report a comparison of early- and late-onset adverse events and the course of adverse events over 26 weeks of treatment. Method: Adverse events were recorded at each visit in a uniform format by open-ended questioning, regardless of perceived causality. New or worsened events reported in either the first 4 weeks of treatment (early-reporting interval) or weeks 22 through 26 of treatment (late-reporting interval) were compared. Results: Patients (N = 299) whose depression (DSM-III-R) remitted with 12 weeks of fluoxetine treatment entered continuation therapy, and 174 completed 26 weeks of therapy. All events that occurred in ≥ 5% of patients early in treatment decreased in frequency over time (p
- Published
- 1999
30. Blood Pressure Changes During Short-Term Fluoxetine Treatment
- Author
-
Jerrold F. Rosenbaum, Jay D. Amsterdam, Jan Fawcett, Charles M. Beasley, Frederick W. Reimherr, Frederick M. Quitkin, and Felipe Garcia-Espana
- Subjects
Adult ,Male ,Adolescent ,Blood Pressure ,Venlafaxine ,Sitting ,Placebo ,law.invention ,Double-Blind Method ,Randomized controlled trial ,law ,Fluoxetine ,medicine ,Humans ,Pharmacology (medical) ,Depression (differential diagnoses) ,Aged ,Depression ,business.industry ,Middle Aged ,Psychiatry and Mental health ,Blood pressure ,Anesthesia ,Hypertension ,Antidepressive Agents, Second-Generation ,Female ,Reuptake inhibitor ,business ,medicine.drug - Abstract
Recent reports of sustained hypertension in some patients receiving venlafaxine have rekindled concerns about antidepressant-induced hypertension. This study examined sitting and standing systolic and diastolic blood pressure, pulse rate, and rate of sustained hypertension in 796 depressed patients (mean +/- SD age, 40 +/- 11 years) taking fluoxetine 20 mg daily for up to 12 weeks. A modest reduction in sitting and standing systolic (p0.001) and diastolic (p0.001) blood pressure measures were observed in the entire patient sample. Patients with pretreatment diastolic blood pressure60 mmHg (N = 32) showed a modest increase in mean diastolic blood pressure (p0.001), whereas patients with pretreatment diastolic blood pressureor = 90 mmHg andor = 95 mmHg (N = 57) had a modest reduction in mean diastolic blood pressure (p0.001). Patients with preexisting, stable cardiovascular disease (including hypertension) (N = 35) showed no significant blood pressure change (p = not significant). Of the patients receiving fluoxetine, 1.7% had sustained hypertension foror = 3 consecutive clinic visits-a rate significantly lower than that previously reported with venlafaxine (4.8%) (chi2 = 13.3, p0.001) and similar to that previously seen with placebo (2.1%). In conclusion, these data demonstrate a low rate of sustained hypertension (1.7%) during short-term fluoxetine treatment.
- Published
- 1999
31. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol
- Author
-
Hal Morgenstern, Roy N. Tamura, William M. Glazer, Kevin J. Ferguson, Mary Anne Dellva, Gary D. Tollefson, and Charles M. Beasley
- Subjects
Olanzapine ,Dyskinesia, Drug-Induced ,Pediatrics ,medicine.medical_specialty ,medicine.medical_treatment ,050109 social psychology ,Tardive dyskinesia ,Rate ratio ,Benzodiazepines ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Risk Factors ,Haloperidol ,Humans ,Medicine ,0501 psychology and cognitive sciences ,Risk factor ,Antipsychotic ,business.industry ,05 social sciences ,Pirenzepine ,medicine.disease ,Survival Analysis ,030227 psychiatry ,Psychiatry and Mental health ,Dyskinesia ,Anesthesia ,Schizophrenia ,Abnormal Involuntary Movement Scale ,medicine.symptom ,business ,Antipsychotic Agents ,medicine.drug - Abstract
BackgroundTardive dyskinesia is important in the side-effect profile of antipsychotic medication.AimsThe development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years.MethodsTardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD); it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated.ResultsThe relative risk of tardive dyskinesia for the overall follow-up period for haloperidol (n=522) v. olanzapine (n=1192) was 2.66 (95% CI=1.50–4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n=513) and 7.45% with haloperidol (n=114). The relative risk throughout this follow-up period was 11.37 (95% Cl=2.21–58.60).ConclusionOur results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.
- Published
- 1999
32. [Untitled]
- Author
-
Dara Ganoczy, Susan H. Hamilton, Dennis A. Revicki, Charles M. Beasley, and Laura A. Genduso
- Subjects
Olanzapine ,medicine.medical_specialty ,medicine.drug_class ,Public Health, Environmental and Occupational Health ,Atypical antipsychotic ,Schizoaffective disorder ,medicine.disease ,Extrapyramidal symptoms ,Schizophrenia ,Internal medicine ,medicine ,Haloperidol ,Schizophreniform disorder ,medicine.symptom ,Psychiatry ,Psychology ,medicine.drug ,Diagnosis of schizophrenia - Abstract
Background: Little information is available on the impact of the atypical antipsychotic olanzapine on quality of life (QOL). A 6-week, double-blind randomized multicenter trial, with a long-term extension, was conducted to evaluate the clinical efficacy and QOL of olanzapine and haloperidol in treating schizophrenia and other psychotic disorders. Methods: A total of 828 outpatients provided QOL data. Study patients were aged greater than 18 years with a DSM-III-R diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and baseline BPRS (items scored on 0–6 scale) total scores, ≥18 were randomized to 6 weeks of treatment with olanzapine 5 to 20 mg/day or haloperidol 5 to 20 mg/day. Patients entered a 46-week double-blind extension if they demonstrated minimal clinical response and were tolerant to study medication. The Quality of Life Scale (QLS) and SF-36 Health Survey were used to evaluate QOL. Results: During the 6-week acute phase, olanzapine treatment significantly improved BPRS total (p = 0.004), PANSS total scores (p = 0.043), QLS total (p = 0.005), intrapsychic foundations (p < 0.001) and interpersonal relations scores (p = 0.036), and SF-36 mental component summary scores (p < 0.001) compared with haloperidol. During the extension phase, olanzapine treatment significantly improved PANSS negative scores (p = 0.035) and improved QLS total (p = 0.001), intrapsychic foundations (p < 0.001), and instrumental role category scores (p = 0.015) versus haloperidol treatment. Significantly more haloperidol patients discontinued treatment due to adverse events during the acute and extension phases (p = 0.041 and p = 0.014, respectively). Changes in QLS total and MCS scores were associated with changes in clinical symptoms, depression scores and extrapyramidal symptoms. Conclusions: Olanzapine was more effective than haloperidol in reducing severity of psychopathology and in improving QOL in patients with schizophrenia and other psychotic disorders. The QOL benefits of olanzapine, although modest, may be important for long-term treatment.
- Published
- 1999
33. Efficacy and Safety of Fluoxetine in Treating Bipolar II Major Depressive Episode
- Author
-
Frederick W. Reimherr, Charles M. Beasley, Jerrold F. Rosenbaum, Edward Schweizer, Felipe Garcia-Espana, Jay D. Amsterdam, Jan Fawcett, and Frederick M. Quitkin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Bipolar Disorder ,Adolescent ,medicine.drug_class ,Placebo ,law.invention ,Double-Blind Method ,Randomized controlled trial ,Recurrence ,law ,Fluoxetine ,Sleep Initiation and Maintenance Disorders ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Bipolar disorder ,Age of Onset ,Child ,Major depressive episode ,Psychiatry ,Aged ,Retrospective Studies ,Headache ,Hamilton Rating Scale for Depression ,Mood stabilizer ,Middle Aged ,medicine.disease ,Discontinuation ,Psychiatry and Mental health ,Treatment Outcome ,Antidepressive Agents, Second-Generation ,Female ,medicine.symptom ,Psychology ,medicine.drug - Abstract
As many as 45% of patients with major depressive episode also meet DSM-IV criteria for bipolar II (BP II) disorder. Although some clinicians advocate using a mood stabilizer in treating BP II depression, antidepressant monotherapy has been less well studied in this disorder. As part of a prospective, placebo-controlled, relapse-prevention study in 839 patients, the efficacy and safety of short- and long-term fluoxetine treatment in patients with BP II major depression compared with patients with unipolar (UP) major depression was retrospectively examined. Eighty-nine BP II patients (mean age, 41+/-11 years) were compared with 89 age- and gender-matched UP patients and with 661 unmatched UP patients (mean age, 39+/-11 years). All received short-term fluoxetine therapy at 20 mg daily for up to 12 weeks. Complete remission was defined as a final Hamilton Rating Scale for Depression score < or = 7 by week 9 that was then maintained for 3 additional weeks. Remitted patients were then randomly assigned to receive double-blind treatment with one of the following: (1) fluoxetine 20 mg daily for 52 weeks; (2) fluoxetine for 38 weeks, then placebo for 14 weeks; (3) fluoxetine for 14 weeks, then placebo for 38 weeks; or (4) placebo for 52 weeks. Antidepressant efficacy was similar in BP and UP patients during short-term therapy. Discontinuation for lack of efficacy was lower in BP II (5%) than in UP (12%) patients (p = not significant [NS]), whereas dropouts for adverse events were similar in BP II (11%) and UP (9%) patients. During long-term relapse-prevention therapy, relapse rates were similar in BP II and UP patients (p = NS). During short-term fluoxetine therapy, three BP II (3.8%) versus no matched UP (p = NS) and 0.3% unmatched UP (p = 0.01) patients had a "manic switch." During long-term fluoxetine therapy, one (2%) BP II and three (1%) unmatched UP patients (one taking placebo) had a manic switch (p = NS). In conclusion, fluoxetine may be a safe and effective antidepressant monotherapy for the short-term treatment of BP II depression with a relatively low manic switch rate. Fluoxetine may also be effective in relapse-prevention therapy in patients with BP II disorder.
- Published
- 1998
34. Safety of Abrupt Discontinuation of Fluoxetine
- Author
-
Frederic M. Quitkin, Jay D. Amsterdam, David Michelson, Frederick W. Reimherr, Jan Fawcett, Jerrold F. Rosenbaum, John Zajecka, and Charles M. Beasley
- Subjects
Adult ,Male ,Randomization ,Lightheadedness ,Placebo-controlled study ,Placebo ,Dizziness ,law.invention ,Double-Blind Method ,Randomized controlled trial ,law ,Fluoxetine ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,Adverse effect ,Depressive Disorder ,Middle Aged ,Substance Withdrawal Syndrome ,Discontinuation ,Psychiatry and Mental health ,Anesthesia ,Antidepressive Agents, Second-Generation ,Female ,medicine.symptom ,Psychology ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Selective serotonin reuptake inhibitors may be associated with new adverse events after abrupt discontinuation. Hypothesizing that the long half-life of fluoxetine would be protective, this study analyzed the effects of abrupt fluoxetine discontinuation during a randomized, double-blind, placebo-controlled study of depression maintenance treatment. After 12 weeks of fluoxetine treatment (20 mg/day), 395 responders were abruptly randomized to placebo (N = 96) or to continued fluoxetine (N = 299). Patients were seen at weeks 1, 2, 4, and 6 after randomization. Reports of new or worsened adverse events were similar for both groups at each visit after randomization. Patient discontinuations related to adverse events were also similar in both groups. Mild, self-limited lightheadedness or dizziness occurred in a small percentage of patients who discontinued fluoxetine treatment but was of little clinical significance. No cluster of symptoms suggestive of a discontinuation syndrome was observed. Abrupt discontinuation of fluoxetine treatment was well tolerated and did not seem to be associated with significant clinical risk. Fluoxetine may offer a potential safety advantage over shorter-acting agents with respect to treatment interruption and/or discontinuation and may be a better choice for those patients who are likely to miss doses because of travel or forgetfulness.
- Published
- 1998
35. Standard olanzapine versus placebo and ineffective-dose olanzapine in the maintenance treatment of schizophrenia
- Author
-
Gary D. Tollefson, Charles M. Beasley, Pierre V. Tran, Wentley Al, and Mary Anne Dellva
- Subjects
Adult ,Male ,Olanzapine ,medicine.medical_specialty ,Psychosis ,Adolescent ,Exacerbation ,Placebo ,Drug Administration Schedule ,law.invention ,Placebos ,Benzodiazepines ,Double-Blind Method ,Maintenance therapy ,Randomized controlled trial ,Recurrence ,Risk Factors ,law ,Internal medicine ,Brief Psychiatric Rating Scale ,medicine ,Humans ,Life Tables ,Psychiatry ,Aged ,Psychiatric Status Rating Scales ,Pirenzepine ,Middle Aged ,medicine.disease ,Survival Analysis ,Psychiatry and Mental health ,Treatment Outcome ,Schizophrenia ,Acute Disease ,Female ,Schizophrenic Psychology ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Objective Two studies compared the efficacy of standard-dose oral olanzapine (5 to 15 mg a day) with placebo and with ineffective-dose olanzapine (1 mg a day) in maintenance therapy of schizophrenia. Methods The studies were 46-week double-blind extensions of multicenter studies that assessed the efficacy of olanzapine in the acute treatment of schizophrenia. Subjects were 120 adults who met DSM-III-R criteria for schizophrenia with an acute exacerbation and who had a minimum score of 24 on the Brief Psychiatric Rating Scale, who had responded to acute therapy (defined as at least a 40 percent reduction in the BPRS score from baseline or a score of 18 or less during up to six weeks of treatment), and who were outpatients at their last acute-phase visit. Relapse was defined as hospitalization for psychopathology. Relapse risk was analyzed using Kaplan-Meier survival analysis and life table analysis. Patients who relapsed were discontinued from the studies. Results In the first study (N = 58), patients in the standard-dose olanzapine group experienced a significantly lower relapse risk (p = .002) over one year than patients treated with placebo. The estimated one-year risk of relapse with olanzapine was 28.6 percent, compared with 69.9 percent with placebo. Results were similar in the second study (N = 62); patients treated with standard-dose olanzapine had a significantly reduced risk of relapse (p = .018) over one year compared with patients treated with ineffective-dose olanzapine. The estimated one-year risks of relapse were 19.6 percent for standard-dose olanzapine and 45.5 percent for ineffective-dose olanzapine. Conclusions Olanzapine is superior to placebo and ineffective-dose olanzapine in the maintenance therapy of schizophrenia.
- Published
- 1997
36. Olanzapine Plasma Concentrations and Clinical Response in Acutely Ill Schizophrenic Patients
- Author
-
Todd M. Sanger, Paul J. Perry, and Charles M. Beasley
- Subjects
Adult ,Male ,Olanzapine ,medicine.medical_specialty ,Psychosis ,medicine.drug_class ,medicine.medical_treatment ,Atypical antipsychotic ,Placebo ,Benzodiazepines ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Chemotherapy ,medicine.diagnostic_test ,Pirenzepine ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Schizophrenia ,Therapeutic drug monitoring ,Anesthesia ,Plasma concentration ,Female ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenic patients. After a 2- to 9-day placebo lead-in, 79 inpatients with schizophrenia according to DSM-III-R criteria were placed on an olanzapine dosage of 10 mg/day or 1 mg/day for up to 6 weeks. Blood samples were obtained weekly during this period. Receiver operating characteristic curve analyses of Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale rating scale data suggested a minimum effective therapeutic concentration of 9 ng/mL. Using an intent-to treat analysis, 45% of the patients with olanzapine plasma concentrationsor = 9.3 ng/mL responded (or = 20% decrease in BPRS), whereas only 13% of the patients with concentrations9.3 ng/mL responded. Use of olanzapine plasma concentrations of9 ng/mL as a predictor for treatment response in acutely ill schizophrenic patients is practicable because this therapeutic marker significantly increases the likelihood of a patient responding to olanzapine.
- Published
- 1997
37. Fluoxetine in Medically Stable, Depressed Geriatric Patients
- Author
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Charles M. Beasley, S.H. Hamilton, Daniel N. Masica, and David J. Goldstein
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Body Mass Index ,Double-Blind Method ,Weight loss ,Fluoxetine ,Internal medicine ,Weight Loss ,medicine ,Humans ,Outpatient clinic ,Pharmacology (medical) ,Depression (differential diagnoses) ,Aged ,Aged, 80 and over ,Depressive Disorder, Major ,Chemotherapy ,business.industry ,Weight change ,Middle Aged ,Surgery ,Clinical trial ,Psychiatry and Mental health ,Antidepressive Agents, Second-Generation ,Female ,medicine.symptom ,business ,Reuptake inhibitor ,medicine.drug - Abstract
This study assessed the effect of fluoxetine 20 mg/day on weight loss in older patients treated for major depression in a multicenter, double-blind placebo-controlled, 6-week clinical trial. Thirty U.S. outpatient clinics affiliated with psychiatric programs participated in the study that involved 671 medically stable outpatients at least 60 years old who had normal cognition and met DSM-III-R criteria for major depression. Weight was recorded at weekly visits. As a measure of adiposity, patients were categorized into two groups, high and low/normal body mass index (BMI) groups. Analyses were done for each group. The high BMI group, but not the low/normal BMI group, had a statistically greater proportion of fluoxetine-treated patients who lost at least 5% of their baseline weight. Overall mean weight change for the fluoxetine-treated patients was about 1% compared with essentially no change for placebo-treated patients. Only one patients, who was treated with fluoxetine and in the low/normal BMI group, discontinued from the study because of weight loss. Although 5% weight loss occurred in more fluoxetine-treated than placebo-treated patients, most of the patients who lost weight had higher adiposity at baseline. There was not a statistically significant difference in the proportion of fluoxetine-treated and placebo-treated patients in the low/normal group who had at least 5% weight loss. Medically relevant weight loss in older patients treated with fluoxetine was uncommon.
- Published
- 1997
38. Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol
- Author
-
Roy N. Tamura, Janet H. Potvin, Pierre V. Tran, Gary D. Tollefson, and Charles M. Beasley
- Subjects
Adult ,Male ,Olanzapine ,Dyskinesia, Drug-Induced ,medicine.medical_specialty ,Tardive dyskinesia ,Severity of Illness Index ,Drug Administration Schedule ,Placebos ,Benzodiazepines ,Extrapyramidal symptoms ,Internal medicine ,medicine ,Haloperidol ,Humans ,Schizophreniform disorder ,Dose-Response Relationship, Drug ,Incidence ,Pirenzepine ,medicine.disease ,Psychiatry and Mental health ,Treatment Outcome ,Psychotic Disorders ,Dyskinesia ,Schizophrenia ,Anesthesia ,Female ,Abnormal Involuntary Movement Scale ,medicine.symptom ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Objective: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors’ goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. Method: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N=707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N=197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatmentemergent tardive dyskinesia. Results: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. Conclusions: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment. (Am J Psychiatry 1997; 154:1248‐1254)
- Published
- 1997
39. Fluoxetine and norfluoxetine plasma concentrations in major depression: a multicenter study
- Author
-
Frederick W. Reimherr, Mady Hornig-Rohan, Jan Fawcett, Jerrold F. Rosenbaum, David Michelson, Frederic M. Quitkin, Jay D. Amsterdam, and Charles M. Beasley
- Subjects
Adult ,Male ,medicine.medical_specialty ,Bipolar disorder not otherwise specified ,Drug Administration Schedule ,Sex Factors ,Fluoxetine ,Internal medicine ,Blood plasma ,medicine ,Humans ,Prospective Studies ,Depression (differential diagnoses) ,Psychiatric Status Rating Scales ,Depressive Disorder ,Major affective disorder ,Mean age ,medicine.disease ,Psychiatry and Mental health ,Treatment Outcome ,Endocrinology ,Multicenter study ,Plasma concentration ,Female ,Psychology ,medicine.drug - Abstract
Objective: Prior studies examining the relationship between fluoxetine plasma concentrations and response in major depression have either found no relationship between plasma concentration and response or suggested a curvilinear relationship with a therapeutic window. To elucidate this relationship, plasma concentrations of fluoxetine, norfluoxetine, fluoxetine plus norfluoxetine, and fluoxetine/norfluoxetine ratio were compared to therapeutic response. Method: A total of 839 patients (577 women, 262 men; mean age=40 years [SD=11]) with a DSM-III-R diagnosis of major affective disorder who were in the course of either major depression or bipolar disorder not otherwise specified and had a minimum baseline score of 16 on the 17-item Hamilton Depression Rating Scale were initially treated. Response was defined as follows: 1) nonresponders had less than a 50% reduction from baseline Hamilton depression score, 2) nonremitting responders had a 50% or more reduction from baseline Hamilton depression score but a final score higher than 7, and 3) remitters had a final Hamilton depression score of 7 or lower. Plasma fluoxetine and norfluoxetine concentrations were measured after 8 weeks of fixed-dose treatment at 20 mg/day. Results: Plasma concentration data were available from 615 patients. Plasma concentrations were similar in responders, both remitting and nonremitting (N=411), and nonresponders (N=204) for fluoxetine concentrations, for norfluoxetine concentrations, as well as for the sum of fluoxetine and norfluoxetine and for the ratio of fluoxetine to norfluoxetine. No apparent relationship was observed between plasma drug concentrations and clinical response. Conclusions: Plasma concentrations of fluoxetine and norfluoxetine do not appear to be related to clinical outcome and should not be used to make treatment decisions. (Am J Psychiatry 1997; 154:963‐969)
- Published
- 1997
40. Extrapyramidal Symptoms and Tolerability of Olanzapine Versus Haloperidol in the Acute Treatment of Schizophrenia
- Author
-
Gerilyn M. Kiesler, Pierre V. Tran, Gary D. Tollefson, Charles M. Beasley, Janet H. Potvin, and Mary Anne Dellva
- Subjects
Adult ,Male ,Olanzapine ,Patient Dropouts ,medicine.medical_treatment ,Population ,Akathisia ,Drug Administration Schedule ,Benzodiazepines ,Basal Ganglia Diseases ,Double-Blind Method ,Extrapyramidal symptoms ,medicine ,Haloperidol ,Humans ,education ,Antipsychotic ,education.field_of_study ,Incidence ,Drug Tolerance ,Pirenzepine ,Psychiatry and Mental health ,Treatment Outcome ,Dyskinesia ,Tolerability ,Anesthesia ,Schizophrenia ,Patient Compliance ,Female ,medicine.symptom ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Background: A relative lack of extrapyramidal symptoms (EPS, i.e., the syndromes of dystonia, parkinsonism, akathisia, dyskinesia) is one criterion used to determine whether an antipsychotic is atypical. The extrapyramidal symptom profiles of the novel antipsychotic olanzapine and the conventional antipsychotic haloperidol were compared in a population of 2606 patients from three well-controlled prospective clinical trials. Method: Extrapyramidal symptom data were analyzed for 1796 patients treated with olanzapine (5 to 20 mg/day) and 810 patients treated with haloperidol (5 to 20 mg/day) for up to 6 weeks of therapy. Patients were monitored weekly by three methods of extrapyramidal symptom assessment : (1) detection of extrapyramidal adverse events (signs and symptoms) by casual observation, nonprobing inquiry, and spontaneous report; (2) objective rating scale scores; and (3) use of concomitant anticholinergic medications. Emergence of EPS was assessed by (1) analysis of the incidence of extrapyramidal syndrome categories based on adverse events, (2) the incidence of extrapyramidal syndromes based on categorical analysis of rating scale scores, (3) analysis of mean maximum change in rating scale scores, and (4) categorical analysis of anticholinergic medication use. Outcome of EPS was assessed by (1) analysis of mean change in rating scale scores at endpoint and (2) mean anticholinergic use at endpoint. Results: Olanzapine was statistically significantly (p = .014, p
- Published
- 1997
41. Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial
- Author
-
Susan H. Hamilton, Jean-Noel Beuzen, Ann Marie K. Crawford, Mary Anne Dellva, Olivier Blin, Pierre V. Tran, Gary D. Tollefson, and Charles M. Beasley
- Subjects
Adult ,Male ,Olanzapine ,medicine.drug_class ,Atypical antipsychotic ,law.invention ,Benzodiazepines ,Double-Blind Method ,Randomized controlled trial ,Extrapyramidal symptoms ,law ,medicine ,Haloperidol ,Humans ,Pharmacology (medical) ,Biological Psychiatry ,Pharmacology ,business.industry ,Pirenzepine ,Middle Aged ,medicine.disease ,Barnes Akathisia Scale ,Psychiatry and Mental health ,Neurology ,Schizophrenia ,Anesthesia ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Antipsychotic Agents ,medicine.drug ,Psychopathology - Abstract
A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.
- Published
- 1997
42. Acute phase efficacy and safety of olanzapine: A review
- Author
-
Mary Anne Dellva, Pierre V. Tran, Gary D. Tollefson, Charles M. Beasley, Todd M. Sanger, and A. Kuntz
- Subjects
Pharmacology ,Olanzapine ,Psychiatry and Mental health ,Neurology ,business.industry ,Phase (matter) ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,business ,Biological Psychiatry ,medicine.drug - Published
- 1996
43. Long-term continuation therapy with the novel antipsychotic olanzapine: A review of the clinical experience
- Author
-
Charles M. Beasley, Mary Anne Dellva, Pierre V. Tran, Gary D. Tollefson, and V. Rampey
- Subjects
Pharmacology ,Olanzapine ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Term (time) ,Psychiatry and Mental health ,Continuation ,Neurology ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,Antipsychotic ,Psychiatry ,business ,Biological Psychiatry ,medicine.drug - Published
- 1996
44. Olanzapine in the treatment of schizoaffective disorder
- Author
-
Todd M. Sanger, Yili Lu, G.D. Tollefson, Pierre V. Tran, and Charles M. Beasley
- Subjects
Pharmacology ,Olanzapine ,medicine.medical_specialty ,business.industry ,Schizoaffective disorder ,medicine.disease ,Psychiatry and Mental health ,Neurology ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,Psychiatry ,business ,Biological Psychiatry ,medicine.drug - Published
- 1996
45. The course of primary and secondary negative symptoms in a placebo-and comparator-controlled trial of the typical antipsychotic olanzapine
- Author
-
Todd M. Sanger, Gary D. Tollefson, and Charles M. Beasley
- Subjects
Pharmacology ,Olanzapine ,medicine.medical_specialty ,medicine.drug_class ,business.industry ,Placebo ,Typical antipsychotic ,law.invention ,Psychiatry and Mental health ,Neurology ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Pharmacology (medical) ,Neurology (clinical) ,Psychiatry ,business ,Biological Psychiatry ,medicine.drug - Published
- 1996
46. Extrapyramidal symptoma and tolerability of olanzapine versus haloperidol in acute treatment
- Author
-
Gary D. Tollefson, W. Satterlee, Charles M. Beasley, M. Greaney, Mary Anne Dellva, and Pierre V. Tran
- Subjects
Pharmacology ,Olanzapine ,business.industry ,Psychiatry and Mental health ,Neurology ,Tolerability ,Haloperidol ,Medicine ,Pharmacology (medical) ,Neurology (clinical) ,business ,Biological Psychiatry ,medicine.drug - Published
- 1996
47. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial
- Author
-
Susan H. Hamilton, Todd M. Sanger, Charles M. Beasley, Winston Satterlee, Gary D. Tollefson, and Pierre V. Tran
- Subjects
Adult ,Male ,Olanzapine ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Atypical antipsychotic ,Placebo ,Akathisia ,Benzodiazepines ,Double-Blind Method ,Internal medicine ,Brief Psychiatric Rating Scale ,medicine ,Humans ,Antipsychotic ,Adverse effect ,Psychiatry ,Pharmacology ,Positive and Negative Syndrome Scale ,Pirenzepine ,Schizophrenia ,Female ,medicine.symptom ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Olanzapine is a potential new "atypical" antipsychotic agent. This double-blind, acute phase study compared two doses of olanzapine [1 mg/day (Olz1.0); 10 mg/day (Olz10.0)] with placebo in the treatment of 152 patients who met the DSM-III-R criteria for schizophrenia and had a Brief Psychiatric Rating Scale (BPRS)-total score (items scored 0-6)or = 24. In overall symptomatology improvement [BPRS-total score and Positive and Negative Syndrome Scale (PANSS)-total score], Olz10.0 was statistically significantly superior to placebo. In positive symptom improvement (PANSS-positive score, BPRS-positive score), Olz10.0 was statistically significantly superior to placebo. In negative symptom improvement (PANSS-negative score), Olz10.0 was statistically superior to placebo. Olz 1.0 was clinically comparable to placebo in all efficacy comparisons. The only adverse event to show an overall statistically significant incidence difference was anorexia (reported for 10% of placebo-treated and 0% of Olz10.0-treated patients). The Olz10.0-treated patients improved over baseline with respect to parkinsonian and akathisia symptoms, and these changes were comparable with those observed with placebo. There were no dystonias associated with Olz10.0 treatment. At endpoint, the incidence of patients with elevated prolactin values did not differ statistically significantly between placebo-treated and Olz10.0-treated patients. Olanzapine appears to be not only safe and effective, but a promising atypical antipsychotic candidate.
- Published
- 1996
48. Olanzapine versus Placebo and Haloperidol
- Author
-
Gary D. Tollefson, Pierre Tran, Charles M. Beasley, Susan H. Hamilton, Winston Satterlee, and Todd M. Sanger
- Subjects
Pharmacology ,Olanzapine ,Akathisia ,Placebo ,Barnes Akathisia Scale ,Psychiatry and Mental health ,Anesthesia ,Brief Psychiatric Rating Scale ,medicine ,Haloperidol ,medicine.symptom ,Psychology ,Scale for the Assessment of Negative Symptoms ,Somnolence ,medicine.drug - Abstract
Olanzapine is a potential new "atypical" antipsychotic agent. The double-blind acute phase of this study compared three dosage ranges of olanzapine (5 +/- 2.5 mg/day [Olz-L], 10 +/- 2.5 mg/day [Olz-M], 15 +/- 2.5 mg/day [Olz-H]) to a dosage range of haloperidol (15 +/- 5 mg/day [Hal]) and to placebo in the treatment of 335 patients who met the DSM-III-R criteria for schizophrenia. In overall symptomatology improvement (Brief Psychiatric Rating Scale [BPRS]-total), Olz-M, Olz-H, and Hal were significantly superior to placebo. In positive symptom improvement (BPRS-positive), Olz-M, Olz-H, and Hal were comparable and significantly superior to placebo. In negative symptom improvement (Scale for the Assessment of Negative Symptoms [SANS]-composite), Olz-L and Olz-H were significantly superior to placebo and Olz-H was also significantly superior to Hal. The most common treatment-emergent adverse events included somnolence, agitation, asthenia, and nervousness. No acute dystonia was observed with olanzapine. Treatment-emergent parkinsonism occurred with Olz-H at approximately one-third the rate of Hal, and akathisia occurred with Olz-H at approximately one-half the rate of Hal. Prolactin elevations associated with olanzapine were not significantly greater than those observed with placebo and were also significantly less than those seen with haloperidol.
- Published
- 1996
49. Fluoxetine in depressed patients with renal failure and in depressed patients with normal kidney function
- Author
-
Charles M. Beasley, Richard R. Bergstrom, Michael Blumenfield, Richard J. Solomon, Norman B. Levy, Anjani Dubey, Alvin I. Goodman, and Robert Todd
- Subjects
Adult ,Male ,medicine.medical_specialty ,Personality Inventory ,Metabolic Clearance Rate ,medicine.medical_treatment ,Population ,Urology ,Renal function ,Kidney Function Tests ,Pharmacokinetics ,Renal Dialysis ,Fluoxetine ,Internal medicine ,medicine ,Humans ,education ,Depression (differential diagnoses) ,Aged ,Depressive Disorder ,Chemotherapy ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,Psychiatry and Mental health ,Treatment Outcome ,Endocrinology ,Antidepressive Agents, Second-Generation ,Kidney Failure, Chronic ,Female ,Hemodialysis ,business ,Reuptake inhibitor ,medicine.drug - Abstract
Nine depressed patients with normal kidney function and seven depressed patients with renal failure undergoing hemodialysis were treated with open-label fluoxetine 20 mg/day in an 8-week study. The study was designed to evaluate the pharmacokinetics of fluoxetine during repeated administration and to acquire preliminary data regarding the effectiveness of this antidepressant in a population undergoing hemodialysis. Six patients in each group completed the study. Of these, five patients undergoing hemodialysis and five patients with normal renal function experienced moderate to marked improvement in their depression. Side effects were equal and minor in both groups, indicating that fluoxetine is safe in patients with renal impairment. The mean +/- standard deviation steady-state plasma concentrations of the sum of fluoxetine plus its metabolite norfluoxetine for patients completing 8 weeks (N = 6, both groups) were comparable for the patients undergoing hemodialysis (253 +/- 61 ng/ml) and those with normal kidney function (218 +/- 122 ng/ml; t = 1.5, df = 70, p > 0.13). These data suggest that the efficacy of fluoxetine in patients with renal failure undergoing hemodialysis is comparable to that in patients with normal kidney function. These data further suggest that renal failure and the process of hemodialysis do not materially alter the pharmacokinetics of fluoxetine or its major metabolite norfluoxetine.
- Published
- 1996
50. Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers
- Author
-
Corina, Loghin, Harry, Haber, Charles M, Beasley, Prajakti A, Kothare, Lynnette, Kauffman, John, April, Ling, Jin, Albert J, Allen, and Malcolm I, Mitchell
- Subjects
Adult ,Male ,Aza Compounds ,Cross-Over Studies ,Adrenergic Uptake Inhibitors ,Dose-Response Relationship, Drug ,Propylamines ,Moxifloxacin ,Atomoxetine Hydrochloride ,Electrocardiography ,Young Adult ,Cytochrome P-450 CYP2D6 ,Drug Safety ,Heart Rate ,Quinolines ,Humans ,Topoisomerase II Inhibitors ,Fluoroquinolones - Abstract
The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QT(c) in 131 healthy CYP2D6 poor metabolizer males were compared.Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days -2 and -1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QT(c)M) on day 7 was the primary endpoint.QT(c)M differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QT(c) was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QT(c)M for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration-QT(c) change observed was consistent with the literature.Atomoxetine was not associated with a clinically significant change in QT(c). However, a statistically significant increase in QT(c) was associated with increasing plasma concentrations.
- Published
- 2012
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