Adaptation of the robust method to large distributions of reference values: program modifications and comparison of alternative computational methods.

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.

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.

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.

Reference Limits for Outlier Analyses in Randomized Clinical Trials.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions.

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.

Weight changes over time in adults treated with the oral or depot formulations of olanzapine: a pooled analysis of 86 clinical trials.

Several analytical approaches were used to characterize time progression of weight changes observed in adults treated with olanzapine from a 12,425-patient database of 86 studies of oral and depot formulations of olanzapine (mean modal dose 13.3 mg/day). Descriptive mean profile plots for completer and modified completer groups showed weight increasing throughout each observed period, with apparent slowing in rate of change after 3 or 4 months. Mixed-effects model repeated measures analyses also showed that weight increased most rapidly early in treatment and slowed within 2 to 4 months. The slowing in rate of change was greatest for patients obese at baseline and least for patients underweight at baseline. This pattern was also observed in a nonparametric regression-based profile. Based on visual inspection of profile plots, 2, 3, 4, and 5 months were postulated as potential 'change points' beyond which rate of increase might slow, and the proportions of patients whose slope after each change point was ≤ 90% of the slope before change point were calculated. Over 85% of patients who gained weight showed slowing rate of weight change after each postulated change point. Potential consequences of weight gain should be considered prior to starting olanzapine. Olanzapine-treated patients should receive regular weight monitoring.

Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a brief report.

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.

Suicidality and risk of suicide--definition, drug safety concerns, and a necessary target for drug development: a consensus statement.

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 of major depression, bipolar disorder, schizophrenia, substance abuse/dependence, and other 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 scholarly article, which has been developed by the authors with feedback from all participants at the meeting and represents a consensus view. Any areas of disagreement have been noted. CONCLUSIONS: The term suicidality is not as clinically useful as more specific terminology (ideation, behavior, attempts, and suicide). Most participants applauded the FDA's effort to promote standard definitions and definable expectations for investigators and industry sponsors by endorsing the terminology in the Columbia Classification Algorithm of Suicide Assessment (C-CASA). 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 build upon its new authority to systematically monitor postmarketing events by encouraging the development of a validated instrument for postmarketing surveillance of suicidal ideation, behavior, and risk within informative large health care-related databases in the United States and abroad. Over time, the FDA, industry, and clinical researchers should evaluate the impact of the current Agency requirement that all CNS clinical drug trials must include a 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, and they need to be included to enable premarket assessments of the risks and benefits of medications related to suicidal ideation, suicidal behavior, and suicide in such patients.

Early predictors of weight gain risk during treatment with olanzapine: analysis of pooled data from 58 clinical trials.

This analysis evaluated the usefulness of different predictors in identifying patient risk of substantial weight gain (SWG) during olanzapine treatment. Data were from 58 studies with 3826 patients diagnosed with schizophrenia, schizophrenia spectrum disorders, bipolar mania, bipolar depression, or borderline personality disorder. The primary definition for SWG was gaining >/=12% of baseline weight by endpoint (30 weeks +/-5 weeks); other definitions of SWG were also examined. Potential predictors of SWG included baseline patient characteristics, weight change, and percent weight change at Weeks 1, 2, 3, and 4 after olanzapine initiation. To facilitate model building and validation, the data set was randomly partitioned into training (N = 1912), validation (N = 1149), and test (N = 765) sets and 2 complementary analytic techniques were used: logistic regression with stepwise variable selection followed by receiver operating characteristic analysis for evaluation of resulting candidate models and decision trees. Approximately 24% of patients gained >/=12% of their initial weight, about 30% gained >/=10%, and 45% gained >/=7% or >/=5 kg by the 30-week endpoint. Baseline covariates significantly and positively associated with probability of SWG were lower baseline body mass index, younger age, female sex, United States residency, and African ethnicity. Early weight changes substantially improved the prediction of the risk for longer-term SWG. These results confirm that cut-offs for weight gain during the first 4 weeks of treatment may be useful in evaluating SWG risk for an individual patient.

Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings.

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.

Fluoxetine and adult suicidality revisited: an updated meta-analysis using expanded data sources from placebo-controlled trials.

Selective serotonin reuptake inhibitor treatments have been suggested by some to induce emergence of suicidality (ideation and behaviors). The objective of this study was to assess suicidality emergence by adverse event and rating scale data in the largest available, adult, major depression, double-blind, placebo-controlled, fluoxetine trial database (18 trials). Adverse event reports and comments for patients (fluoxetine, n = 2200; placebo, n = 1551) were searched for suicide-related events that were then classified into Food and Drug Administration categories. For 16 trials, suicidality was also examined by Hamilton Depression Scale item 3 (suicide) scores, and these data were analyzed along with the combination of event-based data and scale-based data. Comparisons between treatments were made for various estimates of worsening (risk) and improvement (benefit) of suicidality. Fluoxetine treatment did not result in greater worsening but was associated with greater improvement and faster resolution of ideation (P < or = 0.05 vs placebo). Data sources were differentially sensitive in detecting changes in suicidal ideation and behaviors. Fluoxetine treatment led to greater benefit rather than risk for suicidality.

Evaluating suicide-related adverse events in clinical trials of fluoxetine treatment in adults for indications other than major depressive disorder.

BACKGROUND: The 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. METHOD: The 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. RESULTS: Within 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. CONCLUSIONS: The risk of treatment-emergent suicidality does not appear to be associated with fluoxetine treatment for adults with various non-MDD conditions.

All-cause treatment discontinuation in schizophrenia during treatment with olanzapine relative to other antipsychotics: an integrated analysis.

OBJECTIVES: Treatment continuation, as measured by time to all-cause treatment discontinuation, is a broad measure of overall treatment effectiveness. This integrated analysis compared the likelihood of discontinuation from olanzapine treatment versus other antipsychotics among patients with schizophrenia. METHODS: Clinical trials of all sponsors were included if they met the following criteria: double-blind, randomized, comparative; duration of 12 weeks or longer; no mandatory discontinuation before 12 weeks; and schizophrenia-spectrum disorders; 20 patients or more per treatment. Weighted mean hazard ratios and 95% confidence intervals were calculated from discontinuation time. Meta-analyses were performed for the following comparators that had at least 2 studies: haloperidol (5 studies), risperidone (5 studies), ziprasidone (2 studies), clozapine (3 studies), and perphenazine (2 studies) (13 studies in total; 3 included more than 1 comparator). Only 1 eligible published study was found for fluphenazine, amisulpride, and quetiapine; therefore, meta-analyses could not be performed for these comparators. RESULTS: Significantly (P < 0.05) greater likelihood of discontinuation relative to olanzapine treatment (hazard ratio [95% confidence interval]) was observed for haloperidol (1.4 [1.2-1.7]), risperidone (1.3 [1.1-1.6]), ziprasidone (1.6 [1.4-2.0]), and quetiapine (1.4 [1.1-1.9]), but not clozapine (1.2 [0.9-1.6]), fluphenazine (1.8 [0.8-4.3]), perphenazine (1.3 [0.7-2.1]), or amisulpride (1.1 [0.8-1.6]). CONCLUSIONS: These data suggest that patients with schizophrenia and related disorders may continue olanzapine treatment longer than haloperidol, risperidone, ziprasidone, or quetiapine treatment.

Early symptomatic worsening during treatment with fluoxetine in major depressive disorder: prevalence and implications.

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.

Treatment-associated suicidal ideation and adverse effects in an open, multicenter trial of fluoxetine for major depressive episodes.

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.

Effects of antipsychotic drugs on I(to), I (Na), I (sus), I (K1), and hERG: QT prolongation, structure activity relationship, and network analysis.

PURPOSE: 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. METHODS: 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. RESULTS: All molecules had little inhibitory effect on ion channels (blocking at concentrations >5 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. CONCLUSION: 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.

Is quality of life among minimally symptomatic patients with schizophrenia better following withdrawal or continuation of antipsychotic treatment?

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.

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.

OBJECTIVES: This study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval. BACKGROUND: Cardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve. METHODS: Effects 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. RESULTS: At 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 < 10 ms [actual = 4.4 ms]; post hoc, upper limit of 95% confidence interval < 5 ms [actual = 4.8]). The active control, ibutilide, significantly increased QTcI by 6.9 and 8.9 ms compared with tadalafil and placebo, respectively. Similar statistical results were obtained with four additional QT correction methods. No subject had a QTcI > or = 450 ms or an increase in QTcI > or = 30 ms with any treatment. CONCLUSIONS: Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.

Tadalafil improved erectile function at twenty-four and thirty-six hours after dosing in men with erectile dysfunction: US trial.

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 <.001 for 10 and 20 mg, respectively) and 36 hours (P < .001 for both doses) postdose. The mean per-patient percentages of successful intercourse attempts for the 24-hour time point were 41.8%, 55.8%, and 67.3% for placebo and tadalafil 10 and 20 mg, respectively; for the 36-hour time point, the mean per-patient percentages were 32.8%, 56.2%, and 61.9% for placebo and tadalafil 10 and 20 mg, respectively. The most common treatment-emergent adverse events were headache, back pain, dyspepsia, and nasopharyngitis. Both 10- and 20-mg tadalafil improved erectile function for up to 36 hours postdosing in men with ED of varied severity.

Efficacy and safety of oral tadalafil in the treatment of men in Canada with erectile dysfunction: a randomized, double-blind, parallel, placebo-controlled clinical trial.

INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent, often undertreated condition. AIM: This 12-week, double-blind, parallel, placebo-controlled study was conducted at 25 sites in Canada to evaluate the efficacy and safety of oral tadalafil, a phosphodiesterase type 5 inhibitor, for the treatment of ED. METHODS: Men with ED of organic, psychogenic, or mixed etiology were stratified by baseline ED severity then randomly assigned to placebo (N = 50), tadalafil 10 mg (N = 103), or tadalafil 20 mg (N = 100), taken as needed (maximum, once daily). MAIN OUTCOME MEASURES: Efficacy was assessed by the International Index of Erectile Function (IIEF), a Sexual Encounter Profile diary, and a global assessment question (GAQ). RESULTS: Tadalafil 10 mg and tadalafil 20 mg significantly improved erectile function compared with placebo (P < 0.001, all measures). At end point, the mean IIEF erectile function (EF) domain scores were 14.5, 21.2, and 23.3 of a possible score of 30 for placebo, tadalafil 10 mg, and tadalafil 20 mg, respectively. Patients treated with tadalafil reported greater change from baseline on the IIEF EF domain score compared with placebo, regardless of baseline ED severity. During treatment, the mean per-patient proportion of successful intercourse attempts was higher for tadalafil 10 mg and 20 mg than for placebo (placebo, 31.9%; tadalafil 10 mg, 56.7%; and tadalafil 20 mg, 61.5%), and a greater proportion of patients reported improved erections with tadalafil (GAQ; placebo, 22.0%; tadalafil 10 mg, 67.0%; tadalafil 20 mg, 79.0%). Fifty percent and 62% of patients treated with tadalafil 10 mg and 20 mg, respectively, achieved successful sexual intercourse after their first dose, compared with 31% with placebo. Treatment-emergent adverse events were generally mild or moderate. CONCLUSION: Tadalafil was an effective, well-tolerated therapy for ED of broad-spectrum etiology and severity.