Craig H. Mallinckrodt

Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia

OBJECTIVE There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xanomeline, a relatively selective muscarinic type 1 and type 4 (M(1) and M(4)) receptor agonist, to determine if this agent is effective in the treatment of schizophrenia. METHOD In this pilot study, the authors examined the efficacy of xanomeline on clinical outcomes in subjects with schizophrenia (N=20) utilizing a double-blind, placebo-controlled, 4-week treatment design. Outcome measures included the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and a test battery designed to measure cognitive function in patients with schizophrenia. RESULTS Subjects treated with xanomeline did significantly better than subjects in the placebo group on total BPRS scores and total PANSS scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function. CONCLUSIONS These results support further investigation of xanomeline as a novel approach to treating schizophrenia.

Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine.

Context: Major depressive disorder causes significant morbidity and mortality. Current therapies fail to fully treat both emotional and physical symptoms of major depressive disorder. Objective: To evaluate duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on improvement of emotional and painful physical symptoms. Design: Randomized, double-blind, evaluation of duloxetine at 40 mg/d (20 mg twice daily) and 80 mg/d (40 mg twice daily) versus placebo and paroxetine 20 mg/d in depressed outpatients. Main Outcome Measures: The primary efficacy measure was the 17-item Hamilton Depression Rating Scale. Visual Analog Scales for pain, Clinical Global Impression of Severity, Patients Global Impression of Improvement, and Quality of Life in Depression Scale were also used. Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Results: Duloxetine 80 mg/d was superior to placebo on mean 17-item Hamilton Depression Rating Scale total change by 3.62 points (95% CI 1.38, 5.86; P = 0.002). Duloxetine at 40 mg/d was also significantly superior to placebo by 2.43 points (95% CI 0.19, 4.66; P = 0.034), while paroxetine was not (1.51 points; 95% CI −0.55, 3.56; P = 0.150). Duloxetine 80 mg/d was superior to placebo for most other measures, including overall pain severity, and was superior to paroxetine on 17-item Hamilton Depression Rating Scale improvement (by 2.39 points; 95% CI 0.14, 4.65; P = 0.037) and estimated probability of remission (57% for duloxetine 80 mg/d, 34% for paroxetine; P = 0.022). The only adverse event reported significantly more frequently for duloxetine 80 mg/d than for paroxetine was insomnia (19.8% for duloxetine 80 mg/d, 8.0% for paroxetine; P = 0.031). Hypertension incidence was not affected by any treatment. Conclusion: Duloxetine therapy was efficacious for emotional and physical symptoms of depression, with a selective serotonin reuptake inhibitor-like profile of side effects.

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial

BACKGROUND Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) that has previously been shown to be effective in the acute treatment of major depressive disorder (MDD). This placebo-controlled study assesses the safety and efficacy of duloxetine (80 or 120 mg/day) and paroxetine (20 mg QD) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD. METHOD In this randomized, double-blind, placebo-controlled trial, adult outpatients (age >or= 18 years) meeting DSM-IV criteria for MDD received placebo (n = 93), duloxetine 80 mg/day (40 mg BID; n = 95), duloxetine 120 mg/day (60 mg BID; n = 93), or paroxetine (20 mg QD; n = 86) for 8 weeks. Patients who had a >or= 30% reduction from baseline in HAMD(17) total score during the acute phase were allowed to continue on the same (blinded) treatment for a 6-month continuation phase. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD(17)) total score, HAMD(17) subscales, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA), Visual Analog Scales (VAS) for pain, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, the 28-item Somatic Symptom Inventory (SSI), and the Sheehan Disability Scale (SDS). Safety and tolerability were assessed using treatment-emergent adverse events, discontinuations due to adverse events, vital signs, ECGs, laboratory tests, and the Arizona Sexual Experiences Scale (ASEX). RESULTS During the acute phase, patients receiving duloxetine 80 mg/day, duloxetine 120 mg/day, or paroxetine 20 mg QD had significantly greater reductions in HAMD(17) total score compared with placebo. Both duloxetine (80 and 120 mg/day) and paroxetine treatment groups had significantly greater improvement, compared with placebo, in MADRS, HAMA, CGI-S, and PGI-I scales. Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day (51%), duloxetine 120 mg/day (58%), and paroxetine (47%) were significantly greater compared with those receiving placebo (30%). The rate of discontinuation due to adverse events among duloxetine-treated patients (80 and 120 mg/day) did not differ significantly from the rate in the placebo group. Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation (80 and 120 mg/day), increased sweating (120 mg/day), and somnolence (120 mg/day). The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5% and 62.8%, respectively. During the 6-month continuation phase, duloxetine (80 and 120 mg/day) and paroxetine treatment groups demonstrated significant improvement in HAMD(17) total score. Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection (duloxetine 80 mg/day), diarrhea (duloxetine 120 mg/day), and headache (paroxetine 20 mg QD). CONCLUSION These data support previous findings that duloxetine is safe, efficacious, and well tolerated in the acute treatment of MDD. Furthermore, these data provide the first demonstration under double-blind, placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment.

Accounting for dropout bias using mixed-effects models.

Treatment effects are often evaluated by comparing change over time in outcome measures. However, valid analyses of longitudinal data can be problematic when subjects discontinue (dropout) prior to completing the study. This study assessed the merits of likelihood-based repeated measures analyses (MMRM) compared with fixed-effects analysis of variance where missing values were imputed using the last observation carried forward approach (LOCF) in accounting for dropout bias. Comparisons were made in simulated data and in data from a randomized clinical trial. Subject dropout was introduced in the simulated data to generate ignorable and nonignorable missingness. Estimates of treatment group differences in mean change from baseline to endpoint from MMRM were, on average, markedly closer to the true value than estimates from LOCF in every scenario simulated. Standard errors and confidence intervals from MMRM accurately reflected the uncertainty of the estimates, whereas standard errors and confidence intervals from LOCF underestimated uncertainty.

Assessing and interpreting treatment effects in longitudinal clinical trials with missing data

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure.

Attrition in Randomized Controlled Clinical Trials: Methodological Issues in Psychopharmacology

Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.

Placebo Response and Antidepressant Clinical Trial Outcome

Placebo response magnitude is suspected to affect the outcome of antidepressant clinical trials. To evaluate this, 52 randomized, double-blind, placebo-controlled clinical trials obtained from the FDA were examined to correlate placebo response magnitude with trial outcome. The magnitude of symptom reduction, percentage mean change from baseline in the Hamilton Depression Rating Scale (HAM-D), was assessed for patients assigned to placebo or an antidepressant. Correlation coefficients between symptom reduction with placebo and antidepressants and between symptom reduction with placebo and magnitude of advantage of antidepressants over placebo were assessed. A statistically significant positive correlation was seen between placebo and antidepressant response magnitude (r = .40, p < .001) and between placebo response magnitude and the advantage of antidepressants over placebo (r = −.592, p < .0001). Only 21.1% of antidepressant treatment arms in trials with high placebo response (>30% mean change from baseline) showed statistical superiority over placebo compared with 74.2% in trials with a low placebo response (≤30). Response magnitude varies and has an important effect on antidepressant clinical trials, illustrating the need for a placebo arm to determine if the trial was sensitive to treatment differences and highlighting the dangers of cross-study comparisons.

Assessing response profiles from incomplete longitudinal clinical trial data with subject dropout under regulatory conditions

Treatment effects are often evaluated by comparing change over time in outcome measures. However, valid analyses of longitudinal data can be problematic, particularly when some data are missing for reasons related to the outcome. In choosing the primary analysis for confirmatory clinical trials, regulatory agencies have for decades favored the last observation carried forward (LOCF) approach for imputing missing values. Many advances in statistical methodology, and also in our ability to implement those methods, have been made in recent years. The characteristics of data from acute phase clinical trials can be exploited to develop an appropriate analysis for assessing response profiles in a regulatory setting. These data characteristics and regulatory considerations will be reviewed. Approaches for handling missing data are compared along with options for modeling time effects and correlations between repeated measurements. Theory and empirical evidence are utilized to support the proposal that likelihood-based mixed-effects model repeated measures (MMRM) approaches, based on the missing at random assumption, provide superior control of Type I and Type II errors when compared with the traditional LOCF approach, which is based on the more restrictive missing completely at random assumption. It is further reasoned that in acute phase clinical trials, unstructured modeling of time trends and within-subject error correlations may be preferred.

Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study

ABSTRACT Objective: The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment1. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor). Research design and methods: This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (≥ 18 years) meeting DSM‑IV criteria for Major Depressive Disorder (MDD) received duloxetine 60 mg once daily (QD; N = 273), escitalopram 10 mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group. Main outcome measures: Onset of efficacy was defined as a 20% decrease from baseline on the 17‑item Hamilton Rating Scale for Depression (HAMD17) Maier subscale that was maintained or exceeded at all subsequent visits. Results: Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, –1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo ( p ≤ 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups. Limitations: Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo. Conclusion: In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8‑week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10 mg QD was better tolerated than duloxetine at a starting dose of 60 mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram. Trial registration: ClinicalTrials.gov identifier: NCT00073411.

Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine.

Abstract: This analysis assessed the effects of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on indices of cardiovascular safety, including heart rate, blood pressure (BP), and electrocardiograms (ECGs), in a large group of clinical trial patients with depression. Data were available from 8 double-blind, randomized, placebo-controlled (n = 777), and active comparator-controlled depression trials. Duloxetine (n = 1139) doses ranged from 40 to 120 mg/d, and fluoxetine (n = 70) and paroxetine (n = 359) were administered at a dose of 20 mg/d. Patients were treated for 8 to 9 weeks. There was a significant increase for duloxetine compared with placebo for heart rate (1.6 vs. −0.6 beats per minute) and for systolic BP (1.0 vs. −1.2 mm Hg); the difference for diastolic BP (1.1 vs. 0.3) was not significant. There were no significant differences between duloxetine and placebo treatment groups in the incidence of sustained (at least 3 consecutive visits) elevations in systolic (duloxetine 1.0%, placebo 0.4%), diastolic (duloxetine 0.4%, placebo 0.4%), or either (duloxetine 1.3%, placebo 0.8%) BP. Moreover, the effect of duloxetine on mean changes in supine systolic and diastolic BP was not significantly different from that of fluoxetine or paroxetine. Drug-placebo differences in mean changes in electrocardiograms (eg, QTc, PR, and QRS intervals) were neither statistically nor clinically significant, with the exception that duloxetine 120 mg/d had significant decreases in PR and QRS intervals compared with placebo. These data demonstrate that duloxetine has modest effects on heart rate and BP and no clinically meaningful effect on electrocardiogram profiles in a relatively healthy cohort of clinical trial patients. The cardiovascular effects of duloxetine appear to be comparable with medications considered to be first-line options for depression.