Joel Raskin

A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain

Background: Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. Objective: To assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP). Methods: In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed. Results: Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient’s Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered. Conclusions: This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain.

An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

AbstractBackground and objective: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). Methods: The cardiovascular safety of duloxetine was assessed using all placebocontrolled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebocontrolled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. Results: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia’s formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. Conclusion: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.

Duloxetine in the treatment of Major Depressive Disorder: A comparison of efficacy in patients with and without melancholic features

BackgroundThe most prominent feature of melancholic depression is a near-total loss of the capacity to derive pleasure from activities or other positive stimuli. Additional symptoms can include psychomotor disturbances, anorexia, excessive guilt, and early awakening from sleep. Melancholic patients may exhibit treatment responses and outcomes that differ from those of non-melancholic patients. Pooled data from double-blind, placebo-controlled studies were utilized to compare the efficacy of duloxetine in depressed patients with and without melancholic features.MethodsEfficacy data were pooled from 8 double-blind, placebo-controlled clinical trials of duloxetine. The presence of melancholic features (DSM-IV criteria) was determined using results from the Mini International Neuropsychiatric Interview (MINI). Patients (aged ≥ 18 years) meeting DSM-IV criteria for major depressive disorder (MDD) received duloxetine (40–120 mg/d; melancholic, N = 759; non-melancholic, N = 379) or placebo (melancholic, N = 519; non-melancholic, N = 256) for up to 9 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score, HAMD17 subscales (Maier, anxiety, retardation, sleep), the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain.ResultsIn data from all 8 studies, duloxetines advantage over placebo did not differ significantly between melancholic and non-melancholic patients (treatment-by-melancholic status interactions were not statistically significant). Duloxetine demonstrated significantly greater improvement in depressive symptom severity, compared with placebo, within both melancholic and non-melancholic cohorts (p ≤ .001 for HAMD17 total score, CGI-S and PGI-I). When analyzed by gender, the magnitude of improvement in efficacy outcomes did not differ significantly between duloxetine-treated male and female melancholic patients. In the two studies that assessed duloxetine 60 mg once-daily dosing, duloxetine-treated melancholic patients had significantly greater improvement compared with placebo on HAMD17 total score, CGI-S, PGI-I, 3 of 4 subscales of the HAMD17, and VAS overall pain severity (p < .01). Estimated probabilities of response and remission were significantly greater for melancholic patients receiving duloxetine 60 mg QD compared with placebo (response 74.7% vs. 42.2%, respectively, p < .001; remission 44.4% vs. 24.7%, respectively, p = .002ConclusionsIn this analysis of pooled data, the efficacy of duloxetine in patients with melancholic features did not differ significantly from that observed in non-melancholic patients.

Drug development in Alzheimer’s disease: the path to 2025

The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.

The safety and tolerability of duloxetine in depressed elderly patients with and without medical comorbidity

Aim and methods:  The impact of medical comorbidity on the efficacy and tolerability of duloxetine in elderly patients with major depressive disorder (MDD) was investigated in this study. Data were obtained from a multicentre, randomised, double‐blind, placebo‐controlled study in 311 patients with MDD aged 65–89. The primary outcome measure was a prespecified composite cognitive score based on four cognitive tests: (i) Verbal Learning and Recall Test; (ii) Symbol Digit Substitution Test; (iii) 2‐Digit Cancellation Test and (iv) Letter‐Number Sequencing Test. Secondary measures included the Geriatric Depression Scale (GDS), 17‐Item Hamilton Depression Scale (HAMD17), Clinical Global Impression‐Severity (CGI‐S) Scale, Visual Analogue Scale (VAS) for pain and 36‐Item Short Form Health Survey (SF‐36). Tolerability measures included adverse events reported as the reason for discontinuation and treatment‐emergent adverse events (TEAEs). The consistency of the effect of duloxetine vs. placebo comparing patients with and without medical comorbidity (vascular disease, diabetes, arthritis or any of these) was investigated.

Neurobiology of Alzheimer’s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions

Background: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms.

The efficacy of duloxetine: A comprehensive summary of results from MMRM and LOCF_ANCOVA in eight clinical trials

BackgroundA mixed-effects model repeated measures approach (MMRM) was specified as the primary analysis in the Phase III clinical trials of duloxetine for the treatment of major depressive disorder (MDD). Analysis of covariance using the last observation carried forward approach to impute missing values (LOCF_ANCOVA) was specified as a secondary analysis. Previous research has shown that MMRM and LOCF_ANCOVA yield identical endpoint results when no data are missing, while MMRM is more robust to biases from missing data and thereby provides superior control of Type I and Type II error compared with LOCF_ANCOVA. We compared results from MMRM and LOCF_ANCOVA analyses across eight clinical trials of duloxetine in order to investigate how the choice of primary analysis may influence interpretations of efficacy.MethodsResults were obtained from the eight acute-phase clinical trials that formed the basis of duloxetines New Drug Application for the treatment of MDD. All 202 mean change analyses from the 20 rating scale total scores and subscales specified a priori in the various protocols were included in the comparisons.ResultsIn 166/202 comparisons (82.2%), MMRM and LOCF_ANCOVA agreed with regard to the statistical significance of the differences between duloxetine and placebo. In 25/202 cases (12.4%), MMRM yielded a significant difference when LOCF_ANCOVA did not, while in 11/202 cases (5.4%), LOCF_ANCOVA produced a significant difference when MMRM did not. In 110/202 comparisons (54.4%) the p-value from MMRM was lower than that from LOCF_ANCOVA, while in 69/202 comparisons (34.2%), the p-value from LOCF_ANCOVA was lower than that from MMRM. In the remaining 23 comparisons (11.4%), the p-values from LOCF_ANCOVA and MMRM were equal when rounded to the 3rd decimal place (usually as a result of both p-values being < .001). For the HAMD17 total score, the primary outcome in all studies, MMRM yielded 9/12 (75%) significant contrasts, compared with 6/12 (50%) for LOCF_ANCOVA. The expected success rate was 80%.ConclusionsImportant differences exist between MMRM and LOCF_ANCOVA. Empirical research has clearly demonstrated the theoretical advantages of MMRM over LOCF_ANCOVA. However, interpretations regarding the efficacy of duloxetine in MDD were unaffected by the choice of analytical technique.

Once-daily duloxetine 60 mg in the treatment of major depressive disorder : Multicenter, double-blind, randomized, paroxetine-controlled, non-inferiority trial in China, Korea, Taiwan and Brazil

Abstract  The aim of the present paper was to compare the efficacy and safety of duloxetine with paroxetine in the acute treatment of major depressive disorder (MDD). In a randomized, double‐blind trial of 8 weeks active treatment, patients with non‐psychotic MDD were randomized to duloxetine 60 mg (n = 238) or paroxetine 20 mg (n = 240) once daily. Efficacy was primarily measured on change in the 17‐item Hamilton Rating Scale for Depression (HAMD17) using a non‐inferiority test with a margin of 2.2. Secondary efficacy measures included the HAMD17 subscales, Hamilton Rating Scale for Anxiety, Clinical Global Impressions–Severity, Patient Global Impressions–Improvement, Somatic Symptoms Inventory and Visual Analog Scales (VAS) for pain. Safety measures included treatment‐emergent adverse events (TEAE), vital signs, weight, laboratory analyses and electrocardiograms. Non‐inferiority of duloxetine to paroxetine was demonstrated because the upper bound of the confidence interval for mean difference in HAMD17 change (0.71) was less than the non‐inferiority margin. Secondary efficacy end‐points did not differ significantly between treatments with the exception of VAS back pain, where the pooled mean was lower in the duloxetine group (17.1) compared with the paroxetine group (20.3, P = 0.048). No significant differences were observed in the number of early discontinuations and overall TEAE. However, significantly greater proportions of patients in the duloxetine group experienced nausea and palpitations. No clinically relevant changes in laboratory values, vital signs, weight or electrocardiograms were observed with either treatment. The present study verifies the utility of duloxetine as an efficacious and safe treatment for both emotional and physical symptoms of MDD in this predominantly Asian patient sample.

Evidence for the efficacy of duloxetine in treating mild, moderate, and severe depression

Clinicians need to know whether duloxetine is effective in patients across a broad range of depressive symptoms and depression severity. Data were pooled from nine randomized, double-blind, placebo-controlled studies in major depressive disorder (total N=2227) comparing duloxetine (40–120 mg/day) with placebo for 8–9 weeks. Patients were retrospectively stratified by baseline score on the HAMD17 into mild (≤19; n=682), moderate (n=1099), or severe (≥25; n=446) groups. Duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in all three cohorts. Significant improvement was seen in HAMD17 items 1 (depressed mood), 3 (suicide), 7 (work and activities), and 10 (psychic anxiety) regardless of severity. The HAMD17 anxiety subscale and items 13 (somatic symptoms-general) and 15 (hypochondriasis) showed significant improvement only in moderately and severely ill patients. Significant improvement in the HAMD17 Maier subscale was seen in all groups by week 1. In all three groups, placebo was significantly superior to duloxetine at early visits on HAMD17 item 12 (somatic symptoms-GI). Mildly and severely ill patients exhibited significant reduction in visual analog scale overall pain severity at the study endpoint. The studies contained fewer patients with very mild or very severe illness, limiting our ability to draw conclusions in these patient populations. Duloxetine demonstrated superior efficacy in the treatment of major depressive disorder, when compared with placebo, regardless of the baseline severity of depressive symptoms, although effect sizes were largest in the most severely depressed patients.

Pharmacotherapy of generalized anxiety disorder: results of duloxetine treatment from a pooled analysis of three clinical trials.

ABSTRACT Objective: Duloxetine is a serotonergic noradrenergic reuptake inhibitor with demonstrated efficacy in each of three independent studies for treatment of adults with generalized anxiety disorder (GAD). A pooled dataset from all completed trials is provided here to show the most likely clinical outcomes associated with duloxetine treatment for GAD. Research design and methods: Data were summed at the individual patient level from three double-blind, placebo-controlled trials of duloxetine treatment: two were 10-week flexible-dose 60–120 mg/day and one was 9-week fixed dose 60 or 120 mg/day. Inclusion/exclusion criteria were consistent across studies. Main outcome measures: Efficacy measures included the Hamilton Anxiety Scale (HAMA) and Sheehan Disability Scale (SDS). Adverse events were queried at every visit in each study. Results: Patients were randomly assigned to duloxetine (n = 668) or placebo (n = 495) treatment. Mean age was 42.4 years; 65% were female. Duloxetine-treated patients improved significantly more from baseline to endpoint on HAMA total score (mean = –11.1 points) compared with placebo-treated patients (mean = –8.0 points, p ≤ 0.001). On the SDS global functioning score, patients in the duloxetine group had a mean improvement from baseline of 46% compared with 25% in the placebo group ( p ≤ 0.001). Nausea was the most common of twelve treatment-emergent adverse events that occurred in the duloxetine group. Limitations: Pooled studies were not for long-term treatment and did not include patients with comorbid psychiatric conditions. Conclusions: In this sample of more than 1100 patients, duloxetine was efficacious for reducing anxiety severity and for increasing patients’ overall role functioning in GAD.