Douglas Feltner

A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder.

Pregabalin is a novel compound under development for the treatment of several types of anxiety disorders. To obtain an initial evaluation of the efficacy and safety of pregabalin in the treatment of generalized anxiety disorder (GAD), we conducted a double-blind, fixed-dose, parallel-group, placebo and active-controlled multicenter 4-week study that compared 271 patients randomized to receive pregabalin 50 mg tid (N = 70), pregabalin 200 mg tid (N = 66), placebo (N = 67), or lorazepam 2 mg tid (N = 68), followed by a 1-week double-blind taper. The primary efficacy parameter was change from baseline to endpoint (last observation carried forward) in the Hamilton Anxiety Scale (HAM-A) total score; adjusted mean change scores on the HAM-A were significantly improved for pregabalin 200 mg tid (difference of 3.90 between drug and placebo; p = 0.0013 [ANCOVA], df = 252) and for lorazepam (difference of 2.35; p = 0.0483 [ANCOVA], df = 252), with the significant difference between the pregabalin 200 mg tid and placebo groups seen at week 1 of treatment (p = 0.0001 [ANCOVA], df = 238). Safety analysis, which included assessment of spontaneously reported adverse events, laboratory monitoring, and withdrawal symptoms, showed pregabalin to be generally well-tolerated. The most common adverse events seen with pregabalin 200 mg tid were somnolence and dizziness. They were usually mild or moderate in intensity and were often transient. Pregabalin-treated patients had a higher completion rate than lorazepam-treated patients. This study supports the hypothesis that pregabalin is effective and safe in short-term therapy for GAD. More studies are needed to determine the best dosing regimen to optimize efficacy and tolerability.

A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression.

OBJECTIVE The corticotropin-releasing hormone (CRH) system is implicated in the pathogenesis of several psychiatric disorders, including major depressive disorder. This study was designed to evaluate the safety and efficacy of CP-316,311, a selective nonpeptide antagonist of corticotropin-releasing hormone type 1 (CRH(1)) receptors, in the treatment of recurrent major depressive disorder. METHOD Of a total of 167 patients with recurrent major depression who were screened, 123 were randomly assigned to receive 400 mg of CP-316,311 twice daily, or 100 mg of sertraline daily, or placebo in a 6-week fixed-dose, double-blind, double-dummy, parallel-group, placebo- and sertraline-controlled trial. The primary efficacy analysis compared the change in score from baseline to endpoint on the 17-item Hamilton Depression Rating Scale (HAM-D) between the CP-316,311 and placebo groups. A group sequential design was used to support early trial termination based on efficacy or futility at a planned interim analysis. RESULTS The evaluable data set for the interim analysis included 28 patients in the CP-316,311 group, 31 patients in the placebo group, and 30 patients in the sertraline group. In the interim analysis, the change from baseline in the HAM-D score at the final visit was not significantly different between the CP-316,311 and placebo groups, while change from baseline between the sertraline and placebo groups was significantly different. Given these results, futility was declared for CP-316,311 and the trial was terminated. CONCLUSIONS Although CP-316,311 was safe and well tolerated in this study population, it failed to demonstrate efficacy in the treatment of major depression.

Efficacy of the Novel Anxiolytic Pregabalin in Social Anxiety Disorder: A Placebo-Controlled, Multicenter Study

Abstract: Pregabalin is a novel compound in the development for the treatment of anxiety disorders. The safety and efficacy of pregabalin for the treatment of social anxiety disorder was evaluated in a double-blind, multicenter clinical trial in which 135 patients were randomized to 10 weeks of double-blind treatment with either pregabalin 150 mg/d, pregabalin 600 mg/d, or placebo. The primary efficacy parameter was change from baseline to end point in the Liebowitz Social Anxiety Scale (LSAS) total score. Safety was assessed through clinical and laboratory monitoring, and recording spontaneously reported adverse events. Ninety-four patients (70%) completed the 11-week double-blind treatment phase. LSAS total score was significantly decreased by pregabalin 600 mg/d treatment compared with placebo (P = 0.024, analysis of covariance). Significant differences (P ≤ 0.05) between pregabalin 600 mg/d and placebo were seen on several secondary measures including the LSAS subscales of total fear, total avoidance, social fear, and social avoidance, and the Brief Social Phobia Scale fear subscale. Pregabalin 150 mg/d was not significantly better than placebo on any measures. Somnolence and dizziness were the most frequently occurring adverse events among patients receiving pregabalin 600 mg/d. In conclusion, pregabalin 600 mg/d was an effective and well-tolerated treatment of social anxiety disorder.

Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing.

Abstract: Pregabalin is a new anxiolytic that acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the α2-δ subunit of voltage-gated calcium channels. The current study evaluated the anxiolytic efficacy of BID versus TID dosing of pregabalin in patients with generalized anxiety disorder. Outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition generalized anxiety disorder and having baseline Hamilton Anxiety (HAM-A) total scores ≥20 were randomized to 6 weeks of double-blind treatment with pregabalin 200 mg/d (BID; N = 78), 400 mg/d (BID; N = 89), or 450 mg/d (TID; N = 88) or placebo (N = 86). Mean improvement in HAM-A total score at last observation carried forward end point was significantly greater on pregabalin 200 (P = 0.006), 400 (P = 0.001), and 450 mg/d (P = 0.005) compared with placebo. Pairwise comparisons of BID versus TID dosing found no difference in HAM-A change score at end point. All 3 pregabalin dosage groups showed significantly greater efficacy versus placebo at end point on the HAM-A psychic and somatic anxiety factor scores. Improvement on both factors was rapid: significance versus placebo was achieved as early as the first assessment at week 1, with ≥30% reduction in HAM-A severity and equal or greater improvement for every subsequent visit in ≥38% of patients in all 3 pregabalin dosage groups (P ≤ 0.001). Pregabalin was well tolerated, and despite the fixed-dose study design, discontinuations caused by adverse events ranged from 9% to 13%-comparable with that observed with placebo (8%). This study demonstrates that pregabalin is an effective treatment of generalized anxiety disorder, with BID dosing showing similar efficacy and comparable tolerability with TID dosing.

How Modeling and Simulation Have Enhanced Decision Making in New Drug Development

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer’s disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the “Learn-Confirm” paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products” made this scientific approach to the drug approval process possible.

Long-term efficacy of pregabalin in generalized anxiety disorder.

A multicenter, randomized, placebo-controlled, double-blind study was conducted to evaluate the efficacy of pregabalin in preventing relapse of generalized anxiety disorder (GAD) after response to short-term treatment. Outpatients (n=624) with GAD for ≥1 year received open-label pregabalin (450 mg/day) for 8 weeks and, if a clinical response was observed, were randomized to receive either pregabalin (450 mg/day; n=168) or placebo (n=170) for 24 weeks. The primary efficacy parameter was time to relapse. Among responders to open-label acute treatment with pregabalin, time to relapse of GAD was significantly longer for patients treated with pregabalin compared with placebo (P<0.0001). Fifty per cent of the placebo group had relapsed by day 23, and at study endpoint, 65% had relapsed. In the pregabalin group, only 42% had relapsed by study end. Total attrition during double-blind treatment was somewhat higher on pregabalin compared with placebo (21.4 vs. 15.3%); attrition owing to adverse events (AEs) was also somewhat higher on pregabalin (6.0 vs. 2.4%). AEs were relatively low in the double-blind phase; only three AEs occurred with an incidence of more than 5% on pregabalin and placebo, respectively: infection (14.9 vs. 11.2%), headache (10.1 vs. 11.2%), and somnolence (6.0 vs. 0%). No safety concerns were identified with long-term treatment. The study indicates that pregabalin is an effective treatment for the prevention of relapse in patients with GAD.

Psychometric evaluation of a visual analog scale for the assessment of anxiety

BackgroundFast-acting medications for the management of anxiety are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive tool. This study evaluates the psychometric properties of a patient-reported Global Anxiety - Visual Analog Scale (GA-VAS).MethodsData from a double-blind, randomized, placebo-controlled study of lorazepam and paroxetine in patients with Generalized Anxiety Disorder were analyzed to assess the reliability, validity, responsiveness, and utility of the GA-VAS. The GA-VAS was completed at clinic visits and at home during the first week of treatment. Targeted psychometric analyses—test-retest reliabilities, validity correlations, responsiveness statistics, and minimum important differences—were conducted.ResultsThe GA-VAS correlates well with other anxiety measures, at Week 4, r = 0.60 (p < 0.0001) with the Hamilton Rating Scale for Anxiety and r = 0.74 (p < 0.0001) with the Hospital Anxiety and Depression Scale - Anxiety subscale. In terms of convergent and divergent validity, the GA-VAS correlated -0.54 (p < 0.0001), -0.48 (p < 0.0001), and -0.68 (p < 0.0001) with the SF-36 Emotional Role, Social Function, and Mental Health subscales, respectively, but correlated much lower with the SF-36 physical functioning subscales. Preliminary minimum important difference estimates cluster between 10 and 15 mm.ConclusionsThe GA-VAS is capable of validly and effectively capturing a reduction in anxiety as quickly as 24 hours post-dose.

Vocal Acoustic Biomarkers of Depression Severity and Treatment Response

BACKGROUND Valid, reliable biomarkers of depression severity and treatment response would provide new targets for clinical research. Noticeable differences in speech production between depressed and nondepressed patients have been suggested as a potential biomarker. METHODS One hundred five adults with major depression were recruited into a 4-week, randomized, double-blind, placebo-controlled research methodology study. An exploratory objective of the study was to evaluate the generalizability and repeatability of prior study results indicating vocal acoustic properties in speech may serve as biomarkers for depression severity and response to treatment. Speech samples, collected at baseline and study end point using an automated telephone system, were analyzed as a function of clinician-rated and patient-reported measures of depression severity and treatment response. RESULTS Regression models of speech pattern changes associated with clinical outcomes in a prior study were found to be reliable and significant predictors of outcome in the current study, despite differences in the methodological design and implementation of the two studies. Results of the current study replicate and support findings from the prior study. Clinical changes in depressive symptoms among patients responding to the treatments provided also reflected significant differences in speech production patterns. Depressed patients who did not improve clinically showed smaller vocal acoustic changes and/or changes that were directionally opposite to treatment responders. CONCLUSIONS This study supports the feasibility and validity of obtaining clinically important, biologically based vocal acoustic measures of depression severity and treatment response using an automated telephone system.

Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder

Prior research suggests that SSRIs may have greater efficacy for psychic compared to somatic anxiety, while benzodiazepines show greater somatic efficacy. The goal of this analysis was to evaluate the efficacy of pregabalin (PGB) in treating psychic and somatic symptoms of anxiety. Data were combined from six short-term, double-blind, placebo-controlled, fixed-dose trials of PGB in patients with generalized anxiety disorder (GAD). The following PGB daily dose groups were studied: 150 mg (n=210), 300-450 mg (n=455), and 600 mg (n=406), benzodiazepines (6 mg/d lorazepam and 1.5 mg/d alprazolam, n=299), vs. placebo (n=484). Changes in Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety factors and individual items were analysed. Treatment with 300-600 mg PGB significantly improved both the HAMA psychic and somatic anxiety factors. In contrast, treatment with 150 mg PGB appeared to be less effective, achieving significance only on the psychic anxiety factor. PGB (300-450 mg) was associated with significant improvement on 13 out of 14 HAMA items, while treatment with 600 mg PGB was associated with significant improvement in 10 out of 14 HAMA items. Treatment with benzodiazepines was also associated with significant improvement in both psychic and somatic anxiety factors, with significant improvement occurring in 5 out of 14 HAMA items. The results of this pooled analysis indicate that both PGB and benzodiazepines had significant efficacy in treating both HAMA psychic and somatic anxiety. A dose-response effect was evident for PGB that reached a plateau at a dose of 300 mg/d.

Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs

BACKGROUND Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders in primary care, although it is often underrecognized and undertreated. GAD is chronic, disabling, and associated with other health problems. Treatment response is often unsatisfactory, but the clinical evidence base for new treatments has expanded substantially in the past decade and suggests a growing range of options for reducing the burden of GAD. The objective of this article was to review current literature on GAD and its management to provide an overview of the clinical importance of GAD in primary care and available treatments. DATA SOURCES Recent studies (ie, over the past decade) on the epidemiology and treatment of GAD were identified by searching Medline using the term generalized anxiety disorder only and in combination with the terms epidemiology and treatment and for each drug class (benzodiazepines, azapirones, antidepressants, antihistamines, alpha-2-delta ligands, and antipsychotics) and for named drugs (buspirone, venlafaxine, duloxetine, fluoxetine, escitalopram, olanzapine, paroxetine, pregabalin, quetiapine, and risperidone in addition to psychological therapies and cognitive-behavioral therapy. The literature search was conducted in August 2008 for the period 1987-2009. STUDY SELECTION Studies were included if judged to be relevant to a review of the epidemiology and management of GAD. Articles were excluded if they were not written in English or were published more than 10 years before the literature search was conducted. A few older studies were included for which more recent research evidence was not available. Recent national and international guidelines for the management of GAD were also reviewed. DATA EXTRACTION/SYNTHESIS Most currently available interventions have similar overall efficacy, and treatment choices should reflect the situation of individual patients. Important unmet needs exist for treatments (1) that work rapidly, with (2) broad spectrum benefits, (3) that can improve rates of remission and well-being, (4) are devoid of risk for withdrawal symptoms, and (5) have few if any adverse interactions with other drugs. Additional needs include (6) safer drugs for the elderly, (7) safe and effective drugs for children with GAD, (8) further evaluation of psychotherapy, and (9) understanding the appropriate circumstances for, and optimal choices of, drug combination. CONCLUSION While the development of novel treatments evolves, current management approaches can focus on improving identification and defining optimal use of available therapies for GAD.