David Hackett

Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR.

OBJECTIVE To characterize the response to the serotonin and norepinephrine reuptake inhibitor, venlafaxine extended release (XR), during the long-term treatment of generalized anxiety disorder. METHODS Data from two double-blind, placebo-controlled, 6-month trials of venlafaxine XR for the treatment of generalised anxiety disorder were pooled. Criteria for response (> or = 50% improvement from baseline HAM-A score) and remission (HAM-A score < or = 7) and their temporal profile were used to characterize patient improvement over 6 months of treatment with venlafaxine XR and placebo. RESULTS Venlafaxine XR was associated with significantly (P<0.001) higher response and remission rates (66 and 43%, respectively) compared with placebo (39 and 19%), regardless of the level of baseline anxiety. In the venlafaxine XR group, 61% of the patients who had responded but not remitted by week 8 showed remission by the end of 6 months. In comparison, only 39% of placebo responders who did not qualify for remission at the end of the first 8 weeks of therapy remitted by the end of the 6 months (P=0.007). Relapse occurred in 6% of venlafaxine XR-treated patients and 15% of placebo-treated patients (P<0.01). CONCLUSION This analysis provides further insight into the outcome of long-term treatment of generalised anxiety disorder with venlafaxine XR and shows for the first time that long-term treatment might be necessary to achieve and maintain remission of symptoms.

Predictors of outcome following venlafaxine extended-release treatment of DSM-IV generalized anxiety disorder: a pooled analysis of short- and long-term studies.

This pooled analysis evaluated potential predictive abilities of baseline demographic factors, psychiatric history, and DSM-IV diagnostic criteria for short- and long-term outcome after treatment with venlafaxine extended release (XR) or placebo in patients with generalized anxiety disorder (GAD). Pooled data from 1,839 patients in five placebo-controlled studies of venlafaxine XR for GAD were analyzed by logistic regression. Odds ratios (ORs) were used to quantify pretreatment factors’ abilities to predict response (50% reduction, baseline Hamilton Rating Scale for Anxiety [HAM-A] severity) and remission (total HAM-A score ≤7) following venlafaxine XR or placebo treatment. All analyzed factors showed statistically significant outcome associations after 8 or 24 weeks of treatment, or both, in placebo- or venlafaxine-XR-treated patients or both. Substance abuse history, DSM-IV diagnostic criteria of sleep disturbances, difficulty concentrating, and restlessness had the strongest associations with outcome. Sleep disturbances predicted significant positive response in both groups, but more so in the placebo group. Restlessness consistently predicted poor response and lack of remission with either treatment; difficulty concentrating predicted short-term remission with placebo only. Substance abuse history predicted positive outcomes with placebo only. Sex, age, depression history, panic disorder history, prior benzodiazepine and nonbenzodiazepine use, being easily fatigued, muscle tension, and irritability were modestly outcome-predictive or showed treatment condition interactions. In the largest pooled analysis to date, pretreatment factors were associated with treatment outcome in patients with GAD receiving venlafaxine XR or placebo. The strongest trends emerged for history of substance abuse or dependence and symptoms of restlessness, sleep disturbance, and difficulty concentrating.

A method for controlling for a high placebo response rate in a comparison of venlafaxine XR and diazepam in the short-term treatment of patients with generalised anxiety disorder

This randomised, double-blind, placebo-controlled study compared the efficacy of venlafaxine XR (75 or 150 mg/d) with diazepam (15 mg/d) over an 8-week treatment period in 540 non-depressed outpatients with generalised anxiety disorder (GAD). At week 8, significant improvements from baseline were observed in the venlafaxine XR, diazepam and placebo groups. Although these improvements were higher in the first two groups than in the placebo group for each of the primary efficacy variables (Hamilton Rating Scale for Anxiety (HAM-A) total, HAM-A psychic anxiety factor, Hospital Anxiety and Depression Scale (HAD) anxiety sub-scale and Clinical Global Impression (CGI) improvement), there were no statistically significant differences between groups. These non-positive results were thought to be due to the very high placebo response observed in some centres. To understand the variability of the study, a secondary preplanned analysis was performed. This involved sub-dividing the study centres according to their ability to detect a two-point mean difference between diazepam and placebo at week 8 on the HAM-A total score. Centres able to show such a difference were termed verum-sensitive. Improvements from baseline to week 8 in venlafaxine XR-treated patients from verum-sensitive centres were significantly greater than in placebo on each of the primary efficacy measures (P </= 0.05). This suggests that those centres able to detect an anxiolytic effect of diazepam were also able to detect an anxiolytic effect of venlafaxine XR. Significant differences in baseline demographics, rates of adverse event reporting and rates of patient discontinuations were noted between patients enrolled at verum-sensitive and verum-insensitive sites. These results reflect the importance of study centre selection in accurately determining efficacy in placebo-controlled trials.

Effectiveness of venlafaxine, extended release formulation, in the short-term and long-term treatment of generalized anxiety disorder: results of a survival analysis.

A survival analysis of data from two placebo-controlled, randomized, long-term (6-month) studies was used to examine the effectiveness of venlafaxine, extended release (XR) formulation, in patients with generalized anxiety disorder (GAD). Patients in a placebo-controlled, flexible-dose study received 75 to 225 mg/day venlafaxine XR, while patients in a placebo-controlled, fixed-dose study received once-daily venlafaxine XR doses of 37.5 mg, 75 mg, or 150 mg. The survival analysis was based on the clinician’s decision to discontinue treatment in a placebo-controlled study and incorporated data from all patients who were randomized. In each study, placebo-treated patients discontinued treatment due to lack of efficacy more frequently and earlier than those receiving venlafaxine XR (p < 0.001, log-rank test). A dose-response relationship was apparent, with the lowest rate of withdrawal seen at the highest venlafaxine XR dose. Survival curves for discontinuations due to adverse events did not differ significantly in either study. These results were consistent with the conventional intent-to-treat efficacy assessments of changes in anxiety severity, highlighting the superiority of venlafaxine XR over placebo in the long-term treatment of GAD. Overall, these results demonstrate the clinical effectiveness of venlafaxine XR in the short-term and long-term treatment of GAD.