Remission of generalized anxiety disorder after 6 months of open-label treatment with venlafaxine XR.

BACKGROUND: Remission has become one of the leading outcome criteria in clinical trials. Data collected by this research group assessed the rate of remission after 6 months of treatment of generalized anxiety disorder (GAD) with venlafaxine XR, to search for predictors of remission and to define how early on in treatment later remission can be predicted. METHOD: Two hundred sixty-eight patients with a GAD diagnosis enrolled into an open-label 6-month-treatment trial with venlafaxine XR (75-225 mg/day). Remission was defined by a Hamilton anxiety scale total score ≤7. Logistic regression approaches were used to find out how early on in treatment later remission could be predicted, as well as to determine predictors of remission. In addition, adverse events were also followed over time. RESULTS: While the total enrolled patient sample (n = 268) had a remission rate of 53%, 6-month completers (n = 159) had a remission rate of 79%. The only statistically significant predictor of remission, independent of baseline anxiety and depression levels, was a low Eysenck neuroticism score. The remission status outcome could best be predicted after 8 weeks of treatment when a CGI-I score of 1 or 2 predicted later remission with 78% accuracy and later nonremission with 91% accuracy. The incidence of adverse events decreased over the 6-month period, with sexual adverse events decreasing the least. CONCLUSION: The only significant predictor of remission was a low score on the Eysenck neuroticism scale. The earliest reliable prediction of later remission, based on improvement, could be made after 8 weeks of treatment with 91% accuracy.

L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials.

OBJECTIVE: The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD: In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS: In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS: Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

Time to relapse after 6 and 12 months' treatment of generalized anxiety disorder with venlafaxine extended release.

CONTEXT: Generalized anxiety disorder (GAD) is a chronic disorder in need of reliable data to guide long-term treatment. OBJECTIVES: To assess the benefits of 6 and 12 months' treatment of GAD with venlafaxine hydrochloride extended release (XR) in patients who improved after 6 months' open-label venlafaxine XR treatment. DESIGN: After 6 months' open-label venlafaxine XR treatment, improved patients were randomized to venlafaxine XR or placebo for 6 months. All venlafaxine XR patients still in the study at 12 months were randomized to receive venlafaxine XR or placebo, and all placebo patients continued taking placebo for another 6 months. SETTING: One urban site (5 locations). PATIENTS: Of 268 patients with a diagnosis of GAD entering the open-label venlafaxine XR treatment phase, 158 (59.0%) completed 6 months, and 136 (50.7%) entered relapse phase 2 (6-12 months). Fifty-nine (43.4%) of 136 patients entered phase 3 (12-18 months). INTERVENTION: Six months' open-label treatment with venlafaxine XR, followed by double-blind venlafaxine XR or placebo for 2 relapse phases, each lasting 6 months. MAIN OUTCOME MEASURES: Time to relapse while receiving venlafaxine XR or placebo after 6 and after 12 months of treatment. Relapse was strictly defined to safeguard against assigning patients with venlafaxine XR discontinuation symptoms or temporary anxiety increase as relapse. RESULTS: For objective 1, relapse rates in phase 2 (months 6-12) were 9.8% on venlafaxine XR and 53.7% on placebo (P < .001). For objective 2, relapse rates after 12 months on placebo (32.4%) were lower than after 6 months on venlafaxine XR (53.7%) (P < .03). CONCLUSIONS: Treatment of GAD with an antidepressant should be continued for at least 12 months. Preliminary data demonstrate that improved patients who relapse while off their antianxiety medication after at least 6 months of treatment will again most likely respond to a second course of treatment with the same medication. Trial Registration clinicaltrials.gov Identifier: NCT00183274.

Ziprasidone treatment of refractory generalized anxiety disorder: a placebo-controlled, double-blind study.

This 8-week, randomized, double-blind, placebo-controlled, flexible-dose trial assessed the efficacy, safety, and tolerability of ziprasidone in adults with treatment-resistant generalized anxiety disorder (GAD). Seventy-three subjects with treatment-resistant GAD were recruited, and 62 were randomized to either ziprasidone or placebo treatment at a ratio of 2:1 using a flexible dosing strategy (20-80 mg daily). Randomization was stratified into 2 subtypes of patients, those in whom the study drug was used as augmentation and those who have stopped their ineffective medications before entering the present trial (nonaugmented group). The subjects' clinical status was monitored weekly throughout the course of the study and included the Hamilton Anxiety Scale (primary outcome measure), the Clinical Global Impression Improvement and Severity of Illness scales, the Hamilton Depression Scale, the Sheehan Disability Scale, the Hospital Anxiety and Depression Scale, and the Abnormal Involuntary Movements Scale. Sixty-two patients were randomized to ziprasidone (n = 41) or placebo (n = 21). The dropout rate was 24%, consisting of 2 placebo patients and 13 ziprasidone patients. There was no statistically significant difference in the Hamilton Anxiety Scale score reduction between the drug and placebo groups. However, statistical trends were observed for an augmentation-study medication interaction effect, with ziprasidone patients producing more improvement in the nonaugmented than in the augmented group. This study provides pilot data for an augmentation-study medication interaction effect with ziprasidone patients producing more improvement in the nonaugmented than in the augmented group. Based on the data obtained in this trial and the subsequent power analyses, a future double-blind placebo-controlled trial should include at least 150 treatment-resistant GAD nonaugmented patients randomized to ziprasidone and placebo in a 1:1 ratio.

A paradigm for facilitating pharmacotherapy at a distance: sertraline treatment of the night eating syndrome.

OBJECTIVE: To test a novel method of facilitating pharmacotherapy at a distance and assess the effectiveness of sertraline for the treatment of night eating syndrome (NES). METHOD: The effectiveness of the selective serotonin reuptake inhibitor sertraline in the treatment of NES was assessed at a distance. NES is characterized by a delay in the circadian rhythm of food intake, with evening hyperphagia and/or nighttime awakenings and ingestions. Persons who contacted us through our Web site, e-mail, or telephone for help with their NES completed a Night Eating Questionnaire and received a semistructured interview (Night Eating Syndrome History and Inventory) to determine the presence of NES. Fifty such persons received treatment with sertraline from their own physicians, to whom we offered consultation. Participants completed questionnaires every 2 weeks for 8 weeks and received a final telephone interview to assess their progress. Outcomes were compared with those from an earlier face-to-face open-label trial of sertraline. The study was conducted from September 2003 to May 2005. RESULTS: Both the questionnaires and interviews showed improvements in 5 key aspects of NES: the general Night Eating Symptom Scale, evening hyperphagia, nighttime awakenings, nocturnal ingestions, and the Beck Depression Inventory (all p < .001), and the mean body weight of the 41 overweight and obese subjects, reported by survey, fell 3.0 kg (p = .01). These results are similar to those obtained in an earlier face-to-face trial of sertraline with NES. CONCLUSION: The study confirmed the effectiveness of sertraline in the treatment of NES and introduced a paradigm for facilitating pharmaco-therapy at a distance.

Early response and 8-week treatment outcome in GAD.

Our objective was to compare the predictive value of early response to treatment outcome in patients with generalized anxiety disorder (GAD) treated with benzodiazepines, serotonin receptor (5HT-1A) partial agonists, or placebo. Data from two double-blind GAD studies were combined. Subjects were evaluated with the Hamilton Anxiety Scale (HAM-A) and the Clinical Global Impression of Improvement (CGI-I) scale over 8 weeks. Categories of response at weeks 1 and 2 were defined by the HAM-A total score. Analyses of covariance and Kaplan-Meier survival analyses were the primary analyses used to assess 8-week end point treatment outcomes as a function of early improvement. HAM-A change from baseline to weeks 1 and 2 significantly predicted last observation carried forward (LOCF) response at week 8 for both medications and for placebo (P<.001). Early improvement was a strong predictor for treatment outcome irrespective of whether active medication or placebo was the treatment agent.