Efficacy and safety of mifepristone for the treatment of psychotic depression

Open-label studies and randomized clinical trials have suggested that mifepristone may be effective for the treatment of major depression with psychotic features (psychotic depression). A recent study reported a correlation between mifepristone plasma concentration and clinical response. The current study aimed to evaluate the safety and efficacy of mifepristone and, secondarily, to test whether response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold. A total of 433 patients who met criteria for psychotic depression were randomly assigned to receive 7 days of either mifepristone (300, 600, or 1200 mg) or placebo. Response was defined as a 50% reduction in psychotic symptoms on both days 7 and 56. Cochran-Mantel-Haenszel tests compared (1) the proportion of responders among patients assigned mifepristone versus placebo and (2) the proportion of responders among the subset of patients with plasma concentrations greater than 1660 ng/mL versus placebo. Mifepristone was well tolerated at all 3 doses. The proportion of responders randomized to mifepristone did not statistically differ from placebo. Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo. The study failed to demonstrate efficacy on its primary end point. However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression.     

Placebo-controlled continuation treatment with mirtazapine: acute pattern of response predicts relapse.

Pattern of response to antidepressants has been proposed as a method to identify patients whose improvement is more likely due to drug vs those whose improvement on drug is more likely to be a placebo effect. It is hypothesized that those with 'true-drug initial response pattern' are most likely to benefit from continuation treatment. The relationship between acute patterns of response and subsequent placebo-controlled continuation treatment with the antidepressant mirtazapine is examined. A total of 410 outpatients were treated openly with mirtazapine for 8-12 weeks. Patients who remitted in the acute phase were randomized to continue the same dose of mirtazapine or switched to placebo. Acute phase responders were classified as 'placebo initial response pattern' (early responders and nonpersistent responders) and 'true-drug initial response pattern' (delayed and persistent responders). Of those with a 'true-drug initial response pattern,' 10/40 (25.0%) relapsed with continuation mirtazapine, and 23/41 (56.1%) relapsed when switched to placebo. The difference (31.1%) is significant. Of those with a 'placebo initial response pattern,' 5/36 (13.9%) relapsed with continuation mirtazapine, and 12/39 (30.8%) relapsed with placebo substitution. This difference (16.9%) is not statistically significant. Moreover, the relapse rate for 'true-drug initial response pattern' patients switched to placebo (56.1%) was also significantly greater than for 'placebo initial response pattern' patients switched to placebo (30.8%). It has been suggested that patients with late onset and persistence are more likely to have improved because of drug. This hypothesis gains support from this study because of the different relapse rates of 'true-drug' responders on drug and placebo. The low relapse rate for patients with an acute placebo pattern switched to placebo suggests specific drug effect played a smaller role in their initial improvement.     

Predictors of the placebo response in functional dyspepsia

BACKGROUND: Trials in functional dyspepsia report placebo response rates of 30% to 40%. AIM: We aimed to identify predictors of the placebo response. METHODS: Patients from primary, secondary and tertiary practices with functional dyspepsia defined by Rome II criteria were enrolled into one of four clinical trials; 220 patients were randomized to receive placebo. Scintigraphic assessment of gastric emptying at baseline was repeated at the end of the treatment in those with delayed emptying. After a 2 week run-in period, patients were followed for 8 weeks on placebo. Response was assessed on a weekly basis and a responder was defined as satisfactory relief of meal-related symptoms on at least 50% of weeks. RESULTS: The mean age was 44 years (range 18-82) and 74% were female; 76 (35%) were placebo responders. The predominant symptom was an unstable measure over the trial. Independent predictors of a lower placebo response were lower body mass index and a more consistent predominant symptom pattern (both P < 0.05). No association was seen with age, gender, centre type, baseline symptom score, baseline or change in gastric emptying, or baseline quality of life. CONCLUSION: In functional dyspepsia, a consistent predominant symptom pattern and lower body mass index may be associated with a lower placebo response rate.     

Long-term treatment of obsessive-compulsive disorder after an acute response: a comparison of fluoxetine versus placebo

Few controlled studies have evaluated the long-term continuation of pharmacotherapy for relapse prevention in patients with obsessive-compulsive disorder (OCD). This study assessed efficacy and safety of fluoxetine versus placebo in preventing relapse of OCD during a 52-week period in responders to short-term administration of fluoxetine. Patients who met DSM-IV criteria for OCD and had a Yale-Brown Obsessive Compulsive Scale score > or = 19 were treated with single-blind fluoxetine 20, 40, or 60 mg/day (based on physician assessment of response and tolerability). After 20 weeks, responders were randomly assigned to receive continued treatment with fluoxetine or placebo and were monitored for relapse for up to 52 weeks. Of 130 patients who entered the study, 71 (55%) were randomly assigned to receive fluoxetine (N = 36) or placebo (N = 35). Patients who received fluoxetine had numerically lower relapse rates compared with those who received placebo, although the difference was not significant (Kaplan-Meier 1-year relapse rates: fluoxetine, 20.6%; placebo, 31.9%; one-tailed p value = 0.137). In additional analyses evaluating patients on the basis of fluoxetine dose at randomization, patients who continued treatment with fluoxetine 60 mg/day (N = 52) had significantly lower rates of relapse than those who were switched to placebo (Kaplan-Meier 1-year relapse rates: fluoxetine, 17.5%; placebo, 38.0%; one-tailed p value = 0.041). Those who responded to the acute treatment phase with 40 (N = 18) or 20 (N = 1) mg/day had low overall rates of relapse, and the difference between continued fluoxetine and placebo treatment for these patients was not significant. For responders to the 60 mg/day dosage, those patients who continued treatment with fluoxetine were provided greater protection against relapse than those patients switched to placebo.     

Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression

Rationale High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials.Objective The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD.Methods Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine (n=24) or venlafaxine (n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of 10.Results Of the medication-treated and placebo-treated subjects, 52% (13/25) and 38% (10/26) responded. Placebo responders had lower pretreatment frontocentral cordance in the theta frequency band than all other subjects (P<0.006) and medication responders in particular (P<0.004). Placebo responders also had faster cognitive processing time, as assessed by neuropsychological testing, and lower reporting of late insomnia (P<0.03). Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression, in which these three pretreatment measures accurately identified 97.6% of eventual placebo responders.Conclusions These findings suggest that combined clinical, neurophysiological, and cognitive assessments of prospective subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response to placebo. Prospective validation of these results in a larger, independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospective identification of placebo responders.From the Laboratory of Behavioral Pharmacology, UCLA Neuropsychiatric Institute, and the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA.     

Side effects and time course of response in a placebo-controlled trial of fluoxetine for the treatment of geriatric depression

A high rate of improvement among patients who receive placebo in controlled trials of antidepressants can complicate the evaluation of true drug effect. Placebo response may be a reaction to the psychosocial factors of study participation or a function of changes in the natural course of depression. Drug side effects may also influence patients' expectations, and they should be distinguished from the somatic symptoms associated with major depression. The authors reanalyzed data from a large, multicenter, placebo-controlled clinical trial of fluoxetine treatment of geriatric depression to evaluate similarities and differences between responders and nonresponders in both treatment groups. Specifically, the authors examined weekly somatic complaints as possible predictors of response and of dropout, as well as the time course and onset of response. Fluoxetine was superior to placebo on all outcome measures. Among somatic complaints associated with fluoxetine response, headache before and after randomization was associated with a good response and anxiety after randomization was associated with a poor response. Somnolence before and after randomization was associated with a good placebo response. Early and persistent improvement occurred among similar proportions of responders in both groups. The difference between fluoxetine and placebo seemed to be a persistent response beginning during the 4th week. Pretreatment somnolence was associated with early, persistent improvement in both groups and may serve as a marker for placebo response.     

The double-blind variable placebo lead-in period: results from two antidepressant clinical trials.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.     

Efficacy of Venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine

This study evaluated the anxiolytic efficacy, safety and tolerability of a flexible dose of venlafaxine extended release (ER) compared with placebo and paroxetine in the short-term treatment of generalized social anxiety disorder (SAD). Adult outpatients with generalized SAD (n = 434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks. The primary efficacy variable was the Liebowitz social anxiety scale total score. Secondary efficacy variables included the patient-rated social phobia inventory and the proportion of responders in each group (a responder was defined as having a clinical global impression-improvement score of 1 or 2). Treatment with venlafaxine ER was associated with significantly greater improvement than treatment with placebo for all primary and secondary efficacy variables (p < 0.05). No significant differences in primary or secondary efficacy variables were observed between the venlafaxine ER and paroxetine groups. The week 12 response rates were 69%, 66% and 36% for the venlafaxine ER, paroxetine and placebo groups, respectively. Both active treatments were generally well tolerated and were associated with a similar incidence of adverse events. This study shows that venlafaxine ER is an effective, safe and well-tolerated drug treatment for SAD.     

Defining treatment response to donepezil in Alzheimer's disease: responder analysis of patient-level data from randomized, placebo-controlled studies

BACKGROUND: Defining treatment success in progressive diseases, such as Alzheimer's disease (AD), can be challenging. OBJECTIVE: To explore the impact of employing different criteria to define a treatment 'responder' using analyses of patient-level data from randomized, placebo-controlled studies of donepezil in AD. METHODS: Trials were included in the analysis if they met several criteria, including the following: randomized, placebo-controlled trial of donepezil 10 mg/day in mild-to-moderate AD; cognition measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) or Mini-Mental State Examination (MMSE); and a 24-week endpoint and outcomes that included global assessments. Definitions of response were: improvements in cognition plus one other domain; improvement in cognition only; improvement or improvement/no change in global response; and improvement/stabilization/less than expected decline by < or = 2 or < or = 4 or < or = 6 points on the ADAS-cog. RESULTS: Five studies identified from the literature search met the specified criteria for inclusion. The response to donepezil measured by ADAS-cog varied from 26% to 63% and that of placebo from 14% to 47%, depending on the definition of improvement used. For definitions that included a less than expected decline on ADAS-cog, the more modest the effect defined, the less the drug versus placebo difference and the higher the percentage of patients meeting this definition. CONCLUSIONS: The definition of treatment 'response' in a progressive neurodegenerative disease can encompass a variety of outcomes, including short-term improvement, longer-term stabilization and a slowed decline in one or more clinically relevant symptoms or symptom domains. The ability to identify groups of people who respond to donepezil underscores the clinical utility of the medication and may contribute to more focused assessments of the cost effectiveness of cholinesterase inhibitors.     

Citalopram in the treatment of dysthymic disorder

This study aimed to provide preliminary data on the tolerability and effectiveness of citalopram for patients with dysthymic disorder. Twenty-one adult subjects meeting DSM-IV criteria for dysthymic disorder were enrolled in this 12-week open-label study, of whom 15 had pure dysthymia (e.g. no major depression in the past 2 years). Citalopram was initiated at 20 mg/day, and increased to a maximum of 60 mg/day. Response was defined as 50% or greater drop in score on the Hamilton Depression Rating Scale (HDRS) and a Clinical Global Impressions-I score of 1 ('very much improved') or 2 ('much improved'). Of these 15 pure dysthymic disorder subjects, all completed the trial, and 11 (73.3%) were treatment responders. All paired sample t-tests were highly significant, demonstrating significant average improvement on all measures of symptomatology and functioning. Scores on the 24-item HDRS decreased from 22.3+/-4.3 at baseline to 9.1+/-7.8 at week 12 [t(14)=6.1, P<0.001]. In addition, improvement was noted in self-reported measures of temperament and social functioning. The average final dose of citalopram was 39 mg/day. Side-effects were reported by nine of 15 subjects (60%), most frequently gastrointestinal symptoms (n=5), dry mouth (n=5) and sexual side-effects (n=3). These findings suggest the effectiveness and tolerability of citalopram in treating dysthymic disorder. Double-blind prospective studies are needed comparing citalopram both to placebo and to other medications, assessing both initial and sustained response to treatment.     

Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo

The purpose of this double-blind 14-week trial was to compare the efficacy of sustained-release methylphenidate (MPH) to placebo (PBO) in treating adult attention deficit hyperactivity disorder (ADHD) symptoms in current cocaine dependent (CD) treatment seekers. The randomized sample consisted of 106 participants who were predominately male (83%) and 60% Caucasian, 14% Hispanic, 20% African-American and 6% other. All participants met DSM-IV criteria for ADHD and CD. There were no significant demographic differences between the two treatment groups. All participants received weekly individual cognitive behavioral therapy. There was no difference in retention rate based on treatment group (p=.91). The majority of the PBO group and the MPH group reported >30% improvement in their ADHD symptoms (55% versus 47%), with no significant difference between the two groups (p=.44). Using a combined outcome measure (>30% reduction in ADHD symptoms and CGI <3), the response rates were similar for both groups (28% PBO versus 30% MPH; p=.83). Longitudinal analyses of the urine toxicology data using generalized estimating equations, revealed a decrease in the probability of cocaine positive urine samples during the trial for the MPH group compared to the PBO group (p=.001). Further analysis suggested that for the MPH group, ADHD treatment responders, based on a semi structured clinical interview, were more likely to have a reduction in cocaine use compared to the non-ADHD responders. Although sustained-release MPH did not show superiority over PBO in treating ADHD symptoms, this trial provides some evidence that improvement in ADHD symptoms (clinician rated) among those patients receiving MPH, but not placebo, was associated with a reduction in cocaine use.     

Symptoms as predictors of response in depression

Sertraline, a novel selective serotonin re-uptake inhibitor, has been proven as effective as amitriptyline and imipramine, and more effective than placebo, in double-blind controlled studies in patients with major depressive disorder. The question 'Do symptoms predict response to treatment?' is an important one in clinical practice. In order to try and answer this question, four double-blind clinical trials in major depressive disorder have been examined for clinically important symptoms and subgroups at entry to the studies. The Hamilton Depression Rating Scale (HAM-D, 17-item) was used throughout and the data for sertraline-treated patients were split in several different ways. The response to treatment was defined as the percentage of patients achieving a CGI-improvement score of 1 or 2 at the end of treatment. Patients with severe depression at entry had a response rate of > 80%, which was comparable to that of patients with moderate depression. A similar response rate was seen in the presence of DSM-III-defined melancholia, high anxiety, insomnia, psychomotor agitation or retardation. Finally, in order to examine the effect of old age on the response to treatment, one of the four studies, which included only patients aged 65 or older, was examined separately. In this study responders were defined as those with >50% reduction in baseline HAM-D at the end of treatment. Approximately 70% were found to be responders in both the moderate and severe depression subgroups.     

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms

Objective: To assess the characteristics of tolterodine extended-release (ER) 4?mg responders and suboptimal responders (≤50% decrease in UUI episodes/24?h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8?mg in tolterodine suboptimal responders.

Methods: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24?h at week ?2 received open-label tolterodine ER 4?mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4?mg for 1 week, 8?mg for weeks 2–12) or placebo once daily. Post-hoc analyses compared the percentage change from week ?2 to week 0 in UUI episodes/24?h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8?mg among tolterodine suboptimal responders.

Results: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24?h at week ?2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24?h after tolterodine treatment at week 0 (80.0% versus 15.3%; p?p?=?.0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response.

Conclusions: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8?mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.     

Efficacy of tianeptine vs placebo in the long-term treatment (16.5 months) of unipolar major recurrent depression*

To compare the efficacy and acceptability of tianeptine vs placebo in the long-term treatment of unipolar major recurrent depression, 268 hospitalized and ambulatory patients meeting DSM III-R criteria for major depression with a 21-item Hamilton depression rating scale (HDRS) score >/= 17 and at least one episode in the previous 5 years received tianeptine in a 6-week multicenter open study. At D42, 185 responders (intention-to-treat population) were randomized for ethical reasons into two unbalanced groups to receive tianeptine 37.5 mg/day (n= 111) or placebo (n= 74) for 16.5 months; 173 of the 185 responders were defined as strict responders (per-protocol population) by an HDRS score which was both < 15 and at least halved vs D1, combined with clinical confirmation by the investigator. The groups were similar at baseline except in the severity of the depressive episode (greater in the tianeptine group: 33 vs 18%, p= 0.018). Relapse (before 6 months) and recurrence (after 6 months) were defined by an HDRS score >/= 15 and/or clinical global impression score >/= 4, and clinical confirmation by the investigator. Visits were at D63 and M3, M6, M9, M12, M15, and M18. Efficacy was measured by the number of relapses and recurrences and their time of onset (Kaplan-Meier survival curve analysis). Between D42 and M18 (intention-to-treat population), relapse and recurrence were less frequent on tianeptine vs placebo (16 vs 36%, p= 0.002). Comparison over time also showed a higher proportion of patients without relapse or recurrence on tianeptine (p< 0.001); the intergroup difference increased with follow-up duration. Secondary analysis of relapse in the intention-to-treat group showed a higher proportion on placebo (p= 0.002); secondary analysis of recurrence over time showed that the difference in the percentages of recurrence-free patients was nonsignificant in the intention-to-treat population (p= 0.067) but significant in the per-protocol population (p= 0.036) in favor of tianeptine. Acceptability did not differ between the groups. Treatment-induced adverse events were rare and mild in both groups. These data support the use of tianeptine in the long-term treatment of unipolar major recurrent depression. Relapse and recurrence were decreased two- to threefold on tianeptine vs placebo with no difference in acceptability between the two groups. Copyright 1997 Doin Editeurs     

Reproducibility of a symptom response to omeprazole therapy in functional dyspepsia evaluated by a random-starting-day trial design

BACKGROUND: Satisfactory treatment options for functional dyspepsia are lacking. Single subject trial designs may identify subgroups of patients with a uniform response to therapy. AIM: To test reproducibility of response in a new random-starting-day trial design developed to identify acid-related symptoms in functional dyspepsia. METHODS: One hundred and nineteen patients with functional dyspepsia completed a 12-day, double-blind random-starting-day trial with an initial placebo run-in followed by switch to omeprazole on a randomized and blinded day (between days 5 and 9) with active treatment continuing for the rest of the trial. Response was defined as a sustained > or =50% reduction of a daily symptom-score within 3 days of active treatment. Fifty-nine patients repeated the random-starting-day trial at relapse of symptoms. RESULTS: After exclusion of placebo responders, 14% (15 of 106) were classified as responders in the first and 20% (10 of 50) in the subsequent random-starting-day trial series. Sixty-eight per cent (40 of 59) of the patients reproduced their initial response with a chance-corrected agreement of 0.29. Comparing response patterns using different symptom rating-scales showed good correlation (kappa 0.60). CONCLUSION: Reproducibility of response in a random-starting-day trial was imperfect, mainly because of the low response rates and strict response criteria. Lack of symptom stability impairs the value of the random-starting-day trial and only patients with frequent and stable symptoms should be evaluated in this design.     

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 > or =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.     

Durability of antidepressant response to vagus nerve stimulation (VNS)

This study characterized the durability of improvement in patients who responded early or late while receiving vagus nerve stimulation (VNS). In both a pilot and pivotal study, patients were identified who had at least a 50% reduction in symptom scores 3 months (early responders) or 12 months (late responders) after starting VNS. Probabilities were determined for maintenance of response at 12-month and 24-month time-points. Consistency of improvement throughout the 24-month study period was evaluated, testing for change in serial depression ratings. In the pilot study, 30.5%, 23.7% and 45.8% were early responders, later responders, and non-responders, respectively. These rates were 14.6%, 19.5%, and 65.9% in the pivotal trial. The potential confound of alterations in antidepressant treatment was examined in the pivotal trial. In the pilot study, 72.2% and 61.1% of early responders (n=18) were responders at 12 and 24 months, respectively; 78.8% of late responders (n=14) were responders at 24 months. In the pivotal trial, of early responders (n=30), 63.3% and 76.7% maintained response at 12 and 24 months, respectively; of late responders (n=40), 65.0% maintained response at 24 months. Early and late responders had fewer changes in medication than non-responders across the pivotal study period. In both studies, analyses of serial depression ratings showed stable improvement in early and late responders. These samples had exceptional levels of chronicity and treatment resistance. Yet patients who showed substantial clinical benefit maintained the improvement at remarkably high rates. This durability of benefit was not attributable to alterations in other treatments.     

Identifying response to acid suppressive therapy in functional dyspepsia using a random starting day trial – is gastro‐oesophageal reflux important?

BACKGROUND: Single subject trials offer an alternative approach to identify and characterize responders to a specific treatment. AIM: To test a new single subject trials design, called random starting day trial, to identify acid-related symptoms in dyspepsia. METHODS: A total of 119 patients with functional dyspepsia entered a 12-day, double-blind random starting day trial. All patients started on placebo and switched to omeprazole 80 mg/day at a randomized and blinded day between day 5 and day 9, with active treatment continuing for the rest of the trial. Based on changes of a daily symptom score, response was defined as a sustained > or =50% reduction of symptoms within 3 days of active treatment. RESULTS: Thirteen of 119 patients (11%) were classified as spontaneous responders because of complete symptom relief before switching to omeprazole. Of the remaining 106 patients, 15 (15.6%) were classified as responders. Five of six (83%) responders compared with 28 of 53 (53%) non-responders had pathological reflux. Multivariate testing identified symptoms suggestive of gastro-oesophageal reflux predictive of response. CONCLUSIONS: The random starting day trial design could identify a subset of dyspeptic patients with a uniform symptomatic response to acid-suppressive therapy. Response seems to be associated with gastro-oesophageal reflux. The random starting day trial needs to be further validated to be considered as a reliable instrument in clinical research.     

Follow-up of patients who improved during placebo washout

Depressed patients who showed significant improvement after a 10-day placebo washout trial were followed for 3 months. Twenty-five relapsed and 20 remained well. Relapsing patients more frequently had a family history of depression, more had prior psychiatric treatment, their illness course was more chronic once ill, mean age of onset was younger, and fewer had obvious precipitants. More relapser had RDC diagnoses of intermittent depressive disorder. Among those with major depressive disorder, fewer relapsers met subtype criteria for simple, situational, or recurrent. Nonaffective psychiatric disorders were present in 64% of relapsers and no placebo responders who remained well. Overall, 10-day placebo responders included patients with different clinical characteristics and subsequent course.     

Assessing the efficacy of 2 years of maintenance treatment with venlafaxine extended release 75-225 mg/day in patients with recurrent major depression: a secondary analysis of data from the PREVENT study

The objective of this study was to evaluate the long-term efficacy of venlafaxine extended release (ER) < or =225 mg/day in patients with recurrent major depressive disorder (MDD). In this double-blind trial, outpatients with recurrent MDD (N=1096) were randomized to 10 weeks of acute-phase treatment with venlafaxine ER (75-300 mg/day) or fluoxetine (20-60 mg/day) followed by a 6-month continuation phase and two consecutive 12-month maintenance phases. At the start of each maintenance period, venlafaxine ER responders were randomized to double-blind venlafaxine ER or placebo. In this analysis, data from responders to acute and continuation treatment were analyzed during the combined maintenance phases while receiving venlafaxine ER < or =225 mg/day. Failure to maintain response was defined as an increase in maintenance dose to 300 mg/day or recurrence. Differences were calculated using Kaplan-Meier methods and compared using log-rank tests. Continuation-phase responders (n=114) receiving venlafaxine ER < or =225 mg/day comprised the analysis population (venlafaxine ER: n=55; placebo: n=59). The estimated probability for remaining well across 24 months of maintenance treatment was 67% for venlafaxine ER and 41% for placebo (P=0.007). Venlafaxine ER effectively maintained response at doses < or =225 mg/day for up to 2.5 years in patients with recurrent MDD. The findings are consistent with those of the full data set.