ABSTRACT: Our prior work has shown that there is improvement in self-reported sleep in persons receiving placebo in hypnotic clinical trials. We examined the components of the "placebo response" in a hypnotic clinical trial.
This was an exploratory analysis of a randomized, double-blind clinical trial of eszopiclone versus placebo in the treatment of persons with depression and insomnia who were also receiving fluoxetine at a clinic of a teaching hospital. Sixty adults with both depression and insomnia symptoms, who were free of significant primary sleep disorders, received open-label fluoxetine for 9weeks. Patients were further randomized 1:1 to receive either masked eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. We examined the respective contributions of three factors associated with the "placebo effect": (1) regression to the mean, (2) expectancy, and (3) social desirability.
There was evidence for regression to the mean for the continuous measurement of the Insomnia Severity Index (ISI) and the Hamilton Depression Rating Scale. There was evidence for expectancy in self-reported Wake After Sleep Onset, continuous measurement of ISI, and dichotomous remission/non-remitter measurement of ISI. There was evidence of social desirability affecting self-reported Total Sleep Time.
Factors that have been associated with the "placebo effect" are operating in hypnotic clinical trials. However, the role of each factor differs depending upon which self-reported variable is being considered. The findings have implications for clinical trial design in insomnia.
Sleep Medicine 06/2011; 12(6):557-64. · 3.40 Impact Factor
ABSTRACT: Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and longitudinal population-based studies. A link between insomnia and suicide has not been previously examined in the setting of a clinical trial. Herein we describe the relationship between insomnia and suicidal thinking during the course of a clinical trial for depression with insomnia.
Sixty patients aged 41.5±12.5 years (2/3 women) with major depressive episode and symptoms of insomnia received open-label fluoxetine for 9 weeks and also received blinded, randomized eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI), and suicidal ideation was assessed with The Scale for Suicide Ideation (SSI). Depression symptoms were assessed with the depressed mood item and the anhedonia item from the Hamilton Rating Scale for Depression-24 (HRSD24), as well as a sum score for all non-sleep and non-suicide items from the HRSD (HRSD20). Measurements were taken at baseline and weeks 1, 2, 4, 6, and 8. SSI was examined by generalized linear mixed models for repeated measures as the outcome of interest for all 60 participants with ISI and various mood symptoms as independent variables, with adjustment for age, gender, treatment assignment, and baseline SSI.
Higher levels of insomnia corresponded to significantly greater intensity of suicidal thinking (p<0.01). The depressed mood item of the HRSD, and the sum of the HRSD20, both corresponded to greater suicidal thinking (p<0.001). The anhedonia item did not correspond with suicidal thinking. When both ISI and the depressed mood item, or ISI and the anhedonia item, were included together in the same model, the ISI remained an independent predictor of suicidal thinking.
The results support the concept that insomnia may be a useful indicator for suicidal ideation and now extend this idea into clinical trials. Insomnia remains an independent indicator of suicidal ideation, even taking into account the core symptoms of depression such as depressed mood and anhedonia. The complaint of insomnia during a depression clinical trial might indicate that more direct questioning about suicide is warranted.
Sleep Medicine 10/2010; 11(9):822-7. · 3.40 Impact Factor
ABSTRACT: Insomnia is associated with poor health related quality of life (HRQOL) in depressed patients. Prior clinical trials of hypnotic treatment of insomnia in depressed patients have shown improvement in HRQOL, but in these studies HRQOL was relegated to a secondary outcome, and objective measures of sleep were not undertaken.
Double-blind, randomized, placebo-controlled clinical trial.
Outpatient clinic and sleep laboratory.
60 depressed, insomniac outpatients.
One week of open-label fluoxetine (FLX), followed by 8 more weeks of FLX combined with either eszopiclone (ESZ) 3 mg or placebo at bedtime.
The primary HRQOL measure was the daily living and role functioning subscale (DLRF) of the Basis-32. Other measures included the Q-LES-Q, self-reported sleep, PSG, actigraphy, depression severity (HRSD).
At the end of randomized treatment, patients receiving ESZ had lower (better) DLRF scores (0.81 +/- 0.64) than those receiving placebo (1.2 +/- 0.72), p = 0.01. The effect size for DLRF was 0.62, indicating a moderate effect. An advantage for ESZ was also seen in other measures of HRQOL, and most assessments of antidepressant efficacy and sleep. Women reported better end of treatment HRQOL scores than men.
ESZ treatment of insomnia in depressed patients is associated with multiple favorable outcomes, including superior improvement in HRQOL, depression severity, and sleep.
Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 08/2010; 6(4):322-9. · 3.23 Impact Factor
ABSTRACT: The patch test procedure is frequently employed to help determine or confirm the cause of allergic contact dermatitis (ACD). The T.R.U.E. Test has become a global standard and is the commercially available patch test system currently used within the United States. Although many studies report T.R.U.E. Test data, none has measured the overall prevalence and relevance of reactions to the allergens tested by the T.R.U.E. Test. Our objective is to describe the prevalence and relevance of contact dermatitis allergens as tested by the T.R.U.E. Test.
We conducted a search of the MEDLINE database from 1966 to June 2000 for all publications on the use of the T.R.U.E. Test in the clinical evaluation of ACD in human subjects. Inclusion and exclusion criteria were applied. For each study, we identified and recorded the number of subjects tested, the number of patients with positive reactions, and the number with relevant reactions. Data were analyzed using the SAS system (Cary, NC).
Ours is the first study to compile the entire corpus of published T.R.U.E. Test data and to examine these data using meta-analytic techniques. The meta-analysis shows that nickel (14.7% of tested patients), thimerosal (5.0%), cobalt (4.8%), fragrance mix (3.4%), and balsam of Peru (3.0%) are the most prevalent allergens. The 5 least prevalent allergens are paraben mix (0.5%), black rubber mix (0.6%), quaternium-15 (0.6%), quinoline mix (0.7%), and caine mix (0.7%). By contrast, North American Contact Dermatitis Data Group (NACDG) data show that the 5 most prevalent allergens are nickel (14.3%), fragrance mix (14%), neomycin (11.6%), balsam of Peru (10.4%), and thimerosal (10.4%). NACDG data indicate that the prevalence of allergy to cobalt is 9.2%. In order to assess the clinical importance of T.R.U.E. Test allergens, we employ the Significance-Prevalence Index Number (SPIN). Based on SPIN, the most clinically important allergens tested by the T.R.U.E. Test are nickel (SPIN=894), cobalt (266), fragrance mix (158), colophony (141), and thiuram mix (138).
Our results identify the prevalence of common contact dermatitis allergens as tested by the T.R.U.E. Test and are in general agreement with previously published reports using other patch test methods. Over 3700 allergens have been identified as causing ACD, of which the T.R.U.E. Test tests only 23. Thus, the T.R.U.E. Test is a screening test at best. Comparison with NACDG data suggests that clinically important allergens may be missed by the T.R.U.E. Test.
Journal of the American Academy of Dermatology 10/2004; 51(3):349-53. · 3.99 Impact Factor
ABSTRACT: The effects associated with placebo (EAP) have been incompletely described in clinical trials of insomnia treatment. We conducted a meta-analysis of insomnia medication trials for the purpose of estimating the magnitude of sleep EAP.
We reviewed Medline for 1966 through 2000 for the meta-analysis. The subject heading of insomnia restricted to the subheading of drug therapy was crossed against the results of a search on the subjects heading placebo and text word placebo. We selected only papers that examined primary insomnia, incorporating both placebo and active medication therapies in a randomized, double-blind, parallel-group design. We required that results be reported for 1, 2, 3, or 4 weeks of treatment, and that outcomes be reported in hours/minutes.
Five papers satisfied our requirements for eligibility, comprising 213 patients receiving placebo for a 2-week interval. Subjective sleep latency demonstrated a significant reduction (mean+/-S.E.) of 13.1+/-2.0 min (95% confidence interval (CI) 9.2, 17.0) for the placebo group after combining the data across studies. Subjective total sleep time demonstrated a significant increase of 13.5+/-5.4 min (95% CI 2.9, 24.0). Polysomnographic (PSG) sleep latency demonstrated a non-significant reduction of 2.5+/-4.3 min (95% CI -5.9, 10.9).
The confirmation of EAP in insomnia clinical trials argues for the retention of a placebo control in future insomnia clinical trials.
Sleep Medicine 02/2003; 4(1):57-62. · 3.40 Impact Factor
ABSTRACT: Toenail onychomycosis is a challenge for clinicians to treat, and this challenge is compounded by conflicting information in the medical literature concerning the efficacy of the two principal agents used in its treatment: terbinafine and itraconazole.
The purpose of this meta-analysis is to compare the efficacy of terbinafinewith that of itraconazole in the treatment of toenail onychomycosis caused by dermatophytes.
A Medline search was performed for all English language publications from 1966 to June 1999 on the use of terbinafine and itraconazole in the treatment of toenail onychomycosis. Included were randomized studies in which subjects received no less than 3 months (or cycles) and no more than 4 months (or cycles) of either terbinafine or itraconazole. Data were abstracted and statistical analyses (random effects model, fixed effects model, and Peto's method) were applied.
Thirteen studies were included from the original literature review of 1636 total referenced reports; four studies did not fulfill our inclusion or exclusion criteria. The primary analysis of six studies directly comparing terbinafine to itraconazole resulted in an odds ratio ranging from 1.8 (95% CI = 1.8, 2.8) to 2.9 (1.9, 4.1). The secondary analysis of three studies comparing either itraconazole or terbinafine to placebo estimated an odds ratio of 1.1-1.7. The former shows that terbinafine is 80%-190% more likely to result in mycologic cure than is itraconazole; the latter demonstrates a 10%-70% greater likelihood. The difference between the relative efficacies of terbinafine and itraconazole was highly statistically significant (p < 0.0001).
Meta-analysis of the published worldwide literature finds that terbinafine is significantly more effective than itraconazole at achieving mycologic cure of toenail onychomycosis.
Journal of Cutaneous Maedicine and Surgery 7(4):306-11. · 0.98 Impact Factor