Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms.</p> <p>Methods</p> <p>A <it>post hoc </it>analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects.</p> <p>Results</p> <p>Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, <it>low </it>anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm.</p> <p>Conclusion</p> <p>This study was a <it>post hoc </it>analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported.</p> <p>Trial Registration</p> <p>International Clinical Trials Registry ISRCTN98972974.</p

Duloxetine compared with fluoxetine and venlafaxine: use of meta-regression analysis for indirect comparisons

BACKGROUND: Data comparing duloxetine with existing antidepressant treatments is limited. A comparison of duloxetine with fluoxetine has been performed but no comparison with venlafaxine, the other antidepressant in the same therapeutic class with a significant market share, has been undertaken. In the absence of relevant data to assess the place that duloxetine should occupy in the therapeutic arsenal, indirect comparisons are the most rigorous way to go. We conducted a systematic review of the efficacy of duloxetine, fluoxetine and venlafaxine versus placebo in the treatment of Major Depressive Disorder (MDD), and performed indirect comparisons through meta-regressions. METHODS: The bibliography of the Agency for Health Care Policy and Research and the CENTRAL, Medline, and Embase databases were interrogated using advanced search strategies based on a combination of text and index terms. The search focused on randomized placebo-controlled clinical trials involving adult patients treated for acute phase Major Depressive Disorder. All outcomes were derived to take account for varying placebo responses throughout studies. Primary outcome was treatment efficacy as measured by Hedge's g effect size. Secondary outcomes were response and dropout rates as measured by log odds ratios. Meta-regressions were run to indirectly compare the drugs. Sensitivity analysis, assessing the influence of individual studies over the results, and the influence of patients' characteristics were run. RESULTS: 22 studies involving fluoxetine, 9 involving duloxetine and 8 involving venlafaxine were selected. Using indirect comparison methodology, estimated effect sizes for efficacy compared with duloxetine were 0.11 [-0.14;0.36] for fluoxetine and 0.22 [0.06;0.38] for venlafaxine. Response log odds ratios were -0.21 [-0.44;0.03], 0.70 [0.26;1.14]. Dropout log odds ratios were -0.02 [-0.33;0.29], 0.21 [-0.13;0.55]. Sensitivity analyses showed that results were consistent. CONCLUSION: Fluoxetine was not statistically different in either tolerability or efficacy when compared with duloxetine. Venlafaxine was significantly superior to duloxetine in all analyses except dropout rate. In the absence of relevant data from head-to-head comparison trials, results suggest that venlafaxine is superior compared with duloxetine and that duloxetine does not differentiate from fluoxetine

Sleep and circadian rhythms in mood disorders

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65629/1/j.1600-0447.2007.00968.x.pd

Advances in understanding and treating ADHD

Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability

Episódio depressivo maior, prevalência e impacto sobre qualidade de vida, sono e cognição em octogenários The prevalence of major depression and its impact in the quality of life, sleep patterns and cognitive function in a octogenarian population

OBJETIVOS: Determinar a prevalência de depressão maior em uma população de sujeitos acima de 80 anos residentes na comunidade, comparar os padrões de sono e a função cognitiva entre controles normais e sujeitos com depressão maior e estimar a freqüência de outros transtornos psiquiátricos entre controles e sujeitos deprimidos. MÉTODOS: De uma população de 219 habitantes com mais de 80 anos, residentes em um município semi-rural no sul do Brasil (município de Veranópolis, RS), selecionou-se uma amostra randômica e representativa de 77 sujeitos (35%). Desse grupo, 5 sujeitos que apresentavam critérios de DSM-IV para depressão maior foram comparados com 50 controles sem diagnóstico de demência, delirium ou qualquer transtorno do humor. Os padrões de sono foram avaliados pelo Índice de Pittsburgh de Qualidade do Sono e por um diário do ciclo sono/vigília completado ao longo de duas semanas. Para a avaliação cognitiva, foram usados 5 testes neuropsicológicos: teste de lembranças seletivas de Buschke-Fuld; teste lista de palavras da bateria do CERAD; teste de fluência verbal; e 2 subtestes da bateria de memória de Wechsler. RESULTADOS: A prevalência de depressão maior foi de 7,5%. Sujeitos com esse diagnóstico, quando comparados a sujeitos do grupo-controle, apresentavam mais freqüentemente comorbidade com transtorno de ansiedade generalizada, usavam mais benzodiazepínicos e tinham uma pior qualidade de vida pela escala "Short-form 36". Os idosos deprimidos, quando comparados aos controles, tinham os mesmos padrões de sono e apresentavam o mesmo desempenho nos testes neuropsicológicos. CONCLUSÃO: Os resultados corroboram o conceito de que episódios depressivos são freqüentes entre idosos com mais de 80 anos, causando impacto sobre a qualidade de vida associada à saúde e cursando comorbidade freqüente com transtorno de ansiedade generalizada. Entre os idosos octogenários residentes na comunidade, a depressão maior não aparecia clinicamente sob a forma de "pseudodemência" depressiva e nem tinha impacto sobre os padrões de sono.<br>OBJECTIVES: To determine the prevalence of major depression in a community-dwelling population aged 80 years or more. The secondary objective was to compare this population's sleep patterns, cognitive function and frequency of other psychiatric disorders with a normal control group and other subjects with major depression. METHODS: A representative sample of 77 subjects (35%) aged 80 years or more was randomly selected from the rural southern county of Veranopolis, Brazil. Of them, 5 subjects met the DSM-IV criteria for major depression disorder and 50 control subjects (without dementia, delirium or any mood disorder) were compared. Sleep patterns were assessed using the Pittsburgh Sleep Quality Index and a 2-week-sleep/wake diary. Five neuropsychological tests (the Buschke-Fuld Selective Reminding Test, the CERAD battery word list, the Verbal Fluency Test, and two sub-tests of the Wechsler memory scale) were used for cognitive evaluation. RESULTS: The point prevalence rate for major depression was 7.5%. When compared to the control group, subjects with major depression had a higher frequency of generalized anxiety disorder as a comorbid condition, used more benzodiazepines and had a worse life quality according to the Short-form 36 scale. Depressed elderly people showed the same sleep patterns, and performed in the same manner in the cognitive tests as controls. CONCLUSION: The results corroborate the hypothesis that major depressive disorder is frequently found among the elderly population aged 80 or more. This disorder causes impact on life quality concerning health, and often occurs in association with generalized anxiety disorder. Among elderly aged 80 or more living in this community, major depression neither manifested as a form of depressive pseudo-dementia, nor did it have any impact on sleep patterns