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E.04.02 Impact of pragmatic trials in depression
E.04. Impact of publicly funded mega-trials in daily psychiatric practice
E.03. Gene–environment interactions: from epidemiology to neural mechanisms E.03.02 Gene°environment interactions (G°E) in alcohol dependence P. Gorwood ° , Y. LeStrat, N. Ramoz. INSERM, U675, Paris, France Gene–Environment interactions approach could explain some epidemiological and clinical factors associated to addictive behaviors. Twin studies first help to disentangle the respective role of environment and genetic effects, finding convincing evidence for common genetic vulnerability in several addictive behaviors. Assessing gene x environment interaction, need specifically designed studies, using multiplicative or additive approaches. Focusing on this GxE interaction already showed its relevancy in many recent studies, using both epidemiological and molecular approaches. For example, in a non-human primate model of alcohol dependence assessing the respective role of genetic vulnerability and severe fostering conditions, the only group that has a significant risk of using spontaneously alcohol is the group of monkeys that have both risk factors, i.e. being peer-raised and having the short allele (Barr et al., 2005). Such approach was used to assess which factors are involved in the high mortality rate of alcohol-dependence. We analysed the survival status of a male alcohol-dependent sample (n = 126) recruited 9 years before, and compared the 61 surviving patients to the 41 patients who died during this period (representing 81% of the initial sample). We found that the C allele of the 5-HT1b gene, and tobacco dependence, were found in excess in the nonsurviving patients. Gene–Environment interactions approach could help to select more accurately specific candidate genes, to identify more homogenous subgroups of patients (as sharing the same genetic vulnerability), to understand how genetic factors mediate the risk for associated psychiatric disorders, and ultimately, may lead to more focused, i.e. more efficient, prevention strategies. References [1] Enoch MA, 2006 Dec, Genetic and environmental influences on the development of alcoholism: resilience vs. risk. Ann NY Acad Sci 1094, 193–201. [2] Barr CS, Newman TK, Lindell S, Shannon C, Champoux M, Lesch KP, Suomi SJ, Goldman D, Higley JD, 2004 Nov, Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Arch Gen Psychiatry 61(11), 1146−52.
E.04. Impact of publicly funded megatrials in daily psychiatric practice E.04.02 Impact of pragmatic trials in depression S.A. Montgomery ° . Imperial College School of Medicine University of London, London, United Kingdom We have learned over many years that in order to obtain valid results on the efficacy of treatments we must turn to randomised double-blind placebo-controlled studies for efficacy and to prospective comparator superiority studies for superior efficacy.
S223
Pragmatic trials fail on almost every count. This type of trial cannot test efficacy but is directed to so-called effectiveness, or how a treatment shown to be effective in scientific clinical trials performs in routine clinical practice. Advocates of this approach suggest that pragmatic trials, in addressing the patients who are treated in the real world situation, can be used for valid comparison of treatments. However, pragmatic trials, by their nature may well depend on investigators who are less than careful in selecting patients with a correct diagnosis and/or severity appropriate for the treatment under examination. Pragmatic studies rarely use placebo-controlled methodology and are rarely blinded, allowing investigator driven halo bias to contaminate the results. They amount to little more than seeding studies to publicise the sponsor’s favoured treatment and should be treated with caution. Good studies designed prospectively to investigate superiority show which antidepressants are superior. DUAG showed the superiority of clomipramine in 3 studies, venlafaxine has been shown to be superior to fluoxetine (Clerc et al 1996), escitalopram is superior to citalopram (Moore et al., 2005) and paroxetine (Boulenger et al., 2006). These are the results which good clinicians treasure and which have a positive influence on evidence based medicine. References [1] Moore N, Verdoux H, Fantino B, 2005, Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol 20, 131–137. [2] Clerc GE, Ruimy P, Verdeau Pailles J, 1996, A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol 9, 139–143. [3] Boulenger J-P, Huusom AK, Florea I, Baekdal T, Sarchiapone M, 2006, A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients. Curr Med Res Opin 22, 1331–1341.
E.04.03 The impact of publicly-funded vs. industryfunded AD trials on clinical practice L.S. Schneider ° . University of Southern California Keck School of Medicine, Dept. of psychiatry and neurology, Los Angeles, USA Five drugs are licensed for AD; vitamins, herbals, neutraceuticals are used. Psychotropics, including antipsychotics, are used to treat behavioral symptoms. The vast majority of clinical trials are funded by pharmaceutical manufacturers who publish those with positive results, and use them as publicity events, in advertisements, and medical conference feeding activities. “Negative” results tend not to be published or only after much delay. Thus, physicians are most aware of positive results from manufacturersponsored trials and not the negative results. The few trials of putative anti-dementia treatments that have been publicly funded, however, tend to show null results and have had outsized influence on practice. The initial NIH-funded tacrine trial, in the 1980s provided evidence that, although controversial, was sufficient to spur development of cholinesterase inhibitors. An NIH trial in 1993 comparing vitamin E and selegiline to placebo suggested that the drugs maintained function such that patients avoided worsening, stimulating widespread use of vitamin E even though the trial was underpowered. (A decade later another NIH trial undermined vitamin E’s efficacy). In the early 2000s, at a time when estrogen replacement was embraced in the US as a symptomatic and preventative AD
E.03. Gene–environment interactions: from epidemiology to neural mechanisms E.03.02 Gene°environment interactions (G°E) in alcohol dependence P. Gorwood ° , Y. LeStrat, N. Ramoz. INSERM, U675, Paris, France Gene–Environment interactions approach could explain some epidemiological and clinical factors associated to addictive behaviors. Twin studies first help to disentangle the respective role of environment and genetic effects, finding convincing evidence for common genetic vulnerability in several addictive behaviors. Assessing gene x environment interaction, need specifically designed studies, using multiplicative or additive approaches. Focusing on this GxE interaction already showed its relevancy in many recent studies, using both epidemiological and molecular approaches. For example, in a non-human primate model of alcohol dependence assessing the respective role of genetic vulnerability and severe fostering conditions, the only group that has a significant risk of using spontaneously alcohol is the group of monkeys that have both risk factors, i.e. being peer-raised and having the short allele (Barr et al., 2005). Such approach was used to assess which factors are involved in the high mortality rate of alcohol-dependence. We analysed the survival status of a male alcohol-dependent sample (n = 126) recruited 9 years before, and compared the 61 surviving patients to the 41 patients who died during this period (representing 81% of the initial sample). We found that the C allele of the 5-HT1b gene, and tobacco dependence, were found in excess in the nonsurviving patients. Gene–Environment interactions approach could help to select more accurately specific candidate genes, to identify more homogenous subgroups of patients (as sharing the same genetic vulnerability), to understand how genetic factors mediate the risk for associated psychiatric disorders, and ultimately, may lead to more focused, i.e. more efficient, prevention strategies. References [1] Enoch MA, 2006 Dec, Genetic and environmental influences on the development of alcoholism: resilience vs. risk. Ann NY Acad Sci 1094, 193–201. [2] Barr CS, Newman TK, Lindell S, Shannon C, Champoux M, Lesch KP, Suomi SJ, Goldman D, Higley JD, 2004 Nov, Interaction between serotonin transporter gene variation and rearing condition in alcohol preference and consumption in female primates. Arch Gen Psychiatry 61(11), 1146−52.
E.04. Impact of publicly funded megatrials in daily psychiatric practice E.04.02 Impact of pragmatic trials in depression S.A. Montgomery ° . Imperial College School of Medicine University of London, London, United Kingdom We have learned over many years that in order to obtain valid results on the efficacy of treatments we must turn to randomised double-blind placebo-controlled studies for efficacy and to prospective comparator superiority studies for superior efficacy.
S223
Pragmatic trials fail on almost every count. This type of trial cannot test efficacy but is directed to so-called effectiveness, or how a treatment shown to be effective in scientific clinical trials performs in routine clinical practice. Advocates of this approach suggest that pragmatic trials, in addressing the patients who are treated in the real world situation, can be used for valid comparison of treatments. However, pragmatic trials, by their nature may well depend on investigators who are less than careful in selecting patients with a correct diagnosis and/or severity appropriate for the treatment under examination. Pragmatic studies rarely use placebo-controlled methodology and are rarely blinded, allowing investigator driven halo bias to contaminate the results. They amount to little more than seeding studies to publicise the sponsor’s favoured treatment and should be treated with caution. Good studies designed prospectively to investigate superiority show which antidepressants are superior. DUAG showed the superiority of clomipramine in 3 studies, venlafaxine has been shown to be superior to fluoxetine (Clerc et al 1996), escitalopram is superior to citalopram (Moore et al., 2005) and paroxetine (Boulenger et al., 2006). These are the results which good clinicians treasure and which have a positive influence on evidence based medicine. References [1] Moore N, Verdoux H, Fantino B, 2005, Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder. Int Clin Psychopharmacol 20, 131–137. [2] Clerc GE, Ruimy P, Verdeau Pailles J, 1996, A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol 9, 139–143. [3] Boulenger J-P, Huusom AK, Florea I, Baekdal T, Sarchiapone M, 2006, A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients. Curr Med Res Opin 22, 1331–1341.
E.04.03 The impact of publicly-funded vs. industryfunded AD trials on clinical practice L.S. Schneider ° . University of Southern California Keck School of Medicine, Dept. of psychiatry and neurology, Los Angeles, USA Five drugs are licensed for AD; vitamins, herbals, neutraceuticals are used. Psychotropics, including antipsychotics, are used to treat behavioral symptoms. The vast majority of clinical trials are funded by pharmaceutical manufacturers who publish those with positive results, and use them as publicity events, in advertisements, and medical conference feeding activities. “Negative” results tend not to be published or only after much delay. Thus, physicians are most aware of positive results from manufacturersponsored trials and not the negative results. The few trials of putative anti-dementia treatments that have been publicly funded, however, tend to show null results and have had outsized influence on practice. The initial NIH-funded tacrine trial, in the 1980s provided evidence that, although controversial, was sufficient to spur development of cholinesterase inhibitors. An NIH trial in 1993 comparing vitamin E and selegiline to placebo suggested that the drugs maintained function such that patients avoided worsening, stimulating widespread use of vitamin E even though the trial was underpowered. (A decade later another NIH trial undermined vitamin E’s efficacy). In the early 2000s, at a time when estrogen replacement was embraced in the US as a symptomatic and preventative AD