Correspondence
Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada (PDV); Pharmacy Department, Institut Universitaire en Santé Mentale de Montréal, Montréal, QC, Canada (PDV, EK); and Department of Medicine and Medical Specialities, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada (EK) 1
2
3
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62. Velligan DI, Weiden PJ, Sajatovic M, et al. Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. J Psychiatr Pract 2010; 16: 34–45. Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry, 11 edn. Hoboken, NJ: Wiley-Blackwell, 2012.
In their multiple-treatments metaanalysis1 ranking reported efficacy and tolerability of 15 antipsychotics, Stefan Leucht and colleagues’ tabulated the standardised mean difference (SMD) for all pairwise treatment comparisons and order of efficacy ranking. We have concerns with the limitations of the ranking analysis based on multiple-treatments metaanalysis when the treatment network is sparse, asymmetric, and quality-biased. For example, the SMD for amisulpride (vs placebo) and the majority of treatment comparisons between the 15 antipsychotics (figure 2)1 were based on indirect evidence, rendering impossible verification of the necessary consistency assumptions when comparing any two treatments through a third comparator.2 The results for amisulpride, ranked second best after clozapine, particularly illustrate these challenges. All amisulpride treatment comparisons were missing, except for five trials versus olanzapine (four with reporting bias), six trials versus haloperidol (three with reporting bias), and four trials versus risperidone (one with reporting bias). To derive SMDs for amisulpride, these 15 active-controlled trials were combined with trials sharing a common comparator of olanzapine (63 trials), haloperidol (88 trials), or risperidone (57 trials). Our previous studies suggest the magnitude of SMD decreased significantly with 1874
increased placebo response,3 leading to diminished treatment effect size over time.4,5 It is therefore difficult to interpret an efficacy ranking order based on SMD when comparing and combining studies done in different populations of patients at different time periods, thereby generating inconsistencies, which cannot be assessed. COS has served as a paid consultant for Pfizer, Sunovion US, Memory Pharmaceutical, and Wyeth. OA participated in the Pfizer sponsored study of ziprasidone HCl, and received grant support, funding, or has served as a paid consultant for Janssen-Ortho, Eli Lilly US, Eli Lilly Canada, Novartis, Sepracor US, and Sunovion US. GR has received support from Novartis Canada, Medicure, and Neurocrine Bioscience, did research sponsored by Pfizer, and has received consultant fees from CanAm Bioresearch, and Winnipeg, as well as speaker’s fees from Novartis.
*Cynthia O Siu, Ofer Agid, Gary Remington [email protected] Data Power, Flemington, NJ 08822, USA (COS); and Center for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada (OA, GR) 1
2
3
4
5
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62. Song F, Altman D, Glenny AM, Deeks J. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003; 326: 472. Agid O, Siu CO, Potkin SG, et al. Meta-regression analysis of placebo response in antipsychotic trials 1970–2010. Am J Psychiatry 2013; 170: 1335–44. Kemp AS, Schooler NR, Kalali AH, et al. What is causing the reduced drug placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophr Bull 2010; 36: 504–09. Chen YF, Wang SJ, Khin NA, Hung HMJ, Laughren TP. Trial design issues and treatment effect modeling in multi-regional schizophrenia trials. Pharmaceut Statist 2010; 9: 217–29.
Authors’ reply Philippe Vincent and Edouard Kouassi make a valid point about the complex pharmacokinetics of some newer antipsychotic drugs. We believe that knowledge of these pharmacokinetics is essential for getting the best results from treatment and that these issues might be under-recognised in clinical practice. For example, even though the
majority of the trials included in our meta-analysis1 were phase 3 studies with strict protocols, it cannot be ruled out that ziprasidone or lurasidone were sometimes taken without sufficient food. To check plasma levels can be a good idea, but these are expensive and subject to substantial interindividual variability. We agree with Cynthia Siu and colleagues that the validity of a multiple-treatments meta-analysis increases the more the network is connected. In an ideal world all treatments would have been compared directly, but this will never be the case across 15 antipsychotic drugs. The value of and need for indirect evidence is greater in the absence of direct evidence (ie, randomised controlled trials comparing antipsychotics headto-head).2 Therefore, a sparse network is an incentive for multiple-treatments meta-analysis, not an obstacle. With regard to the amisulpride example, it was reassuring that its efficacy results were consistent with those of previous conventional pairwise meta-analyses.3,4 In the discussion,1 we acknowledged that increasing placebo response is a major concern of current antipsychotic drug trials that might have affected the results of the newest drugs. We addressed such potentially confounding effects by multiple sensitivity and metaregression analyses (among others by excluding placebo-controlled studies or haloperidol-controlled studies, and by implementing publication year in the model), but there might be other ones. Moreover, there is evidence that increasing placebo response has been paralleled by an (albeit less pronounced) increase in drug response, which could theoretically attenuate increasing placebo response (see table 2 in Khin and colleagues’ report5). If it were all about publication year, chlorpromazine and haloperidol would have turned out as the most efficacious drugs. The dogma of equal efficacy of antipsychotic drugs was established in 1969,6 but it has never been systematically addressed in a comprehensive way since. Since www.thelancet.com Vol 382 December 7, 2013
Correspondence
antipsychotic drugs are quite different in their receptor binding profiles, it seems obvious that they must differ in efficacy, the question is only how much. We reiterate our interpretation that most efficacy differences are small and usually gradual rather than discrete. The differences in side-effects are overall larger. SL has received honoraria for lectures from Abbvie, AstraZeneca, Bristol-Myers Squibb, ICON, Eli Lilly, Janssen, Johnson & Johnson, Roche, Sanofi-Aventis Lundbeck, and Pfizer; and for consulting or advisory boards from Roche, Eli Lilly, Medavante, BristolMyers Squibb, Alkermes, Janssen, Johnson & Johnson, and Lundbeck. Eli Lilly has provided medication for a study with SL as the primary investigator. JRG was expert witness for Dr Reddys Laboratories and is Chief Investigator on the CEQUEL trial to which GlaxoSmithKline have contributed and supplied investigational drugs. The other authors declare that they have no conflicts of interest.
*Stefan Leucht, Andrea Cipriani, John R Geddes, Georgia Salanti, John M Davis [email protected] Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany (SL); Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK (SL, AC, JRG); Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Verona, Italy (AC); Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, University Campus Ioannina, Ioannina, Greece (GS); Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA (JMD); and Maryland Psychiatric Research Center, Baltimore, MD, USA (JMD) 1
2
3
4
5
6
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62. Mills EJ, Ioannidis JP, Thorlund K, Schunemann HJ, Puhan MA, Guyatt GH. How to use an article reporting a multiple treatment comparison meta-analysis. JAMA 2012; 308: 1246–53. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373: 31–41. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60: 553–64. Khin NA, Chen YF, Yang Y, Yang P, Laughren TP. Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. J Clin Psychiatry 2012; 73: 856–64. Klein DF, Davis JM. Diagnosis and drug treatment of psychiatric disorders. Baltimore, MD: Williams and Wilkins, 1969.
www.thelancet.com Vol 382 December 7, 2013
Surgical clinical trials— need for international collaboration
New Zealand
Australia Canada
International collaboration in research provides multiple benefits including improving methodological quality, generalisation of the results, and specifically in surgery, greater ease in the recruitment of patients.1 However, collaborations do not seem to be reflected in scientific publications. Between 2007 and 2013, 6957 surgical clinical trials were published in journals indexed in the Web of Science; however, only 1241 (17·8%) were done by international collaborations, although authors were affiliated in 90 different countries. Moreover, collaborative research was done mostly by investigators in Europe and North America (figure). In disciplines other than surgical clinical trials, there appears to be more international collaboration; more than 30% of the publications were done by authors affiliated in at least two countries.2 We note that international collaboration between authors from at least two continents or regions is low with 755 papers (10·9%), and even fewer papers (93 [1·3%]), involved at least three continents. The scarcity of collaboration between North America and Europe and countries in Asia, Oceania, Central or South America, or Africa is concerning, in view of the dependence of these regions on international collaboration for scientific production. For example, North America published 14 papers with countries in Africa; this accounted for 1·1% of the total international collaboration but was 20·9% of the total production of the African countries. There are multiple barriers to collaboration, from technological barriers to institutional policies. Among the strategies for increasing
Austria
Switzerland Japan
UK Sweden
China USA
Brazil
Germany Spain
France
Italy 49* 27*
Netherlands
Belgium
Figure: International collaboration network in surgical clinical trials Only interactions involving more than 19 published studies are shown. *Lines are proportional to 27 and 49 papers in collaboration, respectively.
international collaboration, it is crucial for young researchers to participate in research and publication1,3 to gain experience to boost research and future contacts for the establishment of new research centres in their countries of origin. In South America, this strategy led to the training of highly educated staff which has widened the collaborative networks and had a positive effect on research; experience that could be transferred in the surgical setting. We declare that we have no conflicts of interest.
Charles Huamaní, *Gregorio González-Alcaide [email protected] University of Valencia, Valencia 46020, Spain (GG-A); and Instituto Nacional de Salud, Lima, Peru (CH) 1
Søreide K, Alderson D, Bergenfelz A, et al. Strategies to improve clinical research in surgery through international collaboration. Lancet 2013; 382: 1140–51.
1875
Faculty of Pharmacy, Université de Montréal, Montréal, QC H3T 1J4, Canada (PDV); Pharmacy Department, Institut Universitaire en Santé Mentale de Montréal, Montréal, QC, Canada (PDV, EK); and Department of Medicine and Medical Specialities, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada (EK) 1
2
3
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62. Velligan DI, Weiden PJ, Sajatovic M, et al. Assessment of adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. J Psychiatr Pract 2010; 16: 34–45. Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry, 11 edn. Hoboken, NJ: Wiley-Blackwell, 2012.
In their multiple-treatments metaanalysis1 ranking reported efficacy and tolerability of 15 antipsychotics, Stefan Leucht and colleagues’ tabulated the standardised mean difference (SMD) for all pairwise treatment comparisons and order of efficacy ranking. We have concerns with the limitations of the ranking analysis based on multiple-treatments metaanalysis when the treatment network is sparse, asymmetric, and quality-biased. For example, the SMD for amisulpride (vs placebo) and the majority of treatment comparisons between the 15 antipsychotics (figure 2)1 were based on indirect evidence, rendering impossible verification of the necessary consistency assumptions when comparing any two treatments through a third comparator.2 The results for amisulpride, ranked second best after clozapine, particularly illustrate these challenges. All amisulpride treatment comparisons were missing, except for five trials versus olanzapine (four with reporting bias), six trials versus haloperidol (three with reporting bias), and four trials versus risperidone (one with reporting bias). To derive SMDs for amisulpride, these 15 active-controlled trials were combined with trials sharing a common comparator of olanzapine (63 trials), haloperidol (88 trials), or risperidone (57 trials). Our previous studies suggest the magnitude of SMD decreased significantly with 1874
increased placebo response,3 leading to diminished treatment effect size over time.4,5 It is therefore difficult to interpret an efficacy ranking order based on SMD when comparing and combining studies done in different populations of patients at different time periods, thereby generating inconsistencies, which cannot be assessed. COS has served as a paid consultant for Pfizer, Sunovion US, Memory Pharmaceutical, and Wyeth. OA participated in the Pfizer sponsored study of ziprasidone HCl, and received grant support, funding, or has served as a paid consultant for Janssen-Ortho, Eli Lilly US, Eli Lilly Canada, Novartis, Sepracor US, and Sunovion US. GR has received support from Novartis Canada, Medicure, and Neurocrine Bioscience, did research sponsored by Pfizer, and has received consultant fees from CanAm Bioresearch, and Winnipeg, as well as speaker’s fees from Novartis.
*Cynthia O Siu, Ofer Agid, Gary Remington [email protected] Data Power, Flemington, NJ 08822, USA (COS); and Center for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada (OA, GR) 1
2
3
4
5
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62. Song F, Altman D, Glenny AM, Deeks J. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003; 326: 472. Agid O, Siu CO, Potkin SG, et al. Meta-regression analysis of placebo response in antipsychotic trials 1970–2010. Am J Psychiatry 2013; 170: 1335–44. Kemp AS, Schooler NR, Kalali AH, et al. What is causing the reduced drug placebo difference in recent schizophrenia clinical trials and what can be done about it? Schizophr Bull 2010; 36: 504–09. Chen YF, Wang SJ, Khin NA, Hung HMJ, Laughren TP. Trial design issues and treatment effect modeling in multi-regional schizophrenia trials. Pharmaceut Statist 2010; 9: 217–29.
Authors’ reply Philippe Vincent and Edouard Kouassi make a valid point about the complex pharmacokinetics of some newer antipsychotic drugs. We believe that knowledge of these pharmacokinetics is essential for getting the best results from treatment and that these issues might be under-recognised in clinical practice. For example, even though the
majority of the trials included in our meta-analysis1 were phase 3 studies with strict protocols, it cannot be ruled out that ziprasidone or lurasidone were sometimes taken without sufficient food. To check plasma levels can be a good idea, but these are expensive and subject to substantial interindividual variability. We agree with Cynthia Siu and colleagues that the validity of a multiple-treatments meta-analysis increases the more the network is connected. In an ideal world all treatments would have been compared directly, but this will never be the case across 15 antipsychotic drugs. The value of and need for indirect evidence is greater in the absence of direct evidence (ie, randomised controlled trials comparing antipsychotics headto-head).2 Therefore, a sparse network is an incentive for multiple-treatments meta-analysis, not an obstacle. With regard to the amisulpride example, it was reassuring that its efficacy results were consistent with those of previous conventional pairwise meta-analyses.3,4 In the discussion,1 we acknowledged that increasing placebo response is a major concern of current antipsychotic drug trials that might have affected the results of the newest drugs. We addressed such potentially confounding effects by multiple sensitivity and metaregression analyses (among others by excluding placebo-controlled studies or haloperidol-controlled studies, and by implementing publication year in the model), but there might be other ones. Moreover, there is evidence that increasing placebo response has been paralleled by an (albeit less pronounced) increase in drug response, which could theoretically attenuate increasing placebo response (see table 2 in Khin and colleagues’ report5). If it were all about publication year, chlorpromazine and haloperidol would have turned out as the most efficacious drugs. The dogma of equal efficacy of antipsychotic drugs was established in 1969,6 but it has never been systematically addressed in a comprehensive way since. Since www.thelancet.com Vol 382 December 7, 2013
Correspondence
antipsychotic drugs are quite different in their receptor binding profiles, it seems obvious that they must differ in efficacy, the question is only how much. We reiterate our interpretation that most efficacy differences are small and usually gradual rather than discrete. The differences in side-effects are overall larger. SL has received honoraria for lectures from Abbvie, AstraZeneca, Bristol-Myers Squibb, ICON, Eli Lilly, Janssen, Johnson & Johnson, Roche, Sanofi-Aventis Lundbeck, and Pfizer; and for consulting or advisory boards from Roche, Eli Lilly, Medavante, BristolMyers Squibb, Alkermes, Janssen, Johnson & Johnson, and Lundbeck. Eli Lilly has provided medication for a study with SL as the primary investigator. JRG was expert witness for Dr Reddys Laboratories and is Chief Investigator on the CEQUEL trial to which GlaxoSmithKline have contributed and supplied investigational drugs. The other authors declare that they have no conflicts of interest.
*Stefan Leucht, Andrea Cipriani, John R Geddes, Georgia Salanti, John M Davis [email protected] Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany (SL); Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK (SL, AC, JRG); Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Verona, Italy (AC); Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, University Campus Ioannina, Ioannina, Greece (GS); Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA (JMD); and Maryland Psychiatric Research Center, Baltimore, MD, USA (JMD) 1
2
3
4
5
6
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–62. Mills EJ, Ioannidis JP, Thorlund K, Schunemann HJ, Puhan MA, Guyatt GH. How to use an article reporting a multiple treatment comparison meta-analysis. JAMA 2012; 308: 1246–53. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373: 31–41. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60: 553–64. Khin NA, Chen YF, Yang Y, Yang P, Laughren TP. Exploratory analyses of efficacy data from schizophrenia trials in support of new drug applications submitted to the US Food and Drug Administration. J Clin Psychiatry 2012; 73: 856–64. Klein DF, Davis JM. Diagnosis and drug treatment of psychiatric disorders. Baltimore, MD: Williams and Wilkins, 1969.
www.thelancet.com Vol 382 December 7, 2013
Surgical clinical trials— need for international collaboration
New Zealand
Australia Canada
International collaboration in research provides multiple benefits including improving methodological quality, generalisation of the results, and specifically in surgery, greater ease in the recruitment of patients.1 However, collaborations do not seem to be reflected in scientific publications. Between 2007 and 2013, 6957 surgical clinical trials were published in journals indexed in the Web of Science; however, only 1241 (17·8%) were done by international collaborations, although authors were affiliated in 90 different countries. Moreover, collaborative research was done mostly by investigators in Europe and North America (figure). In disciplines other than surgical clinical trials, there appears to be more international collaboration; more than 30% of the publications were done by authors affiliated in at least two countries.2 We note that international collaboration between authors from at least two continents or regions is low with 755 papers (10·9%), and even fewer papers (93 [1·3%]), involved at least three continents. The scarcity of collaboration between North America and Europe and countries in Asia, Oceania, Central or South America, or Africa is concerning, in view of the dependence of these regions on international collaboration for scientific production. For example, North America published 14 papers with countries in Africa; this accounted for 1·1% of the total international collaboration but was 20·9% of the total production of the African countries. There are multiple barriers to collaboration, from technological barriers to institutional policies. Among the strategies for increasing
Austria
Switzerland Japan
UK Sweden
China USA
Brazil
Germany Spain
France
Italy 49* 27*
Netherlands
Belgium
Figure: International collaboration network in surgical clinical trials Only interactions involving more than 19 published studies are shown. *Lines are proportional to 27 and 49 papers in collaboration, respectively.
international collaboration, it is crucial for young researchers to participate in research and publication1,3 to gain experience to boost research and future contacts for the establishment of new research centres in their countries of origin. In South America, this strategy led to the training of highly educated staff which has widened the collaborative networks and had a positive effect on research; experience that could be transferred in the surgical setting. We declare that we have no conflicts of interest.
Charles Huamaní, *Gregorio González-Alcaide [email protected] University of Valencia, Valencia 46020, Spain (GG-A); and Instituto Nacional de Salud, Lima, Peru (CH) 1
Søreide K, Alderson D, Bergenfelz A, et al. Strategies to improve clinical research in surgery through international collaboration. Lancet 2013; 382: 1140–51.
1875
