International Journal of Psychiatry in Clinical Practice, 2005; 9(3): 154 /156
GUEST EDITORIAL
Is there a differential efficacy of new generation antipsychotic drugs?
STEFAN LEUCHT1 & JOHN M. DAVIS2 1
Klinik und Poliklinik fuer Psychiatrie und Psychotherapie der Technischen Universitaet Muenchen, Muenchen, Germany, and 2Department of Psychiatry, University of Illinois, Chicago, IL, USA
Although all issues have not yet been resolved, the new generation of so-called ‘atypical’ antipsychotics (NGAs) has replaced conventional antipsychotics in many countries. While it is quite clear that the new drugs have different side-effect profiles, there is also speculation as to whether they differ in terms of efficacy. Meta-analyses which simultaneously assessed the efficacy of several new drugs have consistently shown that some NGAs were statistically significantly more effective than conventional antipsychotics, while other NGAs were not [1 /4]. Although the interpretation of the results differed, no author concluded that comparing NGAs based on their differences from conventional antipsychotics is a proof for differential efficacy. Leucht et al. [3] made it clear that ‘‘The small differences in the mean effect sizes for efficacy must not be regarded as real differences. A formal statistical comparison of mean effect sizes was not undertaken. Despite the similarity of studies on new antipsychotics, certain differences in study designs, such as slightly different inclusion criteria, study durations, comparators, or dose regimens, would make such statistics inappropriate’’ (Ref. [4], p. 188). Or, Davis et al. cautioned that ‘‘we do not believe that it is valid to infer efficacy differences between two or more second generation antipsychotics from effect size comparisons between second generation antipsychotics and first generation antipsychotics. Head-tohead comparisons are necessary for proof’’ (Ref. [1], p. 560). Nevertheless, the companies whose drugs showed up best in these publications have admittedly ‘‘hijacked’’ the results for their marketing campaigns. In this context we believe that the main value of the article of Tandon and Jibson in this issue of International Journal of Psychiatry in Clinical Practice lies in
the fact that they used a different perspective to look at differential efficacy of NGAs [5]. They strongly argue against the claim of differential efficacy between NGAs by introducing a new version of meta-analysis that they call ‘‘a combined overview analysis’’. Instead of calculating effect sizes for the differences between new antipsychotics and comparators, they did away with all comparators and directly summarised the mean change from baseline to endpoint of the PANSS obtained by the different NGAs in their studies. Using this method they found no differences in efficacy between olanzapine, quetiapine and risperidone. The methodological limitations of this approach were mentioned in the article. However, we consider it important to explain more concretely to the reader the most important problem of this approach: it is the lack of a comparator. The method would therefore theoretically admit the absurd situation that an antipsychotic was less effective than placebo in its trials, but could still be more effective than other antipsychotics if the overall PANSS reduction in its trials was high. A re-analysis of two pivotal risperidone studies [6,7] showed that the mean PANSS reduction from baseline was around 20% [8]. We re-analysed three pivotal short-term studies comparing amisulpride with other conventional antipsychotics [9 /11]. In these the mean reduction of the BPRS was 48% (Leucht et al., manuscript). Thus, using the approach of Tandon and Jibson [5], amisulpride would turn out to be much more effective than risperidone, although it actually is not, since two large double-blind studies comparing amisulpride and risperidone directly showed no difference in efficacy [12,13]. The most likely reason for the smaller overall response in the risperidone studies compared to the amisulpride studies was that the former examined a more chronic
Correpondence: PD Dr. Stefan Leucht, Klinik und Poliklinik fuer Psychiatrie und Psychotherapie, der Technischen Universitaet Muenchen, am Klinikum rechts der Isar, Ismaningerstr. 22, 81675 Muenchen, Germany. Tel: /49 89 4140 4249. Fax: /49 89 4140 4888. E-mail: [email protected]
ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510029165
Editorial population, because in Marder and Meibach [6] the mean length of the current hospitalisation was 29.3 weeks, with a maximum of 1184 weeks. Also, in two Japanese studies that were not considered by Tandon and Jibson [5], there was minimal reduction of symptoms in both the quetiapine and the comparator groups. Including these trials could substantially reduce quetiapine’s efficacy in their approach [14,15]. There are several further reasons why taking absolute increase improvement scores on a given rating scale and comparing them is not valid, besides the fact that acute patients will generally respond much better than chronic patients. There are other setting and population differences. The basic tenet of modern experimental science is the use of a control group, and this principle is neglected by ‘‘combined overview analysis’’. Meta-analyses using effect size scores derived from comparisons with other antipsychotics rather than change-scores on the PANSS, however, are by no means sufficient to counteract the problem. Patients in a trial of amisulpride are randomised against the comparator in that trial. Olanzapine would be randomised against the comparator in another trial, but the two drugs are not randomised with respect to each other. Therefore, the protection of randomisation is absent. Again specific characteristics of the respective studies may have an impact on the results. Parenthetically, we should add that the haloperidol dose is not the only issue here. In contrast to the reasoning of Tandon and Jibson [5], only two out of nine risperidone studies included in the meta-analysis by Leucht et al. [3] used 20 mg/day haloperidol. The largest study that received a great degree of statistical weight in the meta-analysis used only 10 mg/day of haloperidol [16], but it showed a superiority of risperidone, while a quetiapine study using only 12 mg/day of haloperidol did not [17]. On the only occasion where Leucht et al. tentatively compared new generation antipsychotics statistically (to propose hypotheses at a time when hardly any head-to-head comparisons were available), they used effect sizes derived from comparisons with placebo [3]. The placebo approach avoids problems associated with comparator dose. Unfortunately, Tandon and Jibson [5] omit this point, focusing rather on our comparisons with conventional antipsychotics, which they interpreted more strongly than we did ourselves. However, only a few placebo controlled studies are available; and other factors such as different patient characteristics, different definitions for intent to treat or different study durations can be just as problematic. Let us now speculate from a theoretical point of view on the current textbook wisdom that all antipsychotic drugs have the same overall efficacy. In the pre-atypical era this notion was based on the argument that all antipsychotics shared the same mechanism of action / an antagonism of dopamine
155
receptors. But even the antipsychotics available at that time had very dissimilar receptor binding profiles. Nowadays it is a widely accepted theory that other receptor systems, especially serotonin receptors, are important mediators of the efficacy of some NGAs in addition to dopamine. It is clearly possible that certain properties of a given NGA might have more beneficial effects through specific mechanisms that they do not share with other compounds. The notion that all antipsychotics are more or less as effective originated from a seminal book that still makes for excellent reading [18]. This first comprehensive review revealed no efficacy differences between the antipsychotics available at that time, with the exception of mepazine and promazine being least effective. But most of the studies reviewed in 1969 were comparisons of phenothiazines. For example, there is a clinical impression that haloperidol is more effective than low-potency antipsychotics, such as chlorpromazine. However, during the preparation of a Cochrane review comparing these two standard antipsychotics, we identified only a handful of very small, inconclusive randomised controlled trials [19]. We still have no sufficient understanding of the biological basis of schizophrenia or know with certainty all the properties of the new generation antipsychotic drugs that might benefit these patients. Therefore we believe that it is not at all an obvious a priori assumption that all antipsychotics have the same efficacy. Nevertheless, the currently available knowledge suggests that, if there are any differences in efficacy between NGAs, they are probably small; but given the high number of patients with schizophrenia, they could still be important at a public health level. There is no doubt that the issue of differential efficacy of the NGAs can be solved only by fair headto-head comparisons of NGAs. But, unfortunately, many of the industry-sponsored studies published to date showed conflicting results. Until the first large studies using public funding, such as CATIE have been published, any differential efficacy of NGAs remains a hypothesis, and the article of Tandon and Jibson [5] an argument against this hypothesis.
References [1] Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553 /64. [2] Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: Systematic overview and meta-regression analysis. Br Med J 2000;321: 1371 /6. [3] Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A metaanalysis of randomized controlled trials. Schizophr Res 1999; 35:51 /68. /
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[4] Leucht S, Pitschel-Walz G, Engel R, Kissling W. Amisulpride / An unusual atypical antipsychotic. A meta-analysis of randomized controlled trials. Am J Psychiatry 2002;159: 180 /90. [5] Tandon R, Jibson MD. Comparing efficacy of first-line atypical antipsychotics: No evidence of differential efficacy between risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Int J Psychiatry Clin Pract 2005;7(3): 204 /12. [6] Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825 /35. [7] Chouinard G, Jones B, Remington G. Canadian placebocontrolled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13:25 /40. [8] Davis JM, Chen N. Clinical profile of an atypical antipsychotic: Risperidone. Schizophr Bull 2002;28:43 /61. [9] Wetzel H, Grunder G, Hillert A, et al. Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology / A double-blind controlled study comparing a selective D-2-like antagonist to a mixed D-1-/D- 2-like antagonist. Psychopharmacology 1998;137:223 /32. [10] Mo¨ller HJ, Boyer P, Fleurot O, Rein W. Improvement of acute exacerbations of schizophrenia with amisulpride: A comparison with haloperidol. Psychopharmacology 1997; 132:396 /401. [11] Puech A, Fleurot O, Rein W. Amisulpride, an atypical antipsychotic, in the treatment of acute episodes of schizophrenia: A dose-ranging study vs. haloperidol. Acta Psychiatr Scand 1998;98:65 /72. /
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[12] Sechter D, Peuskens J, Fleurot O, et al. Amisulpride vs. risperidone in chronic schizophrenia: Results of a 6-month double-blind study. Neuropsychopharmacology 2002;27: 1071 /81. [13] Peuskens J, Bech P, Mo¨ller HJ, et al. Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Psychiatry Res 1999;88:107 /17. [14] Kudo Y, Nomura J, Ikawa G, et al. Clinical evaluation of quetiapine fumarate for the treatment of schizophrenia: A double-blind controlled study using mosapramine hydrochloride as a control. Rinsyo Iyaku 2000;16:1807 /42. [15] Murasaki M, Koyama T, Fukushima Y, et al. Clinical evaluation of quetiapine fumarate on schizophrenia: Comparative double-blind study with haloperidol. Seishin Igaku 2001;4:127 /55. [16] Peuskens J, Risperidone Study Group. Risperidone in the treatment of patients with chronic schizophrenia: A multinational, multi-centre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995;166:712 /26. [17] Arvanitis LA, Miller BG, Seroquel Trial 13 Study Group. Multiple fixed doses of ‘‘seroquel’’ (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo. Biol Psychiatry 1997;42:233 /46. [18] Klein DF, Davis JM. Diagnosis and drug treatment of psychiatric disorders. Baltimore, MD: Williams & Wilkins; 1969. [19] Mentschel C, Kane JM, Leucht S. Haloperidol versus chlorpromazine for schizophrenia (protocol). In: The Cochrane Library. Chichester, UK: John Wiley & Sons; 2003. /
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GUEST EDITORIAL
Is there a differential efficacy of new generation antipsychotic drugs?
STEFAN LEUCHT1 & JOHN M. DAVIS2 1
Klinik und Poliklinik fuer Psychiatrie und Psychotherapie der Technischen Universitaet Muenchen, Muenchen, Germany, and 2Department of Psychiatry, University of Illinois, Chicago, IL, USA
Although all issues have not yet been resolved, the new generation of so-called ‘atypical’ antipsychotics (NGAs) has replaced conventional antipsychotics in many countries. While it is quite clear that the new drugs have different side-effect profiles, there is also speculation as to whether they differ in terms of efficacy. Meta-analyses which simultaneously assessed the efficacy of several new drugs have consistently shown that some NGAs were statistically significantly more effective than conventional antipsychotics, while other NGAs were not [1 /4]. Although the interpretation of the results differed, no author concluded that comparing NGAs based on their differences from conventional antipsychotics is a proof for differential efficacy. Leucht et al. [3] made it clear that ‘‘The small differences in the mean effect sizes for efficacy must not be regarded as real differences. A formal statistical comparison of mean effect sizes was not undertaken. Despite the similarity of studies on new antipsychotics, certain differences in study designs, such as slightly different inclusion criteria, study durations, comparators, or dose regimens, would make such statistics inappropriate’’ (Ref. [4], p. 188). Or, Davis et al. cautioned that ‘‘we do not believe that it is valid to infer efficacy differences between two or more second generation antipsychotics from effect size comparisons between second generation antipsychotics and first generation antipsychotics. Head-tohead comparisons are necessary for proof’’ (Ref. [1], p. 560). Nevertheless, the companies whose drugs showed up best in these publications have admittedly ‘‘hijacked’’ the results for their marketing campaigns. In this context we believe that the main value of the article of Tandon and Jibson in this issue of International Journal of Psychiatry in Clinical Practice lies in
the fact that they used a different perspective to look at differential efficacy of NGAs [5]. They strongly argue against the claim of differential efficacy between NGAs by introducing a new version of meta-analysis that they call ‘‘a combined overview analysis’’. Instead of calculating effect sizes for the differences between new antipsychotics and comparators, they did away with all comparators and directly summarised the mean change from baseline to endpoint of the PANSS obtained by the different NGAs in their studies. Using this method they found no differences in efficacy between olanzapine, quetiapine and risperidone. The methodological limitations of this approach were mentioned in the article. However, we consider it important to explain more concretely to the reader the most important problem of this approach: it is the lack of a comparator. The method would therefore theoretically admit the absurd situation that an antipsychotic was less effective than placebo in its trials, but could still be more effective than other antipsychotics if the overall PANSS reduction in its trials was high. A re-analysis of two pivotal risperidone studies [6,7] showed that the mean PANSS reduction from baseline was around 20% [8]. We re-analysed three pivotal short-term studies comparing amisulpride with other conventional antipsychotics [9 /11]. In these the mean reduction of the BPRS was 48% (Leucht et al., manuscript). Thus, using the approach of Tandon and Jibson [5], amisulpride would turn out to be much more effective than risperidone, although it actually is not, since two large double-blind studies comparing amisulpride and risperidone directly showed no difference in efficacy [12,13]. The most likely reason for the smaller overall response in the risperidone studies compared to the amisulpride studies was that the former examined a more chronic
Correpondence: PD Dr. Stefan Leucht, Klinik und Poliklinik fuer Psychiatrie und Psychotherapie, der Technischen Universitaet Muenchen, am Klinikum rechts der Isar, Ismaningerstr. 22, 81675 Muenchen, Germany. Tel: /49 89 4140 4249. Fax: /49 89 4140 4888. E-mail: [email protected]
ISSN 1365-1501 print/ISSN 1471-1788 online # 2005 Taylor & Francis DOI: 10.1080/13651500510029165
Editorial population, because in Marder and Meibach [6] the mean length of the current hospitalisation was 29.3 weeks, with a maximum of 1184 weeks. Also, in two Japanese studies that were not considered by Tandon and Jibson [5], there was minimal reduction of symptoms in both the quetiapine and the comparator groups. Including these trials could substantially reduce quetiapine’s efficacy in their approach [14,15]. There are several further reasons why taking absolute increase improvement scores on a given rating scale and comparing them is not valid, besides the fact that acute patients will generally respond much better than chronic patients. There are other setting and population differences. The basic tenet of modern experimental science is the use of a control group, and this principle is neglected by ‘‘combined overview analysis’’. Meta-analyses using effect size scores derived from comparisons with other antipsychotics rather than change-scores on the PANSS, however, are by no means sufficient to counteract the problem. Patients in a trial of amisulpride are randomised against the comparator in that trial. Olanzapine would be randomised against the comparator in another trial, but the two drugs are not randomised with respect to each other. Therefore, the protection of randomisation is absent. Again specific characteristics of the respective studies may have an impact on the results. Parenthetically, we should add that the haloperidol dose is not the only issue here. In contrast to the reasoning of Tandon and Jibson [5], only two out of nine risperidone studies included in the meta-analysis by Leucht et al. [3] used 20 mg/day haloperidol. The largest study that received a great degree of statistical weight in the meta-analysis used only 10 mg/day of haloperidol [16], but it showed a superiority of risperidone, while a quetiapine study using only 12 mg/day of haloperidol did not [17]. On the only occasion where Leucht et al. tentatively compared new generation antipsychotics statistically (to propose hypotheses at a time when hardly any head-to-head comparisons were available), they used effect sizes derived from comparisons with placebo [3]. The placebo approach avoids problems associated with comparator dose. Unfortunately, Tandon and Jibson [5] omit this point, focusing rather on our comparisons with conventional antipsychotics, which they interpreted more strongly than we did ourselves. However, only a few placebo controlled studies are available; and other factors such as different patient characteristics, different definitions for intent to treat or different study durations can be just as problematic. Let us now speculate from a theoretical point of view on the current textbook wisdom that all antipsychotic drugs have the same overall efficacy. In the pre-atypical era this notion was based on the argument that all antipsychotics shared the same mechanism of action / an antagonism of dopamine
155
receptors. But even the antipsychotics available at that time had very dissimilar receptor binding profiles. Nowadays it is a widely accepted theory that other receptor systems, especially serotonin receptors, are important mediators of the efficacy of some NGAs in addition to dopamine. It is clearly possible that certain properties of a given NGA might have more beneficial effects through specific mechanisms that they do not share with other compounds. The notion that all antipsychotics are more or less as effective originated from a seminal book that still makes for excellent reading [18]. This first comprehensive review revealed no efficacy differences between the antipsychotics available at that time, with the exception of mepazine and promazine being least effective. But most of the studies reviewed in 1969 were comparisons of phenothiazines. For example, there is a clinical impression that haloperidol is more effective than low-potency antipsychotics, such as chlorpromazine. However, during the preparation of a Cochrane review comparing these two standard antipsychotics, we identified only a handful of very small, inconclusive randomised controlled trials [19]. We still have no sufficient understanding of the biological basis of schizophrenia or know with certainty all the properties of the new generation antipsychotic drugs that might benefit these patients. Therefore we believe that it is not at all an obvious a priori assumption that all antipsychotics have the same efficacy. Nevertheless, the currently available knowledge suggests that, if there are any differences in efficacy between NGAs, they are probably small; but given the high number of patients with schizophrenia, they could still be important at a public health level. There is no doubt that the issue of differential efficacy of the NGAs can be solved only by fair headto-head comparisons of NGAs. But, unfortunately, many of the industry-sponsored studies published to date showed conflicting results. Until the first large studies using public funding, such as CATIE have been published, any differential efficacy of NGAs remains a hypothesis, and the article of Tandon and Jibson [5] an argument against this hypothesis.
References [1] Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553 /64. [2] Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: Systematic overview and meta-regression analysis. Br Med J 2000;321: 1371 /6. [3] Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A metaanalysis of randomized controlled trials. Schizophr Res 1999; 35:51 /68. /
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[4] Leucht S, Pitschel-Walz G, Engel R, Kissling W. Amisulpride / An unusual atypical antipsychotic. A meta-analysis of randomized controlled trials. Am J Psychiatry 2002;159: 180 /90. [5] Tandon R, Jibson MD. Comparing efficacy of first-line atypical antipsychotics: No evidence of differential efficacy between risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Int J Psychiatry Clin Pract 2005;7(3): 204 /12. [6] Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825 /35. [7] Chouinard G, Jones B, Remington G. Canadian placebocontrolled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13:25 /40. [8] Davis JM, Chen N. Clinical profile of an atypical antipsychotic: Risperidone. Schizophr Bull 2002;28:43 /61. [9] Wetzel H, Grunder G, Hillert A, et al. Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology / A double-blind controlled study comparing a selective D-2-like antagonist to a mixed D-1-/D- 2-like antagonist. Psychopharmacology 1998;137:223 /32. [10] Mo¨ller HJ, Boyer P, Fleurot O, Rein W. Improvement of acute exacerbations of schizophrenia with amisulpride: A comparison with haloperidol. Psychopharmacology 1997; 132:396 /401. [11] Puech A, Fleurot O, Rein W. Amisulpride, an atypical antipsychotic, in the treatment of acute episodes of schizophrenia: A dose-ranging study vs. haloperidol. Acta Psychiatr Scand 1998;98:65 /72. /
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[12] Sechter D, Peuskens J, Fleurot O, et al. Amisulpride vs. risperidone in chronic schizophrenia: Results of a 6-month double-blind study. Neuropsychopharmacology 2002;27: 1071 /81. [13] Peuskens J, Bech P, Mo¨ller HJ, et al. Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Psychiatry Res 1999;88:107 /17. [14] Kudo Y, Nomura J, Ikawa G, et al. Clinical evaluation of quetiapine fumarate for the treatment of schizophrenia: A double-blind controlled study using mosapramine hydrochloride as a control. Rinsyo Iyaku 2000;16:1807 /42. [15] Murasaki M, Koyama T, Fukushima Y, et al. Clinical evaluation of quetiapine fumarate on schizophrenia: Comparative double-blind study with haloperidol. Seishin Igaku 2001;4:127 /55. [16] Peuskens J, Risperidone Study Group. Risperidone in the treatment of patients with chronic schizophrenia: A multinational, multi-centre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995;166:712 /26. [17] Arvanitis LA, Miller BG, Seroquel Trial 13 Study Group. Multiple fixed doses of ‘‘seroquel’’ (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo. Biol Psychiatry 1997;42:233 /46. [18] Klein DF, Davis JM. Diagnosis and drug treatment of psychiatric disorders. Baltimore, MD: Williams & Wilkins; 1969. [19] Mentschel C, Kane JM, Leucht S. Haloperidol versus chlorpromazine for schizophrenia (protocol). In: The Cochrane Library. Chichester, UK: John Wiley & Sons; 2003. /
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