- Email: [email protected]
Polypharmacy for psychiatric treatments in Japan
CORRESPONDENCE
Ethics of testing drugs with readily available alternatives Sir—We agree with John A Lewis and colleagues (April 13, p 1337)1 about the important part played by section 29 of the Declaration of Helsinki in ensuring that patients are not disadvantaged or exploited when they take part in clinical trials combining medical research with medical care. However, it is the potential disadvantage for patients destined to receive the test treatment that can raise ethical concerns. An important consideration is how placebo-controlled trials are to satisfy public-health needs when several alternative treatments are already on the market. The possibility exists that reliance on a drug being better than placebo might allow on to the market drugs that are less active (or less safe, tolerable, convenient, etc) than those already available, which generally offer consolidated properties and lower costs. A placebo-controlled trial could give enough information on a test drug to prove that it is safe and more effective than no treatment. However, most placebo-controlled trials are done because they make it easier to show an effect and, therefore, claim efficacy to the regulatory authorities. Such trials, for example, in subgroups of depressive or hypertensive patients resistant or intolerant to available treatments would be welcome, since they would respond to patients’ needs. However, they are not generally planned because this approach would restrict the indication and, consequently, limit the market and profits. In the real world of public health, patients are mostly already using other products, so their choice, and that of their physicians, is between continuing on the current drug or switching to the new one. Placebo-controlled trials may not help in making this important choice because they cannot provide firm scientific evidence of any real clinical advantage for patients over current alternatives. Why should it be acceptable to do trials that do not answer the public-health question of whether the new treatment provides any additional benefit over existing ones, in terms of safety, efficacy, convenience of administration or else? If a new product has potential advantages in areas other than efficacy, active control trials can be designed to measure them. These trials might cost more because more patients are needed to prove potentially small improvements, but in some cases they can be done and can reliably show any such gains in
efficacy, safety, adherence, or convenience. When relying only on placebocontrolled trials, useful resources are wasted and patients exploited for commercial purposes, by not providing the answers that they and their physicians actually need. In our view, these considerations too, and not just the protection of patients taking part in clinical trials, were behind the intent of those who signed the Declaration of Helsinki. It is worth reminding that article 6 of the Declaration reads “The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures . . .”. *Silvio Garattini, Fernando de AndresTrelles, Vittorio Bertelé, Luca Li Bassi *Mario Negri Institute for Pharmacological Research, Via Eritrea 62, 20157 Milan; and Universidad Complutense de Madrid, Spain (e-mail: [email protected]) 1
Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Placebocontrolled trials and the Declaration of Helsinki. Lancet 2002; 359: 1337–40.
Polypharmacy for psychiatric treatments in Japan Sir—Antipsychotic drugs have been the mainstream treatment for schizophrenia since the discovery of the psychotropic effect of chlorpromazine in 1952. However, before the advent of atypical antipsychotics (serotonin-dopamine anatagonists, SDA), negative symptoms such as affective flattening, avolition, and alogia were hardly expected to improve, and patients presenting these symptoms were deemed to worsen progressively and withdraw socially. There is, however, evidence that a substantial proportion of patients with treatment-refractory schizophrenia now benefit from SDAs such as clozapine. The current aim is to further improve the quality of life and the work status of these patients.1,2 Despite the availability of new drugs and accumulating evidence, the gulf between the recommended remedy and clinical practice seems wide. The guidelines for pharmacotherapy laid down by experts recommend one monotherapy.3 This recommendation is reasonable to assess efficacy of a particular drug before switching to another. In Japan, however, polypharmacy commonly prevails. In a survey of 2405 inpatients with schizophrenia treated in 16 national psychiatric hospitals, 50% were receiving three or more antipsychotrics concomitantly; 18% were receiving four or more. Among the 457 patients taking
THE LANCET • Vol 360 • August 24, 2002 • www.thelancet.com
risperidone, 59% received two or more types of antipsychotics.4 New drugs seem to be simply added to current ones. Moreover, along with multiple antipsychotics, two or more types of anticholinergic drugs and hypnotics are generally given to schizophrenic patients for many years or even decades. Consequently, secondary negative symptoms and extrapyramidal side-effects are highly likely and cannot be overlooked. Why does this happen in modern psychiatry? Japan has long had the tradition of administering Chinese medicines in an add-on manner. Combination of many different types of herb was historically considered an art; in effect, there is a degree of using one’s own discretion in medicine. This situation is reflected symbolically in a compound that consists of chlorpromazine, promethazine, and phenobarbital, which is still used as a hypnotic, especially for patients with schizophrenia. The notion of multi-acting receptor-targeted antipsychotic agents (MARTA) for atypical antipsychotics should not be used as the justification for administering multiple neuroleptics. Nor can polypharmacy be viewed as an augmentation strategy. The difficulties of polypharmacy may also, to a lesser extent, be relevant to other countries.5 Approaches to reduce the price of drugs by the health-policy makers in Japan are indirect, and active measures to improve this practice are strongly required. *Nori Takei, Ataru Inagaki, and the JPSS-2 research group *Department of Psychiatry and Neurology, Stanley Foundation Research Centre in Japan, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (e-mail: [email protected]) 1
2
3
4
5
Revicki DA, Genduso LA, Hamilton SH, Ganoczy D, Beasley CM Jr. Olanzapine versus haloperidol in the treatment of schizophrenia and other psychotic disorders: a quality of life and clinical outcomes of a randomized clinical trial. Qual Life Res 1999; 8: 417–26. Meyer PS, Bond GR, Tunis SL, McCoy ML. Comparison between the effects of atypical and traditional antipsychotics on work status for clients in a psychiatric rehabilitation program. J Clin Psychiatry 2002; 63: 108–16. Taylor D, McConnell H, Duncan-McConnell D, Kerwin R. 2001 prescribing guidelines, 6th edn. London: Martin Dunitz, 2001. Inagaki A, Yoshizumi A, Oshima I, et al. JPSS-2 ni okeru yakubutsu ryouhou algorism ni tsuite. Presented at the meeting of the “Heisei 13 nendo kenkyu houkokukai”, Dec 10, 2001, Tokyo. Rittmannsberger H, Meise U, Schauflinger K, Horvath E, Donat H, Hinterhuber H. Polypharmacy in psychiatric treatment: patterns of psychotropic drug use in Austrian psychiatric clinics. Eur Psychiatry 1999; 14: 33–40.
647
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Ethics of testing drugs with readily available alternatives Sir—We agree with John A Lewis and colleagues (April 13, p 1337)1 about the important part played by section 29 of the Declaration of Helsinki in ensuring that patients are not disadvantaged or exploited when they take part in clinical trials combining medical research with medical care. However, it is the potential disadvantage for patients destined to receive the test treatment that can raise ethical concerns. An important consideration is how placebo-controlled trials are to satisfy public-health needs when several alternative treatments are already on the market. The possibility exists that reliance on a drug being better than placebo might allow on to the market drugs that are less active (or less safe, tolerable, convenient, etc) than those already available, which generally offer consolidated properties and lower costs. A placebo-controlled trial could give enough information on a test drug to prove that it is safe and more effective than no treatment. However, most placebo-controlled trials are done because they make it easier to show an effect and, therefore, claim efficacy to the regulatory authorities. Such trials, for example, in subgroups of depressive or hypertensive patients resistant or intolerant to available treatments would be welcome, since they would respond to patients’ needs. However, they are not generally planned because this approach would restrict the indication and, consequently, limit the market and profits. In the real world of public health, patients are mostly already using other products, so their choice, and that of their physicians, is between continuing on the current drug or switching to the new one. Placebo-controlled trials may not help in making this important choice because they cannot provide firm scientific evidence of any real clinical advantage for patients over current alternatives. Why should it be acceptable to do trials that do not answer the public-health question of whether the new treatment provides any additional benefit over existing ones, in terms of safety, efficacy, convenience of administration or else? If a new product has potential advantages in areas other than efficacy, active control trials can be designed to measure them. These trials might cost more because more patients are needed to prove potentially small improvements, but in some cases they can be done and can reliably show any such gains in
efficacy, safety, adherence, or convenience. When relying only on placebocontrolled trials, useful resources are wasted and patients exploited for commercial purposes, by not providing the answers that they and their physicians actually need. In our view, these considerations too, and not just the protection of patients taking part in clinical trials, were behind the intent of those who signed the Declaration of Helsinki. It is worth reminding that article 6 of the Declaration reads “The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures . . .”. *Silvio Garattini, Fernando de AndresTrelles, Vittorio Bertelé, Luca Li Bassi *Mario Negri Institute for Pharmacological Research, Via Eritrea 62, 20157 Milan; and Universidad Complutense de Madrid, Spain (e-mail: [email protected]) 1
Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Placebocontrolled trials and the Declaration of Helsinki. Lancet 2002; 359: 1337–40.
Polypharmacy for psychiatric treatments in Japan Sir—Antipsychotic drugs have been the mainstream treatment for schizophrenia since the discovery of the psychotropic effect of chlorpromazine in 1952. However, before the advent of atypical antipsychotics (serotonin-dopamine anatagonists, SDA), negative symptoms such as affective flattening, avolition, and alogia were hardly expected to improve, and patients presenting these symptoms were deemed to worsen progressively and withdraw socially. There is, however, evidence that a substantial proportion of patients with treatment-refractory schizophrenia now benefit from SDAs such as clozapine. The current aim is to further improve the quality of life and the work status of these patients.1,2 Despite the availability of new drugs and accumulating evidence, the gulf between the recommended remedy and clinical practice seems wide. The guidelines for pharmacotherapy laid down by experts recommend one monotherapy.3 This recommendation is reasonable to assess efficacy of a particular drug before switching to another. In Japan, however, polypharmacy commonly prevails. In a survey of 2405 inpatients with schizophrenia treated in 16 national psychiatric hospitals, 50% were receiving three or more antipsychotrics concomitantly; 18% were receiving four or more. Among the 457 patients taking
THE LANCET • Vol 360 • August 24, 2002 • www.thelancet.com
risperidone, 59% received two or more types of antipsychotics.4 New drugs seem to be simply added to current ones. Moreover, along with multiple antipsychotics, two or more types of anticholinergic drugs and hypnotics are generally given to schizophrenic patients for many years or even decades. Consequently, secondary negative symptoms and extrapyramidal side-effects are highly likely and cannot be overlooked. Why does this happen in modern psychiatry? Japan has long had the tradition of administering Chinese medicines in an add-on manner. Combination of many different types of herb was historically considered an art; in effect, there is a degree of using one’s own discretion in medicine. This situation is reflected symbolically in a compound that consists of chlorpromazine, promethazine, and phenobarbital, which is still used as a hypnotic, especially for patients with schizophrenia. The notion of multi-acting receptor-targeted antipsychotic agents (MARTA) for atypical antipsychotics should not be used as the justification for administering multiple neuroleptics. Nor can polypharmacy be viewed as an augmentation strategy. The difficulties of polypharmacy may also, to a lesser extent, be relevant to other countries.5 Approaches to reduce the price of drugs by the health-policy makers in Japan are indirect, and active measures to improve this practice are strongly required. *Nori Takei, Ataru Inagaki, and the JPSS-2 research group *Department of Psychiatry and Neurology, Stanley Foundation Research Centre in Japan, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo (e-mail: [email protected]) 1
2
3
4
5
Revicki DA, Genduso LA, Hamilton SH, Ganoczy D, Beasley CM Jr. Olanzapine versus haloperidol in the treatment of schizophrenia and other psychotic disorders: a quality of life and clinical outcomes of a randomized clinical trial. Qual Life Res 1999; 8: 417–26. Meyer PS, Bond GR, Tunis SL, McCoy ML. Comparison between the effects of atypical and traditional antipsychotics on work status for clients in a psychiatric rehabilitation program. J Clin Psychiatry 2002; 63: 108–16. Taylor D, McConnell H, Duncan-McConnell D, Kerwin R. 2001 prescribing guidelines, 6th edn. London: Martin Dunitz, 2001. Inagaki A, Yoshizumi A, Oshima I, et al. JPSS-2 ni okeru yakubutsu ryouhou algorism ni tsuite. Presented at the meeting of the “Heisei 13 nendo kenkyu houkokukai”, Dec 10, 2001, Tokyo. Rittmannsberger H, Meise U, Schauflinger K, Horvath E, Donat H, Hinterhuber H. Polypharmacy in psychiatric treatment: patterns of psychotropic drug use in Austrian psychiatric clinics. Eur Psychiatry 1999; 14: 33–40.
647
For personal use. Only reproduce with permission from The Lancet Publishing Group.