Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Stop irresponsible conclusions
- Peter Moleman (28 July 2006)
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Antipsychotics are not equally effective
- Peter M Haddad, Omair Niaz (29 July 2006)
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Compliance: A factor
- Mercy E Ochuko-Emore (30 July 2006)
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Reply to Rapid Responses
- Jari Tiihonen (1 August 2006)
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Peter Moleman, Professor of Biological Aspects of Psychopathology Moleman Psychopharmacology, H.v.d. Boschstraat 11, 3958 CA, Amerongen, The Netherlands.
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Dear Sirs, The conclusion of Tiihonen et al.: “Patients treated with perphenazine depot, clozapine, or olanzapine have a lower risk of rehospitalisation or all cause discontinuation of their initial treatment than patients treated with haloperidol” is blatantly wrong, because incomplete. The wording suggests that the differences observed are related to the properties of the drugs, but there is no way to discern differences between drugs from differences between patients in this study. The conclusion would be justified if inextricably bound up with “Whether this is the result of differences between the particular drugs or between the particular patients receiving these drugs, can not be discerned”. It should be added that no relevant data are available about these patient characteristics. This is not just a theoretical consideration. I could refer to studies showing antipsychotics not being given at random in relation to patients characteristics. But I will refrain from this exercise, because it would detract from the main point: the authors should prove that there is no difference between the groups of patients receiving different drugs. I can not understand the BMJ publishing this study without these data. Of course differences between groups of patients exist in the study by Tiihonen et al., as shown by one example. In the discussion on limitations of their study they do refer to the common problem of selection bias in studies such as theirs and go on to mention: “Since […] clozapine is used only in treatment resistant patients (the most severely ill), it is unlikely that selection bias could explain the better outcome associated with these drugs.” Of course, the treatment resistant patient reacting to clozapine fares well. But what are the authors comparing here? A better outcome with clozapine in patients resistant to a first choice antipsychotic in comparison to the outcome on this first choice antipsychotic in patients not resistant to it? Cause for more concern than the publication of irresponsible conclusions is the fact that this leads to generalisations like in the editorial of the same issue of the BMJ: “In this week's BMJ Tiihonen and colleagues show that, in practice, some older drugs such as perphenazine are as efficacious as the newer ones. (Editorial: Psychological and social interventions for schizophrenia)”. The clinician who considers to use these results for treatment decisions in his own patients is ill advised. Competing interests: Speaker fees, consultancy fees or research funding: Astra Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Eli-Lilly, GlaxoSmithKline, ICN, Janssen, Lundbeck, Organon, Pfizer, Solvay-Duphar, Synthon, Wyeth |
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Peter M Haddad, Consultant Psychiatrist Cromwell House, Bolton, Salford and Trafford Mental Health NHS Trust, Salford, M30 0GT, Omair Niaz
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EDITOR – The naturalistic follow-up study by Tiihonen et al1 indicates that antipsychotics are not equally effective in the treatment of schizophrenia. Following a first admission with schizophrenia patients treated with clozapine, olanzapine or perphenazine depot had substantially lower risks of rehospitalisation, and discontinuation of treatment for any reason, than patients treated with oral haloperidol. The increased effectiveness of clozapine is understandable in terms of its superior efficacy in treatment resistant schizophrenia2. The increased effectiveness of perphenazine depot presumably derives from it ability to reduce non-compliance, a common problem in schizophrenia that can be overt or covert3. In Tiihonen et al’s study the less favorable outcome for oral perphenazine, in contrast to the depot preparation, supports this hypothesis. The effectiveness of clozapine and perphenazine depot may also partly reflect the regular clinical contact and supervision which is integral to both treatments; with a depot this relates to its administration and with clozapine to regular haematological monitoring. The results are unlikely to reflect a prescribing bias as depots are largely used in patients who comply poorly with oral medication and clozapine is restricted to use in treatment resistant schizophrenia. Despite its effectiveness perphenazine depot was not commonly used. This may reflect negative perceptions about depots4. In a Cochrane review a greater proportion of patients treated with depot than with oral medication showed global improvement, perhaps reflecting depots reducing partial compliance5. Tiihonen et al’s work adds to the view that depot antipsychotics are effective for some patients. Like all antipsychotics, depots should be prescribed on an individual basis following full discussion with the patient and considering a range of factors. In summary, at a pharmacological level clinical outcomes in schizophrenia can be improved by employing drugs that are either more efficacious or by improving medication compliance, one way of which is to use a depot preparation. Peter M. Haddad, Consultant Psychiatrist, Cromwell House, Bolton, Salford and Trafford Mental Health NHS Trust, Salford, M30 0GT Peter.Haddad@bstmht.nhs.uk Omair Niaz, Specialist, Registrar in Psychiatry, Sheffield Care Trust Competing interests: PMH has received honoraria for lecturing and/or attending advisory boards from Eli Lilly, Janssen-Cilag and Novartis. 1. Tiihonen J, Walhbeck K, Lonnqvist J, Klaukka T, Ioannidis JP, Volavka J, Haukka J. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333:224-7. 2. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001:158;518-26. 3. Lindstrom E, Bingefors K. Patient compliance with drug therapy in schizophrenia. Economic and clinical issues. Pharmacoeconomics 2000;18:106 -24. 4. Patel MX, Nikolaou V, David AS. Psychiatrists' attitudes to maintenance medication for patients with schizophrenia. Psychol Med. 2003;33:83-9. 5. Adams CE, Fenton MK, Quraishi S, David AS. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001;179:290-9 Competing interests: PMH has received honoraria for lecturing and/or attending advisory boards from Eli Lilly, Janssen-Cilag and Novartis. |
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Mercy E Ochuko-Emore, SHO in Psychiatry Hellesdon Hospital, Norwich. NR6 5BE
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These authors concluded that patients treated with perphenazine depot, clozapine, or olanzapine have a substantially lower risk of rehospitalisation than do patients treated with haloperidol. Interestingly, perphenazine depot even had a lower risk of rehospitalisation than olanzapine and clozapine. This could be as a result of compliance(depot vs oral medication) which was not addressed in this article. Studies have shown that patients with schizophrenia have poor compliance for various reasons. Cramer and Rosenheck(1998)1, reported an average adherence rate for all antipsychotics of 58%(range 24-90%). Two reviews on depot medication suggest a non-adherence rate of 24%(range 0- 54%).(Young et al. 1986, 1999).2,3. Therefore perphenazine depot outperforming both old and new generation oral antipsychotic may be as a result of poorer compliance with oral medication and nothing to do with effectiveness. References: 1. Cramer,J.A & Rosenheck, R.(1998) Compliance with medication regimens for mental and physical disorders. Psychiatric services, 49, 196- 200. 2. Young,J.L, Zonana,H.V & Shepler,L.(1986) Medication non compliance in Schizophrenia: codification and update. Bullentin of the American Academy of Psychiatry and the Law, 14, 105-122. 3. Young,J.L, Spitz,R.T, Hillbrand, M et al(1999) Medication adherence failure in Schizophrenia: a forensic review of rates, reasons, treatments and prospects. Journal of the American Academy of Psychiatry and the Law, 27, 426-444. Competing interests: None declared |
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Jari Tiihonen, Professor Dept of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, FI-70240 Kuopio, FINLAND
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Dear Sirs, In his rapid response ”Stop irresponsible conclusions” Peter Moleman claims that “authors should prove that there is no difference between the groups of patients receiving different drugs” and “no relevant data are available about these patient characteristics”. Of course groups of patients receiving different drugs differ from each other and, of course, we have taken this into account in the statistical analysis. If Moleman had looked at the Figure and the Table he would have noticed that in addition to crude relative risk, also adjusted relative risks are presented. E.g., in the Figure text we explained that relative risks of rehospitalization are adjusted for sex, age at onset of follow-up, number of previous relapses, duration of first hospitalization, calendar year, and length of follow-up by a multivariate regression and propensity score method (fully adjusted column). This propensity score method is generally considered the best method to adjust the effect of confounding factors in observational studies. A more comprehensive description of demographic and clinical variables is shown in Table 1 of the longer online version of the manuscript (DOI 10.1136/bmj.38881.382755.2F). Clozapine use was associated with the lowest risk of all cause discontinuation of initial medication, and Moleman asks “what are the authors comparing here?” We compared the risk of discontinuation among those patients who bought clozapine within 30 days of discharge after their first hospital treatment period vs. those patients who bought haloperidol. (The first antipsychotic medications used in the community.) Mercy Ochuko-Emore states in the response “Compliance: a Factor” that “perphenazine depot outperforming both old and new generation oral antipsychotic may be as a result of poorer compliance with oral medication and nothing to do with effectiveness”. We have addressed this issue in our article: Our results show that depot perphenazine is associated with markedly better outcome than oral perphenazine. We stated in our original version of the manuscript that this is probably explained by the route of administration (depot being superior to oral), but this part of text was omitted in the edition process (due to word limit). We would like to state that there is a difference between efficacy and effectiveness: Compliance may have nothing to do with efficacy, but it is a crucial factor contributing to effectiveness. In their response “Antipsychotics are not equally effective”, Peter Haddad and Omair Niaz suggest that, concerning route of administration, depot medications are superior to oral medications. We totally agree with this comment. Jari Tiihonen Department of Forensic Psychiatry University of Kuopio Niuvanniemi Hospital FI-70240 Kuopio, Finland E-mail: jari.tiihonen@niuva.fi Competing interests: None declared |
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