Electronic Letters to:
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eLetters: Electronic letters published:
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Re: Risperidone for adolescent schizophrenia: double blind study
- Ashok Kumar Jainer, Dr Ahmad Mahmood, St. Michael's Hospital, Coventry &Warwickshire Partnership Trust CV34 5QW (19 March 2009)
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Re: Re: Risperidone for adolescent schizophrenia: double blind study
- Magali Haas, Marielle Eerdekens, Stuart Kushner, Julia Singer, Ilse Augustyns, Vivek Kusumakar (deceased), Jorge Quiroz, Gahan Pandina (30 March 2009)
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Ashok Kumar Jainer, Dr The Caludon Centre, Coventry & warwickshire Partnership Trust, Coventry CV2 2TE, Dr Ahmad Mahmood, St. Michael's Hospital, Coventry &Warwickshire Partnership Trust CV34 5QW
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ashokjainer{at}hotmail.com Ashok Kumar Jainer, et al.
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We read with keen interest the study by Haas et al (1), which compares the efficacy and safety of two dosing regimes of risperidone.. We would like to make a few comments. . Firstly we would like to raise concern with regards to the design of the study. As both groups were receiving a flexible dose of risperidone in the first four weeks. The dose was to remain stable only during the last 4 weeks which was a very short duration. Patients started showing substantial response in the first week onwards. It is not possible to rule out the placebo effect and difficult to determine the dose related response. Surely this design cannot establish the optimal effective dose as the dose was changing very often especially in the first four weeks. Secondly the patients in control group were not allowed the assured effective treatment. The control group subjects were receiving risperidone tenfold less than the intervention group. This dose was as good as a placebo. This raised serious doubts as to whether the lower dose was also effective or it was a placebo effect. This is clearly evident as a substantial improvement compared to base line was noted in both groups within seven days. It also raises ethical issues as authors decided to continue a presumably ineffective dose (0.15-0.6 mg/day) in a controlled group for 8weeks( 2). Patients in this group had a higher discontinuation rate due to lack of efficacy. It was unethical to continue with such a low dose, we also wonder why the author arbitrarily decided to have a tenfold less dose in controlled group. We would like to question why authors did not try to compare the intervention drug with existing drug such as olanzepine, As Hill (3) pointed that the key point is how a new treatment compares with existing treatment rather than whether it is better than nothing. In the light of improper design and use of an ineffective dose in control group seriously raises doubt about the validity of the conclusion. References: 1. Haas M, Eerdekens M, Kushner S, Singer J, Augustne I, Quiroz J et al . Efficacy, safety and tolerability of two risperidone dosing regimens in adolescent schizophrenia: double-blind study Br J psychiatry 2009;194:158-164 2. WMA (2008) Ethical Principles for Medical Research Involving Human Subjects 3. Hill AB: Medical ethics and controlled trials. BMJ 1963;1:1043-1049 Declaration of interest : none |
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Magali Haas, Clinical Scientist J&J Pharmaceutical Research & Development, Marielle Eerdekens, Stuart Kushner, Julia Singer, Ilse Augustyns, Vivek Kusumakar (deceased), Jorge Quiroz, Gahan Pandina
Send letter to journal:
mhaas8{at}its.jnj.com Magali Haas, et al.
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We appreciate Dr. Jainer’s and Mahmood’s assessment and critiques and would like to address the concerns regarding our recent publication on risperidone in adolescent schizophrenia. Several of the limitations of our study design as mentioned by Jainer and Mahood have been addressed within the publication discussion section. The study was not designed to establish an optimal dose or evaluate efficacy versus placebo. Thus, as we noted, no conclusions can be made in this regard. The objective of this study was to determine if there was a difference between two dose ranges; this goal was achieved. The use of an active comparator was not possible because there was no drug approved for use in children or adolescents suffering from this disorder at the time the study was conducted. The dose ranges were chosen to compare the adult therapeutic dose, known to be effective in schizophrenia, with a low dose. This low dose was presumed subtherapeutic, but not known to be ineffective. Notably, in studies in children with disruptive behavior disorder where the allowable flexible dose range included doses < 0.6mg/day, risperidone was shown to be efficacious (1, 2). Additionally, at the time this study was designed, a low-dose comparator was preferred over placebo, although thinking on the appropriateness of using placebo control in studies of antipsychotics has evolved since then (3). A placebo effect in terms of treatment response cannot be ruled out in our study, and presumably any placebo response would have affected both dose arms similarly. Numerous safeguards were implemented to minimize risk to patients in the study from the outset. The protocol was reviewed by and received approval from an independent ethics committee and individual institutional review boards. All patients and caregivers were advised that both doses were experimental and the lower dose might be an ineffective treatment. Accordingly, all enrolled patients were initially hospitalized and only adequately-stabilized patients could be discharged to continue in the trial as out-patients. Patients could discontinue treatments at any time. All patients were monitored closely throughout the duration of the trial to further ensure patient safety. Our conclusions remain valid, as they pertain to the comparative favourable efficacy benefits achieved in this study with risperidone treatment in the 1.5-6.0 mg/day dose range compared with the lower range. Both regimens were well-tolerated with low discontinuation rates due to adverse events. References: 1. Aman MG, De Smedt G, Derivan A, Findling RL, Group RDBS. Double-blind, placebo-controlled study of risperidone in the treatment of disruptive behaviors in children with subaverage intelligence. Am J Psychiatry 2002; 159: 1337–46. 2. Reyes M, Buitelaar J, Toren P, Augustyns I, Eerdekens M. A randomized, double-blind, placebo- controlled study of risperidone maintenance treatment in children and adolescents with disruptive behavior disorders. Am J Psychiatry 2006; 163: 402–10. 3. Stroup.TS, Alves, WM, Hamer, RM, Lieberma, JA. Clinical trials for antipsychotic drugs:design conventions, dilemmas and innovations. Nature Rev 2006;5:133-146 |
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