Electronic Letters to:
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eLetters: Electronic letters published:
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Ethical issues in clinical trials
- Adarsh Shetty (5 July 2007)
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ANTIDEPRESSIVE TREATMENT AFTER MYOCARDIAL INFARCTION
- King Han Kho (5 July 2007)
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Too little too late: treating depression to improve survival after acute coronary syndrome
- Ania Korszun, A.Korszun, S. Stansfeld and M. Frenneaux (5 July 2007)
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Untitled
- Omer Khan MRCPsych, Adetokunbo Adeshina, SHO in Psychiatry , Oxfordshire and Buckinghamshire Mental Health Trust (1 August 2007)
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Reply to Korszun and Shetty
- Peter de Jonge, Joost P. van Melle and Johan Ormel (1 August 2007)
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Reply to Dr Kho
- Peter de Jonge, Joost P. van Melle, and Johan Ormel (24 August 2007)
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Adarsh Shetty, Specialist Registrar in General Adult Psychiatry Nottinghamshire Healthcare NHS Trust, Psychiatric Unit, Derby City Hospital, Derby DE22 3NE.
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dradarshshetty{at}yahoo.co.in Adarsh Shetty
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Dear Editor, Van Melle et al (2007) present findings from their randomized controlled trial examining the effects of antidepressant treatment for depression following myocardial infarction. I would like to make a comment on the design of the study. The authors allocated patients to two arms: antidepressant treatment and care as usual. Patients in the care as usual arm were not told about their research diagnosis of depression. The authors quote Zelen’s article from the New England Journal of Medicine in 1979, thus implying that they are following the research design he proposed. However, Zelen’s method seems best suited for trials where there is a ‘gold standard’ control treatment available and the trial is attempting to evaluate a new experimental treatment (Zelen, 1979). In this design, the ethical concerns are mainly about randomising before consent is sought. It must be pointed out that after randomisation, consent is sought from patients in the experimental arm. If they decline, they are moved to the ‘gold standard’ arm (Torgerson, 2001). I am not sure if van Melle et al’s trial fits into this category. Furthermore, there are ethical issues about not informing patients about their diagnosis of depression. I am disappointed that the paper did not discuss these in further detail. Their information pack stated that all patients were free to seek help with their mood problems. Patients may feel tired and low in mood but may not recognise this as depression, for which there are effective interventions available. Is it ethical to withhold information regarding the diagnosis from such patients? Will patients seek help if they are not told they are suffering from depression? Doing research can raise difficult ethical issues and I hope this letter will encourage some debate on this. Declaration of interest: No interests to declare. References: Torgerson, D.J. (2001) Contamination in trials: is cluster randomisation the answer? British Medical Journal, 322, 355-357. van Melle, J.P., de jonge, P., Honig, A., et al (2007) Effects of antidepressant treatment on long-term depression status and cardiac prognosis in depressed MI patients. British Journal of Psychiatry, 190, 460-466. Zelen, M. (1979) A new design for randomized clinical trials. New England Journal of Medicine, 300, 1242-1245. |
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King Han Kho, Psychiatrist GGZ Delfland, St Jorisweg 2, 2612 GA, Delft, The Netherlands
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khkho{at}xs4all.nl King Han Kho
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The study by Melle et al (2007) found no difference in efficacy and cardiac prognosis between treatment with antidepressive medication vs. care as usual in patients suffering from depression after a myocardial infarction (MI). Carney and Freedland (2007) commented that the lack of difference in treatment efficacy prohibits the demonstration that effective treatment of depression improves survival. They emphasized the need for developing highly efficacious treatments for depression following MI. Such a treatment however already exists as electroconvulsive therapy (ECT), which has been shown to have superior efficacy compared to antidepressive medication (The ECT UK review group 2003). A trial using ECT as an intervention will more likely find a superior efficacy compared to treatment as usual and may demonstrate that effective depression treatment improves survival. Because of concerns about the cardiac risks some textbooks do not recommend the use of ECT within three months following a MI. Zielinski and Roose (1993) found a higher rate of cardiac complications during ECT in patients with a pre-existing cardiac abnormality compared to patients without a pre-existing cardiac abnormality. Most complications however were transitory and did not prevent the completion of the ECT course. Rice et al (1994) found that ECT increased the risk of minor but not of severe complications. They pointed to the advances in ECT techniques resulting in the improved safety of ECT in cardiac patients. The risk of ECT has to be weighed against the risk of an inadequate treatment of depression, which is known to increase the risk for mortality (Melle et al, 2007). Considering the high risk of cardiac events of 13% in the 18 months following a MI found by Melle et al (2007), which may partly be attributable to inadequate treatment of depression, treatment with ECT could be safer because of its superior efficacy as an antidepressant. van Melle, J.P., de Jonge, P., Honig, A., et al (2007) Effects of antidepressant treatment following myocardial infarction. Br J Psychiatry, 190, 460-6. Carney, R.M. & Freedland, K.E., (2007) Does treating depression improve survival after acute coronary syndrome?: Invited commentary on... Effects of antidepressant treatment following myocardial infarction. Br J Psychiatry, 190, 467-8. The ECT UK review group (2003) Efficacy and safety of electroconvulsive therapy in depressive disorder: a systematic review and meta-analysis. Lancet, 361,799-808. Zielinski, R.J., Roose, S.P., Devanand, D.P., et al (1993) Cardiovascular complications of ECT in depressed patients with cardiac disease. Am J Psychiatry, 150, 904-9. Rice, E.H., Sombrotto, L.B., Markowitz, J.C., et al (1994) Cardiovascular morbidity in high-risk patients during ECT. Am J Psychiatry, 151, 1637-41. |
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Ania Korszun, Professor of Psychiatry and Education Wolfson Institute of Preventive Medicine, Barts and the London, A.Korszun, S. Stansfeld and M. Frenneaux
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a.korszun{at}qmul.ac.uk Ania Korszun, et al.
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In the June 2007 issue of BJP, van Melle and colleagues reported that cardiac prognosis post-MI was not improved by antidepressant treatment (MIND-IT trial). The SADHART and ENRICHD trials reported similar findings and Carney and Freedland, in their commentary in the same issue, suggest these negative findings are due to insufficient statistical power in the trials. These results are disappointing, but perhaps they might have been anticipated? There is strong evidence that individuals with depression show increased morbidity and mortality from CHD (Rugulies, 2003) but the mechanisms involved remain unclear. Individuals with a history of recurrent depression, who are otherwise healthy, show increased inflammation, platelet activation, endothelial dysfunction, and reduced heart rate variability and baroreceptor sensitivity. However, with the exception of platelet function which improves with SSRIs, these anomalies are not corrected by antidepressant treatment. Further, endothelial function and baroreceptor sensitivity, which can lead, respectively, to progression of the atherosclerotic process and to sudden cardiac death, do not improve when depressive symptoms are in remission (Broadley, Korszun, Abdelaal, et al, 2006). Thus there is no evidence that treatment of depressive symptoms post-MI corrects these underlying pathological processes and, if not, cardiac outcomes disclosed by clinical trials are unlikely to show improvement irrespective of their statistical power. By analogy, although hyperglycemia characterizes diabetes, tight glucose control alone only modestly impacts on cardiovascular events. Similarly, depressive illness is a syndrome characterized by acute episodes of depression, but other systemic abnormalities are present and persist between acute depressive episodes. Accordingly, it may be unreasonable to believe that treatments assessed by their influence on the affective state alone will reduce cardiovascular events. Whilst it is important to alleviate the suffering associated with developing depression post-MI and improve prognosis by addressing the secondary effects of depression e.g. reduced compliance with treatment and poor health behaviours, treatment needs to be aimed at earlier stages of the disorder. Atherosclerosis begins in childhood and becomes manifest much later in life with MI as a very late presentation. Similarly, depression is a life-long disorder with onset in early adulthood. It should be noted that, currently, depression is not even included in cardiovascular risk tables and that individuals with depression might benefit from introduction of statins, or other preventative measures. We agree with Carney and Freedland that treatments for depression might alter the risk of cardiac events via pathways that are unrelated to their effects on depression. However, if the focus of research were shifted to the study of earlier stages of CHD in depressed patients, this could be clarified by monitoring earlier indices of CHD in relation to treatment of depression. It is also recognized that mechanisms for associations between depression and onset of CHD may differ from those between depression and progression of CHD post-MI. These pathways need to be better understood and present evidence suggests that survival times following MI could be improved by developing treatments for depression that also target the underlying cardiovascular abnormalities and augmenting these by preventative programmes for CHD in individuals with mood disorders. CHD and depression are two major public health problems and it is of concern that reports of depression treatments failing to enhance survival post-MI may result in less interest in studying the links between them. Broadley, A. J., Korszun, A., Abdelaal, E., et al (2006) Metyrapone improves endothelial dysfunction in patients with treated depression. J Am Coll Cardiol., 48, 170-175. Rugulies, R. (2003) Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med, 23, 51-61. |
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Omer Khan MRCPsych, SHO in Psychiatry Oxfordshire and Buckinghamshire Mental Health Trust, Adetokunbo Adeshina, SHO in Psychiatry , Oxfordshire and Buckinghamshire Mental Health Trust
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omer.khan{at}berkshire.nhs.uk Omer Khan MRCPsych, et al.
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We note the findings of Melle et al(2007) which showed antidepressant treatment did not alter long-term depression post-myocardial infarction status or improve cardiac prognosis. Interesting in the SADHART study (Glassman et al, 2002) it was observed that the effect of sertraline on depression status over 6 months was greater in patients with severe and recurrent depression. Although the SADHART study was not designed to assess the effects of treatment on cardiovascular prognosis there was a tendency for fewer severe cardiovascular events in the sertraline group. We feel that the above findings bear further investigation particularly given the possibility of a dose-response relationship between depression severity and cardiac mortality (Penninx et al, 2001). We note that in the Melle et al study the mean BDI score during hospitalisation was 11.9(s.d. 7.2) and 11.7(s.d. 6.4) in the intervention and care as usual groups respectively, indicating a significant number of participants in the study with Beck Depression Inventory category diagnosis of either minimal or mild depressive illness. We also note issues of statistical power, the use of different medications (mirtazapine and citalopram versus sertraline), and the initiation of treatment at 3 months compared to 1 month post cardiac event in the Melle et al and SADHART studies respectively We suggest further studies are needed and should focus particularly on patients with greater severity of depressive illness. Declaration of interest: No interests to declare. References: Glassman, A. H., O’Connor, C. M., Califf, R. M., et al (2002) Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA, 288, 701 –709. Depression and Cardiac Mortality: Results From a Community-Based Longitudinal Study Brenda W. J. H. Penninx; Aartjan T. F. Beekman; Adriaan Honig; Dorly J. H. Deeg; Robert A. Schoevers; Jacques T. M. van Eijk; Willem van Tilburg Arch Gen Psychiatry. 2001;58:221-227. Beck, A. T., Steer, R. A. & Brown, G. K. (1987) Beck Depression Inventory – 2nd Edition Manual. Psychological Corporation, Harcourt. |
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Peter de Jonge, assistant professor Rijksuniversiteit Groningen, Joost P. van Melle and Johan Ormel
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peter.de.jonge{at}med.umcg.nl Peter de Jonge, et al.
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To explain why antidepressant treatment with SSRI’s does not improve cardiac prognosis, Korszun and colleagues suggest that SSRI’s may not alter the mechanisms through which depression leads to increased cardiovascular morbidity and mortality. However, two other explanations may be more plausible. First, the effects of antidepressant treatment on depression itself are not strong enough. In both ENRICHD and SADHART, the response rates of patients in the active treatment arm hardly exceeded those of patients receiving usual care or placebo. Second, the cardiotoxic effects of depression are limited to patients for whom antidepressant treatment is not effective (1,2). We have shown that the cardiotoxic effects of depression are concentrated in incident post-MI depressions, while results from SADHART have indicated that sertraline is only effective in non-incident depressions (of interest, Korszun and colleagues mention mechanisms related to recurrent depression which appears not be to cardiotoxic). If antidepressant treatment is only effective in non- cardiotoxic depressions, no effects on cardiovascular prognosis can be expected. Shetty raises ethical concerns about our study (3), because we used Zelen’s method of randomisation. Control patients were not told about their diagnosis of depression and, as argued by Shetty, therefore may have ‘missed’ an adequate treatment offer. However we feel that in 1999, when the study started, Zelen's method was both scientifically useful and ethical, because no controlled comparative studies had yet investigated the clinical efficacy and safety of antidepressant drugs in post-MI depression. At that date, the proportion of depressed MI patients who were treated for their post-MI depression was negligible. In addition, serious concerns existed about the safety of antidepressant drugs in cardiac patients. Moreover, in our study, patients with a significant risk of suicide or a severe depression were excluded from randomization and referred for psychiatric treatment outside the study. Finally, all patients received usual care, i.e. had cost-free access to all usual treatment facilities like normal cardiac rehabilitation programmes and family physician healthcare. We therefore feel it was ethical to use Zelen’s method in our study and scientifically useful as our control patients were truly representative of usual care patients. 1. de Jonge P, van den Brink RHS, Spijkerman TA, Ormel J. Only Incident Depressive Episodes Following Myocardial Infarction Are Associated With New Cardiovascular Events. J Am Coll Cardiol 2006; 48(11): 2204-8 2. Grace SL, Abbey SE, Kapral MK, Fang J, Nolan RP, Stewart DE. Effect of depression on five-year mortality after an acute coronary syndrome. Am J Cardiol 2005; 96(9): 1179-85 3. van Melle JP, de Jonge P, Honig A, Schene AH, Kuyper AM, Crijns HJ, Schins A, Tulner D, van den Berg MP, Ormel J. Effects of Antidepressive Treatment on Long-Term Depression Status and Cardiac Prognosis of Depressed MI Patients. Br J Psychiatry 2007; 190: 460-6 |
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Peter de Jonge, assistant professor University of Groningen, Joost P. van Melle, and Johan Ormel
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peter.de.jonge{at}med.umcg.nl Peter de Jonge, et al.
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We agree with Dr Kho that we need to develop new treatments for post- MI depression, but at this moment we believe there it is premature to consider electroconvulsive therapy (ECT) as an effective alternative. In our experience over the last years, specifically those types of depression that are least similar to the ones seen in general psychiatry, i.e. depressions that occur for the first time in someone’s life just after an MI (incident depressions) (1) and those that are dominated by feelings of exhaustion rather than negative self-esteem or suicidality (2), are the most cardiotoxic. At this moment, to our knowledge the mechanism(s) explaining this remains unclear. Similarly, it is not known whether ECT will be effective in these subtypes (while it appears that antidepressive medication is not). In fact, the studies mentioned by Kho suggest increased rather than decreased cardiovascular events. The importance of developing new, effective treatments for post-MI depression is high as it will improve quality of life but perhaps also survival, as rightfully argued by Kho. Carney and colleagues (3) showed that responders to antidepressive medication had a better cardiovascular prognosis than non-responders using data from ENRICHD. In the MIND-IT study we recently confirmed that non-response to mirtazapine and citalopram was associated with more cardiovascular events compared to responders and even untreated controls, which remained after controlling for several confounders including early cardiovascular events (4). However, as it is unclear what factors are related to response to antidepressive medication (for instance, this may well include the presence of somatic symptoms of depression) (5), it also remains uncertain whether it might be an improved state of the heart disease that influences depression or reversely that treatment of depression results in an improved cardiovascular prognosis. Still, although causality remains unproven, it suggests that more effective treatments may have cardiovascular effects as well. We are not yet convinced that this will be ECT but we encourage researchers to explore this possibility. 1. de Jonge P, Ormel J, van den Brink RHS, van Melle JP, Spijkerman TA, Kuijper A, van Veldhuisen DJ, van den Berg MP, Honig A, Crijns HJGM, Schene AH. Symptom dimensions of Depression following Myocardial Infarction and their Relationship with Somatic Health Status and Cardiovascular Prognosis. Am J Psychiatry 2006; 163:138-144. 2. de Jonge P, van den Brink RHS, Spijkerman TA, Ormel J. Only Incident Depressive Episodes Following Myocardial Infarction Are Associated With New Cardiovascular Events. J Am Coll Cardiol 2006; 48(11): 2204-8 3. Carney RM, Blumenthal JA, Freedland KE, Youngblood M, Veith RC, Burg MM, Cornell C, Saab PG, Kaufmann PG, Czajkowski SM, Jaffe AS. Depression and Late Mortality After Myocardial Infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) Study. Psychosom Med 2004; 66: 466-474. 4. de Jonge P, Honig A, van Melle JP, Schene AH, Kuyper AMG, Tulner DM, Schins A, Ormel J. Non-Response to Treatment for Depression Following Myocardial Infarction is Associated with Subsequent Cardiac Events. In press. Am J Psychiatry; sept 2007. 5. Tylee A, Gandhi P. The importance of somatic symptons in depression in primary care. J Clin Psychiatry 2005; 7: 167-176. |
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