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Are antidepressants an independant risk factor for ischaemic heart disease?
- Peter Cansfield (22 September 2001)
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Is dothiepin really different?
- W P Plummer (24 September 2001)
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Antidepressants and ischaemic heart disease
- K F Ashley (27 September 2001)
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Dothiepin and ischaemic heart disease
- Joe Reilly (30 October 2001)
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Depression not Dosulpin increases IHD
- Alan Thomas (30 October 2001)
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Peter Cansfield, Specialist Registrar in Public Health Leicestershire Health Authority
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Julia Hippisley-Cox et al claim they have found good evidence for an association between dosulepin (Dothiepin) and subsequent ischaemic heart disease. However this interpretation of their results appears unwarranted. As they state, depression is a known independent risk factor for ischaemic heart disease. Their best estimate for the increased risk due to depression alone is their adjusted odds ratio of 1.41. Adjusted odds ratios for most of their different groupings of antidepressants are of this order and all include the value 1.41 well within their confidence intervals. Moreover where antidepressants are more likely to have been prescribed for reasons other than depression (‘amitritptyline ever’ and ‘other antidepressant’ categories) the best estimates of adjusted odds ratios fall much closer to 1.0. Historically amitriptyline and dosulepin (Dothiepin) have greater cumulative use and therefore representation than some of the other groups and statistical significance appears to be related to this. As the authors state, they were unable to control for level of depression and it is not unreasonable to postulate that a ‘dose response’ relationship between depression and antidepressant exposure is related to depth and severity of depression. Whilst there are short-term cardiovascular effects with most antidepressants that may precipitate myocardial infarction, the argument for cardiotoxicity many years after exposure seems less plausible. However, depressive illness is often recurrent and may be the underlying risk factor operating over longer time periods. |
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W P Plummer, Consultant Psychiatrist East Kent Community Alcohol Service.
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Dear Editor, Hippisley-Cox et al. present the results of a case controlled study in which a statistically significant association is found between past use of dothiepin (dosulepin) and ischaemic heart disease. The associations between other tricyclic antidepressants and other classes of anti- depressant with ischaemic heart disease are not significant. It is not correct to conclude from this analysis, as the authors do, that 'the increased risk [of ischaemic heart disease] is due to dosulepin.' There is, in fact, an increased risk with all the antidpressants reported and the confidence intervals for all of them overlap considerably. All confidence intervals include the odds ratio of 1.63 for taking 'any antidepressant ever.' It is possible for groups to be statistically distinct when their confidence intervals overlap, but this distinctness has not been demonstrated. The authors have not presented any analyses which suggest that the odds ratio for any individual antidepressant differs from this overall value. In order to do so, they would need to perform a test of heterogeneity between the individual antidepressants, or classes of antidepressants. This is the equivalent in logistic regression to an analysis of variance in ordinary regression. Alternatively, if they believed a priori that dothiepin was different they could carry out various tests of whether its odds ratio was different to that of the other antidepressants or groups of antidepressants. This means making a direct comparison between the groups, not simply comparing p - values for comparison of the odds ratios with the 'null' value of one. (Comparisons between dothiepin and other antidepressants would not be valid, if the investigators simply found during analysis that dothiepin had the most extreme value for the odds ratio and then tested it). This study is also unable to distinguish the effects of antidepressant treatment from any possible direct effects of depression. The prescription of antidepressents seems to be almost completely confounded with the illness of depression itself. Associations are reported between higher doses of dothiepin and longer treatment with this drug and ischaemic heart disease, but there is likely to be a strong association between the severity of depression and the dose and length of any antidepressnat treatment. It is interesting to note that only a third of patients were treated with a dose of dothiepin which would have had any antidepressant activity (>100 mg per day) and only a third were given more than four prescriptions, when it is recommended that antidepressant treatment should continue for at least six months after the remission of depressive symptoms. If antidepressants do have health risks, it is worrying that they are being used in treatment regimes which are likely to be ineffective. Another, more esoteric, statistical point is that when matched case controlled studies are analysed, it is good practice to include the factors which were used for matching in the logistic regression equation when undertaking analysis. The authors do not specifically state that they have included age sex and general practice as factors in either the raw analysis or the adjusted analysis of their data. In general, to do so will increase the effect size of any risk factor under investigation, provided that the factors used for matching are genuinely confounding variables (If they are not, there is no point in matching!). |
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K F Ashley, Consultant in Oral and Maxillofacial Surgery 36 Hampton Park Road, Hereford, HR1 1TH.
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Editor- The paper from the Division of General Practice at the University of Nottingham disturbed me. In my facial pain patients I have found dolesulpin (dothiepin) very effective in the treatment of atypical facial pain. This condition is defined as pain for which no other cause is apparent, which does not respond significantly to standard non-opiate analgesic agents and which is usually accompanied by early morning waking. The dose needed ranges from 25mg to 225mg nightly. The correct dose for the individual patient is that which corrects the sleep disturbance. Six months treatment is usually effective with the occasional patient needing twelve. After reading the paper I spent the next few hours checking my records for all patients prescribed dolesulpin by their GP's, at my suggestion, in the past year. I wrote suggesting that their GP's comsider switching them to amitriptyline, at the same dose, though in the past I have found this agent less effective than dolesulpin and more difficult to establish the individual effective dose. I have not found lofepramine effective in this group. Dolesulpin was introduced more than thirty years ago. Its rapid correction of early morning waking and relief of other symptoms in three weeks, with tolerable side effects, have led to its continued use. I have read Peter Cansfields' and W P Plummers' responses on your web site and fear I may have acted too quickly in response to this paper. On medicolegal grounds alone we need an authoritative opinion. |
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Joe Reilly, consultant psychiatrist Tees & NE Yorks NHS Trust
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The finding of a link between increasing doses of dothiepin (1) and development of ischaemic heart disease is an important one, which if genuinely causative should influence our prescribing for depression. It deserves careful scrutiny. The authors have found an effect more than five years after prescription of dothiepin which is at least as strong as that for more recent exposure. This challenges biological plausibility as their listed mechanisms all operate only for the duration of prescription and are essentially reversible. There are other explanations for this finding. Tricyclic antidepressants may directly damage the myocardium in a less reversible manner, inducing cardiac enzyme release and antimyosin antibody response (2), an effect which demands further investigation in humans. Perhaps a more likely explanation is that any relationship with drug therapy is confounded by depression itself as a risk factor for ischaemic heart disease, and the authors acknowledge this. If so, why is there no link between SSRIs and ischaemic heart disease in this study? In the same issue of the BMJ, the link between serotonin reuptake properties of antidepressants and increased risk of gastrointestinal bleeding is confirmed (3), so SSRIs may in fact protect against cardiovascular disease via their antiplatelet effects. Finally we should consider the most basic test of causation applied to any association in an observational study, that of temporality. The outcome in this study is diagnosis of ischaemic heart disease rather than onset of the condition itself. Occult cardiovascular disease usually precedes the onset of symptoms by several years, and it is possible that ischaemic heart disease may have predated dothiepin prescription in at least some cases in this study. The ‘vascular depression’ hypothesis ranks occult vascular disease as a potent risk factor for late-life depression (4,5)which could obviously coexist with occult ischaemic heart disease. The consequent prescription of dothiepin could fully explain this association, particularly as the study population is predominantly elderly. The association of tricyclic antidepressant therapy in normal doses and ischaemic heart disease is very worthy of further investigation via other methodologies including cohort studies and biological studies of mechanisms, but it would be premature on the basis of this paper alone to alter prescribing. The emphasis should remain on dothiepin’s acute and profound cardiotoxic effects in overdose and in those with existing cardiac disease, which are reasons enough to be cautious about its use. 1. Hippisley-Cox J, Pringle M, Hammersley V, Crown N, Wynn A, Meal A, Coupland C. Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care. BMJ 2001; 323: 666-669 2. Marti V, Ballester M, Udina C, Carrio I, Alvarez E, Obrador D, et al. Evaluation of myocardial cell damage by In-111-monoclonal antimyosin antibodies in patients under chronic tricyclic antidepressant treatment. Circulation 1995;91:1619-1623. 3. Walraven van C, Mamdani MM, Wells PS, Williams JI. Inhibition of serotonin uptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001; 323:655-657 4. Alexopoulos GS, Meyers BS, Young RC, et al. “Vascular depression” hypothesis. Arch Gen Psychiatry 1997; 54:915–22 5. Thomas AJ. Ferrier IN. Kalaria RN. Perry RH. Brown A. O'Brien JT. A neuropathological study of vascular factors in late-life depression. Journal of Neurology, Neurosurgery & Psychiatry. Vol 70(1) (pp 83-87), 2001 Kevin Lewis, Consultant Psychiatrist; Joe Reilly (Corresponding
Author), Consultant Psychiatrist, Tees and North East Yorkshire NHS Trust,
Parkside Community Mental Health Centre, Park Road North, Middlesbrough
TS1 3LF Alison Coak, Assistant Psychologist; Sue Hunter, Principal Pharmacist, Tees and North East Yorkshire NHS Trust, St Luke's Hospital Marton Road, Middlesbrough. |
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Alan Thomas, Lecturer in Old Age Psychiatry Wolfson Research Centre, Newcastle General Hospital,University of Newcastle upon Tyne
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The Editor Hippisley-Cox and colleagues reported1 previous use of the antidepressant dosulepin (dothiepin) is associated with increased ischemic heart disease (IHD) and suggested the relationship may be causal. However, we believe there are good reasons for a different interpretation. The unadjusted odds ratios in table 2 run from 1.28 to 1.73 for all types of antidepressants as well as for those receiving no antidepressant treatment. Taken together, an alternative interpretation is that it is depression itself, rather than antidepressant use, that is the main factor driving the subsequent increase in IHD. The apparent specificity for dosulpin might well be, as the authors suggest, due to its more frequent use in more severe depression. There have been a large number of prospective studies demonstrating depression to be an independent risk factor for the subsequent development of IHD and the relative risk in these studies is higher than that found in the report by Hippisley-Cox, e.g. 4.5 by Pratt et al 19962 and 2.1 by Ford et al 19963. These studies also found a dose-response relationship between the severity of depression and the risk of IHD. This would be consistent with the view that it is depression itself that is a risk factor for IHD and that dosulpin (and other antidepressants) may not have any direct effects. Furthermore, there are a number of potential biological mechanisms by which depression could either lead to or exacerbate IHD. For example, depression has robust associations with abnormalities in platelet activity and raised levels of proinflammatory cytokines4 which would increase the atherogenic process. Such mechanisms have a greater biological plausibility for explaining an increase in IHD than those mentioned in the report to try and explain the association with dosulpin, which are more relevant to increasing arrhythmias and sudden cardiac death. Dr A.J.Thomas
Prof J.T.O'Brien
Department of Psychiatry, University of Newcastle upon Tyne, Wolfson Research Centre, Newcastle General Hospital NE4 6BE We are not aware of any competing interests. 1. Hippisley-Cox J, Pringle M, Hammersley V, Crown N, Wynn A, Meal A, et al. Antidepressants as risk factor for ischemic heart disease: case- control study in primary care. BMJ 2001;323:666-9. 2. Pratt LA, Ford DE, Crum RM, Armenian HK, Gallo JJ, Eaton WW. Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up. Circulation 1996;94(12):3123-9. 3. Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men: the precursors study. Archives of Internal Medicine 1998;158(13):1422-6. 4. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Archives of General Psychiatry 1998;55(7):580-92. |
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