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Rapid Responses: Rapid Responses published:
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Antidepressant dosage
- Dr Alasdair J Macdonald (4 November 2002)
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Psychiatric care is dangerous.
- Richard G Fiddian-Green (5 November 2002)
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Sleep disorder may explain results
- Juliet R Cohen (5 November 2002)
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Determination of the individual dose of tricyclics
- Keith F Ashley, Nil (5 November 2002)
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Should tricylic antidepressants be used at all?
- Robert Fleetcroft (5 November 2002)
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Is it possible to rely upon a history to avoid doing harm?
- Richard G Fiddian-Green (5 November 2002)
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low dose tricyclics are not justified by the evidence
- Hugh M Jones (7 November 2002)
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Re: low dose tricyclics are not justified by the evidence
- Toshi A Furukawa (10 November 2002)
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Re: Re: Low dose Tricyclics justified from a holistic and patient compliance aspect
- Mohammed I Khan (12 November 2002)
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? Insufficient evidence to change current guidelines
- Imad M Ali (18 November 2002)
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Non-superiority and Equivalence
- Janet E Martin (18 November 2002)
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Tricyclics - a ‘therapeutic dose’ is one which helps the individual patient
- Richard N Byng (27 November 2002)
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Low dose tricyclics: making the best use of the available evidence
- JOHN R GEDDES, Professor Nick Freemantle, University of Birmingham, Dr Andrea Cipriani, University of Oxford (11 December 2002)
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The parrallel with low-dose antipsychotic prescribing
- Karl Marlowe (12 December 2002)
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Re: Low dose tricyclics: making the best use of the available evidence
- Toshi A Furukawa, Hugh McGuire, and Corrado Barbui (21 December 2002)
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Dr Alasdair J Macdonald, Honorary Consultant Psychiatrist Carleton Clinic, Carlisle CA1 3SX
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Dear Editor, The thorough review by Furukawa et al is hampered by their chosen cutoff dose. 150mg of most tricyclic antidepressants is the mean dose for an adult population, not the maximum dose. A comparison using a cut-off point of 100mg is a comparison between two groups both receiving subtherapeutic doses so it is not surprising that no beneficial difference is demonstrated. If there is no response to an antidepressant after 3-4 weeks the dose should be increased. Using subtherapeutic doses for prolonged periods is commonplace only with antidepressants. It would not be considered acceptable practice with any other class of drug. AJMacdonald
1 Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002;325:991-5.(2 November.) Competing interests: None declared |
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Richard G Fiddian-Green, None None
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Dr Alasdair Macdonald’s recommendation on dosage is of great concern (1). If endogenous or severe depression is the product of an energy deficit and the cascade of events that initiates, as is possible if not probable, then the last thing one wants to do is to administer an antidepressant that compounds the severity of the problem (2). Whilst low degrees of impairment of mitochondrial oxidative phosphorylation may induce a compensatory increase the efficiency of oxidative phosphorylation and express growth (3) factors which might even promote hippocampal neurogeneisis larger doses may induce apoptosis and gliosis. Of particular concern is the potential for the additive of other medications, recreational drugs, air pollution, environmental toxins, and even aging that have similar effects upon energy metabolism to render a supposedly safe doses of antidepressants harmful (5,6). Tricylcic antidepressants are no exception (7,8,9). The real concern is that the antidepressants will increase the risk of developing organ dysfunctions and failure during the course of an acute illness and increase the likelihood of developing chronic disease including neurodegenerative diseases and heart failure with advancing age. The bottom line is that we do not have a clue how the normal mind works let along know how the abnormal mind works and have absolutely no credible means of either establishing or rejecting a psychiatric diagnosis with confidence. There is most certainly no means of detecting if and when an antidepressant crosses the fine line between doing good and doing harm. I frankly think psychiatrists have probably been leaving an unappreciated trail of destruction behind them. The really scary thing they do not seem to appreciate it. 1. Antidepressant dosage Dr Alasdair J Macdonald (4 November 2002) 2. Depression: a metabolic perspective. Richard G Fiddian-Green bmj.com/cgi/eletters/325/7370/934#26529, 26 Oct 2002 3. Dual Effect of energy deficit on hippocampal neurogenesis Richard G Fiddian-Green bmj.com/cgi/eletters/325/7370/934#26556, 28 Oct 2002 [Full text] 4. D'Arcangelo D, Facchiano F, Barlucchi LM, Melillo G, Illi B, Testolin L, Gaetano C, Capogrossi MC. Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression. Circ Res. 2000 Feb 18;86(3):312-8. 5. Concerns about prescribing antidepressants Richard G Fiddian-Green bmj.com/cgi/eletters/325/7366/701#25874, 28 Sep 2002 6. The real danger is in the mixing? Richard G Fiddian-Green bmj.com/cgi/eletters/325/7367/736/c#26113, 7 Oct 2002 7.. Bartholoma P, Erlandsson N, Kaufmann K, Rossler OG, Baumann B, Wirth T, Giehl KM, Thiel G. Neuronal cell death induced by antidepressants: lack of correlation with Egr-1, NF-kappa B and extracellular signal-regulated protein kinase activation. Biochem Pharmacol. 2002 Apr 15;63(8):1507-16. 8. Xia Z, Lundgren B, Bergstrand A, DePierre JW, Nassberger L. Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X(L). Biochem Pharmacol. 1999 May 15;57(10):1199-208. 9. Burbenskaya NM, Nartsissov YR, Tsofina LM, Komissarova IA. The uncoupling effect of some psychotropic drugs on oxidative phosphorylation in rat liver mitochondria. Biochem Mol Biol Int. 1998 Jun;45(2):261-8. 10. Do medications make patients better or worse? Richard G Fiddian-Green bmj.com/cgi/eletters/324/7342/859#26617, 30 Oct 2002 Competing interests: None declared |
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Juliet R Cohen, GP St Bartholomews Medical Centre, Manzil Way, Oxford, OX4 1XB
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A common side effect of many of the tricyclics in this study is drowsiness, and this is apparent even at low doses. Amitriptyline is used for this sedative effect to improve sleep in patients with chronic pain and is effective even at 10-20 mg nocte, less than 10% of its therapeutic anti-depressant dose. Sleep disorder, especially insomnia and early morning waking are characteristic features of depression. If your sleep problems improve, daytime function also improves and this can have a powerful effect on symptoms of depression. In treating patients with sleep disorder and symptoms of depression with 10-50mg amitriptyline I have found significant improvement in numbers of hours of sleep and daytime mood and cognitive function. Compliance is less of an issue if low doses are given as other adverse side effects are minimised and patients experience an immediate and measurable benefit from their treatment. Competing interests: None declared |
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Keith F Ashley, Part time private practice 36 Hampton Park Road, Hereford,HR1 1TH, Nil
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EDITOR - Your comment on this paper by Furakawa, McGuire and Barbui states that "the minimal effective dosage and ranges for antidepressants has not been established - a set of numbers that every practising doctor and patient would want to know". For tricyclics this aim cannot be achieved due to their wide variation in absorption and distribution in body fluids: indeed one manufacturer advises that the dose should not be adjusted to plasma levels but to clinical response. With the response to depression taking 2-4 weeks it is not surprising that the faster acting SSRI's have gained popularity. Is their another way to quickly ascertain the correct dose for the individual patient? I use tricyclics for patients, not overtly depressed, with functional facial pain i.e. pain for which no other diagnosis can be found, who respond poorly, if at all, to standard analgesics and who have disturbed sleep with early morning waking. I usually use the sedating tricyclic dothiepin with amitriptyline as an alternative. Patients are started on 25mg to be taken one hour before bedtime, increasing in 25 mg increments each night until they sleep well and are not unduly sedated in the daytime. As with depression their pain takes 2-4 weeks to remit. Most patients require 50-125 mg; rarely a slim lady will require 225mg and a large man will find it difficult to get out of bed in the morning on 25mg. Depressed patients have disturbed sleep. Sedating tricyclics can be given in a single night time dose. For patients with overt depression titration of the dose against sleep disturbance could be effective. It is necessary to start with a low dose as too high a dose can initially prevent sleep. Competing interests: Shares in GlaxoSmithKlein |
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Robert Fleetcroft, GP Gt Yarmouth NR31 6LA
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There are several areas of concern with this meta-analysis. (1) Firstly, there were confounding factors that were not taken into account. Six studies contained patients with comorbid conditions including migraine and rheumatoid arthritis. Antidepressants can improve these physical symptoms, and it is possible this may have a beneficial effect on depression rating scores thus confounding the resulting data. Secondly, there is more to effective treatment than several weeks of antidepressants during the acute phase of the illness. Continuation therapy after recovery is important to reduce the possibility of relapse, and this study does not address whether low dose therapy alters this risk. (2) Finally, it could be argued that antidepressants should not be used at all in the treatment of depression, which would somewhat make this trial redundant. Tricyclic antidepressants are toxic in overdose, often leading to death of the patient, perhaps with the exception of Lofepramine.(3) There is no reliable way to predict which patient will attempt suicide,(4) and surely a safer and just as effective treatment would be an SSRI such as Fluoxetine. 1.Furukawa T, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review BMJ2002;325:991-5 2.Loonen AJM, Peer PGM, Zwanikken GJ. Continuation and maintenance therapy with antidepressant agents. Meta-analysis of research Pharm Weekbl (Sci) 1991;13(4):167-75 3.Henry JA, Alexander CA, Sener EK. Relative mortality from overdose of antidepressants BMJ1995;310:221-224 4.Lin EH, Von Korff M,Wagner EH. Identifying suicide in primary care. J Gen Intern Med 1989 Jan-Feb;4(1):1-6 Competing interests: None declared |
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Richard G Fiddian-Green, None None
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I seriously doubt that it is possible to rely upon a clinical impression of a response to a trial of treatment, derived from a history alone, to avoid the potentially harmful effects of antidepressants? What of an increased risk of developing organ dysfunctions and failure during an acute illness or of developing chronic diseases from the prolonged use of medications especially in elderly patients with co-morbidities? Objective measurements of oxidative phosphorylation should provide the means to assess the risk in a meaningful way. Competing interests: None declared |
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Hugh M Jones, Specialist Registrar Ward DB2 Maudsley Hospital London, SE5 8AZ
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This metanalysis must be considered downright naughty. While masquerading as a contribution to an academic debate about appropriate antidepressant treatment it actually does little more than endorse the widely held prejudice in favour of using low dose tricyclics in depression. Published in a widely read UK general medical journal it will inevitably encourage a practice that is not encouraged by either the Royal College of Psychiatrists or American Psychiatric Association. The subject of optimal tricyclic dose remains controversial but the value of standard dose tricyclic antidepressant treatment compared to placebo is abundantly clear. As the authors here concede but perhaps do not emphasise sufficiently the evidence for low dose tricyclic antidepressant is of generally poor quality. Many of the trials used in their analysis took place before standardised diagnostic or outcome criteria were commonplace. What is less clear is the motivation for their undertaking. Fluoxetine is now available in generic preparations for about £7 per month significantly reducing the financial advantage of older antidepressants. There is some evidence to support the use of tricyclics in severe depression, but presumably the authors would not recommend low dose tricyclics in such patients. The chronic severe nature of depression would make it unethical to recommend a therapy without a secure evidence base. Being charitable one can only hope the therapeutic advice was added to add colour to an otherwise unexceptional meta-analysis. Competing interests: I have received a small grant for a research study on olanzapine by Eli Lilly |
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Toshi A Furukawa, Professor Dept Psychiatry Nagoya City University Medical School, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 JAPAN
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Dr Jones questions our motivation for undertaking this meta-analysis. It was simple. I made a survey of psychiatric practices in Japan and found that (a) benzodiazepines were often co-administered with antidepressants and that (b) tricyclic antidepressants were often given in "inadequate dosage." I naturally condemned these practices. (1) Then, however, I wondered if I had enough evidence to say this, and I wasn't sure. So I undertook two meta-analyses, one dealing with antidepressant-benzodiazepine combined therapy and another on low dosage tricyclic. The first one found that my reproof might be wrong; the combined treatment brought about more response than antidepressant alone up to 4 weeks. The question is now how to judge the balance between this benefit against the known harms of benzodiazepines. (2) And my second meta-analysis again showed that my reprimand (along with similar claims by many others) were ill-founded. And you know what we found. However, we must admit that some of the concerns expressed in the rapid responses are quite understandable. For lack of space, we could not report all sensitivity analyses examining possible confounders. Firstly, we limited our analyses to those employing opertionalized criteria; the results were essentially identical. Secondly, we conducted several subgroup analyses (planned a priori) on older people, primary care patients and psychiatric patients. Although some of the results were underpowered and allowed wide confidence intervals, they were all compatible with the overall results. The details of these sensitivity and subgroup analyses will soon be available in the Cochrane Library. So, we should not turn the argument upside down. If a meta-analysis does not support a certain practice recommended by a guideline, is it this part of the guideline that may be wrong or is it the meta-analysis? There is much corroborative (and sometimes circumstantial) evidence that low dosage antideressants do work and may be better than the recommended range. (a) A Canadian meta-analysis of 15 RCTs involving over 1,000 patients with major depression has shown that selective serotonin-reuptake inhibitors (SSRIs) in standard dosage is as effective as tertiary amine antidepressants in low dosage (100 mg or less) and a meta-analysis of 37 RCTs involving over 3,000 patients has shown that SSRIs in standard dosage is again simply as effective as tertiary amine antidepressants in standard dosage (above 100 mg); in both instances the 95% confidence intervals of the pooled odds ratio were quite narrow. (3) (b) Another very well-conducted meta-analysis became recently available to shed light on this issue from a different perspective (4). It pooled all RCTs comparing two or more doses of the same antidepressant and concluded that doses below 100 mg/day of imipramine equivalents are marginally less effective than the therapeutic range (100-200 mg/day) but produces significantly fewer adverse events. Closer inspection of the included studies reveals, however, that this meta-analysis is based largely on trials involving SSRIs and other newer antidepressants. Thus, although their conclusion is phrased in terms of imipramine equivalent, the results should be interpreted as pertaining mostly to SSRIs and newer antidepressants. (c) Something similar is happening to antipsychotics. It now seems that we used to prescribe an overdose of classical antipsychotics and that the seeming advantage of atypical antipcyhotics in terms of side effects is only because these were compared with an overdose of classical antipsychotics. (5) (1) Furukawa TA, Kitamura T, Takahashi K. Treatment received by depressed patients in Japan and its determinants: naturalistic observation from a multi-center collaborative follow-up study. J Affect Disord 2000;60:173-9. (2) Furukawa T, Streiner DL, Young LT. Antidepressant plus benzodiazepine for major depression. In: The Cochrane Library. Oxford: Update Software, 2002; Issue 3. (3) Trindade, E, Menon, D. Selective serotonin reuptake inhibitors (SSRIs) for major depression. Part I: Evaluation of the clinical literature (Report 3E). Ottawa: Canadian Coordinating Office for Health Technology Assessment, 1997. (4) Bollini P, Pampallona S, Tibaldi G, Kupelnick B, Munizza C. Effectiveness of antidepressants: meta-analysis of dose-effect relationships in randomised clinical trials. Br J Psychiatry 1999;174:297- 303. (5) Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000;321:1371-6. Competing interests: The author has received fees for speaking from several pharmaceutical companies, some of which manufacture various types of antidepressants such as paroxetine, fluvoxamine and milnacipran. |
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Mohammed I Khan, Supernumerary post in Psychiatry, University hospital Aintree, Liverpool, UK University Hospital aintree, Liverpool, Uk, L9 7AL
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As I read the above article, I realized that though most of the information was quite accurate, I disagree on the point that lowdose tricyclics are NOT better than the usual dose for depression. I have seen patients who have been put on the usual dose of TCA's and though the initial response was encouraging, most of them did not show satisfactory compliance. The side effect seen were quite alarming [postural hypotension] and distressing [drymouth, constipation, sedation] to the patient as well. Though the usual level of TCA used is 50mg, in the PHc's), this is below the level, experts recommend as "THERAPEUTIC"[Donoghue and Tylee, 1996; Donoghue et al 1996]. A recent Metaanalysis found that, although low doses anti depressants were less effective than higher dose, they were more effective than placebo, They even caused fewer adverse events, such as noncompliance and sideeffects, than HIGHER DOSES[Bollini et al, 1999] Finally even if we compare the efficacy of TCA's and SSRI's at their therapeutic dosage, the two classes of drugs have equal efficacy when prescribed in therapeutic doses {Song et al 1993; Hotopf et al 1997]. So I feel Low dose TCA's definately are better if we consider it from the patients point of view and compliance, as depression would any way need treatment for more 4-6 months after the first episode. Competing interests: None declared |
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Imad M Ali, Locum Consultant Psychiatrist East Glamorgan Mental Health Unit, Church Village, Rhondda Cynon Taff, South Wales CF38 1AB
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It should be emphasised that Furukawa et al’s interesting study is in fact two separate analyses which look at quite different things(1). It is difficult, therefore, to draw any firm conclusions. The first meta-analysis of 35 studies suggests that low dose tricyclics may improve certain symptoms, some of which may be secondary to depression. This has already been established and as previous correspondents have pointed out, low dose tricyclics are commonly used to treat chronic pain, insomnia and anxiety, whether these symptoms occur secondary to a depressive illness, or as part of self-limiting adjustment and anxiety disorders or exist independently. The question which remains unanswered is whether low dose tricyclics can adequately treat an episode of clinical depression. The authors are careful not to suggest this, but quite correctly only go so far as to state that their meta-analysis only shows that low dose tricyclics are more effective than placebo. The second meta-analysis, which looks at the more interesting question of whether low dose tricyclics are as effective as recommended doses in the treatment of depressive illness, is unfortunately much smaller than the first - six studies comprising of 551 patients. The authors acknowledge some of the weaknesses in their analysis (heterogeneity of the studies, questions over the quality of some studies, over the adequacy of blinding, and the lack of operational criteria and interview schedules to diagnose depression) and other correspondents have pointed out, crucially, that the cut-off point for a therapeutic dose is incorrect, as most authorities recognize that 125mg and not 100mg of a tricyclic is the minimum recommended dose. The only useful result to come out of this small analysis is, therefore, that patients do not tolerate higher doses as well as low doses of tricyclics; again this is an already established finding and adds nothing new to the debate. My concern is that this meta-analysis will be misinterpreted and will have the effect of deterring clinicians from prescribing recommended doses of tricyclics and to thereby fail to adequately treat depressive illness. A report appearing this week in Hospital Doctor “Use of low-dose tricyclics in depression ‘vindicated’” confirms my fear(2). I conducted a study in one teaching general practice in Merthyr Tydfil, South Wales and identified 222 patients receiving long-term antidepressant prescription (mostly tricyclics) for a depressive illness as diagnosed by their General Practitioner (3,4). 62% reported moderate-severe depressive symptoms on the 13-item Beck Depression Inventory (77% response rate). Only a half of these were in receipt of a recommended dose (125mg) of their antidepressant) These patients consulted their GPs more frequently than those reporting few or no depressive symptoms and were likely to consult for psychological complaints, suggesting that GPs were aware of these patients’ continuing distress. In 1998, five years later, the same cohort of 171 patients was traced and there was disappointingly little change; 62% of the group reported moderate-severe depressive symptoms (response rate 80%)(5). Closer analysis of the individual patients revealed that 56% of the total cohort from 1993 reported moderate –severe depressive symptoms both in 1993 and again at follow–up in 1998. The finding of most concern was however that in 1998 only 59% of this group was in receipt of 125mg or more of their tricyclic antidepressant. This study identified a large group of chronic (moderate-severely) depressed patients who were receiving low dose tricyclics. If this is representative of other general practices, then it highlights the need for a depression review clinic in primary care. These patients need regular review and appropriate intervention. If low dose tricyclics work then nothing needs to be done other than the occasional review to consider whether the depression has remitted and whether the medication can be discontinued or alternatives substituted. If, however, patients receiving low dose tricyclics continue to report moderate or severe symptoms, then a review is required followed by appropriate intervention, which may include a trial at a recommended dose of the tricyclic, a change of antidepressant to another class, consideration of psychological and social interventions, or referral to secondary care for consideration of a second opinion or further treatments for resistant depression. The thing not to do is to leave patients to suffer on low dose tricyclics in the belief that these doses are no more effective than recommended doses. I am afraid that this meta-analysis may have the undesirable effect of inducing such therapeutic inertia. References 1 Furukawa AT, McGuire H & Barbui C. Meta-analysis of effects and side-effects of low dosage tricyclics antidepressants in depression:systematic review. BMJ 2002;325:991-5. (2 November) 2 Hitche L & Roberts R. Use of low-dose tricyclics in depression ‘vindicated’. Hospital Doctor 14 Nov 2002 p10. 3 Ali IM Depresion in primary care: a study of long-term antidepressant users.[MSc Thesis]. Cardiff: University of Wales,1994. 4 Ali IM . Long-term treatment with antidepressants in primary care. Are sub-therapeutic doses still being used? Psychiatric Bull 1998;22:15- 19. 5 Ali IM The long-term outcome of depressed patients in primary care. Presented & published in the Proceedings of the Royal College of Psychiatrist’s Annual Meeting, Birmingham, 30 June 1999. Competing interests: I have received a small donation from Lilly for my study and a few small honorariums for talking to professionals on the management of depression. I have attended conferences and symposia, some of which have been sponsored by various pharmaceutical companies. |
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Janet E Martin, Project Leader, Evidence-Based Prescribing Initiative London Health Sciences Centre, London, Ontario, Canada N6A 4G5
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To the Editor – Furukawa et al should be congratulated for this comprehensive meta- analysis of tricyclic antidepressants addressing the important question of dose response.(1) This meta-analysis, along with the author’s editorial response to subsequent comment on the publication, provides a further learning opportunity that should not be foregone – that is the concept of ‘equivalence’ in meta-analysis. A key question practitioners will ask of this meta-analysis is whether low dose tricyclics are equivalent to standard doses. However, in the absence of a clearly devoted research question, it remains unclear whether this review was intended as a superiority or equivalence trial. This should be clarified for the practitioner, as these concepts are not immediately intuitive. The bottomline message that low dose tricyclics “may or may not be as effective as standard dosage tricyclics” was correctly asserted in the original paper. However, a misleading statement was made in subsequent correspondence when the author stated that an earlier Canadian meta- analysis had shown “SSRIs in standard dosage are as effective as tertiary amine antidepressants in low dosage” and “that SSRIs in standard dosage are again simply as effective as tertiary amine antidepressants in standard dosage.”(2) In contrast to the authors’ earlier statement suggesting non-superiority between standard and low dose tricyclics in their meta-analysis, the latter statement claims the Canadian meta- analysis showed SSRIs are “as effective” as tricyclics. These concepts, non-superiority and equivalence, are keenly different.(3) Equivalence cannot be safely defined simply as overlapping confidence intervals, as is the inference given above regarding the Canadian study, which did not explicitly set out to prove equivalence. Rather, if proving equivalence is the intention, then objective criteria should be defined a priori, as for example, 95% CI within the bounds of 0.90 to 1.10 for an aggregate relative effect size of 1.00. Theory aside, how shall the practitioner interpret this meta- analysis? As the authors have aptly stated, standard dose is not significantly better than low dose. But, this does not infer low or standard dose is better or worse than the other. Equally important, neither does it mean they are the same. The bottom-line is that we remain uncertain whether standard and low doses are the same or different. The outer limits of the 95% confidence intervals define just how different they might be, and the possibility of clinically important differences cannot be ruled out. Much larger studies are needed to bring these bounds within the threshold of an acceptable definition of equivalence.(4) 1. Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002;325:991-1000. 2. Trindade, E, Menon, D. Selective serotonin reuptake inhibitors (SSRIs) for major depression. Part I: Evaluation of the clinical literature (Report 3E). Ottawa: Canadian Coordinating Office for Health Technology Assessment, 1997. 3. Greene WL, Concato J, Feinstein AR. Claims of equivalence in medical research: are they supported by the evidence? Ann Intern Med 2000 May 2;132(9):715-22. 4. Edmonds ML, Camargo CA Jr, Brenner BE, Rowe BH. Replacement of oral corticosteroids with inhaled corticosteroids in the treatment of acute asthma following emergency department discharge: a meta-analysis. Chest 2002;121:1798-805. Competing interests: None declared |
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Richard N Byng, Honorary Lecturer Department of General Practice and Primary Care, King's College London, SE11 6SP
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I was pleased to see the review of low dose tricyclic antidepressants providing support for what many GPs see as normal practice. The great variation in metabolism and blood levels has always suggested that some patients will require higher doses than others. But it is not a simple high versus low dose debate about whether low doses do or don’t work. There is now reasonable evidence that they will be effective for some patients. The evidence base is there to guide our shared decision making with the individual patient. The authors could have gone further in describing the implications of their findings for clinical decision making. While for patients in urgent need of improvement aiming for 125mg or more in seven days is necessary, in other situations starting with a low dose can be a logical approach for clinicians and patients to take. It can be useful for those who are wary of medication – ‘low dose’ can be a selling point and there is less chance of medication cessation or unwillingness to make a return appointment following side effects. It is probably sensible to inform patients of the option to increase to a ‘standard dose’ if there is no improvement. Even for those keen to achieve a ‘standard dose’, aiming for this at one month rather than one week may reduce the impact of side effects. If some patients return well after 2 weeks they then be content to continue on maintenance at a lower dose. If they remain well this is a good outcome. Others may achieve remission at standard doses but have intolerable side effects and agree to continuation treatment at a reduced dose. Thoughtful clinicians and patients follow these and other pragmatic courses to ensure that the dose is indeed therapeutic. The important caveat to these remarks is that symptoms must be reviewed and patients should not be left languishing still depressed on doses of less than 100mg. It is the responsibility of clinicians to ensure all means are used to engage patients in a review process which will ensure that as many as possible receive a therapeutic dose – one that makes them better. Competing interests: None declared |
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JOHN R GEDDES, Professor of Epidemiological Psychiatry, University of Oxford University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, Professor Nick Freemantle, University of Birmingham, Dr Andrea Cipriani, University of Oxford
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Sir, We agree with Furukawa and colleagues on the enduring importance of the dosage of tricyclic antidepressants. Unfortunately their analysis is misleading and poorly describes the available data. We concur that there is some evidence from small trials that doses of tricyclic antidepressants between 75-100mg are superior to placebo. The limited available evidence presented by the authors actually indicates that standard doses may, on average, be more efficacious than lower doses, although they may cause more side-effects. This is clinically important, because it would mean that some patients who can tolerate higher doses would be sub-optimally treated on doses <100mg. Furukawa and colleagues presented the responder analysis in the key comparison between low and standard dose drug as random effects relative risks and highlighted the fact that there was no statistically significant difference between doses. In fact, the results at 4 weeks are highly dependent on the choice of statistical method -. Using the responder data from this 4 week comparison, we found that the evidence suggests that standard dose is statistically superior to low dose using practically any other sort of analysis than the one reported. The full random effects odds ratio meta-analysis provides an odds ratio of 0.59 (0.35 to 0.95), which reflects the lack of heterogeneity on the theoretically more efficient odds ratio scale (the exact fixed effects and DerSimonian & Laird methods produce very similar results on the odds ratio scale). The DerSimonian and Laird random effects risk difference analysis suggests that higher dose tricyclics bring about 12% more responses, and the plausible range of response difference described by the 95% confidence interval is from 2% to 21%. This is certainly not equivalence and, indeed, it means that there is limited evidence that standard dose is more effective than low dose although there clearly remains substantial uncertainty. The authors should have treated this as an equivalence question. Focusing on the finding that standard drugs were not statistically significantly superior to low dose drugs is not the relevant question. Estimation is more appropriate than hypothesis testing, and the authors should have considered the width of confidence intervals as providing a plausible range for the estimate of treatment effect. Although the broader confidence interval of the random effects model may be conservative in most situations, this is not the case in equivalence analyses. Even using their own results, the best estimate is that low dose treated patient were 11% less likely to respond than patients treated with standard dose although this could be much as 26% less likely or as low as 7% more likely; the estimates, of course, become less plausible as we move to the edges of the limits. This does not establish convincingly that the higher dose is not superior to the lower dose, although probably does rule out the possibility that low dose is superior to standard dose to a clinically significant degree. Finally, given the paucity of comparative data and the importance of the clinical question, we are surprised that the authors did not consider a meta-regression analysis including all trials of a specific drug v. placebo adding a factor for dose, to add weight to the head to head comparisons. This would have made better use of the available data and avoided the somewhat arbitrary dichotomisation of dose used in their analysis. Yours sincerely, John Geddes, Professor of Epidemiological Psychiatry, University of Oxford Nick Freemantle, Professor of Clinical Epidemiology and Biostatistics, University of Birmingham. Andrea Cipriani, M.D., Research Fellow, University of Oxford Competing interests: None declared |
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Karl Marlowe, Specialist Registrar South London and Maudsley NHS Trust, LEO Services, SW9
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The systematic review of Furukawa et al (1) suggests that low doses/ subtherapeutic doses of tricyclic antidepressants can be efficacious in the treatment of depression. This result goes against the grain of clinical guidelines for the continued prescribing of standard doses of greater than 100mg/day. However, this result has a parallel with the changing guidelines for the treatment of psychosis. In early-onset psychosis, low doses of antipsychotics (Haloperidol 2- 5 mg/day) are clinically effective (2), with the justification that this stage of illness needs a different pharmacotherapy strategy. The use of low dose antidepressants may thus be seen within an early intervention framework. A subgroup analysis of early onset depression would be difficult from past studies, but planned prospective studies with this remit would inform the validity of this systematic review. 1 Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002;325:991-5. 2 Remington G, Kapur S, Zipursky RB. Pharmacotherapy of first-episode schizophrenia. BJPsych 1998; 172 (suppl 33): 66-70. Competing interests: None declared |
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Toshi A Furukawa, Professor of psychiatry Dept Psychiatry Nagoya City University Med School, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 JAPAN, Hugh McGuire, and Corrado Barbui
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We would first like to thank Professor Geddes and his colleagues for their thorough and meticulous reading of our systematic review. We feel that such is indeed the best any authors could hope for for their work. Let us admit from the outset that it came as a big surprise to us ourselves that fixed effects model odds ratio, relative risk and risk difference were indeed statistically significant for the per protocol comparison between low dosage and standard dosage tricyclics at 4 weeks. We looked around and experimented with our data and found that, for the same data set, random effects model odds ratio and relative risk were not significant whereas random effects model risk difference was. We further found that, at 6-8 weeks, odds ratio or relative risk or risk difference were not significant by any analytical method; nor were they at 4 or at 6- 8 weeks if we examined the data on the worst case scenario intention-to- treat analysis. We agree with Professor Geddes et al that estimation is more appropriate here than hypothesis testing. The following line of argument then, we believe, still leads us to the same conclusion as in our original review that gthey [low dosage tricyclics] may or may not be as effective as standard dosage tricyclics but result in fewer dropouts due to side effects.h 1) A separate empirical analysis of ours on the best summary effect measure of meta-analyses showed that random effects model relative risk was the most generalisable and interpretable among fixed or random effects model odds ratios, relative risks and risk differences (1). We therefore planned a priori to stick to this method (Please see our protocol for this meta-analysis in the Cochrane Library). We felt any further experimentation with analytical methods would be a fishing expedition. 2) The very fact that the results vary according to meta-analytic methods weakens our confidence in the statistically significant findings of some of these analyses. Moreover, these significant findings do not hold when we incorporate the dropouts and attempt the worst case scenario intention-to-treat analysis whereby dropouts were considered non- responders in the standard dose arm but as responders in the low dose arm (a fair assumption if we are to recommend standard dose which we know causes more side effects). Furthermore, the findings at 4 weeks are at odds with those at 6-8 weeks, which further decreases our confidence in the superiority of standard dosage regimen. 3) The appropriate estimates for the effectiveness of standard dose over low dose would therefore be, based on the random effects model relative risk and the plausible range of the patient expected event rate (we assumed response rate ranging between 50 and 70% among those receiving standard dosage), absolute benefit increase of 6 to 8% (95% confidence intervals: -5% to 18%) at 4 weeks and of -6 to -8% (95% confidence intervals: -43% to 17%) at 6-8 weeks. At the same time the available data show that the absolute risk increase of dropouts due to side effects might well be 9% (95% confidence interval: 4% to 12%). 4) Thus the currently available best evidence does not rule out clinically important benefit increase on standard dosage over low dosage, while it clearly points to an approximately equal number of patients dropping out for side effects. We therefore remain uncertain whether standard and low doses are the same or different but it seems clear to us that we should not try to increase the dosage above 100 or 125 mg for patients with depression upfront. When patients do not respond to the low dosage regimen, there seem to be several options: increase the same antidepressant, switch to a different antidepressant or augment the antidepressant with lithium or thyroid hormone. It is painfully regrettable to realize that we do not have evidence base to choose among these alternatives. We did not essay meta-regression on our current dataset because we limited placebo-controlled RCTs to those administering 100 mg or less of tricyclics, and there was indeed small variation in dosage. If we were to examine the dose response relationship for tricyclics by meta-regression, we would need to assemble all placebo-controlled trials with tricyclics irregardless of their dosage. That might be an interesting analysis but probably very hard to interpret clinically for two reasons. First we admit that our choice of grouping trials according to dosages was somewhat arbitrary but we thought, and planned a priori accordingly, that such dichotomization is clinically sound and easily understandable; on the other hand, findings from meta-regression would have been translated into practice with more difficulties. Second, we are afraid that meta- regression analyses would still be fraught with (and indeed might even inadvertently mask) the nasty problem of dropouts which would make impossible any firm conclusion to be drawn. (1) Furukawa TA, Guyatt GH, Grifitth LE. Can we individualize the Number Needed to Treat (NNT)? An empirical study of summary effect measures in meta-analyses. Int J Epidemiol 2002;31:72-6. Competing interests: TAF has received fees for speaking from several pharmaceutical companies, some of which manufacture various types of antidepressants such as paroxetine, fluvoxamine and milnacipran. |
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