Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Clarity triumphs over complexity
- Alex J Stockdale (7 March 2008)
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Why is the effect size so small?
- D B Double (8 March 2008)
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Depression is a "Mixed Bag"
- Joseph More (9 March 2008)
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Clarity of expression but a misleading image
- Allan O House (9 March 2008)
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what would be the destiny of people with learning disability
- Rehana Shakir (9 March 2008)
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Efficacy of Antidepressants: How Full Is the Glass?
- Irving Kirsch, Blair T. Johnson (10 March 2008)
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A la recherche du temps passé
- Dermot Walsh (11 March 2008)
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How does antidepressant medication relate to the pathophysiology of depression ?
- Les O. Simpson (11 March 2008)
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limits of RCTs?
- Declan P Fox (12 March 2008)
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Questions remain
- Paul R Matthews (13 March 2008)
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Neuropharmacological therapy of endogenous depression
- Fuad Lechin, Bertha van der Dijs (13 March 2008)
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Correction of typographical error and competing interest addendum
- Erick H. Turner (13 March 2008)
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What about diminishing marginal returns?
- Lucy J Robinson (15 March 2008)
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Why GPs are indifferent to research based evidence. The case of antidepressant prescribing.
- David Kernick (17 March 2008)
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ERRATUM: What about diminishing marginal returns?
- Lucy J Robinson (19 March 2008)
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Use/misuse/abuse of antidepressants--a matter of serious concern
- Tanu Pramanik.BSc,MA.(Sociology), Prof(Dr)Jogenananda PramanikMDFaculty of Medicine,Saint Martinus University,Ottrobanda,Curacao,Netherlands Antilles. (19 March 2008)
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Re: Why GPs are indifferent to research based evidence. The case of antidepressant prescribing.
- P Ken Gillman (19 March 2008)
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Depression, antidepressants, placebo effects and Peter Skrabanek.
- Colin Brewer (22 March 2008)
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Limitations in using sum-scores to assess antidepressant efficacy
- Ulrik F Malt (1 April 2008)
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Alternatives to Prescription Drugs
- Darren Stevens (18 August 2008)
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Alex J Stockdale, FY1 Royal Infirmary of Edinburgh
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I'd like to congratulate Profs Turner and Rosenthal on a superb editorial. They have successfully overcome one of the greatest challenges of medical evidence: presenting critique with clarity. Too often, I have found that the enthusiasm for the complexity or controversy of an idea overcomes the expression of it. Their editorial serves to demonstrate the power of simplicity- the juice in a glass picture allows me to understand and take away their key message. Ever more the importance of outstanding communication of key ideas becomes obvious. If we cannot communicate our ideas without obfuscation to our colleagues, how can we be expected to overcome the scandal hungry media? The next time that the likes of autism and MMR vaccination comes our way, I hope that similarly gifted doctors will line up to give soundbites to the media. Competing interests: None declared |
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D B Double, Consultant Psychiatrist Norfolk & Waveney Mental Health NHS Foundation Trust, Peddars Centre, Norwich NR6 5BE
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We may need to be more circumspect about the prescription of antidepressants than Turner and Rosenthal imply.1 There is agreement that the effect size is not large. However, merely eliminating outcome reporting bias by obtaining the full data set from drug companies does not mean that other sources of bias in clinical trials have also been removed. The true effect size in clinical practice could still be zero if the difference between drug and placebo is due to placebo amplification.2 In particular, methodological difficulties in clinical trials are introduced through unblinding.3 Blindness is relative and both raters and patients can significantly distinguish antidepressant and placebo treatment. Raters' expectations and patients' suggestibility could therefore entirely explain the small effect size found.4 Competing interests: None declared |
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Joseph More, Retired (Psychiatrist) Waltham, Massachusetts 02453
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DSM has abandoned any attempt to accurately diagnose different depressive diseases. Instead, it throws in the same bag anything that looks like depression. It should then come as no surprise, that when you mix not just apples and oranges, but also apples grown on trees, candy in the form of apples, and wax and plastic decorations in the form of apples, you end up with equivocal conclusions. It is well documented that in treating the depressive phase of bipolar illness, antidepressant medication unaccompanied by a mood stabilizer can be harmful. There is merit in separating depressive mood associated with grief from "idiopathic" depression. Different depressive illnesses may well have different responses to different pharmacological interventions, or different psychotherapy techniques. Granted, it is often difficult to make the differential diagnosis between different depressive illnesses. Difficult is not a good excuse to abandon the effort. Competing interests: None declared |
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Allan O House, Professor of Liaison Psychiatry Leeds Institute of Health Sciences, Leeds LS2 9LJ
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I thought the "fluid in a glass" example was clear but misleading. A third of a litre of drink in a glass certainly sounds as if it's worth having; but is a third of a standard deviation difference in score on a depression rating scale worth having? For example, a typical GP sample of depressed patients might have a mean score on the PHQ-9 of 14 (standard deviation 6), improving to 8 on treatment with placebo and 6 on treatment with an antidepressant [1]. That two point difference represents an effect size of 0.3. In the end, we do have to dichotomize data like these, because the decision to prescribe is like that - you either do it or you don't, and you need a rule to help you decide. I don't think NICE is really so wrong to say that an effect size of 0.3 is not a meaningful difference, given the cost and toxicity of antidepressants. The way forward is to design and analyse trials that help us identify more clearly who responds and who doesn't in a population in which response can vary greatly between individuals. In the meantime, we should be working to reduce the current staggering rates of prescribing of antidepressants in primary care [2], where mild and moderate depression is managed. The challenge to mental health specialists is to help primary care clinicians in this task, by coming up with simple cost-effective interventions that are more realistic than referral for psychotherapy. There are candidates, but this rapid response letter isn't the place to rehearse them. References 1. Cameron I, Crawford J et al Psychometric comparison of PHQ-9 and HADS for measuring depression severity in primary care British Journal of General Practice 2008; 58: 32-36 2. Petty D, House A, et al Prevalence, duration and indications for prescribing antidepressants in primary care Age and Ageing 2006; 35(5): 523-526 Competing interests: None declared |
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Rehana Shakir, Staff Grade Ridgeway Partnership, Manor House, Aylesbury, HP20 1EG
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I totally agree with prof Turner and Rosenthal regarding first line treatment of depression. As Kirsch and colleagues have suggested if we are to look in to non pharmacological methods of treatment for depression as first line, what would happen to the people with learning disabilities?. This is a group of people with a high risk of developing mental illnesses. Their quality of life could become dramatically deteriorated with development of a mental illness like depression with learning disability. The only hope these patients have is the pharmacological treatment as any psychological approach would be much difficult and in majority of cases impossible to consider due to severity of their disability. In my practise I have seen many patients with learning disability and depression responding extremely well to antidepressants and they have made a huge difference in their quality of life. If we are to think that antidepressants are not helpful in mild to moderate depression, this group of people would not have the opportunity of treating their illness. Unlike in normal patients, people with learning disability would present to us in various challenging behaviours and clinically it would be difficult for the clinicians to categorize the severity of their illness due to difficulties in communicating and expressing their feelings. Do we deprive these patients of pharmacological treatment just because we could not tick all the boxes of severe depression. I think as shown in the above article our perception of the situation should differ according to the clinical situation and as clinicians we need to think laterally. It would be useful to look at the glass half full than half empty when dealing with people with mental illnesses. Competing interests: None declared |
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Irving Kirsch, Professor of Psychology University of Hull, Hull, UK, Blair T. Johnson
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Turner and Rosenthal (1) noted that our data (2) and theirs are in excellent agreement but contended that our conclusions differ: “In contrast to Kirsch and colleagues’ conclusion that antidepressants are ineffective, we concluded that each drug was superior to placebo.” The difference in conclusions they suggest is more apparent than real: We also noted that the drugs were significantly superior to placebo and added that the benefit attained clinical significance for some groups of patients. Turner and Rosenthal quoted our article as saying that “there seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients” but omitted the final part of our sentence in which we qualified this conclusion. What we really said was: “Given these data, there seems little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments have failed to provide benefit” (2, emphasis added). Psychotherapy is but one of a wide array of alternative treatment options that might be considered. As a sampling, physical exercise, self-help books based on cognitive therapy, omega-3 fatty acid supplements, and hypericum (a herbal remedy) have been found efficacious in outcome studies. Turner and Rosenthal are correct to note that selective publication might be a problem in psychotherapy research as well as in pharmaceutical research. Yet psychotherapy outcome research may suffer less from this problem because this research is not sponsored by a company that has large sums of money dependent on the outcome. In any case, if the placebo effect is large (as has been shown consistently in antidepressant drug trials even in published research), it is likely that any believed-in treatment will benefit patients. The fact that placebo effects in studies of major depression have been growing larger across time (3) is consistent with this perspective. Furthermore, cognitive behavioural treatment recently has been shown to have the benefits of a lower relapse rate, lower cost over the long run, and absence of side effects (4). Therefore, it seems quite sensible to reserve medication for those patients who do not first benefit from other, less problematic forms of treatment. Defining clinical significance necessarily requires the use of cut-off points. Turner and Rosenthal complain that doing so “is problematic because it transforms effect size, a continuous measure, into a yes or no measure, thereby suggesting that drug efficacy is either totally present or absent, even when comparing values as close together as 0.51 and 0.49.” Yet, this problem is not unique to clinical significance: It is true of statistical significance as well. As Turner and Rosenthal note, “tests of statistical significance give a yes or no answer (for example, P<0.05 is deemed significant, P>0.05 non-significant).” They might well have added that “this practice is problematic because it transforms probability, a continuous measure, into a yes or no measure, thereby suggesting that drug efficacy is either totally present or absent, even when comparing p values as close together as .051 and .049.” Establishing cut-off points is as necessary to defining clinical significance as it is to defining statistical significance. We adopted the criteria used by the UK’s National Institute for Health and Clinical Excellence (NICE) because they are the only criteria that clinical authorities have been proposed. As Turner and Rosenthal noted, NICE adopted Cohen’s (e.g., 5) definition of a “medium” effect size for clinical significance. Although it is true that Cohen argued against use of small, medium, and large labels, for better or worse, they have quickly become widely used means to interpret research results, in clinical trials and elsewhere. Cohen intended that a medium effect size “represent an effect of a size likely to be visible to the naked eye of a careful observer” (5). He intended that small effect sizes (0.20) be “noticeably smaller yet not trivial” (p. 156) and that large effect sizes (0.80) “be the same distance above medium as small is below it” (p. 156). Thus, clinical significance of antidepressants is reached when a careful observer can see that medicated patients have noticeably lower depression than patients on placebo. In this light, the NICE criterion seems quite sensible. One might well argue with this criterion for clinical significance just as one might argue with the conventional use of p < .05 as a criterion for statistical significance, but then one needs to propose an alternative. Turner and Rosenthal cleverly asked readers to imagine that antidepressant efficacy can be gauged in terms of a fluid named “d-juice” (based on the d effect size) and stated that “Kirsch and colleagues measured 0.32 litres of d-juice, but because they did not consider the glass sufficiently full (defined arbitrarily as P=0.5), they concluded that the glass contained virtually no d-juice whatsoever.” To the contrary, we documented that anti-depressant medications have efficacy, but that this efficacy did not reach clinical significance except for samples that had the highest levels of initial depression. To continue the metaphor, the amount of d-juice was pitifully small or even non-existent in trials that sampled people with less severe depression, but noticeable in trials that sampled very severely depressed individuals. Lost in Turner and Rosenthal’s discussion of effect size is the fact that effects can be much larger than Cohen’s 0.20 (small), 0.50 (medium), and 0.80 (large); indeed, in theory, d can take the value of infinity (e.g., 6). In this light, even a medium effect size, observed for trials that sampled extremely depressed individuals, could be viewed as inconsequential. Should we be content that antidepressants attain the clinical significance criterion only for the most depressed of very severely depressed patients? The fact is that although antidepressants and placebos reduce depression substantially, the average person in these trials still exhibits significant levels of depression, whether taking placebo or drug. Consequently, we should not assume that antidepressants will fully succeed for the average depressed patient. In short, this trickle of “d-juice” is likely to leave a depressed patient thirsty. Blair T. Johnson, Department of Psychology and Center for Health, Intervention, and Prevention, University of Connecticut, Storrs, Connecticut, United States of America
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Dermot Walsh, Psychiatrist Health Research Board,Dublin,2
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Your editorial (1) on the efficacy of antidepressants brought me back to the BMJ of almost half a century ago. At that time controversy raged about the merits of the first generation of antidepressants versus placebos and comparators. For example Hare et al (2) concluded that "imipramine .... has no specific effect on the clinical manifestation of depression. Evidence is presented to suggest the extension of this view to other 'antidepressive' drugs". Others including myself (3) were of similar opinion. What is interesting is that the control drug often used in these comparisons was amphetamine, up to this time the drug of choice for the treatment of depression. Indeed I remember in my final medical psychiatric clinical of 1953 being examined in Dublin by our extern, Sir Desmond Curran. As the nurse who had brought the patient to me had helpfully, sotto voce, confided "depression" I was well equipped to present my case and when Sir Desmond enquired as to treatment I confidently responded amphetamine 10 mgs bd, sir. I got honours. References 1. Turner EH Rosenthal R. Efficacy of antidepressants. BMJ (2008). 336:516 517 2. Hare EH McCance C McCormick WO. Imipramine and “Drinamyl” in depressive illness: a comparative trial. Brit med.J. (1964).1, 818-820 3. Browne IW Walsh D. Imipramine in depressive illness. Brit med. J (1964) I,982. Competing interests: None declared |
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Les O. Simpson, retired medical research worker Dunedin, New Zealand 9077
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Several publications have shown that episodes of depression are accompanied by reductions in regional cerebral blood flow. Bench et al (1) reported that in the region where cerebral blood was reduced during depression, normal blood flow was recorded when the depression was resolved. To ignore this finding implies acceptance of the idea that normal rates of blood flow are not necessary for normal tissue function. It is very likely the blood flow problem is related to the reduced omega-3 levels in the fatty acid composition of subjects with major depression.(2) However, the importance of omega-3 fatty acids in cell membranes are of special significance in the fluidity of the cell membranes of blood cells, as omega-3 deprived red cells are poorly deformable. This change is associated with increased blood viscosity and impaired capillary blood flow. So it is of pathophysiological significance that Edwards et al (3) reported that in depressed patients, the red blood cell membranes had low levels of omega-3 fatty acids. The authors suggested that a supplement of omega-3 might be beneficial for those with depression. Is there any evidence that antidepressant drugs have any beneficial effects on the reduced regional cerebral blood flow of those suffering from depression ? If not, then can it be explained how antidepressant therapy relates to the pathophysiology of depression ? What the quoted observations imply is that, irrespective of the chosen drug therapy, the management of depression should involve the use of agents which would improve regional cerebral blood flow. References. 1. Bench CJ, Frackowiak RS, Dolan RJ. Changes in regional cerebral blood flow on recovery from depression. Psychol Med 1995;25:247-61. 2. Maes M, Smith R, Christrophe A, et al. Fatty acid composition in major depression: decreased omega-3 fractions in cholesteryl esters and increased C20:4 omega-6/C20:5 omega-3 ratio in cholesteryl esters and phospholipids. J Affect Disord 1996;38:35-46. 3. Edwards R, Peet M, Shay J, et al. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998;48:149-55. Competing interests: None declared |
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Declan P Fox, Freelance physician Based in Newtownstewart, BT784NP, N Ireland
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A quick gander at various doctors I know, including myself, who have suffered major depression---which I define as totally screwing up personal life and ability to work----shows that none of us would have been included in any half-decent RCT of SSRIs or any other antidepressant. What sort of patients are actually being studied in SSRI RCTs and what correspondence is there with the series of depressed patients attending GPs? Has anyone looked at this? If not, I think it should be done ASAP. As for CBT and other therapies as first line for depression, of course I agree with this approach. But is there sufficient knowledge of how deeply and seriously subversive CBT is? Not just as a depression treatment which is more effective than drugs---thereby having major impacts on Big Pharma profits---but also in empowering people who are being messed up by their work environment to do something about said environment? Would the NHS, with its research-proven propensity for bullying and dysfunctional working conditions, actually survive if most mentally ill NHS employees got good CBT as part of their treatment? I doubt it! And we wonder why PCTs and the higher echelons drag their financial feet in providing CBT..... Competing interests: I occasionally get paid by drug companies to talk about basic CBT to GPs. |
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Paul R Matthews, Medical student Uni of Oxford, OX1 2JD
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There has been much discussion of the Kirsch et al paper, both in the media and the blogosphere. While most of the media coverage has been uncritical, some bloggers have expressed reservations about the methodology used in this study. In particular, there are questions as to how the authors found a HAM-D effect size of 1.8 (below the alternative NICE criterion for clinical significance of a difference greater than 3 on the HAM-D) when alternative methods of analysis of the authors' presented data find much larger effect sizes, particularly for paroxetine and venlafaxine. There is also a suggestion that the analytical method used was so biased that it would have failed to find a clinically significant HAM-D effect size even if the analysis had been restricted to the published studies. The finding that increased effect sizes were due to decreased placebo responses in more severe depression also appears to be an artefact of the particular effect size measure used. Finally, almost all the studies in this meta-analysis were in the severe range and there does not appear to be sufficient evidence to make recommendations about treatment in mild or moderate depression. Competing interests: None declared |
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Fuad Lechin, Chief of the Department of Neuroimmunopharmacology, Faculty of Medicine Universidad Central de Venezuela, Apartado 80.983, Caracas 1080-A, Venezuela, Bertha van der Dijs
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NEUROPHARMACOLOGICAL THERAPY OF ENDOGENOUS DEPRESSION Fuad Lechin, MD, PhD; Bertha van der Dijs, MD Universidad Central de Venezuela flechin@telcel.net.ve We will refer to the article by Turner and Roshental (1) dealing with the efficacy of antidepressants. We would like to inform that we demonstrated in 1995 that endogenous depression (ED) is underlied by raised plasma levels of noradrenaline (NA) plus lowered plasma levels of adrenaline (Ad) (2, 3). Our findings have been ratified by many other researchers. In addition to the above, it should be known that NA plasma levels are positively correlated with the activity of the A5-NA pontine nucleus, responsible for the peripheral neural sympathetic activity whereas Ad plasma levels (adrenal sympathetic activity) are positively correlated with the adrenal sympathetic activity. This peripheral sympathetic branch depends on the excitation of the C1-Ad medullary nuclei. Furthermore, both the A5-NA and the C1-Ad nuclei interchange inhibitory axons in such a way that Ad and NA released from both types of central nervous system (CNS) nuclei provoke the inhibition of both targets by acting at pre-synaptic alpha-2 receptors which crowd the above mentioned nuclei (4, 5). In addition to the above, we also demonstrated that patients affected by ED presented low levels of plasma tryptophane (trp) and raised platelet serotonin (p-5HT) levels. With respect to the latter, exhaustive evidence have demonstrated that these peripheral parameters are positively correlated with the activity of dorsal raphe (DR) and median raphe (MR) serotonergic nuclei, respectively (6). Thus, we postulated that endogenous depression presents with a MR-5HT over DR-5HT predominance plus the overactivity of the A5-NA and the hypoactivity of the A6-NA + C1-Ad (4, 5). The above postulation is reinforced by the successful neuropharmacological treatment addressed to revert the above CNS disorder. This target is reached by the administration of small morning dose of an alpha-2 antagonist (yohimbine) plus a NA-uptake inhibitor (desipramine, maprotyline, reboxethine, etc) plus a 5HT-1A antagonist (pindolol, which enhances the firing activity of both the DR-5HT plus the C1-Ad nuclei), and the nocturnal prescription of a small dose of a 5HT-uptake inhibitor (paroxetine, sertraline, fluvoxamine, etc). The addition of a small dose of mirtazapine (alpha-2 + 5HT2 antagonist), favors the release of NA and 5 -HT from the A6-NA or locus coeruleus plus the DR-5HT nuclei, respectively This therapeutical approach should be maintained during 3 to 4 months, at which period should be interrupted (5). References 1. Turner EH, Rosenthal R. Efficacy of antidepressants. BMJ 2008; 336(7643):516-517. 2. Lechin F, van der Dijs B, Orozco B, Lechin ME, Acosta E, Lechin AE, Baez S, Rada I, Arocha L, Leon G, Garcia Z. Plasma neurotransmitters, blood pressure and heart rate during supine-resting, orthostasis and moderate exercise conditions in major depressed patients. Biol Psychiatry 1995;38:166-173. 3. Lechin F, van der Dijs B, Benaim M. Stress versus depression. Review. Prog Neuro-Psychopharmacol Biol Psychiatry 1996;20:899-950. 4. Lechin F, van der Dijs B, Lechin ME. Neurocircuitry and Neuroautonomic Disorders: Reviews and Strategies of Therapy. Basel: Karger AG, 2002. 5. Lechin F, van der Dijs B. Crosstalk between the autonomic nervous system and the central nervous system: Mechanistic and therapeutic considerations for neuronal, immune, vascular, and somatic based diseases. In: Maiese K, editor. Neurovascular Medicine: Pursuing Cellular Longevity for Healthy Aging. New York: Oxford University Press, 2008 (In Press). 6. Lechin F, van der Dijs B, Hernandez-Adrian G. Dorsal Raphe (DR) vs. Median Raphe (MR) serotonergic antagonism. Anatomical, physiological, behavioral, neuroendocrinological, neuropharmacological and clinical evidences: Relevance for neuropharmacological therapy. Prog Neuro- Psychopharmacol Biol Psychiatry 2006;30(4):565-585. Competing interests: None declared |
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Erick H. Turner, assistant professor Dept. of Psychiatry, Oregon Health & Science University, Portland, Oregon
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I wish to correct a typographical error that appears approximately two-thirds of the way into our editorial. The parenthetical phrase that reads, “defined arbitrarily as P≥0.5” should read “defined arbitrarily as d≥0.5”. Competing interests: Following a query from the editor about conflicts of interest I append the following information, which has been disclosed in previously published articles. From 1998 to 2001, I served as a medical reviewer at the US Food and Drug Administration (FDA). Subsequently, but ending in 2005, I provided outside consulting to Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline. From 2004 to 2005, I was on the speaker's bureaus of Eli Lilly, AstraZeneca, and Bristol-Myers Squibb. |
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Lucy J Robinson, PhD Student Dept Psychiatry, Newcastle University, Leazes Wing, RVI, Queen Vic Rd, Newcastle upon Tyne, NE1 4LP
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One factor that seems to have been overlooked in this discussion is whether part of what we are seeing here - the relatively greater efficacy of anti-depressants in the more severely depressed - is simply an expression of the law of diminishing marginal returns. The very severely depressed have a long way to go on the climb back down the 'HAM-D' (Hamilton Depression Rating Scale) ladder and often very small changes in one biological factor (such as sleep or appetite) can have substantial knock-on effects on other symptoms, thereby assisting the individual down several rungs simultaneously. The same degree of gain becomes more difficult to achieve as time goes on or if initial symptom levels are not as high. There may not be as much benefit to be had from the biological changes that antidepressants may bring about when initial symptoms are lower, or in any given individual over time when the more 'stubborn' and trait-like aspects of the illness are all that remain. If this is true, it would be no surprise that the effect size is smaller in those with less severe depressive symptoms. Another aspect that has rarely been appreciated is the appropriateness of treating scales such as the HAM-D as if they are ratio scales, i.e. as if every single-point reduction means the same thing regardless whether it appears in the context of a high or low score. However, the HAM-D (and others like it) is an interval scale - higher scores mean more severe levels of depression, but that is all we can conclude. We cannot say that a person who scores 20 is twice as depressed as a person who scores 10. This becomes a very important point when the discussion boils down to whether an effect size represents a clincally meaningful change. A 2-point reduction in the HAM-D could mean something very different to a person (and to the friends, relatives and carers who are worrying about the person's safety) if it takes them from 'Wishes he were dead' to 'No thoughts of death or suicide', compared to if it takes them from 'Worries about minor matters' to 'No anxiety'. If a small effect size means only a few points change in HAM-D score, unfortunately we can conclude very little about the meaningfulness of that change through merely knowing its magnitude. Naturally, in order to make illnesses such as depression more amenable to research, scales such as this are necessary. But it is essential to remember exactly what we have done in constructing such a scale - put numbers on feelings, emotions and bodily states. But just because we have made them look like numbers, does not mean that they will behave like them. Competing interests: None declared |
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David Kernick, General Practitioner St Thomas Health Centre, Exeter EX4 1HJ
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The current debate over the relevance of antidepressants - the interpretation of meta-analysis, what is clinically significant, uncertainty over major side effects and the confounding influence publication bias, clearly illuminates why GPs are indifferent to research based evidence. I have been prescribing SSRIs for the last 20 years. Psychological interventions are essentially unavailable in the NHS, the medication is cheap and gives few side effects, I don’t have access to a placebo and patients invariably come back saying they feel better. That’s good enough for me. Yours faithfully David Kernick Competing interests: None declared |
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Lucy J Robinson, PhD Student Dept Psychiatry, Newcastle University, Leazes Wing, RVI, Queen Vic Rd, Newcastle upon Tyne, NE1 4LP
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Apologies, depression rating scales are ordinal, not interval scales. The sentence "However, the HAM-D (and others like it) is an interval scale - higher scores mean more severe levels of depression, but that is all we can conclude." should instead have read "is an ordinal scale". Competing interests: None declared |
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Tanu Pramanik.BSc,MA.(Sociology), Medical Sociologist Curacao,Netherlands Antilles, Prof(Dr)Jogenananda PramanikMDFaculty of Medicine,Saint Martinus University,Ottrobanda,Curacao,Netherlands Antilles.
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Tanu Pramanik.BSc.MA(Sociology)Medical Sociologist and Prof(Dr)Jogenananda pramanik.MD faculty of Medicine,St.Martinus University,Ottrobanda, Curacao,Netherlands Antilles. Correspondence:E-mail:j.pramanik@martinus.edu Use/misuse/abuse of antidepressants is a matter of serious concern in current medical practice.We read this insightful editorial with interest and applaude the editors view point(1).Hypothetically, if antidepressants are not worth taking, then what should doctors and patients do? Kirsch and colleagues recommend that if antidepressants are to be used at all they should be used only when alternative treatments have failed to provide a benefit(2).Current clinical recommendation is that when considering the potential benefits of treatment with antidepressants, be circumspect but not dismissive. Large number of antidepressant medicines are available in the market with uncertain efficacy.Therefore a stringent mechanism is urgently required to screen those products.On the otherhand,we need to advocate for alternative methodologis to alliviate depression before prescribing antidepressants.Habit forming antidepressants are causing more harm to our society than others.There are several sub-clinical cases of depression patients in our modern society (3)who lead their life without antidepreesant medicines.There are several methods available to handle depression.Our medical professionals need to be properly oriented and respectful to depression patients.During our teaching and training in medical Universities,we need to emphasize the importance of indifying depression patients at the early stages and take care of them.Medical students need necessary exposure to this area and develop clinical acumen to diagnose the vicious cycle of depressive factors working on potetially vulnerrable groups of people in our society (4). This editorial may be an eye-opener for the govermental and other regulatory agencies operating in different countries to intensify their vigil. References: 1.Editorial:Efficacy of antidepressants BMJ 2008;336:516-517 (8 March), doi:10.1136/bmj.39510.531597.80 (published 4 March 2008) 2.Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008;5:e45. 3.News:Depression affects elderly people's lives more than physical illnesses;Janice Hopkins Tanne BMJ 2004;329:1307 (4 December), doi:10.1136/bmj.329.7478.1307-c 4.Medical students knowledge and attitudes toward senior citizens and aged patients:Prof (Dr)Jogenananda Pramanik.MD,Professor,Dept of Pathology St James School of Medicine,4 Krelendijk,Bonaire Netherlands Antilles.,Tanu Pramanik,BSc,MA.Medical Sociologist.http://www.bmj.com/cgi/eletters/329/7478/1307-c#123057. ----------------------------------------------------------- Competing interests: Authors worked in elderly homes in India,Nepal,China and caribbean Islands. |
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P Ken Gillman, Retired Qld Aus 4750
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I think David Kernick is being very polite and kind to academics and researchers. They have not done terribly well over these last few decades and I suspect if I were a 'GP' I too would have ceased paying much attention to their scribblings long ago. Competing interests: None declared |
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Colin Brewer, Research Director The Stapleford Centre. London SW1W 9NP
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The letter from Dr Dermot Walsh reminds me that in the 1970s I compared suicidal overdose deaths from tricyclic antidepressants in the previous decade with those from amphetamines when, as he notes, the latter were commonly prescribed for depression.[1] Conservatively analysing the annual self-poisoning figures, I found that most years saw 0-2 amphetamine suicides against 2-300 for tricyclics. This important issue only became more widely discussed when the arrival of SSRIs in the late 1980s highlighted tricyclic toxicity. However, given the lack of compelling evidence that SSRIs have specifically reduced suicide rates, it seems quite possible that tricyclics caused more deaths from overdoses than they may have saved from suicide. I referenced a neglected paper by Leyburn[2], who noted the paradox that since the introduction in the late 1950s, of tricyclic antidepressants, which supposedly nipped depression in the bud, the number of admissions for both moderate and severe depression steadily increased. Changes in admission procedures following the 1959 mental health act reforms (removing the need to be declared insane by magistrates) were not considered a major factor in this increase. I do not conclude from current and previous debates that pharmacology has no place in treating depression. However, I entered practice at a time when deliberately prescribing placebos, far from being anathema, was regarded as a potentially useful diagnostic exercise. I even administered placebo Electo-Convulsive Therapy (ECT). Two of the three patients made a good recovery, one of them thanking me for the nicest ECT she had experienced. (The third did not improve even when placebo ECT was followed by the real thing.) Few doctors who qualified in the inevitably anti- placebo culture of patients’ rights have any idea of just how powerful non -specific placebo effects can be and many are perennially surprised at their extent and rediscovery.[3,4] With luck, about 40-50% of depressed (or ‘depressed’) patients respond to the non-specific effects of antidepressant prescribing; an additional 10-20% may respond to their specific pharmacological effects (whatever the alleged mechanisms) and 20–30% do not respond. If these non- responders have ECT, many improve but the large Medical Research Council trial[5] found that the advantage of real over placebo ECT (ie anaesthesia, attention, anticipation) was modest overall. The most seriously depressed patient, whose inclusion caused much ethical discomfort, recovered but was found to have been in the placebo arm. Unfortunately, doctors are probably stuck with current anti-placebo attitudes, at least in societies well-supplied with lawyers and investigative journalists. Of course, these institutions, like patients’ rights, are useful and important but like several other useful developments, they come at a cost. Placebos now flourish only among ‘alternative’ practitioners. They, too, typically underestimate their potency. The late Peter Skrabanek apparently believed that for maximal placebo effect, both prescriber and patient had to believe in it.[6] The evidence strongly suggests that we would be foolish not to. REFERENCES 1. Brewer C. Suicide with tricyclic antidepressants. BMJ 1976;2:110 2. Leyburn P. A critical look at antidepressant drug trials. Lancet 1967, 2(7526), 1135-8. 3. Shapiro A, Shapiro E. The powerful placebo: from ancient priest to modern physician. 1997; Baltimore,. Johns Hopkins. 4. Andrews G. Placebo response in depression: bane of research, boon to therapy. Br J Psychiat. 2001 Mar;178:192-4. 5. Johnstone E, Deakin J, Lawler P, Crow T. et al. The Northwick Park electroconvulsive therapy trial. Lancet 1980; 1317-20. 6. Steer P. Medical Classics. Follies and Fallacies in Medicine by P Skrabanek and J McCormick. BMJ.2008. 336. 673 (Book downloadable at www.medicine.tccl.ie/public_health_primary_care/skrabanek/publications.php) Competing interests: None declared |
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Ulrik F Malt, Professor and Director of Dept Rikshospitalet University hospital, Dept of Neuropsychiatry and Psychosomatic Medicine, 0027 Oslo, N
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The editorial by dr. Turner does not address the limitations of using effect sizes (ES) based on sum-scores derived from rating scales such as the Hamilton (HAM-D) or the Montgomery-Åsberg (MADRS) when evaluating efficacy of antidepressants. Those scales contain items that partly are not related to core phenomena in clinical depression. In our own study comparing the antidepressant effect of emotional support by a GP supplemented with antidepressant drugs or placebo (Malt et al, BMJ 1999), the mean difference in ES of adding drug compared to placebo was similar to the ES reported by both Turner et al (New Engl J Med 2008) and Kirsch et al (PlosMed 2008). However, ES of single items (N=372; intention to treat) revealed significant higher differences in ES compared to the placebo-group for some core symptoms of depression, e.g. insomnia (ES 0.59), pessimistic thoughts (ES 0.54) and reported sadness (ES 0.47)(Malt, Br J Psychiatry 2002). The difference in ES between antidepressants and placebo were much lower for other items such as reduced appetite, observed sadness, concentration problems and suicidal ideation. Our findings suggest that the mere use of total sumscores of rating scales for calculating differences in ES between treatments - as done when analyzing the FDA-data - may obscure important clinical differences between treatments. Future discussion of the efficacy of antidepressant or psychotherapy for the treatment of mood disorder should take such considerations into account. Competing interests: I have received payment for lecturing about psychopharmacology from several pharmaceutical companies, Public Health Trusts and organizations. My spouse is currently medical adviser in Pfizer, Norway |
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Darren Stevens, Business Trainer and Coach Rushden, Northants, NN10 0XL
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As part of a GP surgery in Nottingham, I run a Personal Coaching surgery based on Neuro-Linguistic Programming techniques for those patients who would normally have their antidepressants continually prescribed. The simple fact that this Talking Therapy focuses on the individual and their issues where a doctor is limited by time has an enormous effect on the mental health of the patient. I have proved over the last 8 months that affecting a person's self-esteem and emotional state is far more rewarding for them as individuals than it is to prescribe a drug to chemically alter their state. This is a much better approach for those patients who are not extremely depressed and who need a little nudge on their journey. I would urge all GP's to start thinking outside the box on this one as an hour with me is a lot cheaper than a patient coming back over a number of years, but more importantly, it's better for the patient too. Competing interests: antidepressant use in comparison to NLP-based Coaching |
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