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Clinical trials of antidepressant medications are producing meaningless results

  • Gordon Parker (a1), Ian M. Anderson (a2) and Peter Haddad (a3)
Extract

A recent alert from the UK Committee on Safety of Medicines stated that the dangers of treatment of depression with paroxetine outweigh the benefits in those under 18. Such a warning should focus our minds on the evidence on which clinical practice is based. Antidepressant treatment of depression in the under-18s has been thought to be justified because clinical trials show that it works so well in over-18s. But is that a reasonable assessment of the evidence? Kirsch et al (2002) use the analogy of ‘The Emperor's New Clothes' to describe the findings from their meta-analysis of randomised placebo-controlled trials of antidepressants. They conclude that antidepressant medication appears to have only a small effect on outcome over and above placebo. In this analogy psychiatry is the emperor, drug trials are the fraudsters and the deception is being revealed by a growing body of critical opinion proposing that, once methodological problems with clinical trials are taken into account, antidepressants either do not work at all or have an effect that is so small as to be clinically unimportant (Andrews, 2001; Moncrieff, 2002). A large number of randomised placebo-controlled trials of antidepressants have been carried out over the past decades, mostly funded by the pharmaceutical industry, and it is now recognised that about 50% of negative trials go unpublished (Thase, 1999). Meanwhile, unipolar depression has jumped into the top five of the world's total burden of disease, and there is an imperative need for effective and safe treatments. Do we need more randomised controlled trials (RCTs) of antidepressant medications, or has that research paradigm outlived its usefulness? In this month's debate, Professor Gordon Parker, University of New South Wales and Black Dog Institute, Australia, and Drs Ian Anderson and Peter Haddad from the University of Manchester discuss whether clinical trials for antidepressant medication produce meaningless results.

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References
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Kirsch, I., Moore, T.J., Scoboria, A., et al (2002) The Emperor's new drugs: An analysis of antidepressant medication data submitted to the US Food and Drug Administration. Prevention & Treatment, 5, Article 23. http://www.journals.apa.org/prevention/volume5/pre0050023a.htm
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Moncrieff, J., Wessely, S. & Hardy, R. (1998) Meta-analysis of trials comparing antidepressants with active placebos. British Journal of Psychiatry, 172, 227–23l.
Parker, G. (2001) ‘New’ and ‘old’ antidepressants: all equal in the eyes of the lore? British Journal of Psychiatry, 179, 9596.
Robinson, D. S. & Rickels, K. (2002) Concerns about clinical drug trials. Journal of Clinical Psychopharmacology, 20, 593596.
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Thase, M. (1999) How should efficacy be evaluated in randomised controlled trials of treatments for depression? Journal of Clinical Psychiatry, 60 (suppl. 4), 2331.
Thase, M. (2002) Antidepressant effects: the suit may be small, but the fabric is real. Prevention & Treatment, 5, Article 32. http://www.journals.apa.org/prevention/volume5/pre0050032c.html
Walsh, B.T., Seidman, S.N., Sysko, R., et al (2002) Placebo response in studies of major depression: variable, substantial, and growing. Journal of the American Medical Association, 287, 18401847.
Zimmerman, M. & Posternak, M. A. (2002) Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? American Journal of Psychiatry, 159, 469473.
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The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
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Clinical trials of antidepressant medications are producing meaningless results

  • Gordon Parker (a1), Ian M. Anderson (a2) and Peter Haddad (a3)
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eLetters

Medicine based evidence in psychiatry

Eibert R Heerdink, Assistant Professor
14 October 2003

Dear Sir, As pointed out in the debate by Parker et al. (2003), a gap exists betweenthe results of randomised clinical trials (RCTs) and what is seen in dailypsychiatric practice. While both parties in the debate come to more or less opposing conclusions, they agree upon the fact that the conditions intrials into the efficacy of antidepressants differ from the conditions in the field. We want to argue that these differences often are even greater than suggested in this debate and not limited to antidepressants.

The demographics of subjects included in trials are skewed: men are more often included than women, children and elderly are rarely investigated and subjects in trials often have a low socio-economic status. Furthermore, strict criteria for the diagnosis are used and the duration of the trials is short while the compliance is high. And finally,comorbidity and comedication is most often more frequent and more severe in practice compared to the laboratory conditions of a clinical trial making the patients participating in trials virtually incomparable to those patients eventually taking the drugs in daily practice (Leufkens & Urquhart, 1994). Not surprisingly, only 14% of typical users of antidepressants would comply with the strict inclusion and exclusion criteria that are usually applied in RCTs (Zimmerman & Posternak, 2003).

The gap between trials and psychiatric practice may even be bigger inother areas in psychiatry. Frequently occurring aggressive incidents in psychiatric patients are countered by a broad spectrum of psychotropic drugs as well as coercive measures to immediately reduce danger and harm (Nijman, 1997). However, evidence for these interventions is almost non-existent and mostly based on clinical experience rather than on RCTs. For example, although zuclopenthixol acetate is used in 40% of the patients hospitalised on admission wards in The Netherlands (Hugenholtz, 2003), a Cochrane review concludes that ‘there is a need of more RCTs’ on the use of seclusion and restraint (Sailas & Fenton, 2003). However, is a callfor more RCTs in patients with aggression problems realistic? Factors contributing to uninformative results of RCTs for depression (Parker, 2003) will be even more prominent in trials for aggression. Patients will be unwilling or unable to participate, compliance will be low and when coercive measures are involved randomisation is almost impossible.

How can we bridge the gap between the results of RCTs and the complicated patients we encounter in daily practice? We think that collection of valid data on treatment patterns and effects using standardised measurements in daily psychiatric practice may contribute to evidence of treatments of ‘difficult’ patients. Because of the lack of randomisation, dealing with confounding and other types of bias are challenges in the design and analysis of such pharmacoepidemiologic studies. Pharmacoepidemiological research may provide the essential ‘learning’ component in the cycle that drives drug development, where clinical trials supply the ‘confirming’ part. (Sheiner, 1997) In other words, while clinical trials may form the foundation of evidence based medicine, one should not neglect medicine based evidence in the pursuit ofbetter therapy, especially in the challenging reality of psychiatric practice.

Hugenholtz, G. W., Stolker, J. J., Heerdink, E. R., et al (2003) Short-acting parenteral antipsychotics drive choice for classical versus atypical agents. Eur J Clin Pharmacol, 58, 757-760.

Leufkens, H. G. & Urquhart, J. (1994) Variability in patterns of drug usage. J Pharm Pharmacol, 46 Suppl 1, 433-437.

Nijman, H. L., Merckelbach, H. L., Allertz, W. F., et al (1997) Prevention of aggressive incidents on a closed psychiatric ward. PsychiatrServ, 48, 694-698.

Parker, G., Anderson, I. M. & Haddad, P. (2003) Clinical trials of antidepressant medications are producing meaningless results. Br J Psychiatry, 183, 102-104.

Sailas, E. & Fenton, M. (2000) Seclusion and restraint for peoplewith serious mental illnesses. Cochrane Database Syst Rev, CD001163.

Sheiner, L. B. (1997) Learning versus confirming in clinical drug development. Clin Pharmacol Ther, 61, 275-291.

Zimmerman, M., Mattia, J. I. & Posternak, M. A. (2002) Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? Am J Psychiatry, 159, 469-473.
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Conflict of interest: None Declared

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Fifty years of poor science

Peter Kenneth Gillman, doctor
09 September 2003

1/9/2003

The EditorThe British Journal of Psychiatry17 Belgrave SquareLondon SW1X 8PG.UKWds 288

I declare I have no interest (fees and grants from, employment by, consultancy for, shared ownership in, or any close relationship with, and organisation whose interests, financial or otherwise, may be affected by publication of the letter) in respect of my authorship.

Sir,

This discussion highlights that we psychiatrists have not made satisfactory progress in the 50 yrs antidepressant drugs have been available: perhaps it is time to seek more help from other scientists.

Among the many suggestions that might be made would certainly be comment about our reliance on surrogate markers instead of disease related outcomes (eg death by suicide). This debate is well rehearsed in hypertension research, where even the reliable measure of blood pressure is recognised as a poor surrogate marker of death by stroke or myocardial infarction (Gotzsche, Liberati, Torri, et al, 1996).

The score on a Hamilton scale cannot logically be assumed to be related to the long term illness outcome; nor indeed to the core* changes of depressive illness itself, even in the short term, whatever we suppose they might be. All debate of inter-rater reliability, content validity etc, is redundant, unless and until the long term validity of short term proxy markers (rating scales) is clearly established.

I suggest that if we wish to progress we will benefit from understanding more about the factors that have impeded us thusfar. The degree to which academia relies on drug company funding may be a factor, but we must shoulder blame for being involved in so much third rate science. It is salutary to note that ethical guidelines for research are predicated on the assumption that it must be good science before it can be ethical.

* No pun concerning Prof Parkers’ work is intended here.

Gotzsche, P. C., Liberati, A., Torri, V., et al (1996) Beware of surrogate outcome measures. International Journal of Technology Assessment in Health Care, 12, 238-246.

Names and affiliations; contact informationDr. Ken GillmanConsultant and Director, Department of Clinical Neuropharmacology (DCNP) Pioneer Valley Private Hospital.Honorary Senior Lecturer, Clinical Neuropharmacology. James Cook University.

Emailkg@matilda.net.auPostal addressPO Box 8183Mount PleasantQueensland 4740AustraliaTel:07 4942 1883Fax: 07 4942 8283
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Different faces of depression

Dr.Naseem A. Qureshi, Medical
26 August 2003

Ideally speaking, depression is a biological, psychological, social and cultural phenomenon. Until and unless, each etiological component of depression is addressed while conducting randomized clinical trials (RCTs), no known antidepressant will spew better results over placebos. Although advanced statistical analyses and rigorous selection of patient population are followed in RCTs, it is felt that such trials do not match substantially the depressed patients' real life situations. From my long clinical experience, I feel that antidepressants and electroconvulsive therapy work in some biologically depressed patients butnot in all, psychotherapy works in some psychologically depressed patientsbut not in all, social therapy works in some socially depressed patients but not in all, and finally culturally derived therapies work in culturally depressed patients but again not in all. Therefore, an integrated approach and not just antidepressants will be tremendously useful and therapeutic in larger populations suffering from devastating depression. The depressed patients need ideal help - drug and nondrug. Are wemental health professionals including psychiatrists, psychologists, sociologists, anthropologists, and allied mental health staff offering them all they need or just well-lauded antidepressants. ... More

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Antidepressants Are Not Clinically Effective

Dr P V Finn Cosgrove, Consultant All-Age Psychiatrist
26 August 2003

Anderson I M & Haddad P ask the question, "What if antidepressants do not...work...at least well enough to be important?" [Brit J Psychiat (2003), 183,102-4].

They state that randominsed controlled trials (RCTs) do not tell us about the "effectiveness" of antidepressants, but they do tell us about their "efficacy".

In their well-written article, they say that it is simply not known how effective antidepressants are in clinical practice. Why not? Becausethe drug trials, these RCTs, are not designed by the pharmaceutical industry to tell us clinicans how effective they are in getting patients better.

Anderson & Haddad admit that we have all been misled, presumably by the pharmaceutical companies, into believing that the efficacy of antidepressants against placebo is the same as the effectiveness of antidepressants in the real world of human suffering. They say that firmly held beliefs, such as that antidepressanst are effective in relieving depression, can be delusional, and they imply that psychiatristshave been deluded by this pharmacological orthodoxy.

Candidly, they say, "Our position is, therefore, that we simply DO NOT KNOW how big the effect of antidepressants is in clinical practice....!" No one knows how effective they are! And we do not know this because randomised controlled trials ARE NOT DESIGNED to tell us how effective antidepressants are in clinical practice.

Parker G, writing in the same article, urges us not to abandon antidepressants because they have not been shown to be effective to the clinician. He recommends that 'we reduce the distance between "efficacy" studies and "effectiveness" studies'. This might be harder to achieve than it is to understand what he is talking about!

However, there is another approach to this tragedy. To revisit the monamine hypothesis and to be prepared to use those psychotropics which have not yet been labelled as "antidepressants" by the pharmaceutical industry.

But this needs academic courage and professional boldness, and these are not found in those who are deluded.

The drug companies have deluded us all into believing that increasingserotonin or noradrenaline in the synapse results in effectiveness in the depressed patient, when it does nothing of the sort, but only results in efficacy against placebo.

So the academic courage is to ask whether increasing dopamine in the synapse could result in effective relief of depression, and the professional boldness is to try it out.

We know that dopamine is increased after ECT, and we know that ECT relieves depression.

So, how about the British Association for Psychopharmacology taking the lead and having a seriesof seminars on the antidepressant potential of dopaminergics, whether by means of dopamine reuptake inhibition or by pre-synaptic dopamine release? What a service the BAP would be offering to a deluded psychiatric profession and to a depressed population, unrelieved by so-called "antidepressants"!
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