British Psychiatrists Debate: “Clinical trials of antidepressant medications are producing meaningless results”

Wed, 27 Aug 2003

“The fact that most people support the psychopharmacological orthodoxy is, in itself, no argument and it is important to examine the evidence before drawing conclusions.”

The psychiatric establishment is on trial–its foundation and claimed scientific basis and method–at least for the treatment of depression–has been smashed by an examination of previously concealed evidence from FDA approved controlled clinical trials.

The data submitted to the FDA proves the opposite of what is / has been claimed by the drug industry and its stakeholders: institutional psychiatry, the professional journals, the popular media whose dependency on drug advertising compromises its science reports, and patient “advocacy” groups that serve as cheering squads for those who feed them empty promises “hope.”

Psychiatry is hard put to refute the hard evidence demonstrating that rather than being an effective treatment for depression, antidepressants such as Prozac, Zoloft, Paxil, and the rest of the SSRI group, were worthless–or no better than placebo. These findings have been corroborated by several independent analyses.

Adding fuel to the brewing scandal of institutionalized deception, are the revelations in the UK media that children prescribed Paxil (Seroxat) were at 2 to 3 times the risk of a suicide action than those on placebo. The UK government ban on the drug for children and the current re-evaluation of the data from all SSRIs by the UK and the FDA, threatens to unravel a multi-billion dollar business that has thrived on the basis of false claims.

While American psychiatry remains silent–lest any utterance might tend to incriminate the profession further, a published debate (of sorts) appears in the current British Journal of Psychiatry: “Clinical trials of antidepressant medications are producing meaningless results.” (excerpt below)

The introduction to the debate states: “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.”

The news is that BOTH sides in the debate CONCEDE the fact that clinical trials as currently constituted are rigged, that screening of subjects results in unrepresentative groups of patients, that reporting of findings are biased and therefore invalid, and serve no value for clinicians.

Not addressed in the debate is the obvious: Since placebo does not pose risks, or severe adverse effects that some patients taking an SSRI experienced, the risk / benefit ratio is clearly on the side of placebo. If you also consider that placebo is free, whereas SSRIs involve substantial cost to individuals, insurance companies and taxpayers, the choice is a no brainer.

However, the following statement by British psychiatrists acknowledges psychiatry’s tenuous scientific basis: psychiatry needs drugs to “buttress” (legitimize) its claim to be a medical profession:

“There is enormous investment in our belief that antidepressants work, from its buttressing the scientific basis of psychiatry, through our need as clinicians to have the tools for alleviating distress, to providing a financial return for pharmaceutical companies. However, as we psychiatrists know only too well, firmly held beliefs may, on occasion, be delusional.”

If psychiatry’s firmly held belief in drugs is delusional, what, one wonders is the FDA’s rationale for endorsing, clinically worthless placebo-controlled clinical trials? Clearly such trials do not measure up to what agency officials refer to as “the Gold Standard.”

U. S. psychiatry is faced with another challenge from an organized group of former patients who are on a hunger strike until psychiatry to provides scientifically valid evidence to back up its claims of a biological basis for mental illnesses. See: http://www.mindfreedom.org/mindfreedom/hungerstrike.shtml

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The British Journal of Psychiatry (2003) 183: 102-104
© 2003 The Royal College of Psychiatrists

Debate
Clinical trials of antidepressant medications are producing meaningless results

Gordon Parker, Scientia Professor, Director
School of Psychiatry, University of New South Wales
Black Dog Institute, Prince of Wales Hospital, Sydney, Australia.

Ian M. Anderson, Senior Lecturer in Psychiatry
Neuroscience and Psychiatry Unit, University of Manchester, Room G809
Stopford Building, Oxford Road, Manchester M13 9WL, UK. Tel: 0161 275 7428;
Fax: 0161 275 7429

Peter Haddad, Consultant Psychiatrist
Mental Health Partnership of Bolton, Salford & Trafford, Manchester, UK
Correspondence: Euroa Unit, Prince of Wales Hospital, Randwick 2031,
Australia.

Edited and introduced by Mary Cannon, Kwame McKenzie and Andrew Sims.

Declaration of interest

G.P. is a member of several international and Australian pharmaceutical advisory boards. This report is supported by an NHMRC Program Grant (222708) and a NSW Department of Health Infrastructure Grant.

Declaration of interest

I.M.A. and P.H. have both received honoraria for speaking, been members of advisory boards, received research grants and had support for attending scientific meetings from several pharmaceutical companies involved in the manufacture and marketing of antidepressants.

INTRODUCTION

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?

FOR

Two papers published last year add weight to an argument that efficacy data from clinical trials no longer provide meaningful evidence about the utility of antidepressant drugs. The first (Hypericum Depression Trial Study Group, 2002) reported an 8-week double-blind, randomised placebo-controlled trial of St John’s wort and the selective serotonin reuptake inhibitor sertraline. Despite substantive cell sizes, neither drug was significantly different from placebo in reducing depression severity or disability or in overall improvement. The second paper (Kirsch et al, 2002) analysed efficacy data submitted to the US Food and Drug Administration for the six ‘most widely prescribed antidepressants’ approved between 1987 and 1999. The mean drug–placebo difference (for 38 trials analysed) was two points on the Hamilton Rating Scale for Depression, allowing the authors to conclude that antidepressant drug effects were ‘very small and of questionable clinical significance’. There is great difficulty reconciling such findings with clinical practice.

A related question is whether clinical trials provide any evidence that one type of antidepressant therapy is superior to any other. As reviewed earlier (Parker, 2001), very large databases suggest that different classes of antidepressant drugs are equally efficacious….. …cut…

Thus, analyses such as that by Kirsch et al (2002) suggesting that response to the newer antidepressants only marginally exceeds placebo response is not surprising. In summary, current designs restrict the participation of ‘true’ specific responders, being overly weighted towards pristine subjects with non-biological depressive disorders, with unstable symptomatology and disorders of marginal severity, and disposed to ‘respond’ irrespective of the treatment arm. Extrapolation of such studies to the clinical management of melancholic depression, and possibly other ‘biological’ expressions of depression, is then illogical.

Should loss of confidence in trial data lead to their abandonment? Just as it is not necessary to abandon religion because of antipathy to the local minister, loss of faith in clinical trials might more usefully lead to modifying their faulty components. One strategy would be to reduce the distance between efficacy studies (assessing outcome under controlled conditions) and effectiveness studies (approximating to the clinical world), both by modifying the current efficacy study paradigm and by undertaking clinical panel studies.

It is hard to detect any winners from the current paradigm, whether licensing authorities, the pharmaceutical industry or patients. Current operational strategies for trials are producing specious and irrelevant information, compromising rationality and reality. They need to get real.

AGAINST

Are drug trials of antidepressants more a triumph of marketing than science? Are RCTs a flawed way to test the efficacy of antidepressants? What if antidepressants do not really work, or at least not well enough to be important?

An increasingly vociferous minority is asserting just this (Antonuccio et al, 1999; Kirsch et al, 2002; Moncrieff, 2002). Irving Kirsch in particular has a populist appeal with titles such as ‘Listening to Prozac but hearing placebo’ (Kirsch & Sapirstein, 1998), and most recently ‘The Emperor’s new drugs’ (Kirsch et al, 2002). It is uncomfortable to have our assumptions questioned. There is enormous investment in our belief that antidepressants work, from its buttressing the scientific basis of psychiatry, through our need as clinicians to have the tools for alleviating distress, to providing a financial return for pharmaceutical companies. However, as we psychiatrists know only too well, firmly held beliefs may, on occasion, be delusional. The fact that most people support the psychopharmacological orthodoxy is, in itself, no argument and it is important to examine the evidence before drawing conclusions.

Addressing the most forceful criticism, whether or not antidepressants really work (i.e. have a pharmacologically specific action), we do have to turn to RCT evidence as this is the only way to tease out the effects of placebo v. drug. The key issue is that of publication bias. Kirsch et al (2002) identified all available acute treatment studies comparing newer antidepressants with placebo in evidence submitted to the US Food and Drug Administration. This included previously unreported ‘negative’ studies and is likely to be as complete a data-set as possible. The outcome from pooling the studies is a highly statistically significant effect in favour of antidepressants. Therefore, whatever the size and cause of the effect, the central question as to whether there really is an effect is answered in the affirmative. …cut….

Our position is, therefore, that we simply do not know how big the effect of antidepressants is in clinical practice because RCTs are not designed to tell us this. Clinical trials of antidepressants are not producing meaningless results, because they can tell us which compounds work (i.e. have efficacy). This is vitally important both scientifically and as a cornerstone of the regulatory process, designed to ensure that drugs that are licensed are safe and have a real effect. What is meaningless is to ask the trials questions they cannot answer, such as how well do antidepressants work in usual practice (their effectiveness). The latter question needs different trial designs from that of the standard RCT. This is no easy task and is one that will require more pragmatic/naturalistic approaches to be more inclusive, while attempting to minimise allocation bias. There needs to be careful selection of target groups, comparison treatments and duration of the assessment period. Only then will we be able to estimate the real added value of antidepressants in particular patient groups.

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