Monday, October 20, 2008

The Maudsely debates: anti-depressants and placebo

The Institute Of Psychiatry, London conducts Madusley debates on relevant psychiatric topics between distinguished psychiatrists and neuroscientists and also publishes them as a podcast. The most recent such debate consisted of the issue of whether anti-depressants are any better than Placebos in treating depression. There were knowledgeable arguments on both fronts and no matter what position you hold, hearing the debate would definitely enhance your knowledge about the issues involved.

I, for one, did not knew that anti-depressants worked by addressing the automatic and unconscious attention/ perception and memory biases. While I was aware that CBT worked top-down and affected cognitive biases and brain regions different from that areas affected by anti-depressants that presumably worked on neurotransmitter levels and bottom-up, the revelation that Goodwin's team had found that anti-depressants too work on biases, but unconscious ones, while CBT works on conscious ones, was new and enriching.

On the other hand I agree with many of the methodological issues raised by the speakers who claimed that anti-depressants were no good than placebos : the fact that the results lack 'clinical significance'; being psycho-active they are bound to have some effects and also the fact that the relief may be symptomatic due to 'drug' nature of anti-depressants and not specific and addressing the underlying disease, that the scale (HRSD) measuring depression may be not reflective of DSM criterion and may not be the best measure of disease severity; and I concur, but still think that the current generation of anti-depressants (other medicines) must be some good (over and above the good they bring by way of Placebo effect) especially since research has shown how they work (with a lag of few weeks before showing effects and by primarily inducing neurogenesis and affecting discrete brain areas) and how they are indeed effective at least in severely depressed people. Still all this should be taken with a pinch of salt- we have continuously been replacing outdated models of depression (like serotonin deficiency) by more and more accurate models (like neurogenesis). In my view we need to persist in that direction, though also having a healthy skepticism of what the drug companies might say and market new drugs and models for. Fortunately there are a host of unbiased pharmacists, neuroscientist and psychiatrist out there who are struggling with finding the most accurate model and the most accurate medication/ treatment like CBT for the same; so we don't need to despair. However, to blindly accepted all drugs (and models) , marketed by the Big Pharma, at their face value, and in clear evidence that they have not been proved effective beyond doubt, in clear evidence that negative finding have not been reported diligently and in view of the fact that at many time side -effects are glossed over, I would request not to be seduced overtly by the anti-depressants efficacy hype, but to moderate that with other known efficacious manes like exercise, CBT and yoga (all of which may be working by placebo effect themselves, but which definitely have lesser or no side-effects than anti-depressants. this of course does'nt mean that you give up your medicenes- at least not without consulting your psychiatrist- but supplementing them with other non-drug measures and reducing your reliance on the drugs- as they definitely have side-effects and may not be that efficacious as depicted in advertisements/ popular press.

Here is the summary of the talk from the IoP website:

Inspired by the recent media-frenzy at Prof Irving Kirsch?s research which suggested that antidepressants are no better than placebo, this Maudsley debate had an extremely good turnout.

Professor Kirsch gave us a run through of his research, in which he claimed to have found that there was a statistically significant benefit in the use of SSRIs over placebo - but that the difference was smaller than the standard of ?clinical significance? set down by the UK?s National Institute for Clinical Excellence (NICE) for all but the most depressed patients. His team also found that patients? response to placebo across all the trials was ?exceptionally large? - an indication of the complexity of the disorder. It was only the fact that the most severely depressed patients showed a much lower response to placebo that made the drug response clinically significant in this group of patients.

Against the motion, Professor Guy Goodwin argued that there were crucial flaws to the bounds that Kirsch had used to define clinical effectiveness. He pointed out that these criteria fail to contain an accurate description of depression, for example that they fail to mention persistent negative thoughts and other crucial symptoms that would be included in DSM IV.

For the motion, Dr Joanna Moncrieff alluded to the idea that there may be some sort of conspiracy of complacency and wishful thinking within the psychiatric profession as to the effectiveness of anti-depressants.

An impassioned speech against the motion was then given by Prof Lewis Wolpert. This was inspired by his own experiences of depression, which proved a powerful persuader as to the place that anti-depressants have in the treatment of severe depression.

Prior to the debate the audience were asked to vote which side of the argument they favoured. The leaning was overwhelmingly against the motion, perhaps not surprising in a room full of psychiatrists! After the speakers had made their points votes were recounted and a minority had changed their minds and had been swayed to support the motion. However those against the motion still had the majority.

The original article that sparked this debate is available online at PLOS Medicine, and I'm including the editor's summary below:


Everyone feels miserable occasionally. But for some people—those with depression—these sad feelings last for months or years and interfere with daily life. Depression is a serious medical illness caused by imbalances in the brain chemicals that regulate mood. It affects one in six people at some time during their life, making them feel hopeless, worthless, unmotivated, even suicidal. Doctors measure the severity of depression using the “Hamilton Rating Scale of Depression” (HRSD), a 17–21 item questionnaire. The answers to each question are given a score and a total score for the questionnaire of more than 18 indicates severe depression. Mild depression is often treated with psychotherapy or talk therapy (for example, cognitive–behavioral therapy helps people to change negative ways of thinking and behaving). For more severe depression, current treatment is usually a combination of psychotherapy and an antidepressant drug, which is hypothesized to normalize the brain chemicals that affect mood. Antidepressants include “tricyclics,” “monoamine oxidases,” and “selective serotonin reuptake inhibitors” (SSRIs). SSRIs are the newest antidepressants and include fluoxetine, venlafaxine, nefazodone, and paroxetine.

Why Was This Study Done?

Although the US Food and Drug Administration (FDA), the UK National Institute for Health and Clinical Excellence (NICE), and other licensing authorities have approved SSRIs for the treatment of depression, some doubts remain about their clinical efficacy. Before an antidepressant is approved for use in patients, it must undergo clinical trials that compare its ability to improve the HRSD scores of patients with that of a placebo, a dummy tablet that contains no drug. Each individual trial provides some information about the new drug's effectiveness but additional information can be gained by combining the results of all the trials in a “meta-analysis,” a statistical method for combining the results of many studies. A previously published meta-analysis of the published and unpublished trials on SSRIs submitted to the FDA during licensing has indicated that these drugs have only a marginal clinical benefit. On average, the SSRIs improved the HRSD score of patients by 1.8 points more than the placebo, whereas NICE has defined a significant clinical benefit for antidepressants as a drug–placebo difference in the improvement of the HRSD score of 3 points. However, average improvement scores may obscure beneficial effects between different groups of patient, so in the meta-analysis in this paper, the researchers investigated whether the baseline severity of depression affects antidepressant efficacy.

What Did the Researchers Do and Find?

The researchers obtained data on all the clinical trials submitted to the FDA for the licensing of fluoxetine, venlafaxine, nefazodone, and paroxetine. They then used meta-analytic techniques to investigate whether the initial severity of depression affected the HRSD improvement scores for the drug and placebo groups in these trials. They confirmed first that the overall effect of these new generation of antidepressants was below the recommended criteria for clinical significance. Then they showed that there was virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression. The difference in improvement between the antidepressant and placebo reached clinical significance, however, in patients with initial HRSD scores of more than 28—that is, in the most severely depressed patients. Additional analyses indicated that the apparent clinical effectiveness of the antidepressants among these most severely depressed patients reflected a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants.

What Do These Findings Mean?

These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.

Irving Kirsch, Brett J. Deacon, Tania B. Huedo-Medina, Alan Scoboria, Thomas J. Moore, Blair T. Johnson (2008). Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration PLoS Medicine, 5 (2) DOI: 10.1371/journal.pmed.0050045

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1 comment:

Ward said...

Very good post. I have read some of the research that has question the effectiveness of antidepressants. Like many 'belief' debates it is hard to boil things down to what the real truth is.