Photo: Julia Nicolle, Flickr, here

Maggie Maguire, TT’s mental health issues writer, quotes tormented poet and well known non-complying antidepressant drop-out Leonard Cohen in the debate between those advocating antidepressant therapy and those opposed to it.

Marcia Angell’s two-part article in the New York Review of Books entitled The Epidemic of Mental Illness and The Illusions of Psychiatry was arguably last year’s hottest number in mental health circles and provoked an online head to head between those advocating antidepressant therapy and those opposed to it.

In the negative corner Angell paid particular attention to the work of Irving Kirsch in his book The Emperor’s New Drugs and his argument that the effect of antidepressant treatment in clinical trials is only marginally better than that of placebos.

Kirsch obtained unpublished data under the Freedom of Information Act which showed:

Altogether, there were forty-two trials of the six drugs.(Prozac, Paxil, Zoloft, Celexa, Serzone and Effexor) Most of them were negative. Overall, placebos were 82 percent as effective as the drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely used score of symptoms of depression. The average difference between drug and placebo was only 1.8 points on the HAM-D, a difference that, while statistically significant, was clinically meaningless.

In the opposite corner, Peter Kramer, the author of Listening to Prozac, came out in the New York Times in an article titled In Defense of Antidepressants. Despite its combative title Kramer’s response was nuanced and discursive which added up to a somewhat lukewarm support:

Antidepressants work — ordinarily well, on a par with other medications doctors prescribe.

His main argument appeared to be centred around the fact that there is a problem in the recruitment of participants in drug trials, something which is most likely correct but which does not directly counter the issues Angell raises:

Often subjects who don’t really have depression are included — and (no surprise) weeks down the road they are not depressed. People may exaggerate their symptoms to get free care or incentive payments offered in trials. Other, perfectly honest subjects participate when they are at their worst and then spontaneously return to their usual, lower, level of depression.

This improvement may have nothing to do with faith in dummy pills; it is an artefact of the recruitment process. Still, the recoveries are called “placebo responses,” and in the F.D.A. data they have been steadily on the rise. In some studies, 40 percent of subjects not receiving medication get better.

What are the problems with Angell’s article? Most importantly there is nothing unusual about medications being only marginally better, statistically speaking, than placebos. To explain a little – in the USA, Federal Government approval won’t be granted for a drug that does not prove more effective than a placebo in clinical trials.

In recent times there has been an increasing trend for studies to be aborted because the drug to be tested can’t beat the placebo in clinical trials. The problem is not that the drug to be tested, such as an antidepressant, is necessarily ineffective, but that the placebo response is getting stronger among participants leading to only a marginal difference between drug and placebo or the placebo actually having more effect than the drug. The reason for this increase in strength of the placebo is not clear.

In a fascinating award winning article in Wired Magazine titled Placebos Are Getting More Effective: Drugmakers are Desperate to Know Why, journalist Steve Silberman discusses the miraculously expanding power of the placebo. This 2009 article is essential reading in the anti-depressant/placebo debate as it reorients the entire argument in a new direction; away from the drug, towards the placebo. This reorientation is necessary in order to get the whole, historical picture.

Silberman writes:

From 2001 to 2006, the percentage of new products cut from development after Phase II clinical trials, when drugs are first tested against placebo, rose by 20 percent. The failure rate in more extensive Phase III trials increased by 11 percent, mainly due to surprisingly poor showings against placebo. Despite historic levels of industry investment in R&D, the US Food and Drug Administration approved only 19 first-of-their-kind remedies in 2007—the fewest since 1983—and just 24 in 2008. Half of all drugs that fail in late-stage trials drop out of the pipeline due to their inability to beat sugar pills.

Indeed Kirsch himself notes the importance of abnormal placebo effects, although he comes to this conclusion by a different route to Silberman. Angell says:

Putting all this together, Kirsch says, leads to the conclusion that the relatively small difference between drugs and placebos might not be a real drug effect at all. Instead, it might be an enhanced placebo effect, produced by the fact that some patients have broken [the] blind and have come to realize whether they were given drug or placebo. If this is the case, then there is no real antidepressant drug effect at all. Rather than comparing placebo to drug, we have been comparing “regular” placebos to “extra-strength” placebos.

If you read the Wired article together with the Wikipedia on placebos, it gives an understanding of the placebo response – a most fascinating phenomenon arising from the therapeutic setting in which medication is delivered. The effects of our new miracle drugs are truly second rate when compared to the brain’s complex ability to respond to an effectively delivered expectation of getting better.

Talking about the research conducted by Fabrizio Benedetti in Turin, Silberman says that the placebo effect is a neurological function and not a neurosis or aspect of personality as previously believed.

Now, after 15 years of experimentation, he (Benedetti) has succeeded in mapping many of the biochemical reactions responsible for the placebo effect, uncovering a broad repertoire of self-healing responses. Placebo-activated opioids, for example, not only relieve pain; they also modulate heart rate and respiration. The neurotransmitter dopamine, when released by placebo treatment, helps improve motor function in Parkinson’s patients. Mechanisms like these can elevate mood, sharpen cognitive ability, alleviate digestive disorders, relieve insomnia, and limit the secretion of stress-related hormones like insulin and cortisol.

While the method of recruitment of participants in clinical studies is also seen as a reason for the possibly unnecessary failure of many drug trials, one of the major reasons proposed for the increasing power of the placebo is advertising by drug companies themselves especially in the US where advertising directly to the public is allowed.

The secret of running an effective campaign, Saatchi & Saatchi’s Jim Joseph told a trade journal last year, is associating a particular brand-name medication with other aspects of life that promote peace of mind: “Is it time with your children? Is it a good book curled up on the couch? Is it your favorite television show? Is it a little purple pill that helps you get rid of acid reflux?” By evoking such uplifting associations, researchers say, the ads set up the kind of expectations that induce a formidable placebo response.

While the study of the placebo response is without doubt much more fascinating than the study of conventional drug effects, there is not much money in it, therefore Big Pharma is not going to invest in studying this enhanced placebo effect which Silberman calls the “elephant in the boardroom”.  In order to survive drug companies will have to develop techniques which beat this tendency for enhanced placebo effects.

Several heavy hitters in psychiatric research responded strongly to Angell’s claims. The problem is that their letters could only be found by a rather obscure link at the bottom of the NYRB article, meaning that many people would have missed these important rebuttals.

The author of one of the books reviewed by Angell, Daniel Carlat MD, weighs in with support for antidepressants.

But missing from her review is an unequivocal if perplexing truth about psychiatric drugs—on the whole, they work. Antipsychotics for schizophrenia, stimulants for ADHD, hypnotics for insomnia, benzodiazepines and SSRIs for anxiety disorders—in all these cases, drugs are robustly more effective than placebos in double-blind controlled trials.

Two other academics rebut one of the scarier propositions put forward by Angell and her reviewed authors regarding the alleged potential for psychiatric drugs to actually cause psychiatric illness:

What about the inflammatory claim that psychiatric drugs increase the rates of psychiatric disorders? If so, one would expect to see a steady increase in the prevalence of mental disorders in the population. But the epidemiologic evidence shows otherwise. As Ronald Kessler reported in The New England Journal of Medicine (June 16, 2005), data from the National Comorbidity Survey show that the prevalence of anxiety, mood, and substance disorders has been stable: it was 29.4 percent in 1991 and 30.5 percent in 2003.

Interestingly Angell does not dispute this point in her response to the rebuttals rather she indicates that the growth in numbers of people with bipolar and autism is a result of over diagnosis, which is a different thing altogether.

The two sides of the antidepressant debate are probably never going to occupy the same ground.  If antidepressants work for you then naturally you are going to turn to them as a first response if you are stricken by this horrible condition. If they don’t work for you then you will have to find other treatments such as mindfulness and behavioural techniques.  This is not to say that people who are responsive to antidepressants do not have to use other methods as well.  Depression, which is like being stuck in the mid Atlantic in a leaking boat being circled by white pointers, needs to have everything and anything available thrown at it.

Perhaps the last word in the debate should be provided by tormented poet and well known non-complying antidepressant drop-out Leonard Cohen who spoke about the spontaneous remission of his depression after some 50 years of anguish and anxiety.

“ There was just a certain sweetness to daily life that began asserting itself. I remember sitting in the corner of my kitchen, which has a window overlooking the street. I saw the sunlight that shines on the chrome fenders of the cars, and thought, “Gee, that’s pretty.”

‘I said to myself, “Wow, this must be like everybody feels.” Life became not easier but simpler. The backdrop of self-analysis I had lived with disappeared. It’s like that joke: “When you’re hitting your head against a brick wall, it feels good when it stops”.’

Yes. Bravo. Well said.  And that’s exactly how it feels when the antidepressants kick in.

The New York Review of Books Article

Peter Kramer’s Article in the New York Times

Steve Silberman’s Article in Wired

Maggie Maguire is a blogger who writes mainly on Tasmanian mental health issues.  A born curmudgeon, she takes an insider’s view of the little known workings of the Tasmanian mental health system and the Tasmanian social welfare system in general.  Her main hope is that she can engender some understanding and respect, if not awe, for the singular and different minds that comprise the community of people with mental health issues.