Tuesday, 23 September 2008

Yet more antidepressants

Thanks to paul in the comments below here's a link to the Maudsley debate on antidepressant efficacy, 'This House Believes Antidepressants are no Better than Placebo', featuring Irving Kirsch, Joanna Moncrief (for), Guy Goodwin, and Lewis Wolpert (against).

Interestingly Kirsch turns the question around to argue that there is no evidence that antidepressants are clinically significantly better than placebo (as you may be aware, I've addressed the Kirsch et al PLoS paper before).

Both Kirsch and Moncrief make some good points, but I was struck by Moncrief's claim that because we don't know that antidepressants act specifically against 'the' biological cause of depression, and in fact may have rather more non-specific effects that help to ameliorate the symptoms of depression, we therefore should not use them.* She goes on to argue a completely contradictory point at the end of her speech to claim that because antidepressants are (according to her) no better than placebo they are therefore harmful because they are not inert. Yet her argument that antidepressants are not superior to placebo hinges on the claim that their apparent superority hinges on their active side effects in clinical trials.

Goodwin and Wolpert make some fairly pedestrian counterarguments, some fallacious, largely anecdotal in Wolpert's case. The comments from the floor included some 'service users' ranting and anti-psychiatry, which is quite common at psychiatric talks.

* I've long been drawn to the idea (can't remember who first proposed it) that serotonergic antidepressants flatten emotional responses and noradrenergic antidepressants are activating. But both these effects would seem to me to be very useful in helping to relieve symptoms of depression and facilitate true recovery. Comments from the floor point out that in the rest of medicine we don't abandon treatments proven to work in clinical trials because we don't know their mechanism of action. In fact, it is pretty hard to see what Moncrief would advocate to treat depression instead of antidepressants, surely we can't know that physical exercise or CBT are definitely treating the underlying physical abnormality?


Woobegone said...

I need to listen to this, clearly! when I get back from holiday...

Re: the serotonin is flattening and noradrenaline is activating idea, David Healy believes something similar (maybe he is your source). He´s an author on a blinded trial of citalopram and reboxetine in healthy volunteers which gives some support to this idea. (I don´t have a reference sorry, due to being on holiday, but it´s a great study. I wonder what Healy would have to say to Moncrieff - now that would be a debate.)

anecdotally, though, I have to say that it didn´t work that way for me. when I started on citalopram I felt almost hypomanic for a few days. That effect subsided but even a few months later I certainly have more energy and drive than before starting - of course its hard to distinguish what is a "drug effect" from what is a "recovery from depression" effect, but I would certainly call citalopram "activating" at least as much as "flattening" in my case.

pj said...

Well of course SSRIs are supposed to cause agitation, which is a rather more 'activating' sounding effect than it is an 'emotional flattening' kind of thing. And as you intimate, SSRIs are supposed to be a risk for sending people with bipolar manic, which is more consistent with the traditional view of SSRIs as mood enhancers.

I don't think it was Healy, cos I think I'd have remembered it was him, I first read the theory in some obscure article from a prize article from someone relatively junior, but I don't think the idea originated there.

Anonymous said...

Well, either in the Healy article I mentioned or in some Moncrieff paper (I forget), there is a discussion of the fact that in the early days (1970s), noradrenergic drugs were seen as basically stimulants, whereas 5HT drugs were thought to have some kind of mysterious other psychoactive effect which was nevertheless useful in depression - at the time noone was very clear on what this effect was, and I´m not sure when people started to refer to it as ¨flattening¨.

So I don´t think Healy actually invented the idea, but he has certainly been a major proponent of it. I think he might even have been said to have revived it for the Prozac era? Maybe.

Re: flattening, intuitively yes, one would think that SSRIs would be anti-manic if they really were flattening. I would certainly never in a million years say that citalopram has flattened any of my positive emotions - negative ones yes, but that´s the whole point of an antidepressant, surely?

to continue this theme, the much-discussed side effects of SSRIs have been very mild in my case and those that have occured have done nothing to really reduce my quality of life. I´m increasingly thinking that public fear of the terrible side effects of antidepressants, like scepticism about efficacy, is basically media-driven Bad Science. Then again, I´m not a clinician.

pj said...

I don't know, many people seem to really hate the sexual side effects (anorgasmia etc) - and patients are generally not told about them.

Woobegone said...

that would be nasty if it was severe and unwanted I suppose. although of course some people take SSRIs specifically because they want to delay orgasm, so it can´t be all bad...

anyway enough about that - have you seen this?


Swedish drug authorities respond to Kirsch. Unfortunately they use the "response rate" outcome measure which Kirsch has (in my opinion) rightly criticized years ago.

pj said...

I'm not sure about the failings of response rate. My understanding of Kirsch's criticism is that it is possible that response rate could magnify differences that are actually very small mean score differences. This suggests you ought to look at mean differences as well.

The converse criticism applies to using mean differences, Kirsch et al criticise the small improvements in mean HAM-D score and say that this represents very small symptomatic improvement, but it is possible that this masks very large improvements in some proportion of responders, with minimal improvement in non-responders, suggesting that response rate should be used as well.

In pain studies, which I know a little about, it is often argued that response rate is superior to mean difference for just this reason, we are more interested in getting a good outcome for some proportion of people than knowing that there is a small improvement across the board that may or may not represent clinically significant improvement for individuals.

Woobegone said...

You´re right that simple mean HAMD difference is uninformative and Kirsch puts too far much stock in it. But I´m convinced by his argument that since placebo group HAMD change is often very close to being enough to count as a "response", a small drug effect probably does often lead to a large-ish response rate.

Actually though my main objection to response rates (like my objection to the NICE d=0.5 criterion) is that they´re arbitrary. Why 50% change from baseline, why not 75% or whatever? I guess you have to make up arbitrary cutoffs for research purposes maybe but does it translate to the clinic?

Robert said...
This comment has been removed by a blog administrator.
pj said...

Ah, cheers, been being a bad boy and not checking my email.

Robert said...

hey PJ this guy jxxxx.xxxxxr@googlemail.com is trying to contact you. Please please send him an e-mail.

Robert said...

good move on suppressing the e-mail though (I realized I had been a bad boy).

Oddly I know a prozac user who is sure that it has a leveling effect. Didn't know there was more than one proponent of the view.

Allen Esterson said...

>In fact, it is pretty hard to see what Moncrieff would advocate to treat depression instead of antidepressants...<

Certainly nothing that could be classed under the heading "Psychiatric Imperialism":

Her views on the growth of psychiatry are a caricature of the history of the subject:

"The institution of psychiatry grew up in the 19th century during the emergence and consolidation of industrial capitalism. Its function was to deal with abnormal and bizarre behaviour which, without breaking the law, did not comply with the demands of the new social and economic order. Its association with medicine concealed this political function of social control by endowing it with the objectivity and neutrality of science. [...]
"The medical model of mental illness has facilitated the move towards greater restriction by cloaking it under the mantle of treatment... It enables a society that professes liberal values and individualism to impose and reinforce conformity. It disguises the economics of a system in which human labour is valued only for the profit it can generate, marginalising all those who are not fit or not willing to be so exploited."