Name:

D B Double

Organisation:

Critical Psychiatry Network

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General

We cannot see that we have had a response from the first consultation to what we saw as our main point about the reliance on response rate as a measure of outcome - also on severity. These points are repeated below at 7.7.3. The section in your response was blank - deliberate or error?

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2.6.3

"The treatment of depression is a clear example of this (Kirsch et al, 2002). Drug, and some other, treatments for depression, when compared to wait list controls in the treatment of mild to moderate depression, all produce a substantial and roughly equal fall in depressive symptoms. But, when antidepressants are compared to placebo for this diagnostic group, the clinical
improvements resulting from antidepressants over and above that for placebo is not clinically significant (Kirsch et al, 2002) (our emphasis)."
The problem here is the characterisation of the patients as mild to moderate. Kirsch et al. (2002) wrote that "all but one of the clinical trials were conducted on patients described as moderately to severely depressed (their mean baseline Hamilton Depression Scale [HAM-D] scores ranged from 21.0 to 29.7). One of the trials was conducted on patients with mild depression (mean baseline HAM-D score = 17.21).

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6.11.1.5

This is new to the 2nd draft and seems an unfortunate change given the data.

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7.7.1

"The placebo response may also be short-lived, with more patients on placebo relapsing compared to those on antidepressants (Ross et al, 2002). Longer trials are required to be able to fully elucidate the contributions of placebo and the treatment to clinical response."
This leaves out the clinical trial comparing hypericum, sertraline, and placebo, which showed that 0% relapse among patients who showed a response to placebo and were continued on placebo for an additional 18 weeks (beyond the initial 8 week evaluation period).

Also, the Elkin et al NIMH trial¹ showed the opposite - that people on antidepressants did worse long-term than people on placebo. Also this is certainly one area where you cannot equate being on placebo with no treatment. There is some naturalistic evidence (most recently a paper on getting back to work showing that people who do not take ADs get back to work faster)² that people on ADs do worse than people who don't take them - even controlling for severity.³

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7.7.3

Perhaps the most serious problem is the reliance on treatment response (a 50% reduction in symptoms) as a primary measure of outcome. Response rates are misleading, especially when the criterion for response is close to the mean improvement rate (as it generally is) (Kirsch, in press)⁴. The main point is that a seemingly large difference in response rates (e.g., 50% versus 35%) can be entirely due to clinically insignificant differences between drug and placebo responses (e.g., one point the Hamilton depression scale). To quote from Kirsch (2003):

If improvement is normally distributed and the mean difference in improvement is 1 point, then there will be many patients (e.g., 15-20%) for whom the one point advantage will push them into the responder category (i.e. give them a 50% reduction in symptoms instead of a 46% reduction in symptoms), despite the fact that the difference is not clinically significant. For this reason, differences based on percentage of patients responding are misleading, and 15-20% differences should not be labelled clinically significant.

This being the case, the difference between mean change scores (drug versus placebo) remains the most reliable method of assessing the clinical significance of drug effects. At the very least, this problem with response rates ought to be noted in the report.

The other issue is severity. See comment on 7.7.1 - it may be well be misleading to rely on a few studies, mostly with outpatients, that have shown that the difference in response to antidepressants and placebo is greatest in people who have the most severe depression. Studies of people in hospital find smaller differences between antidepressants and placebo than do the outpatient studies.⁵ Indeed one study of inpatients showed that response to antidepressants was greatest in the least severely ill.⁶ The prognosis for hospital treated depression is also very poor, with studies finding that more than half of adults and an even higher proportion of older people have not recovered several years later.

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8.2.10.2

We are still not convinced that this adequately represents the evidence about suicidality and SSRIs, particularly in view of the debacle over the use of antidepressants in children.