Depression, Homeopathy and Prozac

It hasn’t taken Tory MP David Tredinnick long to start spitting out dubious EDM’s in defence of homeopathy.

The new parliament is only a little over a month old and he’s already tabled four such motions, including a generic attack on the British Medical Association and three EDMs flagging up  newly published research which purports to demonstrate that homeopathy may provide viable treatments for breast cancer, insomnia and clinical depression.

Thankfully, this particular cloud is already showing signs of having a number of silver linings. The breast cancer study cited by Tredinnick in EDM 285 was roundly dismantled by science bloggers several months ago and series of amendments to Tredinnick’s EDMs (284A1, 285A1, 286A1, 287A1) tabled by the newly elected Lib Dem MP for Cambridge, Julian Huppert, suggests that we have a new champion of scientific reason and rationality ready to step into the breach left by the defeat of Dr Evan Harris at the general election.

(Huppert, according to his Wikipedia entry, has a PhD in Biological Chemisty and experience as a research scientist working on studies of the structure of DNA)

Tredinnick’s overall strategy here is neatly summarised by Tessera in a recent post at The Lay Scientist:

Tredinnick is using the now familiar mantra of “the jury is still out” and “we need more research”. Yet again, this mythical jury hasn’t reached a decision because homeopaths haven’t got the result they want. After 200 plus trials, homeopathy has still not been proven to be better than placebo. That’s like a criminal being found guilty 200 times and continuing to appeal.

There are two mutually incompatible approaches here. Scientists and their supporters are patiently quoting evidence and scientific methodology. Homeopaths and their supporters are using the tactics of a small child trying to wear its parents down. Tredinnick’s debate will follow the well-worn path of scientists presenting the evidence and his side saying ‘Yes, but…’.

No matter how many studies show that homeopathy doesn’t work, its proponents will never give up. It’s a fine example of cognitive dissonance. In other words, when they are presented with evidence that contradicts their beliefs, they put their fingers in their ears and go la la la la la.

In short, a classic example of a zombie argument and one very much in evidence when we come to the other paper cited by Tredinnick in EDM 286:

HOMEOPATHIC MEDICINES IN THE TREATMENT OF MODERATE TO SEVERE DEPRESSION (21.06.2010) Tredinnick, David

That this House welcomes the double-blind study conducted at the outpatient clinic at Jundiai Medical School in São Paulo, Brazil, which consisted of patients with moderate to severe depression; notes that patients were randomly assigned to a double-blind treatment with individualised homeopathic Q-potencies or fluoxetine (Prozac); further notes that the non-inferiority analysis indicated that the homeopathic Q-potencies were not inferior as compared to fluoxetine in treatment of this sample; observes that the study is the first randomised controlled double-blind trial with a reasonable number of subjects to draw conclusions about the homeopathic treatment of depression; acknowledges that homeopathy is recognised as a medical specialty in Brazi; and calls on the Government to carry out further research into this area.

The paper to which Tredinnick refers here is snappily titled ‘Homeopathic Individualized Q-potencies versus Fluoxetine for
Moderate to Severe Depression: Double-blind, Randomized Non-inferiority Trial’ by Adler et al and was published last year (2009) in the journal ‘Evidence-based Complementary and Alternative Medicine‘ – and to make life easier, I’ve uploaded a copy of the full paper to the Ministry, which you can download from this link (pdf).

What we have here is a small but seemingly well constructed and methodologically sound double-blind RCT of homeopathy as a treatment for moderate to severe depression which uses Prozac (Fluoxitine) as an active control with the ‘double-dummy’ method used to blind both the participants and researchers; one that does appear to indicate that homeopathy is broadly comparable, in performance, to SSRI anti-depressants in patients with moderate to severe depression with response and remission rates in the same range as those associated with Prozac (60-70%).

The paper even openly acknowledges its most significant limitation:

A placebo-arm was not included in the present study because it was not authorized by the National Ethic Council. Although placebo interventions are associated with mean response or remission rates of 35%, a placebo effect cannot be ruled out, since the homeopathic Q-potencies were compared with an antidepressant and ‘it is becoming more and more difficult to prove that antidepressants—even well-established antidepressants— actually work better than placebo in clinical trials’ . Nevertheless, it also has to be taken into consideration that the antidepressant-placebo difference seems to be smaller in the trials aiming at mild to moderate depression and the present sample consisted of patients suffering from moderate to severe depression. Placebo-controlled studies would be recommendable to clarify these findings.

On the basis of this piece of research, homeopathy can be considered to be an effective treatment for moderate to severe depression if – and only if – it can be established that SSRI antidepressants are also an effective treatment, an assertion that very much open to question in light of recent research such as that published by Kirsch et al (2008), a large scale meta-analysis of trial data submitted to the US Food and Drug Administration (FDA) that arrived at the following conclusion:

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Nevertheless, the paper goes on to assert that:

This study, in spite of its limitations, illustrates the feasibility of randomized controlled double-blind trials of homeopathy for depression and indicates the noninferiority of individualized homeopathic Q-potencies as compared to fluoxetine in the acute treatment of outpatients with moderate to severe depression.

There are, however, two significant problems with this assertion.

First, the paper contains an error, which is to be found in this paragraph:

This sample consisted of patients with moderate to severe depression, because their mean MADRS depression scores were close to the 31 score cut-off for moderate and severe depression (28).

The reference here – (28) – refers to a paper by Muller et al (2003) which addressed an important flaw in the MADRS scale, a lack of gradation/separation on the scale between moderate and severe depression. The abstract of this paper explains the significance of the 31 score cut-off as follows:

Empirically based MADRS cut-off scores to separate moderate from severe depression on the basis of HAMD(17) and CGI severity ratings in patients with major depression were yielded.

A score of 31 on the MADRS scale is, therefore, the boundary point that differentiates between moderate and severe depression, not the cut-off for moderate and severe depression.

In the study, the mean MADRS score for the two treatment groups were 28.09 +/- 6.88 (Prozac) and 27.21 +/- 6.22. Although both treatment groups included patients with severe depression (MADRS > 31), the mean MADRS scores for both groups fall some way below the cut-off and, importantly, below the equivalent level on the Hamilton Scale at which clinically significant outcomes were identified by Kirsch et al. This put the results of the study well within the range identified by Kirsch et al and being indicative of placebo effects.

The second problem stems from the authors efforts to downplay, if not avoid, the obvious alternative conclusion of this paper – that it lends weight the view that the observed performance of SSRI antidepressants in patients with moderate depression is primarily accounted for by a placebo effect:

A recent meta-analysis of homeopathic trials concluded that the results were ‘compatible with the notion that clinical effects of homeopathy are placebo effects’ (43). However, as demonstrated by Ludtke et al., this conclusion was based on an arbitrarily chosen subset of eight trials, out of 21 high-quality trials and the results favor 6 of 8 Homeopathic Individualized Q-potencies homeopathy, if another threshold to define a ‘large trial’ is used (44). Moreover, the homeopathic interventions were grouped in classical, clinical, complex or isopathy, without any further reference to the specific homeopathic clinical or pharmaceutical methodology used in each one of these groups. Defining the homeopathic methodology being analyzed would have been essential to avoid biased or generalized conclusions.

The problem with relying on Ludtke et al and other similar critiques are dealt with in some detail by Paul Wilson (Hawk/Handsaw) but, for brevity’s sake, this description of the response Paul recieved after commenting on the paper by Rutten and Stolper should give a reasonable idea of what to expect:

Meanwhile, the reply by original authors Rutten and Stolper is an exercise in evasion and obfuscation, and doesn’t really address most of the points that I made. This seems to be fairly typical (and to be fair isn’t only restricted to non-science like homeopathy). In their original paper, Rutten and Stolper claimed that “Cut-off values for sample size [i.e. the number of subjects in a trial, above which the trial was defined as “large”] were not mentioned or explained in Shang el al’s [sic] analysis”. This is simply not true. So what do Rutten and Stolper have to say about this embarrassing error?

Despite producing a paper that is, for the most, well above the usual poor standards of homeopathic reseach, when it comes to the crunch, the authors revert back to the same old zombie argument that the gold standard research methods used in trialling mainstream drug treatments are somehow ill-suited to evaluating the effectiveness of homeopathy. This, it cannot be stressed enough, is pure hogwash.

Far from lending credibility to claims made by homeopaths, this paper merely raises further question about the efficacy of SSRI antidepressants and its in the latter direction that research efforts need to be directed, not towards homeopathy which, as Dara O’Briain correct notes, is nothing more than ‘fucking water’.