The Academic-Medical Establishment

I was at a talk recently regarding the side-effects of a widely used drug, let us call it 'fictoxetine'. Now fictoxetine has long been thought to cause damage to the body, let us say the retina, leading to progressive visual loss and eventually blindness. Fictoxetine can be used for years, even decades, and so patients need to have their vision screened regularly. This talk reported their findings from a systematic review and meta-analysis that sought to find out whether the evidence actually supported this fear.

What they presented was data showing that over 1-2yrs of fictoxetine use visual acuity declined by around 10%. They also reported evidence that found that rates of fictoxetine use in people on a register of blind people were around twice those in the general population. They then concluded from this that fictoxetine doesn't really have as much of a major effect on vision as we had thought so we shouldn't be so worried about it and pontificated on how this myth had become so widespread in the medical community.

The majority of people at that talk took this message at face value and went away with that in their heads, maybe they will change their clinical practice - after all a respected academic in the field of fictoxetine research presented the evidence that showed fictoxetine doesn't have much effect on vision. Didn't he?

Well no, he didn't, the data I've just described is consistent with fictoxetine having really quite a large and serious effect on vision. If the short-term deficits of 10% in acuity over 1-2yrs continued over 10 years that would be a major loss of 40% of visual acuity. The blind register data is neither here nor there, most people would stop fictoxetine in patients with significant visual loss in the hope that they would never reach complete blindness (conversely, maybe they would be more happy to start it in people who were already completely blind than those with some vision).  So the data doesn't support the narrative being given to it but few people feel qualified or confident to gainsay a big name in the field.

And this is true throughout academic medicine, and academia in general, powerful personalities are able to shape the discourse in a scientific field not only through the research they perform but also the wider influence their ideas and opinions carry.

Diversifying the skill mix: or paying peanuts and getting monkeys

This is what Alan Maynard, economist, and influence behind much government thinking on the NHS, thinks is the way forward:

"...can patient care be maintained with fewer staff or changes in skill mix?...Expensive GPs replaced by nurse practitioners, for example? Double GP list sizes and reduce the demand for such physicians by half? Expensive registered nurses could be replaced by assistant practitioners. Evidence suggests skill mix changes such as these could be cost effective. However, the potential for skill mix is limited by the power of the craft guilds, especially the royal colleges."*

That's right, the future of the NHS should be half as many GPs (so there would be half as many appointments available), or replacing GPs with nurses, and replacing nurses with kids off the street. Sounds like a recipe for success.

Funnily enough there have been some papers looking at this, by one A Maynard, doesn't look like overwhelming evidence for his plans:

"Twenty-two large studies...strongly suggest that higher nurse staffing and richer skill mix (especially of registered nurses) are associated with improved patient outcomes"

"An extensive review of published studies where doctors were replaced by other health professions demonstrates considerable scope for alterations in skill mix. However, the studies reported are often dated and have design deficiencies. In health services world-wide there is a policy focus which emphasises the substitution of nurses in particular for doctors. However, this substitution may not be real and increased roles for non-physician personnel may result in service development/enhancement rather than labour substitution. Further study of skill mix changes and whether non-physician personnel are being used as substitutes or complements for doctors is required urgently." 

I must say, my experience of physician's assistants in the US and nurse practitioners in the UK to replace doctors and care assistants to replace ward nurses doesn't incline me to feel positive about the future. Currently the NHS doesn't have enough doctors delivering front line services or enough nurses delivering care on the wards. Diversifying the skill mix is just another way of saying that the magic of 'progress' and 'reform' will make up for cutting front line staff. It won't, no matter how many economists sit on their arses pontificating about how successfully managing minor self limiting ailments means that GP receptionists or your Granny can replace consultant oncologists. And who, at the end of the day, will take the brunt of these cuts, who will be ultimately responsible for what these people do? The handful of properly qualified people who are left, with their professional membership at stake and big lawsuits waiting for them as they desperately try and supervise a million under-qualified drones with no professional stake or commitment to their patient's care.

As a doctor I've spent enough of my life running around after 9-5 nurse practitioners, phlebotomists, ward clerks or whoever** doing the stuff they won't do because they can just wash their hands of it when 5 o'clock (or more likely 3pm) comes around.


* Worth bearing in mind when you hear him talking in the news recently about consultants:

"They don't always keep to their job plans and then get to do the overtime. I think there needs to be much more transparency about consultants' pay.
"The public are just not aware of the sums they can earn. If the data was published it would put pressure on them and reduce some of the figures we are seeing."

Interesting from a man making nearly £50k per year for 12 years from the NHS for chairing the board of the York NHS Hospitals Trust.


** Incidentally, one of the reasons that nurse practitioners are cheaper than junior doctors (a band 6 nurse like a nurse practitioner gets £25,472-34,189; a junior doctor's pay starts at 23,533 and goes up to 31,523 before specialist registrar level; healthcare assistants get £13,653-21,798; band 5 front line nurses get £21,176-27,534)- is that they only work 9-5, so out of hours the ever decreasing number of junior doctors has to cover the stuff the nurse does during the day but with a concomitant reduction in overall numbers to cover the out-of-hours rota and no chance to practice under the supervision of superiors whatever it is the nurse does. Medicine is now no longer 'see one, do one, teach one', it's 'read about one, do one'. That's why people die so much more at night.

Popular political science

Interesting piece of popular political science on PoliticalBetting.com:

A new measure by researchers at the University of Manchester shows a significant problem for Gordon Brown: the mood of the country is against Labour on policy competence.
Green and Jennings argue that it is important to study the public mood across a large number of issues: public ratings of party policy competences move together.
This graph shows the authors’ measure, “macro-competence” over six incumbent governments, annually, from 1950 to 2010 (the final data point is February 2010 – the most recently available).

Newtongate

Brilliant:

If you own any shares in companies that produce reflecting telescopes, use differential and integral calculus, or rely on the laws of motion, I should start dumping them NOW. The conspiracy behind the calculus myth has been suddenly, brutally and quite deliciously exposed after volumes of Newton’s private correspondence were compiled and published.

Are glutamatergic drugs the future for the treatment of schizophrenia?

Just found this on my PC, I wrote it some time ago, before the latest news on the failure of the LY2140023 trial was known (I altered it a little around the time to reflect this). I started it with the intention of doing an updated meta-analysis of glutamatergic drugs in schizophrenia but it became apparent that the quality of the data was so low that I wasn't going to be able to carry out any sensible analysis. I wrote the following as a summary of what I'd wasted my time doing, it isn't really publishable quality but I thought people might be interested if psychiatry is their area (I could have put it on a pre-print server like Nature Precedings but they don't like clinical treatment data).

Abstract

There is growing evidence for the role of glutamate in the aetiology of schizophrenia and a number of glutamatergic drugs are being developed and trialled. This systematic review finds that there is evidence for beneficial effects on symptoms in schizophrenia for both adjuvant NMDA glycine binding-site agonists and monotherapy with a type II metabotropic glutamate receptor agonist (LY2140023). LY2140023 represents the first successful placebo controlled clinical trial of non-dopamine based antipsychotic therapy for schizophrenia but the evidence for its greater efficacy over glycine binding-site agonists is tentative at best. It is unclear why the apparently antagonistic effects of post-synaptic NMDA co-agonism and reduced glutamate release via pre-synaptic inhibition from type II metabotropic agonism both appear to have beneficial effects on schizophrenic symptoms, nor why the latter is so much more successful than direct NMDA antagonism. Ongoing trials should help to clarify the promising results found to date.

Introduction

All existing antipsychotics work via the dopamine D2 receptor (1) but this class of medication has several important limitations. Although effective at treating ‘positive’ symptoms of schizophrenia (such as hallucinations and delusions) antipsychotics have limited impact on ‘negative’ symptoms (such as emotional blunting) or cognitive deficits, and it is these that are thought to have most relevance for prognosis (2). Side-effects are significant and range from considerable weight gain and hyperprolactinaemia to movement disorders such as extra-pyramidal effects and tardive dyskinesia. Although clozapine, and the atypical antipsychotics have been considered superior to typical antipsychotics any advantages appear to be fairly marginal (3).

While pathophysiological investigations of schizophrenia have traditionally concentrated on the dopaminergic system (4, 5) there is increasing evidence from gene association and neuropathological studies for an involvement of the glutamatergic system (6). For some time there have been hopes that medications which interact with the glutamatergic system may be able to ameliorate some of the negative and cognitive deficits of schizophrenia. In this review I appraise the current clinical evidence in a narrative systematic review of double blind randomised controlled clinical trials of adjuvant or monotherapy with glutamatergic drugs in schizophrenia.

Methods

Glutamatergic drugs were defined as those primarily acting via glutamate receptors or the glutamatergic system (e.g. re-uptake inhibition). Medline was searched via PubMed using the ‘broad’ and ‘therapy’ clinical study filters and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched up to January 2009. Search terms were ‘schizophrenia’ AND either ‘glutamate*’ or the names of specific glutamatergic compounds discussed below (glycine, d-cycloserine etc.). Unpublished trials from the CENTRAL database were not included in the results because no data was available, this may produce a degree of publication bias in the studies considered. Following from previous reviews I concentrate on overall symptoms as determined by the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS), negative symptoms as determined by the PANSS negative subscale or the Scale for the Assessment of Negative Symptoms (SANS), and positive, cognitive, and general symptoms from the relevant PANSS subscales.

Results

Searches produced 522 records from Medline and 102 records from CENTRAL with 18 trials previously covered by a Cochrane review and a further 18 new studies identified. Trials were generally of good quality although small in size and of short duration. Reporting of blinding methods was poor, and outcome measures and statistical methodology were well validated but varied between trials making comparisons difficult. The initial goal to perform a meta-analysis using the additional data from newly identified studies was abandoned due to the difficulty in extracting usable data. All trials mentioned in this review are placebo controlled unless stated otherwise.

Glutamatergic stimulation

One model for pathology in schizophrenia is a hypoglutamatergic state or N-methyl-d-aspartate (NMDA) receptor dysfunction. Consistent with this proposal blockade of the NMDA receptor with phencyclidine or ketamine produces a psychotic syndrome similar to schizophrenia, including negative and cognitive symptoms. In pre-clinical trials, the use of co-agonists at the glycine binding-site of the NMDA receptor has been shown to modify some of the effects of NMDA antagonism (7).

The genes G72 and d-amino acid oxidase (DAAO) have been implicated in the genetics of schizophrenia (8) and are involved directly in neurotransmission at the NMDA receptor glycine binding-site, with DAAO metabolising the endogenous agonist d-serine.

These findings suggest that glycine binding-site agonists may potentially act to facilitate NMDA neurotransmission and correct underlying glutamate hypofunction in schizophrenia.

Adjuvant therapy

There have been a number of reports that augmentation of antipsychotics with agonists at the glycine binding-site preferentially improve negative and cognitive symptoms (7). A Cochrane Review has looked at the endogenous agonists glycine and d-serine and the partial agonist d-cycloserine as adjuvant therapy in schizophrenia (9). From data published up to 2003 they found 18 double blind randomised controlled trials, all short (≤12 weeks) with small numbers (358 subjects randomised in total).

d-cycloserine appeared to be ineffective on all measures, with trends towards harm compared to placebo. Glycine and d-serine were effective on some global measures and symptom scores. These comparisons all involved few patients (<150)>

Three further adjuvant studies of daily d-cycloserine have since been published and none of these found a beneficial effect on symptoms confirming the negative findings from the Cochrane review (10-12). However, an 8-week study of once weekly d-cycloserine adjuvant therapy in 38 patients found a statistically significant effect on mean negative scores but not 20% improvement rates or mean positive or cognitive scores (13).

Several studies of full glycine binding-site agonists have also been published since the Cochrane review. A 16-week trial, with 104 patients in the glycine and placebo groups combined, looking at adjunctive glycine found no difference from placebo for mean difference or 20% improvement in negative symptom scores, or for mean differences in cognitive or positive symptom scores (12). Conversely, a cross-over study of 17 patients using high dose glycine added to atypical antipsychotics resulted in a significant decrease in mean negative, cognitive, and positive symptom scores at 6-weeks. There was not a significant increase in 20% improvement rates for overall symptoms but there was for negative symptoms (14).

Similarly, in a cross-over study of 39 patients with adjuvant d-serine and atypical antipsychotics there was a significant decrease in mean negative, cognitive, and positive symptom scores, and also extra-pyramidal side-effects at 6-weeks, with 20% improvement rates significant for overall symptoms and negative symptoms (15). However, in a trial of d-serine added to risperidone, with 44 patients with acute exacerbations of schizophrenia in the d-serine and placebo groups combined, there was no statistically significant mean difference in overall or negative symptom scores at 6-weeks (16). Another small cross-over trial of 12 patients on clozapine also found no difference in mean overall, negative, positive, or general scores at 12-weeks (17).

Finally, d-alanine, another glycine binding-site agonist, has been tested as a adjuvant therapy in a 6-week study of 32 patients which found a significant benefit in mean scores on overall, negative, positive, and cognitive symptom scales (18).

The Cochrane review and later studies suggests that the partial agonist d-cycloserine is ineffective as adjuvant treatment in schizophrenia but the balance of evidence is still equivocal for the full glycine binding-site agonists. A reasonable estimate of the NNT for a 20% improvement in symptoms would be of the order of five patients but there is an obvious need for better and more consistent reporting to facilitate comparisons between trials and meta-analysis, particularly for cross-over trials. From the evidence these drugs appear to be well tolerated but they are not very practical to use, requiring fairly high doses diluted in liquid. Most trials have been fairly short, except for one 6 month trial of d-cycloserine, so estimates of long-term efficacy and tolerability are needed.

An alternative method of promoting agonist activity at the glycine binding site is the use of glycine re-uptake inhibitors. The glycine transporter-1 inhibitor N-methyl-glycine (sarcosine) has been examined in three studies. A 6-week trial of sarcosine with 38 patients showed benefits on mean differences in overall, negative, positive, cognitive, and general symptoms. These results were dependent on the analysis method, but mean differences at 6 weeks appear robust for overall and general symptoms (19).

Another 6-week study of sarcosine added to risperidone in acute exacerbations of schizophrenia, with 44 patients in the sarcosine and placebo arms combined, found significant changes in mean overall, negative, cognitive, and general symptom scales (although these depended on the analysis method used), with a significant difference in the rates of clinical response (defined as a 30% reduction in overall symptoms) (16). However, in a 6-week study of sarcosine added to clozapine with 20 patients there was no significant effect on mean difference in overall, negative, positive, cognitive, or general symptom scales (20). Pooling 6-week mean differences from all three studies will not result in significant effects because the statistical differences in the original studies largely depends on using regression to control for baseline imbalance in severity.

There has been some suggestion that use of glycine agonists with clozapine results in lower efficacy, perhaps because clozapine already has some glutamatergic activity. The Cochrane review found no evidence of differential efficacy of these drugs when used with typical or atypical antipsychotics, or with clozapine, and later studies have not provided any strong evidence to contradict this finding.

The compound CX516 is an ‘AMPAkine’ and allosterically binds to the ionotropic α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor prolonging channel opening. It has been studied as an adjuvant therapy in schizophrenia with no significant benefit found in mean overall, negative, positive, cognitive, or general symptom scales (21, 22). A tiny trial of eight patients also failed to find evidence of benefit for CX516 as monotherapy (23).

Monotherapy

Recently a small trial of 20 patients was published looking at 6-weeks of sarcosine monotherapy for acute exacerbation of schizophrenia. This was not placebo controlled but rather compared high and low doses of sarcosine. There were no significant benefits of a higher dose on mean overall, negative, positive, or general symptom scales, but on the dichotomous outcome of 20% improvement in overall symptom score there was a significant benefit over the lower dose, and this was found in those subjects who were antipsychotic naïve (24). Although the dichotomous data suggests a NNT under three patients, in the absence of a change in mean symptom scores it seems unlikely that this finding reflects a true clinical benefit.

Glutamatergic inhibition

In contrast to the above proposition that glutamate hypofunction contributes to the symptomatology of schizophrenia, there has been some suggestion that glutamate hyperfunction may also play a role. Although superficially contradictory there is evidence that NMDA receptor hypofunction preferentially affects inhibitory interneurons causing disinhibition of pyramidal cells and increased glutamate release in prefrontal cortex (25).

Adjuvant therapy

Given the known effects of NMDA receptor antagonists such as phencyclidine in producing psychotic symptoms there has been little focus on these drugs as therapy. However, memantine is an NMDA antagonist used for the treatment of the cognitive symptoms of Alzheimer’s disease and has been investigated in an 8-week clinical trial of 138 patients as an adjunct to atypical antipsychotics. This study found no significant effect of memantine on global scores, or on overall, positive, negative, or cognitive symptom scales (26). There was also no significant difference in response rates (10% reduction in overall symptom score) but an increased rate of adverse events, including 6% of patients experiencing auditory hallucinations. Another study published only in abstract form has also found no effect of adjunctive memantine on cognitive measures (27).

Monotherapy

In 2007 a glutamate agonist trial was published that caused some considerable interest. This was a 4-week trial of 196 patients with poorly controlled chronic schizophrenia given the compound LY2140023 (versus olanzapine or placebo) (28). LY2140023 is metabolised to LY404039, a selective agonist at metabotropic mGluR2/3 glutamate receptors. The gene for mGluR3 has previously been associated with schizophrenia (6). As an agonist at type II metabotropic autoreceptors LY2140023 would be expected to antagonise rather than potentiate glutamate transmission, a mechanism that contrasts with the NMDA glycine binding-site agonists. However, LY2140023 has been shown to ameliorate the effects of NMDA antagonists in pre-clinical studies. Significant reductions were seen in mean overall, negative, and positive symptom scores for both LY2140023 and olanzapine, but LY2140023 did not show the weight gain associated with olanzapine. The reduction in symptom scores was greater for olanzapine than LY2140023, particularly with positive symptoms, but this difference was not statistically significant. With the dichotomous outcome of improvement (25% reduction) in overall symptoms there was a significant benefit to both LY2140023 and olanzapine compared to placebo suggesting a NNT of less than three patients for olanzapine and around 3.5 for LY2140023.

It is worth noting that while commentators have been quick to hail the advent of a new antipsychotic agent without the extra-pyramidal side-effects of dopamine blockade this study did not find any evidence for a difference using a variety of rating scales for these side-effects, although there was a significant difference in prolactin levels between the two drug groups. A substantial number of patients dropped out of the study (40%, primarily due to lack of efficacy), significantly more in the placebo group although the LY2140023 group also had more dropouts than the olanzapine group.

Discussion

The study of LY2140023 represents the first successful placebo controlled clinical trial of non-dopamine based antipsychotic therapy for schizophrenia* and the results suggest that this and similar compounds represent a promising avenue for developing antipsychotics with a different side-effect profile to that of current medication and the potential for efficacy in patients resistant to current treatments. This study does not establish that LY2140023 is better than olanzapine for negative symptoms, an early hope for these compounds, nor that it has a lower incidence of extra-pyramidal symptoms (since there were few of these in this short study) although prolactin levels were lower and weight gain less. There is an outstanding issue regarding the optimum dosing regime with LY2140023 and it is possible that higher doses could result in a greater antipsychotic effect and more marked effect on negative symptoms. A dosing study has just been completed but the manufacturers have recently announced that this failed to show a benefit of LY2140023 over placebo with no dose response effect – this failure has been ascribed to the large placebo response in the trial and further studies are awaited with interest.

It is worth comparing the NNT in the 2007 LY2140023 study with the evidence from glycine binding-site agonists as adjuvant treatment. The Cochrane review found a NNT for 20% reduction in symptoms of three patients (including evidence from later studies a more reasonable estimate would be five) and high dose sarcosine monotherapy produced a NNT of less than three patients (compared to a low dose of sarcosine). These effects are not markedly dissimilar to the results of LY2140023 and mean differences in negative symptom scales (the main outcome used in the adjuvant studies) for glycine binding-site agonists are of a similar magnitude to LY2140023. However, the difference in mean overall symptom scores is much larger for LY2140023 than the glycine binding-site agonists, and the sarcosine monotherapy trial produced no significant differences in mean symptom scores at all.

These comparisons suggest that, while LY2140023 has evidence for somewhat greater efficacy than glycine binding-site agonists this is a tentative conclusion at best, and may prove to be premature when the results of the latest trial of LY2140023 are published. We are still awaiting the outcome of placebo controlled trials of glycine binding-site agonists as monotherapy, but it is conceivable that use as adjuvant therapy may have underestimated the full antipsychotic effect of these compounds. Similarly, trials of LY2140023 as an adjuvant therapy may show an additive therapeutic benefit over-and-above the effect of conventional antipsychotics, which may be similar to or greater than that of the glycine binding-site agonists.

It is not entirely clear why both NMDA glycine binding-site agonism and reduced glutamate release (via type II metabotropic receptor agonism) appear to have beneficial effects on schizophrenic symptoms, nor why the latter is so much more successful than direct NMDA antagonism. Presumably differential and complex effects on neural circuits underlie this apparent paradox but it highlights how poor our understanding of the glutamatergic pathology of schizophrenia still is. Glutamatergic drugs may still not prove to be the future of schizophrenia treatment, but they are currently offering some hope.

References

* Although the original study found no evidence that LY2140023 or LY404039 interact with dopamine receptors it has been proposed that there may be some action at high-affinity state dopamine D2 receptors (29), and there are considerable interactions between the glutamatergic and dopaminergic systems (6).

1. Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci U S A 1975;72(11):4376-80.

2. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153(3):321-30.

3. Tandon R, Belmaker RH, Gattaz WF, Lopez-Ibor JJ, Jr., Okasha A, Singh B, et al. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008;100(1-3):20-38.

4. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44(7):660-9.

5. Matthysse S. Antipsychotic drug actions: a clue to the neuropathology of schizophrenia? Fed Proc 1973;32(2):200-5.

6. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10(1):40-68.

7. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004;9(11):984-97, 979.

8. Li D, He L. G72/G30 genes and schizophrenia: a systematic meta-analysis of association studies. Genetics 2007;175(2):917-22.

9. Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev 2006(2):CD003730.

10. Duncan EJ, Szilagyi S, Schwartz MP, Bugarski-Kirola D, Kunzova A, Negi S, et al. Effects of D-cycloserine on negative symptoms in schizophrenia. Schizophr Res 2004;71(2-3):239-48.

11. Goff DC, Herz L, Posever T, Shih V, Tsai G, Henderson DC, et al. A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berl) 2005;179(1):144-50.

12. Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon RP, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry 2007;164(10):1593-602.

13. Goff DC, Cather C, Gottlieb JD, Evins AE, Walsh J, Raeke L, et al. Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res 2008;106(2-3):320-7.

14. Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 2004;55(2):165-71.

15. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 2005;57(6):577-85.

16. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch Gen Psychiatry 2005;62(11):1196-204.

17. Diaz P, Bhaskara S, Dursun SM, Deakin B. Double-blind, placebo-controlled, crossover trial of clozapine plus glycine in refractory schizophrenia negative results. J Clin Psychopharmacol 2005;25(3):277-8.

18. Tsai GE, Yang P, Chang YC, Chong MY. D-alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2006;59(3):230-4.

19. Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2004;55(5):452-6.

20. Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 2006;60(6):645-9.

21. Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 2001;21(5):484-7.

22. Goff DC, Lamberti JS, Leon AC, Green MF, Miller AL, Patel J, et al. A placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008;33(3):465-72.

23. Marenco S, Egan MF, Goldberg TE, Knable MB, McClure RK, Winterer G, et al. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res 2002;57(2-3):221-6.

24. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, et al. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry 2008;63(1):9-12.

25. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007;27(43):11496-500.

26. Lieberman JA, Papadakis K, Csernansky J, Litman R, Volavka J, Jia XD, et al. A Randomized, Placebo-Controlled Study of Memantine as Adjunctive Treatment in Patients with Schizophrenia. Neuropsychopharmacology 2008.

27. Lee JG, Kim Y-H, Lee SW. Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: A 12-week, double-blind, placebo-controlled trial (abstract). International Journal of Neuropsychopharmacology 2008;11(Suppl 1):141-2.

28. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007;13(9):1102-7.

29. Seeman P. Glutamate agonists for schizophrenia stimulate dopamine D2High receptors. Schizophr Res 2008;99(1-3):373-4.

Eight out of ten cats prefer...Boots

Via badscience forums I see that there has been a placebo controlled randomised clinical trial of an anti-ageing creme that found a positive effect of the product - expect to hear about it:

Scientists say they have clinical proof that a face cream available on the high street does reduce wrinkles.

Five months' worth of stock of the leading brand sold in a day after Professor Chris Griffiths announced in 2007 it appeared to combat sun damage.

Two years on from the BBC Horizon programme showcasing his work, his team has shown the cream visibly smoothes out the skin.

Boots predicts boom sales of its No 7 Protect & Perfect Intense Beauty Serum.

Now it is certainly good that Boots has conducted a clinical trial, published in the British Journal of Dermatology no less, but it is, I'm afraid, bollocks.

I'm going to ignore everything in the paper other than the clinical trial as they are, to be blunt, irrelevant. So what did they do? Well they randomised 60 adults to placebo or the face cream in question to apply to their hands and face for 6m -and they looked at four measures, clinical scales for fine lines and wrinkles, dyspigmentation, and the overall clinical grade of photoageing and tactile roughness at baseline, 1m, 3m, and 6m.

So what did they find? Well they report that at 6m there was no statistically significant difference on any of the measures - including improvement in facial wrinkles (compared to baseline) where 43% who had used the product improved and 22% of the placebo group (that's a relative improvement of 1.89 times, 95% CI .86-4.0, with a p-value of .11*). As the paper says:

"the test product did lead to a noticeable clinical improvement in facial wrinkles...in 43% of treated individuals after 6 months, compared with only 22% of those treated with the vehicle...In a comparison between groups, this improvement was not statistically significant" (my emphasis)

Huh? Yes, that's right, no differences. So why is this supposed to be a positive study? Well that's because they were rather sneaky, after 6m - at which point their were no significant differences remember - they stopped doing a blinded placebo controlled trial and put all the subjects on the face cream. They then extrapolated (using linear regression, and presumably the 1m, 3m, and 6m response rates) the placebo response to 'guess' what the 12m response rate might be. They found that 70% of the 60 people now getting cream had improved facial wrinkles (not improved hand wrinkles, or improved dyspigmentation, photoageing, or tactile roughness of the hands or face**) while they estimated that only 33% of the extrapolated placebo group would have improved.

Now we don't know anything about this regression because they don't tell us any data from baseline***, 1m, or 3m, but you might argue that 33% seems a rather low rate, and, since we might want any regression to go through 0,0 (since at baseline there can have been no improvement) and only have data from 6m presented we could suggest that 44% would be just as reasonable a 12m response rate for the placebo group.

This is an inherently dodgy way to go about analysing the data (and it gives free additional sample size artificially inflating the power of the study) which is now not even from a blinded randomised trial but instead a open label trial (everyone now knows they're on the cream, not placebo) but if we look at what the results give we might find that, assuming the placebo group is 30 (and, of course, that group doesn't really exist) and the cream group has 60 people we get a response rate of 70% for cream and 33% placebo (2.10 times relative improvement 95% CI: 1.23-3.58, p=.006****) - if we assume my 44% placebo response it is 1.62 times 95% CI: 1.04-2.51, p=.03).

However, we've also forgotten that they made a lot of statistical comparisons, we'll let them off the comparisons at 1m, 3m, and 6m (they're not independent anyway, if this had been a pain relief trial, say, they might have tried to make something of them if they had proven to be signficant early in the trial and then became non-significant later on - but that is unlikely here) but they did do 4 measures on each of the hands and face - that's 8 sets of statistical tests - so our error rate of p=.05 will get inflated with all those tests (which each have a 5% error rate) so we need to correct for that - a simple Bonferroni correction implies that we need to multiply the p-values by 8, which makes the 70%-33% comparison barely significant (p=.048) and the 70%-44% comparison non-significant (p=.24).

It is worth noting that although only 13/30 showed an improvement with 6m treatment when the placebo arm was added in and another 6m of treatment given, assuming the original 13 sustained their improvement, a whacking great 29 further people showed an improvement (i.e. we might think that a second 6m had the same response rate as in the first 6m, doubling the response rate for that first 30, plus an extra 30 people have that same 6m response rate). I find that pharmacologically unlikely*****.

Take home message - they did a randomised blinded clinical trial for 6m and found no statistically significant effects of the Boots cream (or even remotely nearly significant given the necessary multiple testing correction). They then did a non-trial where they essentially made-up placebo control group results and gave the cream to all the real patients in a non-blinded fashion. And then, maybe, they have a borderline statistically significant result.

The data is sufficiently badly presented, and given that the clinical trial is what, ultimately, they'll use to sell it, that I'd say they have deliberately done dodgy stats to hide the negative nature of the data. God knows what the Manchester researchers were thinking, and I despair of the British Journal of Dermatology and its peer review.

I wonder what the following were thinking when they said:

"Nina Goad of the British Association of Dermatologists said: "Approximately one in five people using the cream will get something extra for their money over plain moisturisers. "It is an interesting step forward in research although the long term benefits are unknown. "The main preventable causes of skin ageing are sun exposure and smoking, so if you're worried about wrinkles, limiting these factors is sensible."

Dr Nick Lowe, clinical professor of dermatology at UCLA School of Medicine, said: "The previous rapid study reported from this group measured fibrillin a substance that predicts the formulation of collagen. More collagen should result in skin rejuvenation. "This latest longer study over six months appears to confirm skin rejuvenation as measured by dermatology examination."

Dr Richard Weller, senior lecturer in dermatology at the University of Edinburgh, said: "This is, as far as I am aware, the first properly conducted placebo controlled, double blind trial of an over the counter cosmetic product. Boots are to be congratulated for doing this."

I wonder if they actually read it (it was published on the 28th - the same day as the BBC article - the media have a habit of asking for quotes before anyone gets to read the article).


NHS Behind the Headlines has also covered this story.


Acknowledgements to the observations of willowtree and BenFranklin in the thread.


UPDATE
We can see here from the press release from Manchester that there was specific misrepresentation:

"The study, published online in the British Journal of Dermatology today (Tuesday, April 28), showed that 70% of individuals using the beauty product had significantly fewer wrinkles after 12 months of daily use compared to volunteers using a placebo." (my emphasis)

* Maentel-Haenszel assuming 30 in each group - we can only assume because they give no details of numbers in each group or if any dropped out - looking at the 22% placebo response rate I think that either the two groups were not of equal sizes or there were dropouts because that figure does not give a whole number for number of responses if you assume a sample size of 30 - in the actual study they report p-values derived from Wilcoxon rank tests which doesn't make any sense given the data they present.

** I'll get back to these in a bit

*** IT would certainly be nice to know baseline scores because, since they report improvement over baseline, differences between the two groups in baseline scores (these happen by chance often in trials, particularly small ones like this) could lead to differences in improvement (say, because those who start out less severe have less opportunity to improve because their skin was pretty good already).

**** Obviously these are make believe stats since this would really be a cross-over design and I'm assuming independence, and because, obviously, you just can't make up placebo responses like this.

***** Would have been nice to be able to judge that by showing the 1m, 3m etc data.

Shibboleth

Being an old fashioned kind of guy, I haven't really followed the withdrawal of funding by JISC from Athens in favour of the 'UK Access Management Federation' and 'Shibboleth' technology. But now that my institution has withdrawn Athens compliance, I can tell you that it is just like Athens only it works about 1/10th as well.

Currently I'm working outside the university network (you'd hope within a university network with relevant IP addresses anyone would be able to figure out how to organise access management) but under the new system instead of being able to sign in to Athens once and then access all journal articles via links in commonly used search engines like pubmed, or via links in journal articles, now I have to search the university database of subscribed journals, then enter the citation, then wait while it chugs along at about one mile per hour to finally serve up the paper. If I'm lucky the journal may have got around to adding the 'UK Access Management Federation' to its long list of alternative logins, and then if I find it, and select the relevant UK university from the long list, I may be able to get it to recognise that I've already signed in (saving me the time to type in my login and password, but little else).

So why change? Apparently 'federated access management' (where they ask your institution if you're signed in there, rather than having you sign in directly) is the bees knees, according to JISC:

"Users will have a single sign-on using an institutional ID and password for a wide range of resources, as well as the assurance that their personal data will not be disclosed to third parties.
Librarians will be free of the burden of user name and password administration, and will have new tools for managing licenses and service subscriptions.
IT managers will have more control of the access management process through enhancements to enterprise directories, although this will require additional institutional effort in the short term.
Institutions will have a single service to meet the requirements of e-learning, e-research and library-managed resources. Simplification of the authentication process has also proven to lead to increased use of subscribed services."

It is good to know that in order to allow a single sign-on username and password and to free up a little bit of time for librarians (the rest of that stuff is pie in the sky techno-wank) access to online journals has regressed ten years in terms of useability, speed of access. Am I missing something or is this another example of management idiots fucking it up again? The potential benefits seem minimal and the implmentation is woeful.

Kirsch et al reply

Blair Johnson and the other authors of the Kirsch et al paper in PLoS Medicine reply to the responses to their paper here. Some relevant parts for the discussions here:

"...as we reported in our results, this difference was more apparent than real, disappearing when we controlled for baseline severity. It is worth noting that Turner et al. (2008) found between-group effect size (d) estimates of 0.40 for venlafaxine and 0.26 for nefazodone, both of which are close to the mean of 0.40 for all 12 newer antidepressants and are identical to those for fluoxetine (0.26) and paroxetine (0.42)."

"Leonard took the trouble of re-analyzing the data from our Table 1 and concluded that a clinically significant difference emerged at a lower point of severity than we concluded in our article (i.e., 26 vs. 28). We are grateful that his work confirms our major conclusion, which is that the efficacy of anti-depressants depends on the initial severity of depression. Unfortunately, however, his estimates of the standard deviation underlying each effect size relied on between-subjects’ rather than within-subjects’ formulations. In examining improvement in response to drug or placebo, individual trials conventionally control for the correlation between the HRSD scores at baseline. We adopted this convention in our analyses of drug and placebo improvement. Reassuringly, the analyses at the end of our Results section pertaining to each trial’s drug vs. placebo comparison also used a between-subjects variance formulation and confirmed that clinical significance emerges in the vicinity of an HRSD score of 28."

"We found a nonsignificant benefit of drug compared to placebo for moderately depressed patients. Yet, consistent with our other conclusions, the difference between drug and placebo grows at higher levels of depression. Davies commented on the fact that there were few samples with scores below the category of very severe depression on the Hamilton Rating Scale of Depression (HRSD), a limitation that our Discussion mentioned. "

I note that they don't engage with the finding by 'Leonard' (that's me that is) that there is no real decrease in placebo response with increasing severity, nor do they address my concerns that their use of the measure 'd' (mean change divided by SD of the change) biases the effect size (expressed in HRSD change scores), nor that looking at raw HRSD changes suggests that paroxetine and venlafaxine exceed the NICE 'clinical significance' criteria. I'm not quite sure what they mean by referring to within-subjects variance versus between-subjects variance (since I've changed the analysis based on Robert Waldmann's findings I don't know which analysis they looked at), they could be referring to normalising to the change score SD, which makes little difference compared to my previous analyses, or to analysing the drug group and placebo groups separately, which is just plain statistically wrong (and seems to be what they did, note that my analysis of separate regression lines produces the same results as looking at the between-subjects regression). They refer to their analyses at the end of their results section as confirming their 'within-subjects' results, I wonder if they mean their Figure 4 (repeated here), you might want to compare that to my regression (and their Figure 2) - and decide for yourself whether that confirms that the threshold for 'clinical significance' of 3 HRSD points difference is at baseline HRSD of 28 points as they claim, or 26 as I find.

They also don't really seem sufficiently contrite over their claim that in 'moderate' depression antidepressants should be avoided, given that it was based on a single study plus extrapolating a regression line.

The only real finding, that is robust, is that the difference between placebo and antidepressant response seems to increase with baseline HRSD severity. Although Kirsch et al emphasise that the level at which this difference becomes 'clinically significant' is in severe depression, it is worth noting that in fact the level at which it is significant (around 26 according to both my and their analysis of raw HRSD figures) is pretty much the middle of the pack in terms of the baseline severity of the studies (which were pretty much all in the 'very severe' range over 23 HRSD points - see that figure). [Their finding that the differences between the drugs may be largely explained by the differing baseline of the studies is not unreasonable].

UPDATE

'PJ Leonard' has submitted a response, titled 'Analytical differences', pretty much repeating what I said above:

"It is good of Johnson et al to reply to the responses here. However, I do not think they have sufficiently dealt with some of the reservations concerning their paper.

In particular, I do not think that they have engaged with my finding that using the raw HRSD change scores reveals that the placebo response does not in fact decrease with increasing baseline severity on the HRSD.

I am not clear exactly what they mean when they say that I have used between-subjects analyses to suggest that the effect size (when analysing the raw HRSD change scores) is larger than presented in their paper, whereas they have used within-subjects analyses.

My analyses utilise conventional methods for meta-analysis where the effect size in each study is analysed directly, whereas it seems likely that the low estimated effect size in HRSD units in this study is the result of carrying out the meta-analytic weighting on the drug and placebo groups separately (a 'within subjects' analysis?), and then comparing the effect sizes thus obtained (which would explain the lack of forest plots in the paper).

This is not an acceptable analytic technique because it ignores that there is a relationship between the improvement in placebo and drug groups from the same study, but that the placebo and drug groups from any given study can have grossly different weightings when considered separately (e.g. there would be half as much weighting to the results from the fluoxetine trials in the drug analysis as the placebo analysis, the result of, for example, different sample sizes between the experimental arms).

Normalising the HRSD change to the change standard deviation in each group separately is also unnaceptable because a larger change in HRSD score in the drug group could be associated with a greater variance, although this does not appear to be the case in this study.

Robert Waldmann estimates that there is more bias in analytical method in this paper than publication bias present in the data itself:

http://rjwaldmann.blogspot.com/2008/03/just-cant-let-it-go.html

I note that Figure 4 in the paper of Kirsch et al is actually more consistent with my finding of 'clinical significance' at a baseline of 26 (this threshold is found both by regression on the difference scores, or separate regressions for each group's change score) than their suggestion of 28 points, this difference is undoubtedly because this figure looks at raw HRSD scores, as did my analyses, and because the NICE 'clinical significance' threshold of d > .5 is actually stricter than the NICE threshold of an HRSD difference > 3.

I concur that there is a relationship between baseline HRSD severity and effect size but it is worth noting that almost all studies examined had baselines over 23 points (and were thus in APA/NICE categories of 'very severe' depression) so the threshold of 26 points is a fairly average baseline severity for the studies analysed in this paper (as can be seen from my regression plots or their Figure 4). Any generalisation to less severe categories of depression is unwarranted given that it would depend on extrapolating the regression line to a region with only a single study."

Watson the racist

In the Independent:

"James Watson, a Nobel Prize winner for his part in the unravelling of DNA...He said there was a natural desire that all human beings should be equal but "people who have to deal with black employees find this not true"."

UPDATE
Via GNXP here's Watson's non-retraction:

"Rarely more so than right now, where I find myself at the centre of a storm of criticism. I can understand much of this reaction. For if I said what I was quoted as saying, then I can only admit that I am bewildered by it. To those who have drawn the inference from my words that Africa, as a continent, is somehow genetically inferior, I can only apologise unreservedly. That is not what I meant. More importantly from my point of view, there is no scientific basis for such a belief."

The rest of the article fails to retract or clarify what he is reported as saying, but neither is it clear whether he did in fact say it.

Darwin's Angel

Richard Dawkins briefly faces 'Catholic writer' John Cornwell, author of "Darwin's Angel: an angelic response to The God Delusion" (here, about 22mins in, it's after Nessun dorma).

Cornwell (the new Alister McGrath?) gets rather hungup on Dawkins's comparison between religion labelling and brainwashing children and child sexual abuse. Which is a valid point as I'm certainly not convinced by Dawkins's argument, or at least I'm not convinced that his comparison is enlightening or helpful (although he moderates it somewhat here).

But he gets onto pretty dodgy territory claiming that Dawkins is stirring up hatred against the religious in a manner akin to the Nazis. Dawkins tackles Cornwell's book here, but I wanted to have a look at Cornwell's arguments in a little more detail.

He wrote an article on Dawkins and the God Delusion in the Guardian a few days ago. He starts poorly with the obligatory reference to Stalin trying to wipe out 'religionists', and strangely Hitler - as he is presumably an intelligent man (director of the Science and Human Dimension Project at Jesus College, Cambridge) I can only assume he is referring to the Holocaust with Hitler because there is no evidence he had much of a problem with the idea of religion in general (he was also not a vegetarian while we're knocking myths on the head). It isn't clear what point he's trying to make, but it sets the scene nicely.

His argument then basically runs that Dawkins doesn't recognise that theists can exist in a secular pluralist society, then something about Graham Greene and "faith as "doubt of doubt" as opposed to faith as certitude". It is worth repeating the line about Greene:

"So which central doctrine, I asked Greene, enabled him to describe himself as a Christian?...he felt he had an intuition...to distinguish between fact and fiction. When he read the story in John's gospel of the two disciples racing each other to the empty tomb after Christ's body had disappeared, he felt that it was "authentic reportage". It was this, he went on, that "enabled me to doubt my doubt about the resurrection". Doubt my doubt! What is more, he saw the resurrection less as a literal historical fact and more as a powerful symbolic notion that could be reinterpreted from age to age."

Yep, you read that right, by believing in the resurrection he was being doubting in his faith (doubting his atheism I guess, nice piece of meaningless wordplay), but as well as believing in the resurrection it is also just symbolic and not 'literal' (nah, nah, your rational arguments and evidence can't touch me!) - can anyone say bait and switch?

Quoting Dawkins he then says:

"Then he asserts: "I do everything in my power to warn people against faith itself, not just against so-called 'extremist' faith. The teachings of 'moderate' religion, though not extremist in themselves, are an open invitation to extremism."

Through the excited syntax he is declaring that if you go to church, synagogue, mosque or temple only once a year, you are just as liable to perpetrate fanatical deeds on the basis of faith as an al-Qaida terrorist."

Which strikes me as a complete misreading of Dawkins, who is arguing against the way we are told to prize faith, that is belief in the absence or in the face of evidence, he is arguing that prizing evidence free beliefs we open the door to extremism by failing to ground people's beliefs in the real world.

After making the perfectly valid point that extremism doesn't require religion (I doubt I need to tell you which of our favourite dictators get mentioned) and mentioning two fairly mild commitments made by the Catholic church towards pluralism in the `1960s, Cornwell makes a quite extraordinary assertion that:

"Dawkins claims, however, that religious believers deserve neither respect nor rights in any circumstances."

and backs this up with:

"One of his constant explanations for the spread and lethal nature of religion is based on the idea of cultural traits transmitted by what he calls "memes", items of information that behave like viruses. He writes of those "afflicted with the mental virus of faith, and its accompanying gang of secondary infections". The idea of religious believers as disease carriers is not trivial, for it suggests a contrast between the disease and the theoretically healthy body of society, along with the necessity for antidotes."

"Nazi, Nazi!!!" I can hear him cry through the not so subtle subtext, and in fact, I need not search for he makes it explicit:

"Nazi ideology subscribed from the very outset to the idea of the German people as a type of anatomy subject to bacilli...The Nazi plenipotentiary Dr Gerhard Wagner wrote of the volkisch body being in need of "cleansing", while the language of "immunity" and "radical therapy" became routine."*

So it seems his argument boils down to the standard template of theistic responses to Dawkins: "there is too a God", "you can't argue against my God because actually he's a metaphor for the purposes of this debate", "I want my special treatment, stop oppressing me you Nazi!!!"

*I should probably point out the line "Dawkins' recourse to the analogies of disease and medicine is, of course, entirely well meant, and I know him to be a man of the most liberal sympathies..."

UPDATE: The ever irritating Madeleine Bunting shares her wortheless view on this topic at Comment is Free, note this comment:

"He has repeatedly refused a head-to-head with protagonists such as his Oxford colleague, Professor Alister McGrath"

Note that the McGrath-Dawkins interviews is now available here. Ah Madders, daft as a brush.

Alister McGrath

I've been umming and ahhing about reading a book by Alister McGrath (Professor of Historical Theology at Oxford University no less). He's something of a poster boy for theists having a PhD in some science or other and has published quite a few books about the perils of atheism, at least two focusing on attacking Richard Dawkins directly. I've always hesitated because anything I've heard from him has always sounded so trite and unimpressive, and I'm therefore loath to give him any of my money (normally I'm fairly happy to read books that challenge my beliefs, I find it gets the blood going). Although he doesn't seem to do so well on the national and international stage McGrath gets a lot of coverage on his home ground of Oxford (bigged up with various book signings and talks) and I feel I really should engage with the man just to prove to myself that he is indeed talking crap, particularly as his current argument seems to be that Dawkins is attacking something of a strawman.

To try and avoid having to wade through (and pay for) a whole book (incidentally, his latest, "The Dawkins Delusion" is some 8 quid yet barely more than a pamphlet) I tried to have a look at an article he'd written “Has Science Eliminated God? – Richard Dawkins and the Meaning of Life.” Couldn't access the journal (Science and Christian Belief) but found this presentation on the topic by McGrath.

So, what's he say, well quite a few things, including criticising memes, but let's look at some things he says:

1. At the most general level, the scientific method is incapable of adjudicating the God-hypothesis, either positively or negatively.

2. Dawkins’ arguments lead to the conclusion that God need not be invoked directly as an explanatory agent within the evolutionary process. This is consistent with atheist, agnostic, and Christian understandings of the world, but necessitates none of them.

3. The concept of God as “watchmaker”, which Dawkins spends so much time demolishing, emerged as significant in the eighteenth century, and is not typical of the Christian tradition.

Unfortunately the talk doesn't back up any of these claims or examine them in any depth other than giving a list of quotes from people saying things like "Either half my colleagues are enormously stupid, or else the science of Darwinism is fully compatible with conventional religious beliefs – and equally compatible with atheism." (SJ Gould). He does go into more detail on memes and the "religion does bad things" argument but they aren't really what I wanted to focus on (the talk is called "Has Science Eliminated God?" after all). I suppose I shall have to dig a little deeper to find the substance of an argument.

Rather worryingly, an article by McGrath in the Daily Mail says this:

For instance, Dawkins often compares belief in God to an infantile belief in Santa Claus or the Tooth Fairy, saying it is something we should all outgrow. But the analogy is flawed. How many people do you know who started to believe in Santa Claus in adulthood?

Many people discover God decades after they have ceased believing in the Tooth Fairy. Dawkins, of course, would just respond that people such as this are senile or mad, but that is not logical argument. Dawkins can no more 'prove' the non-existence of God than anyone else can prove He does exist.

Now I may not be a Professor of Theology, but I'm not sure the best argument in favour of God over the Tooth Fairy is that adults believe in it therefore it is true, his only other argument ("Dawkins can no more prove...") applies equally well to the Tooth Fairy of course.

And here we are again with another article:

They know that they can’t prove that God is there, any more than an atheist can prove that there is no God. The simple fact is that all of us, whether Christians or atheists, base our lives on at least some fundamental beliefs that we know we cannot prove, but nevertheless believe to be reliable and significant. We all need to examine our beliefs — especially if we are naive enough to think that we don’t have any in the first place. It’s one of the best antidotes against the ideological fanaticism that The God Delusion manages to deride and represent at one and the same time.

You'd almost think his only argument in favour of God was that you can't disprove it, yah boo sucks. And even that seems arguable if his god is the Christian god.

Some further digging brings up this pamphlet from his "Has Science eliminated God? Richard Dawkins and the Meaning of Life" lecture. It is a good deal more explicit as to McGrath's thesis, which seems to be, at base, fairly trivial. As I surmised above McGrath's main argument against Dawkins is that evolution by natural selection may adequately explain the complexity of life, but that it doesn't disprove the existence of God. He then goes on to argue that Dawkins mischaracterises 'faith' by claiming that the faith of Christianity “commences with the conviction of the mind based on adequate evidence.”

Curiously McGrath does not elaborate on this position, moving on to a digression about God as meme (which won't concern me here, particularly as McGrath makes the extraordinary concession that "Ideas may seem to “behave” in certain respects as if they are viruses" which is presumably all Dawkins's argument requires), about the aesthetics of atheism vs. theism, and a discussion of the evils of religion including the obligatory 'what about Communism?' response (again, I won't deal with it here as it is not germane to the question of the truth or falsity of theism).

Now this all seems a bit thin for someone to have made such a name for himself, and for someone holding a Professorship in Theology. Perhaps his books contain something a bit more meaty, but I really need at least a hint of a substantive argument before I go and give this man my money. But is this argument as thin as I make out? Well let's consider the first article I accessed by Dawkins after skimming the World of Dawkins biography (I started with the oldest, this is from '94):

Religious people split into three main groups when faced with science. I shall label them the "know-nothings", the "know-alls", and the "no-contests"...The "no-contests" are rightly reconciled to the fact that religion cannot compete with science on its own ground. They think there is no contest between science and religion, because they are simply about different things. the biblical account of the origin of the universe (the origin of life, the diversity of species, the origin of man) -- all those things are now known to be untrue.

The "no-contests" have no trouble with this: they regard it as naive in the extreme, almost bad taste to ask of a biblical story, is it true? True, they say, true? Of course it isn't true in any crude literal sense. Science and religion are not competing for the same territory. They are about different things. They are equally true, but in their different ways.

I think McGrath is probably coming from the "no-contest" perspective if he regards evolution by natural selection (and other scientific knowledge) as compatible with both atheism and theism. He clearly can't be a young Earth creationist for instance.

I shall now return to the "no-contests". The argument they mount is certainly worth serious examination, but I think that we shall find it has little more merit than those of the other groups.

God is not an old man with a white beard in the sky. Right then, what is God? And now come the weasel words. these are very variable. "God is not out there, he is in all of us." God is the ground of all being." "God is the essence of life." "God is the universe." "Don't you believe in the universe?" "Of course I believe in the universe." "Then you believe in God." "God is love, don't you believe in love?" "Right, then you believe in God?"

...

It has obviously not the smallest connection with a being capable of forgiving sins, a being who might listen to prayers, who cares about whether or not the Sabbath begins at 5pm or 6pm, whether you wear a veil or have a bit of arm showing; and no connection whatever with a being capable of imposing a death penalty on His son to expiate the sins of the world before and after he was born.

The Fabulous Bible

The same is true of attempts to identify the big bang of modern cosmology with the myth of Genesis. There is only an utterly trivial resemblance between the sophisticated conceptions of modern physics, and the creation myths of the Babylonians and the Jews that we have inherited.

What do the "no-contests" say about those parts of scripture and religious teaching that once-upon-a-time would have been unquestioned religious and scientific truths; the creation of the world the creation of life, the various miracles of the Old and New Testaments,, survival after death, the Virgin Birth? These stories have become, in the hands of the "no-contests", little more than moral fables, the equivalent of Aesop of Hans Anderson. There is nothing wrong with that, but it is irritating that they almost never admit this is what they are doing.

...

I have the impression that clergymen are so used to treating the biblical stories as fables that they have forgotten the difference between fact and fiction. It's like the people who, when somebody dies on The Archers, write letters of condolence to the others.

I'm afraid I'm with Dawkins on this one. Being a Christian carries with it some rather weighty doctrinal baggage, just as belief in Santa or the Tooth Fairy involves commitments to some fundamental truth claims, you can't hide these things away when anyone comes along to point out their falsity. It may well be that atheists can't really disprove some minimally specified deism or non-interventionist first cause god - but this is certainly not the God of McGrath or any other mainstream religious believer - and the truth or falsity of this minimally specified god would not have the implications for our everyday conduct that religious believers want it to have, why worship something that has never asked for it, nor shown any interest in you? How can you derive your moral code from a being that is little more than a brute fact, it's like trying to get stock tips from the Big Bang. By paring down their god until it has no causal ramifications in the world the theists have indeed decreased the implausibility of it, but at the cost of being able to claim any further knowledge of it - in effect they have argued away all the remaining content of their religion. They are no more theists than people who claim to be 'a bit spiritual' or who simply believe that there is 'something out there'.

Migration Watch

My eye was recently caught by an article in the times about Migration Watch and David Coleman (not this, but similar, can't actually find the actual one). So what about these impartial statistics? Well one that was widely covered at the time was the claim that "the benefit to each member of the native population of the UK from immigration is worth about 4p a week - or less than the equivalent of a small Mars bar a month.".

So let's unpack that claim. Forget any sophisticated analysis the 4p figure is based purely on dividing the government's estimated additional GDP due to immigrants divided by the population + net immigration. According to Coleman it is GDP per head that counts, but is it? I think not for some pretty obvious reasons, reasons you'd think would be very obvious to a Professor of Demography. For a start many of these migrants are young and single (often Eastern Europeans) looking to make money to send home or to take home where the cost of living is lower - and thus with the implication that they will not remain in the UK long-term (remember the horror stories about how we don't have enough young working people to ay for healthcare and pensions for the old codgers - well here they are!).

Even if this were not the case these working young adults (unable to claim benefits) take up a disproportionately lower fraction of public spending than does your average Briton (who is quite likely to be old, sick or unemployed). So it seems like GDP per head is precisely the wrong measure of immigrant contributions to GDP, and you have to wonder in that case quite why those chose to focus on that figure rather than a different and more meaningful one.