Tuesday, April 16, 2013

Schizophrenia is a brain disease: The fly brain man cometh



On 12th April, a BBC Radio 4 discussion included a contributor suggesting first that schizophrenia is a brain disease, and secondly that discoveries in the physiology of the fly brain could offer insights into the origin of this ‘disease’.

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An email exchange ensued. It culminated (but possibly hasn't ended) with my colleague, Richard Bentall, offering a concise, but assertive, commentary:   

Dear Dr H,

[My colleague] forwarded me your email to him, which I feel moved to reply to. I am copying in various colleagues who are as concerned as I am about the naive biological reductionism that seems to be dominating media discussions of mental health these days. Briefly, the problems with this view when applied to 'schizophrenia' are:

(i) Schizophrenia is a meaningless construct

There is no syndrome of schizophrenia and nobody can agree on who is schizophrenic. To my knowledge, no statistical study has ever identified a cluster of symptoms that correspond to the Kraepelinian concept or its subsequent revisions. Most recent studies have converged on a multidimensional model that incorporates five dimensions of positive symptoms, negative symptoms, cognitive dysfunction, depression and mania/excitability, or even more complex structural models which encompass patients across the psychosis spectrum (see Demjaha, A., et al. (2009). Combining dimensional and categorical representation of psychosis: the way forward for DSM-V and ICD-11? Psychological Medicine, 39(12), 1943-1955 and Reininghaus, U., Priebe, S., & Bentall, R. P. (in press). Testing the psychopathology of psychosis: Evidence for a general psychosis dimension. Schizophrenia Bulletin, available online). In recent field trials, the proposed DSM-V criteria for schizophrenia generated a derisory kappa of 0.46, showing that clinicians working with a precise definition of the disorder and following a diagnostic interview often could not agree on who was schizophrenic and who was not (Regier, D. A., et al(2013). DSM-5 field trials in the United States and Canada, Part II: Test-retest reliability of selected categorical diagnoses. American Journal of Psychiatry, 170, 59-70)!


(ii) Heritability coefficients are misleading

It is often forgotten that heritability coefficients are, actually, fancy correlation coefficients. We all know, or should know, that correlation does not necessarily prove causality. Heritability coefficients are statements about populations and not individuals so that it is wildly misleading to suggest that high heritability = mostly genetically caused (for a detailed discussion of this, see Bentall, R. P. (2009). Doctoring the mind: Why psychiatric treatments fail. London: Penguin.).

In fact, precisely because heritability coefficients are correlations which attempt to parse up the variance in a trait to genetic and environmental causes, low variance in the environment leads to inflation of heritability. This is why, for example, IQ is highly heritable in middle class families (where environmental variation is low) but very low in working class families (where environmental variation is high) (Turkheimer, E., et al. (2003). Socioeconomic status modifies heritability of IQ in young children. Psychological Science, 14, 623-628). Also, heritability coefficients assume an additive model of genes and environment, which is wildly implausible given what we know know about how genes work. Again, assuming an additive model when there are G x E interactions leads to massive inflation of heritability and an underestimate of environmental effects (Dickins, W. T., & Flynn, J. R. (2001). Heritability estimates versus large environmental effects: The IQ paradox resolved. Psychological Review, 108, 346-369). This is probably why, as you know, molecular estimates of heritability are generally much lower than those based on the methods of classical genetics. The 'missing' heritability in these studies is probably phantom heritability.

Incidentally, you will also know from the genetic studies that you cite, that the consensus amongst geneticists is now that many common alleles (perhaps hundreds) probably each confer a tiny risk of all kinds of psychosis . Although some CNVs have much higher association with psychosis, they account for only a small proportion of patients and are also associated with intellectual disabilities and autism (Owen, M. J. (2012). Implications of genetic findings for understanding schizophrenia. Schizophrenia Bulletin, 38(5), 904-907. doi: 10.1093/schbul/sbs103). This is further evidence, if ever it was needed, that schizophrenia is a meaningless construct and confirms the impossibility of devising a genetic test for the disorder.

(iii) There is massive evidence that environmental factors are causal in severe mental illness

The implications of ii above are that you can't estimate environmental influences from heritability estimates - you have to look for them and measure them. Recent studies have pointed to a wide range of environmental factors associated with psychosis. These include social disadvantage, migration, living in cities and various forms of victimisation. I attach a recent meta-analysis I conducted on the evidence linking childhood adversity to psychosis (Varese, F., et al. (2012). Childhood adversities increase the risk of psychosis: A meta-analysis of patient-control, prospective and cross-sectional cohort studies. Schizophrenia Bulletin, 38, 661–671. doi: 10.1093/schbul/sbs050.) The bare odds ratio between childhood trauma was stable across methodologies (retrospective/prospective) and came in at about 3, much higher than any association with common alleles. More importantly, there is evidence of a dose response effect, with Ors climbing to around 50 for children who have been multiply traumatised. Reaction in the psychiatric community has sometimes been bizarre, with convoluted attempts to explain away the data (see a recent editorial I wrote about this, also attached).

(iv) Brain studies do not provide clear evidence of neurodevelopmental disorder in psychosis

The evidence linking the basal ganglia to psychosis is far from clear cut. The best evidence is from response to antipsychotics, but recent studies suggest that only about 20% of patients show a genuine clinical response (Marques, T. R., et al. (2011). The different trajectories of antipsychotic response: antipsychotics versus placebo. Psychological Medicine, 41(07), 1481-1488). In any case, abnormal basal ganglia activity could just as likely be attributed to environmental factors – animal studies show that chronic victimisation leads to sensitisation of dopamine pathways in this part of the brain (Selten, J.-P., & Cantor-Graae, E. (2005). Social defeat: Risk factor for psychosis? British Journal of Psychiatry, 187, 101-102). Current structural neuroimaging studies of psychosis are probably not to be trusted for a variety of complex methodological reasons (Ioannidis, J. P. A. (2011). Excess significance bias in the literature on brain volume abnormalities. Archives of General Psychiatry, 68, 773-780), not least the emerging evidence that drugs affect brain structure (Ho, B.-C.,et al. (2011). Long-term antipsychotic treatment and brain volumes. Archives of General Psychiatry, 68, 128-137) but, in any case, could also be the consequence of social and environmental factors (Hoy, K., et al. (2011). Childhood trauma and hippocampal and amygdalar volumes in first-episode psychosis. Schizophrenia Bulletin. doi: 10.1093/schbul/sbr085

(v) A narrow neurodevelopmental approach is damaging to patients.

There is little evidence that the biological approach to psychiatry is benefiting patients. Outcomes for patients suffering from 'schizophrenia' have not improved since the Victorian age and an increasing number of people are disabled by psychiatric conditions. This is precisely the opposite to what has happened in physical medicine, where genuine advances have led to improved outcomes and reduced disability (see my Doctoring the Mind, and also Whitaker, R. (2005). Anatomy of an epidemic: Psychiatric drugs and the astonishing rise of mental illness in America. Ethical Human Psychology and Psychiatry, 7, 23-35). Just as importantly, although it is often assumed by doctors that promoting a biological understanding of psychosis will reduce stigma, empirical research provides strong evidence that the opposite is the case (Read, J., et al. Acta Psychiatrica Scandinavica, 114, 303-318; Angermeyer, M. C., et al. (2011). Biogenetic explanations and public acceptance of mental illness: systematic review of population studies. British Journal of Psychiatry, 199, 367-372.)

The claim that biological research (on flies or whatever) will one day lead to a cure for schizophrenia is a common rhetorical trick designed to gain publicity and guarantee grant funding. I have no problem with research on the CNS of flies, which seems valuable in its own right. But linking flies to schizophrenia (whatever that is) is really about self-promotion and is damaging to the interests of patients.

Sincerely etc.



6 comments:

  1. Professor Kinderman, thanks for sharing this. I've just recently watched another recent piece of work in the form of a TEDx talk talking about the same point being made about schizophrenia being a meaningless construct. Here is a link to that: Tedx Talk. I also discovered another website that's getting behind the schizophrenia movement: Schiz Life. Thanks for this information and keep up the good fight :)

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  2. My son recently got taught in school that schizophrenia was when you see and hear things and if you get it you have to take medication for life (although your schizophrenia will actually try to talk you out of it - and then you'll be in trouble!). So I hope you don't mind but I used the concepts behind this letter (and some of the stuff in it) to write a strong letter of complaint to the school.

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  3. My son was victim of a mental intriguing disorder called Schizophrenia unable to distinguish between fantasy and reality.And I have looked for solution, gave him Seroquel, Zyprexa and many medication but they were all worsened the situation, All hope was lost before I met a man who directed me to where I got my medication.It is a herbal medication, It is really good for Schizophrenia, SchizoAffective and Bipolar Disoder Personality treatment, It is better than those I have been using over the years, If you having such problem for advice and necessary solution, contact doson080@gmail.com

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  4. There has been an herbal alternative to approach Schizophrenia, contact jeolard70@gmail.com

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  5. I am Matthias lang, from Orlando u s a, i suffered from schizophrenia
    for 28 years, i lived in pain with the knowledge that i wasn't going to ever be like every normal human, i contacted so many doctors on this issue,and i have use so many western drugs prescribe by various doctors and all was no avail, because i was determined to get my life back, one day i was researching for this on internet and i saw a post about devansh herbal health care who cure different manners of diseases,including schizophrenia, I contacted him via email: devanshherbalheathcare@gmail.com and made purchase of the schizophrenia herb, i received the herb through USPS within 24 hours, when i received the herb i applied it as prescribed, and to god be the glory i was totally cured of schizophrenia within 1 months of usages,my dear brothers and sisters You do not have to suffer more just contact him for his medicine on devanshherbalheathcare@gmail.com.com he will definitely put an end to that problem of yours

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  6. I decided to share this to help someone out there who is still held with schizophrenia.
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