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Neurodevelopmental hypothesis of schizophrenia

  • Michael J. Owen (a1), Michael C. O'Donovan (a1), Anita Thapar (a1) and Nicholas Craddock (a1)


The neurodevelopmental hypothesis of schizophrenia provided a valuable framework that allowed a condition that usually presents with frank disorder in adolescence or early adulthood to be understood at least in part as a consequence of events occurring early in development. However, the implications of the neurodevelopmental hypothesis for nosological conceptions of the disorder can only now be fully appreciated. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology is manifest in childhood and that are often grouped together as ‘neurodevelopmental disorders' such as autism-spectrum disorders, intellectual disability and attention-deficit hyperactivity disorder. These findings challenge the aetiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group of related and overlapping syndromes that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. This has important implications for future research and for the configuration of psychiatric services.

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Corresponding author

Michael J. Owen, MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. Email:


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We are members of the MRC Centre for Neuropsychiatric Genetics and Genomics and the Neuroscience and Mental Health Research Institute in Cardiff University. Our research in this area is supported by the MRC and the Wellcome Trust (076113).

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Neurodevelopmental hypothesis of schizophrenia

  • Michael J. Owen (a1), Michael C. O'Donovan (a1), Anita Thapar (a1) and Nicholas Craddock (a1)


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Neurodevelopmental hypothesis of schizophrenia

  • Michael J. Owen (a1), Michael C. O'Donovan (a1), Anita Thapar (a1) and Nicholas Craddock (a1)
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Schizophrenia: a distinct genetic entity?

Feargus F. O'Croinin, Psychiatrist
30 March 2011

The article by Owen et al (1) is a valuable contribution to our understanding of how the study of genetics is transforming our approach tomental illness. I'm not sure that a case has been made yet to undermine the genetic support for schizophrenia as a distinct entity. The presence of many allelic variants of small disease risk effect suggest other possibilities, for example, that different polygenic combinations of alleles are required to achieve disease status. Another possibility is that schizophrenia be viewed as a disorder of DNA damage and repair, particularly in cases resulting from spontaneous mutations. Further research needs to be done on the roughly 130 genes involved in DNA repair and the contribution of dysfunction in these genes to mental illness.

The presence of copy number variants (CNVs) associated with schizophrenia as well as other disorders identifies a susceptibility and not causality. The same variants are also seen in normal individuals, for example, other family members of the affected individual. (2) There is a highly variable phenotype associated with an implicated CNV and other factors are also required for disease causation.

A suggested solution is to do a complete DNA sequence of individuals with these disorders to identify newly arising CNVs and rare variants thathave large effects. This will help decide whether a common molecular themewill emerge or whether these disorders represent a vast collection of different diseases. (3) Either way, other factors will also be needed to achieve disease status.

I certainly agree with Owen et al (1) that there is a need for further studies and would suggest that these studies include symptom dimensions to help clarify the overlap in clinical symptoms between these disorders, and the linkage, if any, of these symptoms to chromosomal loci.

(1) Owen MJ, O'Donovan MC, Thapar A, Craddock N, Neurodevelopmental hypothesis of schizophrenia. Br J Psych 2011; 198: 173-175.

(2) van Bon BWM, Mefford HC, Koolen DA, Sharp AJ, Nillesen WM, Innis JW et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 2009; 46: 511-523.

(3) Collins FS, The Language of Life; DNA and the revolution in personalized medicine. HarperCollins 2010; 183-210.
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Neurodevelopmental clusters is just as mistaken as DSM/ICD diagnostic categories

Sami B Timimi, Child and Adolescent Psychiatrist
08 March 2011

Owen et al's article is broadly correct. Evidence from a variety of sources indicate that current diagnostic categories used in psychiatry do not appear to correspond with anything that can be meaningfully matched with it beyond the imaginations of the voting committees that brought them into being. Thus we have not identified any aetiological pathways, diagnostic specific

treatments, specific outcomes etc. Owen et al's article adds to this growing literature base by presenting the evidence from molecular genetic studies showing a lack of diagnostic specificity in potential genetic abnormalities/associations. However, the attempt to then replace one set of now obviously failed attempts at diagnostic categories with a new framework that proposes a 'neurodevelopmental' cluster is just as misguided. Now that we are able to look at the level of molecular genetics, what we are finding is something that we have known for a long time: that intellectual impairment/learning difficulties (as a proxy for a degree general neurological impairment) predisposes the sufferer to a greater likelihood of psychiatric/psychological problems in general rather than any specific condition. Thus the constant confound sitting in the background of most these studies is IQ.

For example, in September 2010 the world's media buzzed with the newsthat British researcher's had 'proven' the genetic basis of ADHD (Williams et al, 2010). The study involved the comparison of the genetic code of 366 children ‘with ADHD’ with the genetic code of more than 1047 ‘non-ADHD’ control children. Researchers found 13.9% of children with ADHD had bits of their genetic code that were either duplicated or missing, compared with 7.4% of the ‘control children'. The average recorded IQ of the children ‘with ADHD’ was 86. The IQ of the 1047 ‘non ADHD children’ was not specified, but presumably would average 100. Furthermore when 33 intellectually impaired ‘ADHD children’ (IQ lower than 70) were excluded from the ADHD cohort only

11% of the remaining 333 had the hypothesised 'ADHD' genetic abnormality. Even with the intellectually impaired children removed the average IQ (89)

remains significantly lower than normal. The only valid comparison would be a with a control group with a similar average IQ. Given that the strongest

association was not with ADHD (only 3.6% above the rate in the normal IQ control group) but with intellectual impairment, it is likely this remaining 3.6% would disappear with a valid control group.

The sooner we realise that attempts to biologically categorise something as personal, subjective and multi-dimensional as distress and behavioural deviance is doomed to fail, the sooner we can stop wasting the money and time on one dead end after another.

Williams N, Zaharieva I, Martin A, et al (2010) Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. The Lancet 376, 1401-1408.
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Lifting Lidz

Dr Peter J. Gordon, Old Age Psychiatrist
08 March 2011

Response to the Re-appraisal: Neurodevelopmental hypothesis of schizophrenia

British Journal of Psychiatry, March 2011.

In this reappraisal, the authors contend that ‘only now can the Neurodevelopmental hypothesis of schizophrenia, be fully appreciated’(1). Twenty five years of valued research have indeed passed since Weinberger, Lewis and Murray offered their theory, which in scientific stepping stones, has served primarily to confirm the complexity of aetiological understanding.

I agree that evidence is accumulating, albeit indirectly, for the Neurodevelopmental hypothesis, and I find intuitive the logic of the ‘two hit’ model of Keshavan(2). In this reappraisal, I agree with the authors on three points: that schizophrenia is not a discrete disorder, that thereis likely some overlap with autism,(3) and that in the same 25 years therehas been a complete dearth of maturational studies.

However, the authors, in their determination to expose that there is spectrum allelic risk across a range of psychiatric syndromes, have not actually presented what I would term reappraisal. In particular, environmental factors, such as season of birth effect(4) and obstetric complications(5) are not mentioned. It is more surprising, even allowing for the restrictions of a short article, that this Reappraisal makes no reference of the potential modifying effects of environmental stresses (orotherwise) upon variable allelic expression. Ironically, Paul Gilbert in his e-interview in this month’s ‘The Psychiatrist’ gave social neuroscience as the most promising field of research (6). He mentioned what Owen et al should have; that some genes can be turned on and off by the social environment, especially when young.

As I work as an old age psychiatrist, I encounter the horrid and far too common clinical presentation of Alzheimer’s disease and so my determination is to keep abreast of many, many paths of research in neurodegeneration. This sits as some sort of backdrop to my own re-appraisal of the neurodevelopmental hypothesis of schizophrenia. However, unlike the authors, I am more cautious in suggesting anything like ‘full appreciation.’ Research in the cyto-architecture of Alzheimer’s disease ispresently resulting in more questions than answers: for example - does tauor amyloid pathology come first, or does caspase activation come before that (7)? It is now even being questioned whether the plaque ‘pathology’ which has been macroscopically visible since the days of Dr Batty-Tuke,(8)might be evidence of the ‘healing’ response. Researchers are also beginning to explore the effect of stress upon neural architecture, but thankfully realise that we cannot conclude pathogenesis with certainty until we understand normal maturation (plasticity, pruning, neurogenesis and neural death.)

In Owen et als Reappraisal, where the word environment was mentioned only three times, I was left musing over the ‘proportionality principle (9).' Beyond Eugen Bleuler, others have associated autism and schizophrenia, and here I would dare suggest Theodore Lidz. This thoughtful, but outmoded doctor, along with his wife, studied most closelythe families of sufferers of schizophrenia, and offered conclusions that are not today considered palatable. Yet, perhaps in today’s neurodevelopmental light, the most ‘distant’ fathers of his ‘marital skew’might be classified autistic? Theodore Lidz, as he revealed approaching death, felt diminished by his lack of courageous opposition to ‘biologism.’ I am brought back here to the proportionality principle: Lidzwas as mistaken in his dismissal of biology as the authors of this re-appraisal seem to me of environment. I am reluctant to take any single approach too far, and prefer to weave our biological brain into the narrative of life, and so it is that I conclude contemplating whether perhaps we should keep lifting Lidz rather than closing them?

1. Owen, M.J; O’Donovan, M.C; Thapar, A; and Craddock, N: Reappraisal– Neurodevelopmental hypothesis of schizophrenia; The British Journal of Psychiatry (2011), 198, 173-175

2. Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res 1999;33:513-521.

3. Fatemi, S.H;Letter to the Editors: Co-occurrence of neurodevelopmental genes in aetio-pathogenesis of autism and schizophrenia. Schizophrenia Research 118 (2010) 303–304

4. Eagles, J.M; Hunter, D and Geddes, J.R: Gender-specific changes since 1900 in the season-of-birth effect in schizophrenia. The British Journal of Psychiatry 1995 167: 469-472

5. Verdoux H. et al Obstetric complications and age at onset in schizophrenia: An international collaborative meta analysis of individual patient data. American Journal of Psychiatry 154 1220-1227

6. Gilbert, Paul: e-interview by Dominic Fannon. The Psychiatrist (March 2011), Vol 35, Issue 3

7. Mattson MP, Partin J, Begley JG. Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res. 1998a Oct 5;807(1-2):167-76.

8. Sir John Batty Tuke; He described a new appearance which he called'miliary sclerosis,' which now is known by the name of 'senile plaques.'Journal of Mental Science 1914 60: 170-172

9. Curtice, M; Bashir, F; Khurmi, S; Crocombe, J; Hawkins, T and Exworthy, T: The proportionality principle and what it means in practice. The Psychiatrist (March 2011) Vol 35, Issue 3
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