Skip to main content

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.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Neurodevelopmental hypothesis of schizophrenia
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Neurodevelopmental hypothesis of schizophrenia
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Neurodevelopmental hypothesis of schizophrenia
      Available formats
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:
Hide All

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).

Declaration of interest


Hide All
1 Weinberger, DR. The pathogenesis of schizophrenia: a neurodevelopmental theory. In The Neurology of Schizophrenia (eds Nasrallah, RA & Weinberger, DR): 387405. Elsevier, 1986.
2 Murray, RM, Lewis, SW. Is schizophrenia a neurodevelopmental disorder? BMJ (Clin Res Ed) 1987; 295: 681–2.
3 Harrison, PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122: 593624.
4 van Os, J, Kapur, S. Schizophrenia. Lancet 2009; 374: 635–45.
5 Craddock, N, Owen, MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–6.
6 Wang, WY, Barratt, BJ, Clayton, DG, Todd, JA. Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6: 109–18.
7 Craddock, N, O'Donovan, MC, Owen, MJ. Phenotypic and genetic complexity of psychosis. Invited commentary on … Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 2007; 190: 200–3.
8 Owen, MJ, Craddock, N, Jablensky, A. The genetic deconstruction of psychosis. Schizophr Bull 2007; 33: 905–11.
9 Craddock, N, Owen, MJ. The Kraepelinian dichotomy – going, going … but still not gone. Br J Psychiatry 2010; 196: 92–5.
10 Owen, MJ, Craddock, N, O'Donovan, MC. Suggestion of roles for both common and rare risk variants in genome-wide studies of schizophrenia. Arch Gen Psychiatry 2010; 67: 667–73.
11 Williams, NM, Zaharieva, I, Martin, A, Langley, K, Mantripragada, K, Fossdal, R, et al. Rare chromosomal deletions and duplications are associated with attention deficit hyperactivity disorder and overlap with those conferring susceptibility to autism and schizophrenia. Lancet 2010; 376: 1401–8.
12 Lichtenstein, P, Yip, BH, Björk, C, Pawitan, Y, Cannon, TD, Sullivan, PF, et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009; 373: 234–9.
13 Rutter, M, Kim-Cohen, J, Maughan, B. Continuities and discontinuities in psychopathology between childhood and adult life. J Child Psychol Psychiatry 2006; 47: 276–95.
14 Sebat, J, Levy, DL, McCarthy, SE. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 2009; 25: 528–35.
15 Larsson, HJ, Eaton, WW, Madsen, KM, Vestergaard, M, Olesen, AV, Agerbo, E, et al. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol 2005; 161: 916–25.
16 Daniels, JL, Forssen, U, Hultman, CM, Cnattingius, S, Savitz, DA, Feychting, M, et al. Parental psychiatric disorders associated with autism spectrum disorders in the offspring. Pediatrics 2008; 121: e135762.
17 Greenwood, C, Husted, J, Bomba, M, Hodgkinson, K, Bassett, A. Elevated rates of schizophrenia in a familial sample with mental illness and intellectual disability. J Intellect Disabil Res 2004; 48: 531–9.
18 Keshavan, M, Montrose, DM, Rajarethinam, R, Diwadkar, V, Prasad, K, Sweeney, JA. Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments. Schizophr Res 2008; 103: 114–20.
19 de la Serna, E, Baeza, I, Toro, J, Andrés, S, Puig, O, Sánchez-Guistau, V, et al. Relationship between clinical and neuropsychological characteristics in child and adolescent first degree relatives of subjects with schizophrenia. Schizophr Res 2010; 116: 159–67.
20 Morgan, VA, Leonard, H, Bourke, J, Jablensky, A. Intellectual disability co-occurring with schizophrenia and other psychiatric illness: population-based study. Br J Psychiatry 2008; 193: 364–72.
21 Rapoport, J, Chavez, A, Greenstein, D, Addington, A, Gogtay, N. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry 2009; 48: 10–8.
22 Stahlberg, O, Soderstrom, H, Rastam, M, Gillberg, C. Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders. J Neural Transm 2004; 111: 891902.
23 Rommelse, NN, Franke, B, Geurts, HM, Hartman, CA, Buitelaar, JK. Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder. Eur Child Adolesc Psychiatry 2010; 19: 281–95.
24 Simonoff, E, Pickles, A, Charman, T, Chandler, S, Loucas, T, Baird, G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 2008; 47: 921–9.
25 Simonoff, E, Pickles, A, Wood, N, Gringras, P, Chadwick, O. ADHD symptoms in children with mild intellectual disability. J Am Acad Child Adolesc Psychiatry 2007; 46: 591600.
26 Fioravanti, M, Carlone, O, Vitale, B, Cinti, ME, Clare, L. A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychol Rev 2005; 15: 7395.
27 Joyce, EM, Roiser, JP. Cognitive heterogeneity in schizophrenia. Curr Opin Psychiatry 2007; 20: 268–72.
28 Cannon, M, Caspi, A, Moffitt, TE, Harrington, H, Taylor, A, Murray, RM, et al. Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry 2002; 59: 449–56.
29 Zanelli, J, Reichenberg, A, Morgan, K, Fearon, P, Kravariti, E, Dazzan, P, et al. Specific and generalized neuropsychological deficits: a comparison of patients with various first-episode psychosis presentations. Am J Psychiatry 2010; 167: 7885.
30 Grozeva, D, Kirov, G, Ivanov, D, Jones, IR, Jones, L, Green, EK, et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry 2010; 67: 318–27.
31 Goldberg, D. Should our major classifications of mental disorders be revised? Br J Psychiatry 2010; 196: 255–6.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 32 *
Loading metrics...

Abstract views

Total abstract views: 103 *
Loading metrics...

* Views captured on Cambridge Core between 3rd January 2018 - 18th March 2018. This data will be updated every 24 hours.

Neurodevelopmental hypothesis of schizophrenia

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


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.
... More

Conflict of interest: None Declared

Write a reply

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. ... More

Conflict of interest: None Declared

Write a reply

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
... More

Conflict of interest: None Declared

Write a reply


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *