Schizophrenia: more same than different to neurodevelopmental disorders?

Rather than a discrete entity, schizophrenia sits on a neurodevelopmental continuum of disorders with increasing impairment. Such is the hypothesis expounded by Professor Michael Owen in a lecture at ECNP2018. The neurodevelopmental continuum is based on emerging evidence for shared genetic risk and overlapping pathogenic mechanisms of neurodevelopmental disorders in early ages – intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD) – with schizophrenia and bipolar disorder. The neurodevelopmental continuum underscores the need for a greater integration of research efforts among psychiatric disorders at all ages, and emphasizes the need for a developmental life-course approach to clinical practice. Evidence is mounting for a dynamic decline in cognitive funtion in schizophrenia throughout the disease course.

Schizophrenia is on the neurodevelopmental continuum

Professor Michael Owen (University of Cardiff, UK) is a leading exponent of a new hypothesis in which neurodevelopmental disorders – including schizophrenia – rather than being discrete entities, are better conceptualized as lying on a neurodevelopmental continuum.1 In this model, Professor Owen explained that severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder.

The neurodevelopmental hypothesis of schizophrenia, in which disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, has been widely accepted since the late 1980s.2,3 Until recently, however, schizophrenia was considered as distinct from classical neurodevelopmental disorders: autism spectrum disorders, ADHD and intellectual disability.

The neurodevelopmental continuum model is based on emerging evidence for shared genetic and environmental risk factors and predicts that there are also likely to be overlapping pathogenic mechanisms; it represents the diverse range of outcomes that can follow from disrupted or deviant brain development.

Schizophrenia shares genetic risk and pathogenic mechanisms with early onset neurodevelopmental disorders

Genomic studies have identified large, rare copy number variants (CNVs) that confer risk to schizophrenia, and that the same variants confer risk to intellectual disability, autism spectrum disorders, and ADHD.4-6 There is also evidence that the enrichment of damaging rare coding variants confer risk of schizophrenia, and for overlap between damage variants found in schizophrenia, autism, and intellectual disability. The enrichment of rare mutations correlates with the degree of cognitive symptoms on a severity scale of intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder.

The neurodevelopmental continuum underscores the need for greater communication and integration between communities researching neurodevelopmental disorders in early ages and those studying largely adult-onset psychiatric disorders, such as schizophrenia and bipolar disorder, said Professor Owen.

The neurodevelopmental continuum underscores the need for a developmental life-course approach to psychiatry

There are also implications for clinical practice; Professor Owen encouraged clinicians to take a developmental life-course approach ensuring that patients are effectively managed across their life span, with an awareness that developmental changes over time may be expected and anticipated.

Cognitive symptoms worsen in schizophrenia over time

Dr Avi Reichenberg, Mount Sinai School of Medicine, USA, discussed mounting evidence for a progressive decline in cognitive functioning observed across the disease course of schizophrenia. Cognitive impairment is present early in schizophrenia,7 is dynamic and leads to worsening dysfunction in young adulthood,8 and continues to worsen with advancing age.9

This is evidenced by the results of a recent longitudinal study (AESOP) with 10-year follow-up showing that rather than remaining stable, deficits in general intellectual ability (IQ) observed following the first episode in schizophrenia patients (age 16-65 years) decline with increasing age (Zanelli, unpublished). The decline in specific cognitive domains include: memory, verbal knowledge and some executive functions involved in working memory.

  1. Owen MJ & O'Donovan MC. World Psychiatry 2017;16:227-35.
  2. Weinberger DR. Arch Gen Psychiatry 1987;44:660-9.
  3. Murray RM & Lewis SW. BMJ (Clin Res Ed) 1988;296:63.
  4. Singh T et al. Nat Genet 2017;49:1167-73.
  5. Pardinas AF et al. Nat Genet. 2018;50:381-89.
  6. The Brainstorm Consortium. Science 2018:360:6395.
  7. Woodberry KA et al. Am J Psychiatry 2008;165:579-8.
  8. Mollon J et al. JAMA Psychiatry 2018;75:270-79.
  9. Meier MH et al. Am J Psychiatry 2014;171:91-101.
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