Schizophrenia and the neurodevelopmental continuum:evidence from genomics

Abstract

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention-deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as "neurodevelopmental disorders". An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.

S.16.02 Schizophrenia and the neurodevelopmental continuum; new support from genomics

“…It will be challenging to treat underlying neurodevelopmental mechanisms, and therapeutic approaches, at least in the short and medium term, might need to focus upon symptomatic management of the particular domains (psychopathological, cognitive, sensorimotor) affected in an individual. For the medium and long term, recent genomic findings offer many opportunities for mechanistic research 78 . Moreover, there is evidence from genomics for tractable biology, and the high degree of pleiotropy suggests that therapeutic approaches might be successful across current diagnostic boundaries 47 .…”

Why the clinical utility of diagnostic categories in psychiatry is intrinsically limited and how we can use new approaches to complement them

“…They usually assume either: a) that the realm of psychopathology can be more efficiently described in terms of dimensions, or b) that the neurobiological underpinnings of psychopathology should be the major drivers of psychiatric classifications. These alternative approaches are being put forward both at the level of the entire realm of psychopathology (respectively, by projects such as the Hierarchical Taxonomy of Psychopathology, HiTOP and the Research Domain Criteria, RDoC) and at the level of specific areas of psychopathology (respectively, through models such as the “transdiagnostic psychosis spectrum” and the “neurodevelopmental gradient”).…”

The neurodevelopmental origins of schizophrenia in the penumbra of genomic medicine

“…From the background of this perspective, I found the paper by Owen and O'Donovan appearing in this issue of the journal to be most timely and informative. These investigators have been at the leading edge of a generation of landmark genetic studies, based on rapidly developing molecular techniques for surveying genetic variation across the genome and the availability of large samples of case and control subjects generated by teams of investigators sharing data across many international research centers.…”