Neurodevelopmental model of schizophrenia: update 2012

Abstract

The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood-onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole-population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments.

Figure 1

(a and b) Neuronal proliferation, cell migration, morphological and biochemical differentiation, and circuit formation all depend on cell and cell–environment interactions that control developmental processes, and so can cause altered trajectories.

Figure 2

Cortical gray matter (GM) deficits across age 10–20 years in patients with childhood-onset schizophrenia (COS; upper panel) and their healthy siblings compared with matched healthy controls. Statistically significant gray matter cortical thickness deficits, using mixed-effect models across over 40 000 cortical points in each hemisphere, are represented by colors corresponding to t-values shown in the scale bars. Figure 2 adapted from the research of Greenstein et al. (upper panel), Gogtay et al. (lower panel) and Mattai et al. (lower panel).

Figure 3

Regions where the relationship between COMT Val158Met Val allele dose and cortical thickness change is significantly different in healthy controls (HCs) as compared to probands with childhood-onset schizophrenia (COS). The inset plot illustrates this interaction for the left dorsolateral prefrontal region, where increased Val dose attenuates cortical thinning on HCs, but accelerates it in probands with COS. Note that by adulthood, COS Val homozygotes have persistent cortical thickness deficits compared with HCs, whereas Met homozygotes do not. All colored regions shown survive false discovery rate correction for multiple comparisons at q < 0.05.