Evidence for progression of brain structural abnormalities in schizophrenia: beyond the neurodevelopmental model

Objective: Clinical, neuroimaging, neuropathological and neuropsychological evidence suggests that, in schizophrenia, there is structural and function al disturbance of the hippocampus. The purpose of this paper is to present published findings concerning the nature, timing and course of these putati ve disturbances of hippocampal function and the pathophysiological mechanis ms involved, and to explore whether schizophrenia is a disorder of neurodev elopment, neurodegeneration or a combination of both processes. Method: The available cross-sectional and longitudinal evidence for hippoca mpal involvement in schizophrenia is reviewed and a model of hippocampal in volvement in this disorder, which derives from our own cross-sectional and longitudinal hippocampal imaging data, is described. Results: We propose a three-hit model in which an early neurodevelopmental lesion renders the hippocampus vulnerable to further insult later in life d uring the transition phase to active illness. The available evidence sugges ts that the left hippocampus is particularly vulnerable during these early stages, while further insult involving the hippocampus bilaterally occurs i n those who develop a chronic form of the illness. Conclusions: Intervention strategies should target the most vulnerable stag es of the illness, in particular the transition phase to psychosis, when no vel treatments may prevent the illness or ameliorate its effects.