Is Schizophrenia a Progressive Neurodevelopmental Disorder? Toward a Unitary Pathogenetic Mechanism

Abstract

It matters whether the pathogenetic agent in schizophrenia is static or progressive, since if it is the latter it is worthwhile to search not only for means of prevention but also for interventions that will arrest progression as early as possible.

Schizophrenia Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

“…Compared with normal controls, individuals with schizophrenia seem to undergo an exaggerated reduction of gray matter volume in the context of minimal neuronal loss (Selemon and Goldman-Rakic 1999;McGlashan and Hoffman 2000;Woods 1998). The gray matter volume deficits observed in schizophrenia appear to be already present at the onset of the disease and to be non-progressive (Gur et al 2000a,b; for review see Pearlson and Marsh 1999).…”

“…It is therefore possible that gray matter volume reductions represent genetically loaded deficits (Cannon et al 1998;Seidman et al 1999;Staal et al 2000;Gur et al 2000a,b;Baare et al 2001). These gray matter deficits could be due to an early underdevelopment of synaptic connectivity (which may result in smaller heads) or overaggressive pruning process occurring primarily in the pre-adolescence period which may result in normal head size but smaller brain volume at illness onset (McGlashan and Hoffman 2000;Woods 1998;Giedd et al 1999b;Rapoport et al 1999).…”

“…This possibility is supported by the observation that in discordant twin pairs the affected twin has enlarged lateral ventricles (Baare et al 2001; Ohara et al 1998) which are closely associated with cerebral white matter volume (Symonds et al 1999;Bartzokis et al, unpublished observation). Abnormal white matter development would impair the overall ability of the brain to maintain functional synchrony and, in concert with the continuous decreases in gray matter volumes which occur after early adolescence, result in an irreversible deterioration from previous levels of functioning (Woods 1998;Bartzokis et al 2001). Compared with normal controls, the lack of compensating myelination in the face of the continued normal life-long reductions in gray matter volumes (Bartzokis et al 2001) could contribute to progression of symptoms after illness onset and the appearance of continued brain "degenerative" changes in the absence of gliosis (DeLisi 1997).…”

“…Considerable evidence indirectly supports a progressive loss of brain tissue volume occurring at some point during postnatal development. This evidence includes the larger extracerebral CSF volume with normal skull size in schizophrenia (as reviewed by Woods 1998), as well as postmortem evidence of decreased neuropil (as opposed to neurons themselves) in prefrontal, dorsolateral prefrontal, and occipital cortices (Selemon and Goldman-Rakic 1999;Uranova et al 2001;Cotter et al 2002). Longitudinal imaging studies comparing schizophrenic and control subjects age 10 or older have generally supported this hypothesis.…”

“…The absence of gliosis has been interpreted to suggest that schizophrenia is a neurodevelopmental rather than a neurodegenerative disorder (Weinberger 1987;Weinberger and Lipska 1995). The definition of neurodevelopment has been recently expanded and refined as brain development and maturation that occurs as a consequence of an orderly process which begins in utero and continues into the early twenties (Woods 1998).…”