Experimental Models of Schizophrenia

Abstract

The Kraepelinian subtypes, developed early in the century, recognize the heterogeneity of schizophrenia but do not reliably predict differences in response to classical neuroleptics. The newer distinction of positive and negative syndromes in schizophrenia carry promise as an approach to identifying meaningful clinical and neurobiological dimensions. The present review summarizes the supportive evidence from a series of investigations using the Positive and Negative Syndrome Scale (PANSS), and a hypothesis on the pathophysiology of negative and positive symptoms is advanced. Our data suggest that: (a) positive and negative syndromes in schizophrenia represent stable, independent dimensions and not co-exclusive subtypes; (b) both are unrelated to the progression of illness; (c) they are differentially related to fundamental aspects of schizophrenia, including premorbid adjustment, cognitive development, family psychiatric history, the cognitive and neuropsychiatric profiles, dopaminergic functions, drug response, and subsequent course; (d) together with depression and excitement, they comprise the fundamental symptomatic components of schizophrenia, which, in their interaction, can account for the specific Kraepelinian subtypes. We have proposed that negative symptoms represent the core pathology in schizophrenia and may be understood as a variant of parkinsonism, hence characterized by dopaminergic deficiency and increased cholinergic activity. This view is supported by the striking overlap with Parkinsonism in regard to clinical features, neurochemistry, pharmacology, neuropathology, and neuroradiology. Positive symptoms are thought to reflect increased dopaminergic activity, which may arise as a compensatory adaptive mechanism to overcome the progressive dopamine loss in the maturing brain. The early onset of schizophrenia by comparison to Parkinson's disease may explain why schizophrenia entails more pronounced positive symptoms, development deficits, and cognitive, social, and emotional impairments. We describe evidence that pineal calcification, which may reflect disturbance of melatonin functions, appears to be a nongenetic factor in schizophrenia associated with perinatal injury. This may in part underlie the negative syndrome and its response to antipsychotic compounds with serotonergic (5-HT) antagonism.