The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches

Abstract

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.

Introduction

Schizophrenia is widely considered to be a genetically mediated neurodevelopmental disorder. The neurodevelopmental theory of schizophrenia postulates that etiologic and pathogenic factors occurring long before the formal onset of the illness (probably in gestation) disrupt the course of normal neural development, resulting in subtle alterations of specific neurons and circuits, which confer vulnerability and may ultimately lead to malfunction (Figure 1)Bloom 1993, Lewis and Lieberman 2000, Murray and Lewis 1987, Weinberger 1987. The consequences of these neurodevelopmental aberrations, however, do not immediately cause clinical manifestations in schizophrenia as in other neurodevelopmental disorders, such as autism, fragile X, or Down’s syndrome. Rather, symptoms typically present after a latency period of 1–3 decades. At the same time, high-risk and longitudinal birth cohort studies have identified social, motor, and cognitive dysfunctions and mild physical anomalies during childhood and adolescence, before the onset of illness (Jones 1997). These features, however, are mild in severity and have low predictive validity as individual markers of schizophrenia Erlenmeyer-Kimling and Cornblatt 1987, Fish 1977.