Crow & Harrington Pathogenesis of Psychosis

Psychotic illnesses (schizophrenia and schizoaffective and affective psychosis) have a lifetime prevalence of 2–3% and probably occur at a similar rate in all human societies. No etiologically significant environmental precipitants have been identified, and this suggests that these diseases are primarily genetic. Brain studies reveal that in schizophrenic patients, development of cerebral asymmetry is arrested, which may be associated with a small reduction in cortical mass. Episodes of illness can be ameliorated by dopamine (in particular D2) antagonists, drugs that are antipsychotic rather than merely antischizophrenic. The discovery of at least five dopamine receptor subtypes and their genes paves the way for new approaches to treatment. However, whether psychotic patients undergo a primary disturbance of dopaminergic transmission remains unclear. 0066-4219/94/0401-0219$05.00 219 DEFINITION OF PSYCHOSIS Psychoses (schizophrenic, schizoaffective, and affective illnesses) are common (with a lifetime prevalence of 2–3%) and account for a high percentage of the serious morbidity associated with psychiatric disease. The magnitude of their social impact stems from their onset in early adult life coupled with a strong tendency to recur, or in some cases, to persist and even progress. The defining characteristics of psychoses are psychotic symptoms such as a delusion (a belief held despite evidence to the contrary), a hallucination (sensory experience without adequate external stimulus), or thought disorder. Without a clear understanding of pathogenesis, or a laboratory diagnostic test, such symptoms serve as the clinician’s principal guide to prognosis and treatment. This review examines advances in our understanding of pathogenesis, with a particular focus on brain morphology and neurochemistry studies, and explores innovations in treatment in the context of our current knowledge of etiology and outcome. ORIGINS AND LIMITS OF THE CONCEPT OF SCHIZOPHRENIA The term schizophrenia covers diverse conditions, [the “group of schizophrenias,” according to Eugen Bleuler (1)] but their subdivision has sparked heated controversy, and the distinction between schizophrenia and manic-depressive psychoses, the other major catergory of recurrent adult illnesses, has come under increasing scrutiny. Both of these types of disorders are still classified as functional psychoses, which implies that no change in brain structure occurs. This view is supported in textbooks stating that whereas structural brain changes related to cognitive and intellectual impairments occur in the dementias (chronic organic psychosis), such neural and psychological changes are absent in schizophrenia. However, schizophrenic patients sometimes exhibit severe intellectual impairments, and structural changes in the brain can also occur (2, 3). Although such cases represent one extreme of the spectrum of severity of schizophrenic illnesses, the boundary between schizophrenia and affective disorder at the other end has given rise to considerable doubt as well. Recent studies reveal that these two diseases overlap, thereby refuting the Kraepelinian binary system, which purports that schizophrenia and manic-depressive illness are distinct entities and thus implies that they have different etiologies. Even Kraepelin himself began to question his original findings, and in 1920 (4) he wrote of ...the difficulties which still prevent us from distinguishing reliably between manic-depressive insanity and dementia praecox. No experienced psychiatrist 220 CROW & HARRINGTON