Pieces of the Schizophrenia Puzzle Fall into Place

about prefrontal and temporal cortex and also highlighted interactions with other regions such as the thalaThe great psychiatrists of the late nineteenth and early mus, hippocampal complex, and cingulate gyrus (e.g., twentieth century, who initially identified schizophrenia Weinberger et al., 1988; Andreasen et al., 1994a, 1994b; as a discrete illness, assiduously sought to identify its Selemon et al., 1995; Shenton et al., 1992). neural mechanisms, but were unsuccessful in their Neuropharmacology search. The pathophysiology and etiology of schizoSchizophrenia research was given a new impetus during phrenia remain among the tantalizing puzzles of modern the 1960s by the development of apparent “miracle medicine, although considerable progress has been drugs,” which substantially reduced the symptoms of made during recent years, as this minireview will sumthe disorder and were even transiently considered a marize. Two recent reports in Nature highlight some of potential cure. Emphasis temporarily shifted in the directhe advances that have occurred. The work of Silbertion of viewing schizophrenia as a chemical brain disorsweig et al. (1995) has suggested that a key symptom of der. After severalseminal studies indicated that the therschizophrenia, auditory hallucinations (“hearing voices” apeutic efficacy of the new medications was closely without a perceptual stimulus), may be related to incorrelated with their ability to block dopamine type 2 creases in cerebral blood flow in subcortical and limbic receptors, the dopamine hypothesis of schizophrenia regions of the brain. The work of Dolan et al. (1995) has was developed (Carlsson and Carlsson, 1990; Seeman suggested that impairments in cognition, another key et al., 1976). This hypothesis suggests that psychotic feature of the illness, may be due to dysfunctions in the disorders, which are characterized by symptoms such cingulate cortex that are reversed by dopamine agoas delusions and hallucinations (key features of schizonists. To understand the significance and implications phrenia), are due to a functional excess of dopamine. of these advances toward assembling the schizophrenia The dopamine hypothesis has formed the basis for drug puzzle, we must examine their historical and conceptual development and for understanding mechanisms of context. drug action for several decades. Very recent advances