David A. Lewis*‡ and Jeffrey A. Lieberman†‡* Departments of Psychiatry and Neuroscience University of Pittsburgh School of Medicine this syndrome is increased as well. Recently, chromo-† Departments of Psychiatry, Pharmacology, some 1q21–22 was identified as the location of a major and Radiology vulnerability locus for familial schizophrenia with suffi-University of North Carolina School of Medicine cient power to permit positional cloning of the underlying gene (s)(Brzustowicz et al., 2000). Environmental factors (including exposure to infectious, autoimmune, toxic, or traumatic insults and stress Introduction during gestation or childhood) also may play a role in Schizophrenia is a brain disorder that is expressed in the pathogenesis of schizophrenia, perhaps via subtle the form of abnormal mental functions and disturbed alterations of neurodevelopment (Marcelis et al., 1998). behavior. These manifestations characteristically ap- Moreoever, maturational processes including apoptopear in the late second and third decades of life as a sis, synaptic pruning, and myelination, occurring in the heterogeneous constellation of three classes of clinical postnatal period through adolescence, may unmask the features. Positive symptoms include delusions (false be- genetic vulnerability to schizophrenia (Lewis, 1997; Jarliefs), hallucinations (false perceptions), and thought dis- skog et al., 2000; Raedler et al., 2000). Thus, the etiology organization. Negative symptoms refer to the loss of of schizophrenia has been conceptualized as involving motivation and emotional vibrancy. Disturbances in ba- multiple hits (consisting of genes conferring vulnerability sic cognitive functions, such as attention, executive and environmental insults), which are revealed in the functions, and specific forms of memory (particularly context of developmental maturation of brain circuitry. working memory), are also consistently observed in pa- However, unlike other genetic neurodevelopmental distients and are now thought to be central to the behavioral orders (eg, Down’s syndrome or Fragile X syndrome), disturbances and functional disability of schizophrenia. or severe gestational and birth traumas (eg, fetal hyp-In addition, many patients have concomitant mood oxia or kernicterus), there are no immediate overt manisymptoms including depression and anxiety that may festations of schizophrenia. Rather, most individuals apcontribute to the 10% lifetime incidence of suicide in pear to function normally until they enter the greatest period of risk in late adolescence and early adulthood. schizophrenia.