Invited commentary: Gaining traction on the epidemiologic landscape of schizophrenia.

Background In his scholarly review of the field, Jablensky (1) outlined how the wealth of epidemiologic data about schizophrenia has enriched the "epidemiological horizon" of schizophrenia. This metaphor reminds us of howessential it is to chart the epidemiologic gradients across time and space in order to guide research. In this commentary, I argue that the task for the researcher is not only to continue to refine this map but also to gain "traction" on this landscape to generate, and test, candidate risk factors for schizophrenia. Schizophrenia is a group of imperfectly understood brain disorders characterized by alterations in higher functions related to perception, cognition, communication, planning, and motivation. The syndrome is defined reliably (if not validly) by applying diagnostic criteria related to the presence of hallucinations, delusions, thought disorder, and negative symptoms such as blunted affect and reduced speech (2). Symptoms of the disorder (which has a lifetime morbid risk of about 1 percent) usually emerge in early adulthood, and, although many affected persons make a good recovery, many have intermittent or persistent symptoms for decades. The good news is that advances in biological and psychosocial treatments are improving outcomes for people with schizophrenia and their families. Unfortunately, despite these better treatment options, schizophrenia is still a leading contributor to the global burden of disease (3). Service improvements and the reduction of stigma can cushion the impact of disability; however, even if unlimited funding was available to treat schizophrenia, most of the burden would remain unavoidable. This sober realization keeps the research community focused on finding the causes of schizophrenia. After Herculean efforts, the search for susceptibility genes for schizophrenia appears to be finally paying dividends. Several susceptibility genes have recently been identified, and some of these findings have been replicated (4). Although results are still preliminary, these genes suggest that pathways related to glutamatergic neurotransmission and synaptic formation may be implicated in schizophrenia (5). Complementing the genetic research, there has been a steady accumulation of risk indicators and putative risk-modifying factors derived from the epigenetic/nongenetic domain. Many of these risk factors operate during the prenatal and perinatal period (6). The neurodevelopmental hypothesis of schizophrenia, which rests on a diverse and reasonably robust evidence base (refer to Weinberger and Marenco (7)), proposes that genetic and/or environmental factors disrupt prenatal brain development. The behavioral sequelae of this disruption are thought to be clinically dormant until after puberty, when maturational events lead to emergence of the symptoms of the disorder. More recent revisions of the neurodevelopmental hypothesis have suggested that events proximal to onset of the illness may also be necessary to "precipitate" psychosis. In other words, more than one "hit" may be required to "cause" schizophrenia (8). For example, good evidence now exists showing that migrant status is associated with an increased risk of schizophrenia (9, 10), suggesting that factors operating between the time of migration and illness onset are important.