The third hurdle

consists in linking between putative environmental influences, genes, and the onset of schizophrenia symptoms. For example, famine during a specific period of pregnancy is a putative environmental effect that has an impact on the genetic vulnerability to schizophrenia14 only during a limited time window (critical period) of development, but has no effect outside this period. However, periods as long as 10 to 15 years may elapse between Inhibitors,research,lifescience,medical exposure to the environmental influence and initiation of the disease process (induction period), or in the case of schizophrenia between initiation of disease process (ie, prodrome) and the diagnosis of the disease (latency period). Long periods of time between the critical, induction, and latency

periods make it difficult Inhibitors,research,lifescience,medical to detect the real causal agents, and the strength of association between an exposure to the environmental influence and the disease. Furthermore, some of the risks for schizophrenia, such as intrauterine stress and birth complications, late age of father at conception, drug abuse, head trauma, urbanization, immigration, and poor social status, Inhibitors,research,lifescience,medical are common to other diagnostic categories and behavioral abnormalities than schizophrenia. The difficulties in defining the schizophrenic phenotype further increase the difficulties in associating between the risk and the illness. Again using the cardiovascular paradigm projected several hundred years ago, it would have been difficult to link smoking and plenty of food, Inhibitors,research,lifescience,medical both symbols or prosperity and happiness, to disease. It would have been even more difficult to take the next step and hypothesize that Inhibitors,research,lifescience,medical predisposition to smoke15 or eat excessively16 are affected by individual genetic makeup and that the end result (the metabolic syndrome, the atherosclerotic lesions, and the consequent cardiovascular

malfunction) reflects the interactions between genes and environment.17 Hopefully, in the foreseeable GSK-3 beta phosphorylation future, apparently puzzling findings, such as the synergism between family history and living in an urban area increasing the risk for schizophrenia,18 will be unraveled. Fourth, despite the broad agreement among schizophrenia researchers that premorbid and prodromal else manifestations exist, the characteristics and prevalence of the manifestations are far from well elucidated. To fully elucidate the premorbid and prodromal manifestations and their respective prevalence, it is necessary to follow a randomly sampled birth cohort throughout the entire age of risk for schizophrenia. A related, but less informative, strategy is to follow apparently healthy individuals hypothesized to be at high risk for schizophrenia, such as first-degree relatives of affected individuals.