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Stress-Induced Pathophysiology 2571992). Finally, Pantelis and colleagues (2000) have shown that in imaging studiesof high-risk individuals, the first schizophrenic break (i.e., onset of psychoticsymptoms) is associated with an increased volume of the hippocampus followedby a decrease, which may be indicative of the onset of a pathological process inthis structure.We also have evidence that in a developmental model of schizophrenia (Mooreet al., 2001a, 2006), the rats are more susceptible to stress-induced disruption ofsynaptic plasticity within the hippocampal-prefrontal cortex (Goto & Grace, 2006).The hippocampus itself is a central component in the functioning of the limbicsystem, as it provides a potent contextual gating influence over the accumbens(O’Donnell & Grace, 1995). Indeed, in both the developmental model of schizophrenia(Moore et al., 2006) and in animals treated with phencyclidine (O’Donnell& Grace, 1998b), there is a disruption in the ability of the hippocampus to gateinformation flow within the accumbens. Therefore, pathology of the hippocampusleading to disturbances in hippocampal gating would severely disrupt theability of the schizophrenia patient to selectively attend to salient stimuli and toeffectively screen out distractions (Grace & Moore, 1998). Such a condition wouldleave them constantly bombarded with stimuli demanding attention.Implications for the Onset of Schizophreniaand Its Potential Pharmacological CircumventionTaken together, the results reviewed above suggest that a deficit in the regulationof the response to stress may be a central component in the delayed onset of schizophreniasymptomatology. It also suggests a potential means for preventing thecascade of events during adolescence that are proposed here to lead to the onsetof the first psychotic break and the symptoms of schizophrenia in late adolescence/early adulthood. One method that is currently suggested and is under evaluationto prevent the onset of schizophrenia is preventive treatment with antipsychoticdrugs, which appears to be effective in some but not all individuals when givenduring the prodrome (Cornblatt et al., 2002). In my opinion, this would not be themost effective course to circumvent the onset of psychosis. First, it is not likelyadvisable to treat young adolescents at risk for schizophrenia with antipsychoticdrugs, because these are rather potent pharmacological interventions to be givento a population of which a large percentage are not likely to develop psychosisregardless of treatment (Cornblatt et al., 2001). But moreover, it is not evidentthat treatment with drugs that are primarily dopaminergic antagonists is the bestpharmacotherapeutic approach. Thus, Laruelle (1998) has shown that a hyperdopaminergicstate in schizophrenia is observed in schizophrenia patients onlywhen tested for their response to low doses of amphetamine when the amphetamineadministration also results in the exacerbation of positive symptoms.