Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice.
"ur attempt to understand schizophrenia in neurochemical terms began with the landmark studies of Carlsson and Lindqvist (1) in the 1960s. The results of these studies, based on the action of chlorpromazine, were strengthened by the binding studies carried out in both Seeman's (2) and Synder's (3) laboratories, which showed that antipsychotic potency was correlated with dopamine D2 receptor binding. The one major exception to this correlation is clozapine, which appears to be the most effective available drug for treating schizophrenia symptoms. The most recent version of the resulting dopamine hypothesis suggests that genetic, environmental, and developmental variables play major etiological roles in schizophrenia, but that striatal dopamine presynaptic overactivity remains the final trigger resulting in psychosis. The severity and chronicity of schizophrenia have fueled efforts to identify individuals at risk for schizophrenia, with the assumption that a variety of psychosocial and medical treatments can mitigate the longitudinal course (3). Criteria for high-risk individuals and early intervention programs have been developed, and a discussion about including psychosis risk syndrome in DSM-5 (4, 5) has generated a lively debate. The basis of this debate is that many early intervention programs advocate the use of antipsychotic medications along with psychosocial support. The risk of metabolic side effects in high-risk individuals who do not go on to develop the full disorder violates the basic principle of medical treatment, "First, do no harm." A Cochrane Review (6) of the treatment of high-risk individuals finds insufficient evidence of benefit thus far and suggests further study. The article by Howes et al. (7) in this issue of the/ourna/ details a prospective study involving a group of 30 subjects with prodromal symptoms who fall into an ultra-high-risk category for developing schizophrenia. These patients lacked only active psychotic symptoms to qualify for a diagnosis of schizophrenia and to become regular candidates for antipsychotic medication. Using [̂ F̂]DOPA in a positron emission tomography study, the authors were able to show that on average, the patients with the highest levels of dopamine in the associative area of the striatum were those who converted to active schizophrenia. Increased dopamine synthesis is seen only in those who convert to expressing psychotic symptoms, thus qualifying for a diagnosis of schizophrenia. First, this finding adds to the evidence that dopamine overactivity is the central factor driving the full manifestation of psychosis. This may not be specific for schizophrenia, since one of the six patients who converted to schizophrenia in the Howes et al. study went on to develop a bipolar illness, but it held for all five of those who converted to active schizophrenia. Second, it raises the question; Can such a screen be used to more safely start treating prodromal patients with antipsychotic drugs by identifying those who would convert and treating them selectively? These data strongly support the hypothesis that dopamine overactivity, specifically in the striatum, is strongly associated with the emergence of psychotic symptoms and that overactive dopamine release in the striatum is the proximal cause of psychotic symptoms. This provides the strongest evidence to date that dopamine overactivity is essential for psychosis; however, the data still leave some questions unanswered. The most "Can such a screen be used to more safely start treating prodromal patients with antipsychotic drugs hy identifying those who would convert and treating them selectively?"