Serotonin and dopamine interactions in psychosis prevention

There has been significant recent growth in programmes evaluating preventive treatment for individuals exhibiting prodromal symptoms, at high risk of developing first-episode psychosis. Because of the tremendous human and economic burden of schizophrenia and other psychotic disorders, primary prevention modalities of even modest impact would likely have important public health consequence. Several published clinical trials suggest that antipsychotic medications have beneficial effects in either preventing or postponing the emergence of first-episode psychosis in individuals at high risk of psychosis. It is not clear, however, that antipsychotic drugs are the most effective, or safest, pharmacological treatment for psychosis prevention. Mechanisms for primary prevention (intervening to remove a cause of illness) and treatment are not necessarily similar. All of the medications developed for treatment of psychosis rely on tertiary prevention, and there is no a priori reason to assume that these treatments would be the safest and most effective primary preventive treatment of first-episode psychosis. Evidence suggests that selective serotonin reuptake inhibitors, serotonin 5-HT2A and dopamine D3 receptor antagonists, mood-stabilizing medications, GABAergic, glutamatergic and neuroprotective compounds may also be beneficial primary prevention drugs for first-episode psychosis. While there are indications that effective preventive interventions are feasible, data on safety and efficacy of primary preventive treatment interventions are limited and published studies highlight the enrolment challenges facing efforts to identify the safest and most effective preventive treatment interventions through human clinical trials. Treatments preventing behavioural alterations using developmental animal models with relevance to limbic system neurobiology could therefore be useful in focusing hypotheses regarding effective treatments for psychosis prevention. In one such study, low-dose risperidone pre-treatment prevented behavioural abnormalities following neonatal hippocampal lesions, while higher risperidone pre-treatment was ineffective. These findings support the predictive validity of the neonatal hippocampal lesion model in identifying psychosis prevention interventions, provide theoretical support for the use of low-dose risperidone in prevention of first-episode psychosis and suggest the possibility that higher risperidone doses could be less effective than low dosages in this application. These observations also suggest a potential role for selective 5-HT2A receptor antagonists as drug development targets for psychosis prevention.