Neurochemical models of psychosis risk and onset

No licensed pharmacological treatments exist to prevent the onset of psychosis in people at clinical high risk. This chapter reviews four preclinical models that inform the development of such treatments: neonatal hippocampal lesion, prenatal immune activation, and administration of PCP or methylazoxymethanol acetate (MAM). The neonatal hippocampal model lacks construct validity, evidence linking prenatal immune activation to psychosis is limited, and the chronic PCP model lacks a neurodevelopmental component. The MAM model best reproduces neural and behavioral changes resembling human psychosis onset. Together, these models have advanced understanding of mechanisms underlying psychotic disorders and provide a rationale for novel preventative interventions.

Study at a glance

Abstract

Abstract Although clinical intervention at the clinical high risk stage has the potential to prevent the onset of psychosis, there are still no licensed pharmacological treatments for this purpose. The development of preventative treatments is informed by models of psychosis onset, especially those that reflect the time course and symptomatology of the disorder. This chapter describes four different preclinical models of psychosis onset, involving a neonatal hippocampal lesion, prenatal immune activation, and administration of PCP (phencyclidine) or methylazoxymethanol acetate (MAM), respectively. While all these models are useful, the neonatal hippocampal model lacks construct validity, the evidence linking prenatal immune activation with psychosis is limited, and the chronic PCP model does not have a neurodevelopmental component. The MAM model reproduces a neurodevelopmental trajectory of neural and behavioral changes that resemble those evident in human studies of psychosis onset. Collectively, these models have advanced knowledge of the mechanisms underlying the onset of psychotic disorders and have provided a rationale for novel preventative interventions.