Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of N-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.
Schizophrenia is a debilitating mental disorder that affects about one percent of the population. It is characterized by positive symptoms (e.g., abnormal perceptions and beliefs), negative symptoms (e.g., anhedonia and social withdrawal) and cognitive deficits. It is believed to be multifactorial and heterogeneous in its etiology, such that multiple pathological processes converge on a cluster of affiliated symptoms. Schizophrenia and other psychotic disorders are increasingly thought of as neurodevelopmental disorders, where multiple hits accumulate during critical periods of central nervous system (CNS) development to cause the disorders. The majority of patients with schizophrenia began with a prodromal phase characterized by subclinical symptoms of the disorder, which we will refer to hereafter as a state of clinical high risk for psychosis (CHR) [1,2,3,4]. In some studies, 22% of those meeting the criteria for CHR convert to a psychotic disorder at one year follow-up, as compared to 0.015% in the general population .
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