Endophenotypes in Schizophrenia for the Perinatal Period: Criteria for Validation

Abstract

Endophenotypes are disease-associated phenotypes that are thought to reflect the neurobiological or other mechanisms that underlie the more overt symptoms of a psychiatric illness. Endophenotypes have been critical in understanding the genetics, neurobiology, and treatment of schizophrenia. Because psychiatric illnesses have multiple causes, including both genetic and nongenetic risk factors, an endophenotype linked to one of the mechanisms may be expressed more frequently than the disease itself. However, in schizophrenia research, endophenotypes have almost exclusively been studied in older adolescents or adults who have entered or passed through the age of risk for the disorder. Yet, schizophrenia is a neurodevelopmental disorder where prenatal development starts a cascade of brain changes across the lifespan. Endophenotypes have only minimally been utilized to explore the perinatal development of vulnerability. One major impediment to the development of perinatally-useful endophenotypes has been the established validity criteria. For example, the criterion that the endophenotype be more frequently present in those with disease than those without is difficult to demonstrate when there can be a decades-long period between endophenotype measurement and the age of greatest risk for onset of the disorder. This article proposes changes to the endophenotype validity criteria appropriate to perinatal research and reviews how application of these modified criteria helped identify a perinatally-usable phenotype of risk for schizophrenia, P50 sensory gating, which was then used to propose a novel perinatal primary prevention intervention.

Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis

“…indicated prevention 77 ). Since recent evidence suggests that these are not fully effective 78,79 , preventive efforts could be expanded to the 'pre-symptomatic' 80,81 or potentially the prenatal stage 51,[82][83][84] , targeting those with specific risk factors (i.e. selective prevention 77 ).…”

Neurophysiological Biomarkers in Schizophrenia—P50, Mismatch Negativity, and TMS-EMG and TMS-EEG

“…Deficits in EAP have been extensively studied in patients with schizophrenia, where they are thought to contribute to failures in detecting important environmental cues and filtering of irrelevant stimuli, possibly leading to social withdrawal, hallucinations, cognitive dysfunction, and decreased level of overall day-to-day functioning (1,3,4,6,7,9,10,12,19,88,100,114,168). Here, we reviewed studies examining if MMN and P50 meet the 5 criteria for a marker to be considered an endophenotype (46), as well as their relationship with cognitive and psychosocial functioning to examine their potential to be used as markers to inform interventions targeted at improving these domains. Furthermore, we examined two TMS paradigms, CSP and LICI, for their potential to be used as markers of sensory gating and as endophenotypes in schizophrenia.…”

The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia

“…In a similar scenario to that of LI, P50 gating is a well recognized endophenotype of schizophrenia 75 76 77 . There is a large body of evidence to suggest that many (but not all) patients with schizophrenia have P50 gating abnormalities 78 .…”