The Fragile Brain: Stress Vulnerability, Negative Affect and GABAergic Neurocircuits in Psychosis

Abstract

Persons with schizophrenia exhibit sensitivity to stress and negative affect (NA), both strongly correlated with poor functional outcome. This theoretical review suggests that NA reflects a “fragile brain,” ie, vulnerable to stress, including events not experienced as stressful by healthy individuals. Based on postmortem evidence of altered gamma-aminobutyric acid (GABA) function in parvalbumin positive interneurons (PVI), animal models of PVI abnormalities and neuroimaging data with GABAergic challenge, it is suggested that GABAergic disruptions weaken cortical regions, which leads to stress vulnerability and excessive NA. Neurocircuits that respond to stressful and salient environmental stimuli, such as the hypothalamic-pituitary-adrenal axis and the amygdala, are highly dysregulated in schizophrenia, exhibiting hypo- and hyper-activity. PVI abnormalities in lateral prefrontal cortex and hippocampus have been hypothesized to affect cognitive function and positive symptoms, respectively; in the medial frontal cortex (dorsal anterior cingulate cortex and dorsal medial prefrontal cortex), these abnormalities may lead to vulnerability to stress, NA and dysregulation of stress responsive systems. Given that postmortem PVI disruptions have been identified in other conditions, such as bipolar disorder and autism, stress vulnerability may reflect a transdiagnostic dimension of psychopathology.

Reactive psychoses in the context of the COVID-19 pandemic: Clinical perspectives from a case series

“…9 Therefore, it is paramount to assess suicidal symptoms in this population with brief reactive psychosis, especially in emergency settings where this task can often be passed over because of the rapidly changing psychopathology in such clinical cases. 12 Other important points to keep in mind are the risk of recurrence and the diagnostic instability of such short-lived psychotic disorders. 14 Although brief reactive psychoses have traditionally been considered clinical conditions with good prognosis, in almost half of such cases, their evolution over time is toward severe mental disorders, mostly schizophrenia or, to a lesser extent, bipolar disorder.…”

Serine Racemase Deletion Affects the Excitatory/Inhibitory Balance of the Hippocampal CA1 Network

“…These altered behavioral responses in SR-KO mice could be associated with the reduced inhibitory tone induced by d -serine removal. Indeed, modulation of GABA activity is known to alter several behaviors such as locomotor activity, anxiety-related behaviors, and memory [ 35 , 36 , 37 , 38 , 39 , 40 ].…”

Clinical characterization of brief psychotic disorders triggered by the COVID-19 pandemic: a multicenter observational study

“…Furthermore, it is noteworthy that there is a diagnostic and prognostic overlap between BPD/ATPD and other operationalizations of short-lived psychotic episodes used in the Clinical High Risk for Psychosis (CHR-P) paradigm such as “Brief Limited Intermittent Psychotic Symptoms” (BLIPS) and “Brief Intermittent Psychotic Symptoms” (BIPS) [ 17 – 19 ]. According to the diathesis-stress model [ 20 ], individuals with brief reactive psychosis have a latent psychological vulnerability (such as heightened emotional reactivity) that makes them more vulnerable to psychotic symptoms when faced with stressful environmental factors [ 13 ]. However, the aetiopathology of these psychotic episodes, which share a multifactorial genetic and environmental pathogenesis, has not been established [ 21 , 22 ].…”