Aberrant Fear: Biological Underpinnings Relevant to Psychosis, Antipsychotic Drugs, and Psychotherapeutic Treatments, a Translational Approach

Fear is a transdiagnostic construct implicated in multiple psychiatric disorders, reflecting a partial dissociation between clinical phenotypes and underlying neurobiological mechanisms. Converging evidence suggests that aberrant fear processing plays a central role in cognitive and psychopathological models of psychosis. In this narrative review, we synthesize evidence on the neurobiological mechanisms of aberrant fear modulation in schizophrenia from a translational perspective, integrating findings from neuroimaging, preclinical models, pharmacological interventions, and psychotherapy. Schizophrenia is characterized by aberrant emotional processing and inappropriate neural responses to stimuli with reduced or absent objective salience, reflecting impaired discrimination of relevant environmental information. At the system level, evidence implicates dysregulation of cortico-limbic and salience-processing networks in altered fear learning, threat appraisal, and emotional prediction. Neurochemical findings indicate that dopamine–glutamate dysregulation and associated intracellular signaling pathways act as upstream modulatory mechanisms contributing to these network-level abnormalities. Therapeutic interventions, including antipsychotic drugs and psychotherapeutic approaches, partially modulate these systems, although effects remain heterogeneous. Overall, the evidence supports a hierarchical model in which aberrant fear processing in schizophrenia arises from disrupted salience attribution and impaired integration across cognitive, affective, and neurobiological levels. This intermediate dysfunction links molecular alterations to large-scale network disturbances and clinical symptom expression, providing a framework for more mechanism-based therapeutic strategies.