Defining and operationalizing negative symptom constructs in schizophrenia: A practical guide for clinicians, researchers, and industry stakeholders.

Negative symptoms (NS) are a core dimension of schizophrenia and a major determinant of real-life functioning. The National Institute of Mental Health-Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) initiative and the European Psychiatric Association (EPA) guidance have refined NS conceptualization and promoted the use of second-generation assessment instruments. However, the assessment and treatment of NS remain challenging due to the frequent use of first-generation rating scales, likely heterogeneous underlying mechanisms, longitudinal trajectories, and treatment responsiveness. Several constructs have been developed to address this complexity: primary versus secondary NS, Deficit Schizophrenia (DS), persistent negative symptoms (PNS), and predominant and prominent NS. These reflect different priorities, ranging from etiological specificity to operational feasibility. However, their inconsistent use has limited comparability across studies, complicating the interpretation of research evidence. This editorial provides a practice-oriented framework of the definitions, operationalization and implications of these constructs. The primary versus secondary NS distinction remains foundational despite its operational complexity. DS represents the most specific construct for identifying primary and enduring negative symptoms, but its feasibility is constrained by the need for longitudinal assessment and strict exclusion criteria. The PNS construct offers a pragmatic compromise and is supported by EPA recommendations for clinical trials. Predominant and prominent negative symptoms constructs facilitate recruitment but introduce heterogeneity due to their cross-sectional nature. Overall, NS constructs should be considered complementary rather than interchangeable. Greater conceptual alignment and standardized assessment strategies are essential to improve patient stratification, enhance comparability across studies, and support the development of effective treatments.