Genetic knockouts and the Hierarchical Taxonomy of Psychopathology (HiTOP): a path toward individualized psychiatry (a brief narrative review)

This brief scientific-analytical review examines the limitations of traditional categorical diagnostic systems—the International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM)—in forming homogeneous groups for biological research and applying the obtained results to address clinical challenges. As alternatives, we considered new psychopathological frameworks: the Research Domain Criteria (RDoC) and the Hierarchical Taxonomy of Psychopathology (HiTOP). The review primarily focuses on the HiTOP framework, which is structured hierarchically. Within this system, clinical presentation is viewed as a multi-level structure where the top level is occupied by a general psychopathology factor termed the P factor. The middle level consists of psychopathological domains or spectra encompassing more specific phenotypic manifestations: depression, cognitive impairments, impulsivity, and psychosis. The bottom level comprises individual symptoms (e.g., insomnia or suicidality) characteristic of a particular case but not defining the overall clinical picture. Additionally, the framework accounts for the degree of patient maladaptation associated with a specific symptom, as well as the influence of external factors on symptom severity and the extent of maladaptation. As an illustration of the rationality of this approach, the review presents knockout models of two domains—cognitive and anxiety-related. Using the example of the knockout of several genes (Kmo, Gabrb2, Grm2/3, Grm1, Plcb1, Taar1, Disc1, Slc6a4, Htr1a, Htr2c, Slitrk5), we showed that specific genetic disruptions lead to the manifestation of diverse behavioral phenotypes, particularly various combinations of cognitive and emotional impairments, which often occur as transdiagnostic symptoms across different conditions. The review discusses the potential applications of the HiTOP approach and data obtained from knockout animal studies for the personalization of therapy and the development of more precise biological models of mental disorders.