Chenyang Xu ¹ Yanbao Tao ^2* Yunhan Lin ^1* Jiahui Zhu ^3* Zhuoran Li ⁴ Jiayi Li ^1* Mingqia Wang ¹ Tao Huang ^5* Chuan Shi ^1*

• ¹ Peking University Sixth Hospital, Peking University Institute of Mental Health, National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
• ² The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China
• ³ National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
• ⁴ University of Toronto, Toronto, Ontario, Canada
• ⁵ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China

Background: Increasing evidences suggests that depression is a heterogeneous clinical syndrome. Cognitive deficits in depression are associated with poor psychosocial functioning and worse response to conventional antidepressants. However, a consistent profile of neurocognitive abnormalities in depression remains unclear.Objective: We used data-driven parsing of cognitive performance to reveal subgroups present across depressed individuals and then investigate the change pattern of cognitive subgroups across the course in follow-up.Method: We assessed cognition in 163 patients with depression using The Chinese Brief Cognitive Test(C-BCT) and the scores were compared with those of 196 healthy controls (HCs). 58 patients were reassessed after 8 weeks. We used K-means cluster analysis to identify cognitive subgroups, and compared clinical variables among these subgroups. A linear mixed-effects model, incorporating time and group (with interaction term: time × group) as fixed effects, was used to assess cognitive changes over time. Stepwise logistic regression analysis was conducted to identify risk factors associated with these subgroups. Results: Two distinct neurocognitive subgroups were identified: (1) a cognitive-impaired subgroup with global impairment across all domains assessed by the C-BCT, and (2) a cognitive-preserved subgroup, exhibited intact cognitive function, with performance well within the healthy range. The cognitive-impaired subgroup presented with more severe baseline symptoms, including depressed mood, guilt, suicidality, and poorer work performance. Significant group × time interactions were observed in the Trail Making Test Part A (TMT-A) and Continuous Performance Test (CPT), but not in Symbol Coding or Digit Span tests. Despite partial improvement in TMT-A and CPT tests, the cognitive-impaired subgroup remained lower scores than the cognitive-preserved subgroup across all tests at the study endpoint. Multiple regression analysis indicated that longer illness duration, lower educational levels, and antipsychotic medication use may be risk factors for cognitive impairment.Conclusion: This study identifies distinguishable cognitive subgroups in acute depression, thereby confirming the presence of cognitive heterogeneity. The cognitive-impaired subgroup exhibits distinct symptoms and persistent cognitive deficits even after treatment. Screening for cognitive dysfunction may facilitate more targeted interventions.