Objective: To investigate the therapeutic effect of clozapine combined with agomelatine onnegative symptoms and cognitive fiunction in patients with chronic schizophrenia, as wellas its impact on serum melatonin expression levels.

Methods: 98 patients with chronic schizophrenia from Shanghai Huangpu District MentalHealth Center were included and randomly divided into research group and control groupusing a random number table, with 49 patients in each group. The control group wastreated with clozapine combined with placebo, while the research group was treated withclozapine combined with agomelatine for 12 weeks. Two groups were evaluated forcognitive function, negative symptoms, and depressive symptoms at the time of enrollmentand at the end of the 4th, 8th, and 12th week of treatment, Serum melatonin levels weremeasured by mass spectrometry analysis at the same time point. Statistical analysis wasperformed on the relevant indicators of the two groups.

Results: Excluding dropouts, the study group and control group ultimately included 42 patients each. During the baseline period, there was no statistically significant difference incognitive function dimensions, negative symptoms, depressive symptoms, and serummelatonin levels between the two groups. After 12 weeks of treatment, there werestatistically significant differences in N3 (emotional communication disorder)(P=0.027)vocabulary recall (P=0.016), story recall (P=0.002), graphic recognition(P=0.017)Repeatable Battery for the Assessment ofNeuropsychological Status(RBANS) conversion score P=0.007), Calgary Depression Scale for Schizophrenia (CDss)(P=0.000) score, and serummelatonin levels (P=0.002) between the two groups. Within the group comparison, therewere statistically significant differences in cognitive function, negative symptom anddepression symptom scores, and serum melatonin levels between the treatment group atthe 4th, 8th, and 12th weekends and the baseline period (P<0.01 for all). There was asignificant correlation between changes in serum melatonin levels and improvements instory recall (r²=0.25,P=0.02).

Conclusion: Clozapine combined with agomelatine has significant therapeutic effects onsome dimensions of cognitive function, negative symptoms, and depressive symptoms inpatients with chronic schizophrenia, and the improvement of some cognitive functions issignificantly correlated with changes in serum melatonin levels.