Objective:To investigate the impact of combining selective serotonin reuptake inhibitors(SSRIs)with occupational therapy(OT)on neurological functioning,psychological well-being,and activities of daily living in individuals diagnosed with post-stroke depression(PSD).Methods:A total of 90 patients diagnosed with post-stroke depression were selected as the research subjects.They were divided into two groups according to different treatment methods,namely the control group(n=45)and the experimental group(n=45).The control group received treatment with SSRIs,while the experimental group received a combination of SSRIs and OT.The overall treatment efficacy,levels of norepinephrine(NE),5-hydroxytryptamine(5-HT),brain-derived neurotrophic factor(BDNF),insulin-like growth factor-1(IGF-1),Hamilton depression scale(HAMD)score,activities of daily living(ADL)score,and Pittsburgh sleep quality Index(PSQ)were compared between the two groups before and after treatment,including the incidence of ad-verse reactions.Results:The total effective rates of the the experimental group was higher than that of the control group(95.56％vs.80.00％,P＜0.05).After treatment,the serum levels of NE,IGF-1,5-HT,and BDNF in both groups exhibited improvement compared to pre-treatment levels(P＜0.05).Furthermore,the experimental group demonstrated superior post-treatment serum levels of NE,IGF-1,5-HT,and BDNF when compared to the control group(P＜0.05).After treatment,the ADL scores of both groups exhibited a signifi-cant improvement compared to pre-treatment levels(P＜0.05),the PSQI scores of both groups demonstrated a decrease in comparison to pre-treatment values(P＜0.05).Moreover,the experimental group displayed superior post-treatment ADL and PSQI scores when compared to the control group(P＜0.05).The incidence of adverse reactions in the two groups was 2.22％and 17.78％,respective-ly,with a lower rate observed in the experimental group compared to the control group(P＜0.05).Conclusion:The use of SSRIs com-bined with OT treatment in PSD patients can enhance psychological well-being,improve sleep quality,regulate neurotransmitter levels,thereby enhancing daily functioning and increasing the safety profile of the treatment.This approach offers significant advantages.