After menopause, there is a certain tendency towards depression, with the risk of developing depression being about 3 to 4 times higher than before menopause. Additionally, postmenopausal women experience varying degrees of cognitive decline, which are closely associated with hormonal changes. Therefore, we should pay more attention to the cognitive levels of postmenopausal depression patients. Increasing evidence suggests that changes in cognitive function during menopause may be related to the effects of estrogen on cognitive function, and estrogen therapy can effectively improve cognitive decline. Estrogen is not only associated with cognitive symptoms after menopause, but estrogen intervention is also an adjunctive treatment for postmenopausal depression symptoms. There is a close relationship between cognitive levels and depression, as depression itself is accompanied by cognitive decline, and early cognitive decline can also manifest depressive symptoms. Therefore, the cognitive levels of postmenopausal depression patients are also worthy of further attention.This study is an 8-week randomized controlled trial. The subjects are patients with postmenopausal depression accompanied by cognitive decline, all of whom have undergone natural menopause for at least one year; with HAMD-17 scores ≥17 points; and MOCA scores ≤26 points. This study aims to recruit patients with postmenopausal depression accompanied by cognitive decline from the outpatient or inpatient departments of Beijing Anding Hospital, Capital Medical University. Patients who meet the inclusion criteria will be randomly assigned to the combination group and the control group using a random number method. The combination group will receive estrogen combined with SSRIs, while the control group will only receive Selective serotonin reuptake inhibitors (SSRIs) intervention. Patients' cognitive function and depressive symptoms will be assessed using scales at baseline, 2 weeks, 4 weeks, and the end of 8 weeks of treatment, and safety evaluations will be conducted. The primary efficacy endpoint is the change in MoCA scores from baseline to the end of the study. Secondary efficacy endpoints include changes in HAMD-17, modified Kupperman Scale, ADL Scale, and hormone levels from baseline to the end of the study. The safety of the study drug will be evaluated through adverse event reporting, clinical laboratory tests, and physical examinations.

Inclusion Criteria:

1. Female patients from outpatient or inpatient departments;
2. Patients who sign a written informed consent form;
3. Natural menopause for at least 1 year, with first-onset depression, aged ≤70 years;
4. Meeting the diagnostic criteria for Major Depressive Disorder according to the Diagnostic and Statistical Manual of Mental Disorders-fifth Edition (DSM-5);
5. HAMD-17 score ≥17 points;
6. Presence of cognitive impairment symptoms, Montreal Cognitive Assessment scale (MoCA) <26 points;
7. Education level of primary school or above.

Exclusion Criteria:

1. Patients with significant physical illness, cranial trauma, or other serious unstable physical illnesses;
2. Patients who have participated in another interventional clinical study in the past month;
3. History or current diagnosis of the following psychiatric disorders according to DSM-5: organic mental disorders, Alzheimer's disease, other causes of secondary dementia, schizophrenia, schizoaffective disorder, bipolar affective disorder, delusional disorder, unspecified mental disorders, patients with a history of substance abuse, including alcohol and active substance abuse in the past 12 months, excluding nicotine;
4. Currently taking antidepressants, cognitive enhancers, or other psychiatric medications in the past 2 weeks;
5. Severe speech, visual, or hearing impairments that prevent completion of scale assessments;
6. Individuals with severe suicidal ideation or suicidal behavior;
7. Patients with malignant tumors;
8. Known or suspected history of breast cancer;
9. Known or suspected estrogen-dependent malignant tumors (such as endometrial cancer);
10. Known or suspected progesterone-dependent tumors;
11. Untreated endometrial hyperplasia;
12. Unexplained vaginal bleeding.

"We currently have no plans to provide Individual Participant Data (IPD) to other researchers."