Research on Standardized Electronic Cognitive Training Technique in Early Stage of Senile Depression With Cognitive Impairment
Phase: NA
Conditions: Geriatric Depression, Cognitive Impairment
Sponsor: Capital Medical University

 
                                               
 
Beijing Science and Technology 
Program Project 
Implementation 
 
 
 
 
 
 
Topic Title: Research on Early Standardized Electronic 
Cognitive Training Technology for Elderly Depression with 
Cognitive Impairment 
Project Name: Advantageous Discipline Cultivation Project 
Field: Healthcare 
Category: Public welfare applications 
Municipal Science and Technology Commission In charge 
of the office: Medical and Health Science and Technology 
Division 
The version number: 2.0 
Document date: September .30.2021 
Starting and ending years: January 2020-august 2023 
 
 

 
                                               
Purpose, significance and necessity of the study 
1. Significance and necessity of the study 
Age-related depression (LLD) is the most common mental disease in the old age. 
Because of the increasing prevalence of population aging, it has become one of the 
important factors affecting the quality of life of the elderly. 50-70% of senile depression 
is accompanied by cognitive impairment of different degrees. The patients with senile 
depression with cognitive impairment have higher risk of dementia transformation, 
worse prognosis and higher recurrence rate, which seriously endanger the quality of life 
and social function of patients and increase the economic burden of society and families. 
Therefore, it is urgent to provide evidence-based early intervention strategies for senile 
depression with cognitive impairment. 
At present, the domestic and foreign guidelines do not provide a clear and effective 
treatment plan for the elderly patients with cognitive impairment, and the clinical 
research and practice also lack evidence-based treatment. Selective serotonin reuptake 
inhibitors (SSRIs), the most used antidepressant in elderly depression, cannot 
significantly improve the cognitive impairment of elderly patients with depression, and 
may even aggravate the cognitive impairment of elderly patients with depression. The 
overall efficacy and tolerability of drug therapy for elderly patients with depression and 
cognitive impairment are poor. Studies have confirmed that cognitive training can 
significantly improve the overall cognitive function and the functions of multiple 
cognitive domains of healthy elderly, patients with mild cognitive impairment (MCI) 
and Alzheimer's disease (AD). The previous research results have also initially 
confirmed the cognitive improvement effect of cognitive training on elderly patients 
with depression, providing a new idea for clinical diagnosis and treatment. 
Therefore, based on the urgent needs of the clinic and the foundation of the preliminary 
work, the development and clinical validation of a set of standardized cognitive training 
methods suitable for elderly depressive patients with cognitive impairment will help 
improve the overall efficacy of elderly depressive patients, improve the prognosis of 
patients, save health resources, provide evidence-based medical basis for improving the 

 
                                               
diagnosis and treatment guidelines of elderly depressive patients, It conforms to the 
concept of patient-centered bio psychological social medical model. 
 
2. Research purpose: 
(1) To compare the efficacy of conventional SSRIs combined with electronic 
cognitive training (intervention group) and single conventional SSRIs 
treatment/Blank electronic training (control group) on cognitive impairment in elderly 
patients with depression. 
 
(2) To establish a set of standardized and operable electronic cognitive intervention 
technology for elderly depression patients with cognitive impairment, which is 
applicable to various psychiatric hospitals at all levels. 
 
3. Project basis 
1.China's population aging situation is severe, the prevalence of senile depression is 
high, and the cognitive function is seriously damaged  
The aging situation of China's population is grim. By the end of 2017, the elderly 
population in Beijing had exceeded 20% of the total population. Senile depression is 
the most common mental disorder in the elderly [1], and the prevalence rate has 
increased year by year. Studies have reported that the global prevalence rate of senile 
depression is 0.2% ~ 29% [2-4], while the prevalence rate of senile depression in China 
is about 2.8% [5]. Compared with other age groups, the onset of senile depression is 
more concealed and cognitive function is more likely to decline. 50-75% of senile 
depression patients have cognitive function impairment [6], which is more likely to lead 
to the decline of quality of life and social function impairment [7, 8]. 
2.Elderly depression with cognitive impairment has poor treatment effect, high 
recurrence risk and lack of evidence-based treatment  
Clinical studies have found that the effect of antidepressants in elderly patients with 
cognitive dysfunction is poor, and cognitive impairment may be one of the important 
factors for poor efficacy [9]. Tam [10] et al. Found that the ability of daily living of 

 
                                               
elderly patients with depression decreased significantly, and the severity of depressive 
symptoms and the degree of cognitive impairment were significantly related to the 
ability of daily living. Persistent cognitive impairment may increase the risk of relapse 
of depression [11]. In terms of the treatment and intervention of senile depression with 
cognitive impairment, there are few relevant studies at present, and the domestic and 
foreign depression treatment guidelines do not involve the treatment suggestions on 
senile depression with cognitive impairment. The first-line treatment recommendations 
for senile depression are still based on drug treatment to control symptoms, and there 
is no evidence-based evidence to support the treatment of cognitive impairment. Studies 
have shown that intelligence promoting drugs such as cholinesterase inhibitors have no 
obvious effect on senile depression with cognitive impairment [12]. The drug treatment 
of senile depression with cognitive impairment is not optimistic. There is an urgent 
need to explore a suitable intervention mode for the elderly depression patients with 
cognitive impairment to improve their prognosis. 
3.The results of previous small sample studies suggest that cognitive training can 
improve the cognitive dysfunction of senile depression 
In recent years, more and more researchers have begun to pay attention to the role of 
cognitive training in improving cognition. Studies on the general elderly population 
have found that cognitive training can improve the overall cognitive function and 
multiple cognitive domain functions of healthy elderly and MCI patients [13]. Evidence 
based medicine evidence supports the effect of multi cognitive domains and multi-
modal cognitive training on the overall cognitive function. The cognitive domains 
covered by cognitive training should include but not limited to orientation, perceptual 
ability, attention, memory, executive function, logical reasoning, processing speed and 
language function. At present, the research on cognitive training is mainly focused on 
ad, MCI, healthy elderly and schizophrenia, and the related research on senile 
depression with cognitive impairment is less. Some researchers provided memory 
training for elderly patients with depression and found that the 10-week intervention 
not only improved the cognitive level of patients, but also alleviated their depressive 
symptoms [14]. Cognitive training can improve the attention pre-processing of elderly 

 
                                               
patients with depression and improve the prognosis of patients [15]. The previous small 
sample study of our research group also obtained the same research results. 
This study intends to further screen and optimize the cognitive training technology in 
the previous study and make it electronic. Through an RCT study, the efficacy and 
compliance of the electronic cognitive training technology on the elderly depression 
with cognitive impairment are verified. The purpose is to provide convenient and 
reliable treatment technology for the clinic and solve the dilemma of "no medicine to 
cure" cognitive impairment associated with the elderly depression, to improve its 
prognosis and reduce the disease burden. 
4. Scientific problems 
Cognitive training can improve the cognitive function of elderly depression: the 
previous small sample study found that cognitive training can improve the cognitive 
function of elderly depression patients with cognitive impairment. At present, there is 
no RCT study with strict design to further verify the improvement of cognitive function 
of elderly depression patients by cognitive training, The successful implementation of 
this study can solve the bottleneck problem of "no drug can be treated" in the current 
clinical treatment of cognitive impairment associated with senile depression, provide 
treatment ideas for clinicians to treat senile depression, and provide evidence-based 
support for the clinical treatment guidelines of depression. 
 
Current situation and trend of research and development at home and abroad in 
relevant industries and fields of the subject, as well as the work foundation of the 
unit in relevant fields 
1. Research status at home and abroad 
 
(1) Senile depression with cognitive impairment may persist 
For a long time, most studies on cognitive impairment have focused on schizophrenia, 
MCI, ADand other diseases. It is believed that the cognitive impairment of patients 
with depression is slight, and that the cognitive impairment can be improved with the 
alleviation of depression, and the cognitive impairment associated with depression is 

 
                                               
called "pseudodementia". However, with the deepening of the research, experts and 
scholars at home and abroad have found that cognitive function damage of some 
depressed patients is prominent and persists after the depression symptoms are relieved, 
especially for the elderly patients with depression. They also found that the elderly 
patients with depression without cognitive function damage may also have cognitive 
function damage after the depression mood improves over time [16]. Recent studies 
have found that persistent cognitive impairment may increase the risk of relapse of 
depression. Depression often leads to severe and comprehensive social function decline. 
The degree of social function damage of patients is related to the severity of depressive 
symptoms. Some patients' social function decline persists after the depressive 
symptoms are relieved [17]. 
Studies have shown that cognitive impairment in elderly patients with depression 
mainly involves multiple cognitive domains, including episodic memory, information 
processing speed, executive function, and visuospatial ability [18] [19]. Cognitive 
functions such as speech learning, memory function, psychomotor speed, and executive 
function of elderly patients with depression are more severely damaged than those of 
young patients with depression [20]. 
(2) The treatment effect of senile depression patients with cognitive impairment is 
worse 
At present, the treatment of senile depression with cognitive impairment often pays 
attention to the treatment of depressive symptoms and neglects the treatment of 
cognitive impairment. However, the effect of antidepressant therapy alone is not 
satisfactory for senile depression with cognitive impairment. The study found that the 
short-term efficacy of tricyclic and tetracyclic antidepressants and SSRIs 
antidepressants was generally poor in elderly patients with executive function 
impairment. Some studies have also found that elderly patients with depression, if 
accompanied by information processing speed, episodic memory and language function 
impairment, may have poor antidepressant treatment effect [21]. SSRIs antidepressant 
treatment cannot significantly improve the cognitive impairment of elderly patients 
with depression and may even aggravate the degree of cognitive impairment. Recent 

 
                                               
studies have found that the psychomotor speed and speech learning ability of elderly 
patients with depression continue to decline after treatment with citalopram 
hydrobromide, suggesting that the cognitive impairment of elderly patients with 
depression may be secondary to drug factors [22]. At present, clinicians with cognitive 
impairment in elderly depression are more inclined to choose different kinds of 
intelligence promoting drugs. However, the study found that even if cholinesterase 
inhibitors were added to elderly patients with depression, it had only a small impact on 
the improvement of concurrent cognitive impairment and the conversion rate of AD. it 
also found that cognitive impairment may lead to an increase in the risk of relapse of 
depression. At present, there is no evidence-based drug for cognitive impairment in 
senile depression. 
(3) Previous studies have confirmed that cognitive training can improve cognitive 
impairment 
In recent years, the intervention of cognitive training on brain diseases has been favored 
by experts, scholars and clinical workers at home and abroad for its convenience, safety 
and effectiveness. The results of randomized controlled clinical trials and meta-analysis 
all support that cognitive training can improve the overall cognitive function and 
cognitive domains such as memory and attention function of healthy elderly and MCI 
patients [13, 23, 24]. The research shows that for the elderly with cognitive health, the 
cognitive enhancement effect brought by traditional cognitive training is quite stable, 
although it is affected by training methods, training duration, suitability, and other 
factors. And cognitive training for MCI and AD patients has also been proved to have 
"moderate to high effect amount" [25]. For mild to moderate AD patients, the 
implementation of cognitive training in the whole cognitive field can be an effective 
supplement to drug treatment and maintain the "recovery" effect of this cognition for 
at least 1 year after the training. Most of the existing cognitive training studies focus on 
MCI and ad, but few studies on cognitive impairment associated with senile depression. 
Meta-analysis shows that cognitive training can improve the attention, working 
memory and social function of elderly patients with depression [26]. It has been found 
that cognitive training can improve the executive function and visuospatial ability of 

 
                                               
patients with stable senile depression and reduce the residual symptoms of depression 
[27]. Some researchers provided electronic memory training for elderly patients with 
depression, and found that the intervention lasting for 10 weeks, once a week, for 60-
75min, not only improved the memory level of patients, but also alleviated their 
depressive symptoms [14]. Memory specific training 6 times a week, once for 20min, 
2h a week can improve the episodic memory function of senile depression [28]. 
However, the sample size of these studies is generally small, and the cognitive training 
methods adopted are not designed for the elderly with depression, and they only focus 
on a certain module of the cognitive field for training, lack of intervention research on 
the elderly with depression in the acute phase, and the follow-up time is short. It is 
impossible to judge the long-term efficacy and compliance of cognitive training for the 
elderly with depression. The preliminary open research results of this research group 
have also obtained similar results. The cognitive training methods developed by the 
research team around various cognitive fields such as episodic memory, executive 
function, working memory, attention processing, speech ability, reasoning and 
judgment have accumulated tens of thousands of data in the elderly population in the 
community. The results show that the training is conducted four times a week for 60min 
every day, Training for 12 weeks can significantly improve the cognitive function of 
the elderly in the whole and various cognitive fields. At present, this training method 
has been widely used in AD, MCI, senile schizophrenia, and senile depression in our 
hospital. 
Compared with traditional cognitive training, computer-based electronic cognitive 
training is easier to obtain. A meta-analysis shows that there are individual differences 
in the effects of comprehensive cognitive training and single domain cognitive training 
- the improvement of memory function of MCI patients by comprehensive cognitive 
training is not as good as that by simple memory training [29, 30], while in the healthy 
elderly, the improvement of memory function by memory training is not as good as that 
by executive control or comprehensive cognitive training [13]. Computer based 
cognitive training has been applied to the healthy elderly, MCI patients, AD patients 
and vascular cognitive impairment patients, and its effect has also been confirmed, 

 
                                               
because it has the advantages of personalization and adaptation, and can consider 
comprehensive training programs and individual differences in plasticity in different 
cognitive fields. Personalized computer cognitive training can enhance subjective 
perception of cognitive changes, and higher-level cognitive training may bring 
additional benefits [31]. In consideration of individual differences, when designing 
cognitive training schemes, the advantages of big data and artificial intelligence 
algorithms can be brought into play and the training schemes can be adjusted 
individually. There are many ways to implement cognitive training, such as training 
with paper and pen materials or computer-aided programs, and training through virtual 
reality, biofeedback, etc. Immersive and interactive cognitive training based on virtual 
reality has been proved to have good effects, but no research has applied this training 
method to the elderly with depression. In terms of training dose, the research based on 
the healthy elderly shows that each training time is not less than 30 min, three times a 
week, and the total training time is more than 20 h, which can achieve more obvious 
training effect. 
To sum up, combining the basis of previous work, screening cognitive training tasks 
suitable for the elderly with depression, developing electronic cognitive training tasks, 
and further verifying them in the clinic, with a view to making up for the defects of 
current clinical treatment, improving the prognosis and reducing the disease burden, 
which has great social significance. 
 
2. The research team is supported by the preliminary research results directly related to 
the project 
The applicant and the main members of the team have rich experience in the clinical 
diagnosis, treatment, and research of senile depression, have undertaken many clinical 
studies related to senile mental diseases, and have high scientific research ability. The 
members of the research team are reasonable, and there are experts in clinical, 
psychological, rehabilitation, testing, statistics, and other aspects. The above provides 
sufficient technical and personnel conditions to ensure the development of the research. 
The research team has long carried out research work related to cognitive rehabilitation 

 
                                               
training. At present, a set of comprehensive training tools suitable for the elderly in 
China has been developed around various cognitive fields such as executive function, 
working memory, episodic memory, and continuous attention. It can formulate 
personalized cognitive training programs based on the cognitive evaluation results of 
the elderly and adjust the training programs in time according to the training results and 
follow-up evaluation, so as to achieve the effect of improving the cognitive function of 
the elderly. At present, this cognitive training system has been applied and popularized 
in many domestic institutions and communities. The preliminary results show that it 
can significantly improve the cognitive function of the elderly healthy population, MCI 
and early AD population. The research team has accumulated extensive experience in 
promoting aging research in China and the practice of dementia prevention and control 
in communities and hospitals. 
 
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Task: 
 
Task 1: optimization and electronation of cognitive training program for senile 
depression 

 
                                               
 
Task 2: through an RCT study, verify the cognitive improvement effect of electronic 
cognitive assessment tools on elderly patients with cognitive impairment 
 
Subject objective 
 
1 Qualitative objective: 
 
1) Optimize the cognitive training program of senile depression and form a set of 
electronic cognitive training technology. 
 
2) To compare the improvement of cognitive function of elderly depressive patients 
with cognitive impairment treated with conventional SSRIs antidepressants combined 
with electronic cognitive training technology and single conventional SSRIs 
antidepressants. 
 
2 Quantitative objectives: 
 
1) 64 elderly depressive patients with cognitive impairment completed 52 weeks of 
SSRIs antidepressants combined with electronic cognitive training (once a day, 60min 
each time); 
 
2) 64 elderly depressive patients with cognitive impairment were treated with SSRIs 
antidepressants Blank electronic training for 52 weeks (once a day, 60min each time); 
 
3) To form a cognitive training process for elderly patients with depression, including 
training content, training duration, training guidance and other key contents. 
 
Research design 
 

 
                                               
1) Overall design scheme 
 
This study is a prospective, randomized, controlled study. The screened qualified 
subjects were randomly divided into two groups. One group was the control group, 
receiving clinical routine SSRIs drug treatment combined with blank control method 
(that is, subjects were allowed to use electronic products to browse the web and watch 
the news for 1H every day), and the other group was the intervention group, receiving 
SSRIs drug treatment combined with electronic cognitive training. The whole study 
lasted 52 weeks. 
 
At each visit, the scale evaluation (cognitive function, psychosocial function 
evaluation), the level of Alzheimer associated neurofilament protein (AD7C NTP) in 
urine and the concentration of antidepressants in blood were performed. The 
investigator quantitatively adjusted the patient's medication regimen (including dose 
and type) according to the evaluation results and adjusted the cognitive training regimen 
according to the evaluation results. 
 
2) Drug therapy intervention 
 
The subjects who met the screening criteria did not need cleaning and entered the study 
directly. Considering that the overall efficacy of various antidepressants is similar, and 
to maximize the simulation of the actual situation of clinical treatment, SSRIs treatment 
drugs are used in this study, including fluoxetine, paroxetine, fluvoxamine, sertraline, 
citalopram and escitalopram. The specific types of drugs are not limited. During the 
study, the drug dose was quantitatively adjusted according to the results of each visit 
evaluation combined with the drug concentration. 
The researcher will comprehensively evaluate the effectiveness of the treatment 
according to the above data results, and then make corresponding adjustments 
according to the treatment plan. If the score reduction rate of the Hamilton Rating Scale 
for depression (hrsd-17) is >50% and the drug concentration is within the recommended 

 
                                               
range, the current treatment will be continued; 50% > hrds-17 score reduction rate > 
30% or the drug concentration is lower than the minimum recommended concentration, 
the current treatment can be continued or the dose can be adjusted; If the score reduction 
rate of hrds-17 is less than 30% and the drug concentration is lower than the minimum 
value of the recommended concentration, the dosage should be adjusted. If the score 
reduction rate of hrds-17 is less than 30% and the drug concentration is higher than the 
minimum value of the recommended concentration, the dressing should be changed. If 
intolerable side effects occur, the dose can be reduced, or the dressing can be changed. 
 
Design method of cognitive training program 
Intervention implementation plan 
The total duration of this intervention was 52 weeks, during which training tasks were 
carried out in weeks, and patients were arranged to carry out cognitive training in 
different fields. During the intervention period, patients need to complete a total of 52 
weeks of training plan, including 4 training days per week (it is recommended to ensure 
the frequency of every other day). Each training day includes at least 3 different 
cognitive training. The duration of each training is about 60min, and the total duration 
of each month shall not be less than 16 hours. 
Intervention scheme generation rules 
 
The cognitive training program will push personalized cognitive training according to 
the performance of the subjects in the six areas of episodic memory, executive function, 
working memory, processing speed, speech ability and reasoning judgment. Patients 
need to be evaluated once a month and update the training program according to the 
evaluation performance. 
The specific recommendation principles of the training program in the intervention 
group are as follows: the areas with poor cognitive performance (1.5 standard 
deviations lower than the average value of the norm) are recommended first, and more 
than one and no more than four times in each training cycle; Secondly, recommend 
areas with poor cognitive performance (1 standard deviation lower than the norm), and 

 
                                               
no more than 2 times in each training cycle;  In addition to the above fixed training, if 
the training content does not reach 16 items / week, cognitive training in other fields 
will be randomly pushed; Within each training day, only one cognitive rehabilitation 
training is arranged for each cognitive field;  The difficulty of each cognitive 
rehabilitation training depends on the last training level of the subject. 
Training scheme of the control group: to keep the same electronic use time as that of 
the intervention group, the subjects in the control group are required to open the 
electronic products for 60 minutes every day, 4 days a week. 
 
Intervention mode 
Tablet computer or mobile phone to be used in this intervention training. The training 
will take the principles of psychology and cognitive neuroscience as the core, and 
interactive games as the carrier, covering the cognitive training in six fields: episodic 
memory, executive function, working memory, processing speed, speech ability and 
reasoning judgment, to ensure the scientific on the premise of enhancing interest. 
According to their own conditions, the subjects can choose to go to the hospital to use 
the tablet computer provided by the hospital for training within the reserved time or can 
use their own tablet computer or mobile phone for independent training. The training 
mode of this intervention is flexible. The subjects can start training on different terminal 
devices, and the training records can also be updated in real time. The research team 
will monitor the whole training process. 
 
Research object 
Inclusion criteria: 1. written informed consent signed by patients and their families; 2. 
Age ≥60 years; 3. Meet the diagnostic criteria for single or recurrent major depressive 
disorder in the diagnostic and Statistical Manual of mental disorders Fourth Edition 
(DSM-V); 4. Currently in the acute phase, the total score of hrds-17 at baseline is ≥ 18 
points. 5.There were cognitive impairment symptoms, and the Montreal Cognitive 
Assessment Scale (MoCA) was < 26 points. 6/Education level above primary school. 

 
                                               
Exclusion criteria: 1.patients with history of epilepsy or coronary heart disease or 
other serious unstable physical diseases; 2. Participated in another intervention clinical 
study in the past 1 month; 3. The following mental diseases have been or are currently 
diagnosed by DSM-V: organic mental disorder, Alzheimer's disease, secondary 
dementia caused by other causes, schizophrenia, schizophrenic affective disorder, 
bipolar disorder, delusional disorder, undefined mental disease, patients with drug 
abuse history, including alcohol and active drug abuse in the past 12 months, except 
nicotine; 4.He has been taking antidepressants, mental retardants and other psychiatric 
drugs for the past 2 weeks; 5. Severe aphasia, visual and hearing impairment, etc. 
unable to complete the scale evaluation; 6. Pregnant, lactating women or those planning 
to conceive. 
 
The subject may withdraw from the study for any of the following reasons: the 
investigator considers that it is best for the subject to terminate the treatment due to 
safety factors (such as adverse events); The subjects were lost to follow-up; The subject 
withdrew informed consent. If a subject is lost to follow-up, the staff of the research 
center shall make every effort to contact the subject and determine the reason for his 
withdrawal. Follow up examinations must be recorded. When a subject withdraws 
before completing the study, the reason, date, and final evaluation of withdrawal shall 
be recorded in the CRF and original documents. 
 
Symptomatic assessment 
 
1) Hamilton Anxiety Rating Scale (HAMA): in the baseline period, at the end of the 
2nd, 4th, 8th, 12th, 26th, 38th and 52nd weeks, the rater assessed the anxiety symptoms 
of the subjects. 
 
2) The Hamilton Rating Scale for depression (hrsd-17): subjects were assessed for 
depressive symptoms at the end of the baseline period, 2 weekends, 4 weekends, 8 
weekends, 12 weekends, 26 weekends, 38 weekends and 52 weekends. 

 
                                               
 
3) The Geriatric Depression Scale (GDS): subjects were evaluated for depressive 
symptoms at the end of the baseline period, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 26 
weeks, 38 weeks, and 52 weeks. 
 
4) Neuropsychiatric Inventory (NPI): subjects were assessed for cognitive function at 
the end of the baseline period, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 26 weeks, 38 
weeks, and 52 weeks. 
 
5) Activities of daily living (ADL): the cognitive function of the subjects was assessed 
in the baseline period, 2 weekends, 4 weekends, 8 weekends, 12 weekends, 26 
weekends, 38 weekends and 52 weekends. 
 
Safety evaluation 
 
1) Vital signs: the temperature, pulse and blood pressure of the subjects were monitored 
at the end of the baseline period, 2 weekends, 4 weekends, 8 weekends, 12 weekends, 
26 weekends, 38 weekends and 52 weekends. 
 
2) Adverse event report: adverse event records were made on the subjects at the end of 
the baseline period, the end of the 2nd week, the end of the 4th week, the end of the 8th 
week, the end of the 12th week, the end of the 26th week, the end of the 38th week and 
the end of the 52nd week. 
 
3) Treatment Emergent Symptom Scale (TESS): during the baseline period, the subjects 
were evaluated for side effects at the end of 2 weeks, 4 weeks, 8 weeks, 12 weeks, 26 
weeks, 38 weeks, and 52 weeks. 
 
4) Laboratory examination and electrocardiogram: routine blood test, biochemical 
examination and electrocardiogram examination were conducted at the end of the 

 
                                               
screening period, the end of the 4th week, the end of the 12th week, the end of the 38th 
week and the end of the 52nd week. 
 
Efficacy index 
 
1) Main efficacy indicators: 
 
At the end of the 12th week after treatment, the change value of ADAS cog scale scores 
of the subjects in the two groups compared with the baseline. 
 
2) Secondary efficacy indicators: 
 
1.At each follow-up point, the change value of ADAS cog scale scores of the two 
groups compared with the baseline. 
 
2.At each follow-up point, the change value of hrsd-17 score of the subjects in the two 
groups compared with the baseline; 
 
3.At each follow-up point, the change value of HAMA scale scores of the two groups 
compared with the baseline. 
 
4.At each follow-up point, the change value of GDS score of the subjects in the two 
groups compared with the baseline. 
 
5.At each follow-up point, the change value of NPI scale scores of the subjects in the 
two groups compared with the baseline. 
 
6. At each follow-up point, the change value of ADL scale scores of the subjects in the 
two groups compared with the baseline. 
 

 
                                               
7. Complete remission rate: the difference in the proportion of patients with a total score 
of hrds-17 ≤ 7 at each visit point between the two groups. 
 
8. Effective rate of treatment: the proportion difference between the two groups of 
subjects in the reduction rate of hrds-17 scale at each visit point and the baseline ≥ 50%. 
 
9.Recurrence rate and recurrence time: recurrence is defined as any of the following 
conditions: the subject meets the DSM-IV diagnostic criteria for depressive episode; 
The subject was hospitalized again due to depression; After the treatment was effective 
(ham-d17 score decreased by ≥ 50% compared with the baseline), ham-d17 score 
increased by more than 30% compared with the baseline at any visit point; During the 
maintenance treatment period, after the treatment of the subjects is effective or 
remission, the proportion of relapse and the time of relapse between the two groups at 
each visit point; 
 
Safety index: 
 
i. Abnormal values of vital signs, laboratory examination and electrocardiogram 
examination during the study period. 
 
II. Adverse events and adverse reaction reports during the study period. 
 
Basis for determining sample size 
According to the main research hypothesis of this study, the effect of comprehensive 
intervention group on improving patients' cognition is better than that of conventional 
treatment group. According to the previous similar research results and the expected 
efficacy hypothesis, the difference between the groups of the study group and the 
control group in terms of ADAS cog score reduction after 12 weeks of treatment is 
about 2.2, and the combined standard deviation is 4. Set α= 0.025 (one side), β= 0.20, 
and set the superiority and effectiveness limit value as 3 in combination with the 

 
                                               
previous research and clinical significance, The ratio of the number of cases in the study 
group to the control group was 1:1. The sample size of the study group was 51 cases, 
and the sample size of the control group was 51 cases. Considering the 20% rejection 
rate of similar items, 64 cases need to be included in the study group and the control 
group. 
 
Statistical analysis methods 
Full Analysis Set (FAS): A collection of all randomized cases with valid baseline 
assessments. FAS is the main analysis set. Secondary efficacy measures were analyzed 
using only FAS without carry-over. 
General principles: Statistical analysis was performed using SAS.9.4 statistical analysis 
software.  P value < 0.05 was statistically significant (unless otherwise specified). 
Statistical description: Measurement data are described using mean (standard 
deviation), median (interquartile range), minimum value, and maximum value; skewed 
distribution indicators are normally corrected before analysis, unless otherwise 
specified. Enumeration data were described using the number of cases (percentage). 
Statistical analysis methods 
Full Analysis Set (FAS): A collection of all randomized cases with valid baseline 
assessments. FAS is the main analysis set. Secondary efficacy measures were analyzed 
using only FAS without carry-over. 
General principles: Statistical analysis was performed using SAS.9.4 statistical analysis 
software. A P value < 0.05 was statistically significant (unless otherwise specified). 
Statistical description: Measurement data are described using mean (standard 
deviation), median (interquartile range), minimum value, and maximum value; skewed 
distribution indicators are normally corrected before analysis, unless otherwise 
specified. Enumeration data were described using the number of cases (percentage). 
 
1) Efficacy analysis: 
Primary Endpoint Analysis 

 
                                               
The between-group difference in the change from baseline in the total score of the two 
groups of subjects (ADAS-cog) at the end of 12 weeks 
Statistical analysis of changes from baseline in ADAS-cog total scores at the end of 12 
weeks was performed using MMRM (mixed model for repeated measures). The model 
takes the change of ADAS-cog total score at each time point after treatment relative to 
the baseline as the dependent variable, the baseline ADAS-cog total score is a covariate, 
and the grouping is a fixed effect. Each fixed effect factor and covariate is nested in 
each visit. Inside. According to the model, the adjusted mean of the total ADAS-cog 
total score at the end of treatment in each group compared with the baseline, as well as 
the difference of the adjusted mean between the two groups and its 95% confidence 
interval, the lower limit of the confidence interval and the set optimal value were 
calculated. The comparison of the effect-media value was used as the criterion for 
superiority. 
Secondary endpoint analysis: 
Efficacy evaluation indicators include HRSD-17, HAMA, GDS, NPI, ADL and other 
scales. The differences between groups at the visit point relative to the baseline value 
were analyzed using the same analysis method as the main efficacy indicators. The 
cumulative complete remission rate, treatment response rate, recurrence rate and other 
outcome indicators during the study period were compared between groups using the 
Kaplan-Meier curve, and the COX proportional hazards model was used to evaluate the 
impact of the intervention while controlling for confounding factors such as disease 
duration. 
Safety analysis: The incidence of adverse events and adverse reactions was tested by 
chi-square and described in a list.