Transcranial magnetic stimulation combined with duloxetine improves attentional negativity bias in patients with depression: pilot study for a future trial

Dan-Na Zhou, Chang-Ming Wang, Xu Chen, Lei Feng

Beijing Anding Hospital of Capital Medical University, Beijing, China

Abstract

Key words: attention; depression; duloxetine; negativity bias; transcranial magnetic stimulation

INTRODUCTION

Depression is a disease characterized by low mood, decreased interest in daily activities, and lack of pleasure. It is highly prevalent, with a high recurrence rate and poor medication compliance (Yu et al., 2019). Nonetheless, there are no objective evaluation indicators for its core symptoms, which affects the accuracy of diagnosis, the reliability of efficacy evaluations for interventions, and the therapeutic alliance (American Psychiatric Association, 2013).

Patients with depression often have cognitive deficits in perception, attention, executive control, and decision-making. Attentional negativity bias is a prominent symptom of depression and occurs early in depression development. For example, patients with depression tend to interpret neutral faces as sad faces and happy faces as neutral faces (Bourke et al., 2010; Elliott et al., 2011), and also process negative emotions more rapidly than positive emotions (Gotlib et al., 2004; Suslow et al., 2004; Leyman et al., 2007). Moreover, this attention bias alters after therapy. However, as the negativity bias remains even after recovery from depression (Joormann and Gotlib, 2007), which increases the likelihood of recurrence of the disorder (Bouhuys et al., 1999). Such findings suggest that negativity bias is likely a core symptom of depression and its assessment may enable objective diagnosis.

Previous studies have demonstrated that the attentional negativity bias is associated with higher amygdala activity and lower anterior cingulate gyrus and prefrontal cortex activity compared with controls (Eysenck et al., 2007; Browning et al., 2010). Moreover, functional magnetic resonance imaging (fMRI) of patients with depression has demonstrated that when negative emotions are processed, there is over-activation of the bilateral amygdala (Matthews et al., 2008), while prefrontal cortex activity decreases from baseline (Siegle et al., 2007; Savitz and Drevets, 2009).

Treatment for attention bias in depression should start from the perspective of cerebral cortex excitatory inhibition. Excitatory glutamatergic synapses are closely related to mood disorder, attention, and cognition. Studies have reported that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor mediates 80% of synaptic excitability, which is closely related to prefrontal excitation and inhibition and the attentional negativity bias (Treccani et al., 2016; Yi et al., 2017). Transcranial magnetic stimulation (TMS) provides non-invasive electrical stimulation to nerve tissues such as the cerebral cortex, spinal cord root, and peripheral nerves. TMS can include single-pulse TMS, doublepulse TMS with varying interstimulus intervals administered to the same or different brain areas, and repetitive TMS with different frequencies (Peng et al., 2018). TMS increases synaptic excitability of the cerebral cortex at and around the stimulation site (Peng et al., 2018). Di Lazzaro et al. (2003) reported that TMS increases motor cortex excitability, which is related to AMPA receptor activity. We searched PubMed to retrieve related clinical trials published in recent years using the search terms “transcranial magnetic stimulation” and “depression” (Table 1).

We plan to conduct a trial including patients with depression who will receive oral duloxetine, a conventional inhibitor of selective 5-hydroxytryptamine (5-HT) and norepinephrine reuptake. Control patients will take duloxetine and receive sham stimulation, while a study group will both take duloxetine and receive TMS. The groups will be compared to determine the efficacy of TMS combined with duloxetine versus duloxetine alone to improve attentional negativity bias in patients with depression. Between May, 2010 and December, 2010, we conducted a pilot study for the trial, the results of which are described below.

METHODS/DESIGN

Study design

A prospective, multi-center, randomized, double-blind, shamstimulation, parallel-control trial.

Study setting

Beijing Anding Hospital of Capital Medical University, Beijing, China.

Recruitment

Recruitment will be done via advertising leaflets that will be distributed to patients in the hospital clinics or their family members. Recruitment information will be also disseminated in various WeChat groups. Interested patients or their family members will be given verbal notification, followed by a written test information sheet containing information about the trial, background, objectives, procedures, measurements, and potential advantages and disadvantages as well as potential risks and adverse effects. It also indicates that the patient may exit the study at any time and that cancellation of consent will not affect subsequent treatment.

Inclusion criteria

Patients will be considered for inclusion if they meet the following criteria designated by the expert group: a) meets the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for depression (American Psychiatric Association, 2013); b) Hamilton Rating Scale for Depression-17-Item (HAMD17; Hamilton, 1960) score ≥ 17; c) outpatient aged 18-65 years of either sex; and d) written informed consent from patients and their legal representatives.

Table 1: Clinical trial results of transcranial magnetic stimulation for treatment of depression published recently

Exclusion criteria

Patients presenting with one or more of the following criteria designated by the expert group will be excluded from the study: a) meeting the DSM-IV diagnostic criteria for any mental disorders other than depression; b) having a high risk of suicide, or scoring ≥ 3 for item 3 of the HAMD17-suicide; c) alcohol or drug abuse or dependence within the previous 6 months; d) depression complicated by serious or unstable physical illnesses, including any cardiovascular, neoplastic, renal, respiratory, endocrine (including thyroid dysfunction), digestive, blood (such as bleeding), or nervous system diseases; e) a history of epilepsy, with the exception of convulsions caused by febrile seizures in children; f) those who have undergone psychiatric surgery within 1 year before screening; g) those who have undergone electroconvulsive therapy, TMS or phototherapy within 3 months before screening; h) those taking antipsychotics, antidepressants, and mood stabilizers, and those with a pre-baseline washout period of less than 5 half-lives; i) lactating or pregnant women or those (including men) who are planning to conceive a child, as well as individuals unable to use safe and effective contraception; j) poor medication compliance; k) those who have participated in other drug clinical trials within 3 months before screening; and l) upon request of the researcher for safety reasons.

Withdrawal criteria

Patients presenting with one or more of the following criteria will be withdrawn from this study: a) those in whom efficacy will not be judged according to the prescribed treatment; b) those with incomplete data or other factors affecting safety or efficacy; c) incomplete data and other factors affecting efficacy or safety; d) development of comorbidities or complications that affect safety and efficacy judgments as well as diseases that affect the outcomes; e) introduction of other therapies or drugs to improve efficacy, which makes efficacy of the treatment of interest undetermined.

Grouping and blinding

Patients are randomly assigned to a study or control group using block randomization at a 1:1 ratio. We randomize the admitted 406 consecutive patients as described above and to avoid loss from drop out or withdrawal a further 20% will be included, such that 488 random numbers are generated. The specific section length and seed number are currently stored with the researcher in charge of randomization. When there is only one remaining segment in the random number sequence, an alert is issued to promote the researcher to supplement the random segment and spare segments continue to be generated by a random procedure, and the randomization procedure is repeatable. Randomization is performed with the UNIFORM(n) function equipped with SAS9.4 software. Patients and evaluators are blinded to grouping.

Interventions

Two groups of patients will receive oral duloxetine (enteric capsule; drug license number H20110317, H20110318, H20110319, H20110320; Eli Lilly and Company, IN, USA) in a 60-mg capsule. One capsule will be taken daily at breakfast for 6 successive weeks.

Study group:In addition to oral administration of duloxetine, the study group will receive daily TMS, five times a week, with a 2-day interval between the first five and last five administrations (with a total of 10 times). TMS will be delivered with a Rapid2 transcranial magnetic stimulator (National Food and Drug Administration approval number: 2012-2211591; Magstim Company Ltd., Wales, UK). Stimulation will be administered at a stimulation frequency of 10 Hz and stimulation intensity of 80% motor threshold, with a stimulation time for each sequence of 4 seconds, a two sequence interval of 56 seconds and 20 successive series each day. Stimulation will be applied at the left dorsolateral prefrontal cortex (dlPFC). Patients will sit in a quiet treatment room, holding their head as still as possible. During treatment, patients will be asked to refrain from talking and three trained therapists will complete the operation. Before the first treatment, the resting motor threshold will be measured with single-pulse TMS. This will provide the minimum stimulation intensity that can cause five times greater involuntary movement of the right thumb abductor muscle among 10 applications of TMS. The stimulation site will be located 5 cm anterior of the sagittal plane of the position at which the resting motor threshold is induced. A figure-eight coil with a diameter of 70 mm will be attached to the left dlPFC at the top of the patient's head, and the plane of the coil will be tangential to the scalp.

Control group:Sham stimulation coil will be used, which will mimic the appearance, stimulation frequency, stimulation sound, placing position, and positioning angle with the scalp of the actual TMS. However, the sham stimulation coil will not produce a magnetic field. Therefore, there will be no real magnetic stimulation, and no neuronal action potential will be induced.

Outcome measures

Primary outcome measure

The primary outcome measure is the effectiveness rate after 6 weeks of treatment. This refers to the proportion of patients with a ≥ 50% difference in HAMD17 total score at 6 weeks compared with baseline. The HAMD17 was developed by Hamilton in 1960. It consists of depressed mood, feelings of guilt, suicide, insomnia: early in the night, insomnia: middle of the night, insomnia: early hours of the morning, work and activities, retardation, agitation, anxiety psychic, anxiety somatic, somatic symptoms gastro-intestinal, general somatic symptoms, general symptoms (symptoms such as loss of libido, menstrual disturbances, hypochondriasis, loss of weight, and insight. Higher scores indicate more severe symptoms.

Secondary outcome measures

Several secondary outcome measures are obtained, as described below.

a) Complete remission rate after 6 weeks of treatment, with remission defined as a HAMD17 total score ≤ 7.

b) Effectiveness rate after 1, 2, and 4 weeks of treatment.

c) Change in HAMD17 total score after 1, 2, 4, and 6 weeks of treatment relative to baseline.

d) Changes in Athens Insomnia Scale (AIS) score after 1, 2, 4, and 6 weeks of treatment relative to baseline. The AIS is an internationally accepted self-rating scale to assess sleep quality. It covers sleep induction, awakenings during the night, final awakening, total sleep duration, sleep quality, well-being during the day, functioning capacity during the day, sleepiness during the day. Higher scores indicate poorer sleep.

e) Time and proportion of sleep drug use during the study period after 6 weeks of treatment.

f) Change in Digit Symbol Substitution Test (DSST) score after 1, 2, 4, and 6 weeks of treatment relative to baseline. The DSST requires participants to match as many symbols to numbers as possible in 90 seconds. Higher DSST scores indicate better functioning (Bettcher et al., 2018).

g) Change in 16-item Quick Inventory of Depressive Symptomatology Self-Report Scale (QIDS-SR16) after 1, 2, 4, and 6 weeks of treatment relative to baseline. The QIDSSR16 falling asleep, sleep during the night, waking up too early, sleeping too much, feeling sad, decreased appetite, increased appetite, decreased weight (within the last 14 days), increased weight (within the last 14 days), concentration/decision-making, perception of myself, thoughts of my own death or suicide, general interest, energy level, feeling more sluggish than usual, and feeling restless (agitated, not relaxed, fidgety). Higher scores indicate more severe depressive symptoms (Rush et al., 2003).

h) Change in 7-item Generalized Anxiety Disorder Scale (GAD7) after 1, 2, 4, and 6 weeks of treatment relative to baseline. The GAD7 questionnaire is a self-rating assessment of anxiety with a maximum total score of 21 points. It covers the content: over the last 2 weeks, how often have you been bothered by the following problems? 1 Feeling nervous, anxious, or an edge; 2 not being able to stop or control worrying; 3 worrying too much about different things; 4 trouble relaxing; 5 being so restless that it is hard to sit still; 6 becoming easily annoyed or irritable; 7 feeling afraid as if some awful might happen. Higher GAD7 scores indicate more severe anxiety (Mossman et al., 2017).

i) Change in Sheehan Disability Scale (SDS) score after 1, 2, 4, and 6 weeks of treatment relative to baseline. The SDS questionnaire was developed to assess functional impairment caused by anxiety in domains covering work/school, social life/leisure activities, family life/home responsibilities. Higher SDS scores indicate more severe impairment (Leon et al., 1992).

j) Change in Insight and Treatment Attitude Questionnaire (ITAQ) score after 6 weeks of treatment relative to baseline. The ITAQ was developed by McEvoy et al. (1989) and is used to evaluate a patient's awareness of their disease and their attitudes toward medication. It covers 11 items with a full score of 22.

k) Change in Arizona Sexual Experience Scale (ASEX) score after 1, 2, 4, and 6 weeks of treatment relative to baseline. The ASEX is a 5-item questionnaire designed to measure sexual functioning in several domains including sexual drive, arousal, penile erection/vaginal lubrication, ability to reach orgasm, and satisfaction with orgasm over the past weeks. Each item is rated on a 6-point scale ranging from 1 (hyperfunction) to 6 (hypofunction). There are two versions of the questionnaire, one for men and another for women. The ASEX evaluates sexual functioning from desire, arousal, penile erection or vaginal lubrication, orgasm, and satisfaction. Higher scores indicate more severe sexual dysfunction (McGahuey et al., 2000).

l) Change in Mini-International Neuropsychiatric Interview (MINI) suicide score relative to baseline. It includes 6 items with a full score of 33.

m) Higher MINI suicide scores indicate a higher risk of suicide (Sheehan et al., 1998).

n) Change in Perceived Deficits Questionnaire-Depression (PDQ-D) score after 1, 2, 4, and 6 weeks of treatment relative to baseline. The PDQ-D questionnaire covers four domains including attention/concentration, retrospective memory, prospective memory, and planning/organization. Higher scores indicate more severe dysfunction (Shi et al., 2017).

o) Neuroelectrophysiological parameters Electroencephalogram (EEG) event-related potential experiments will be performed in a shielded soundproof environment with a high-density 128-lead EGI EEG acquisition system (Electrical Geodesics Inc., Eugene, OR, USA). The electrode cap will be a saline coupling medium with a sampling frequency of 1000 Hz. Cz will be used as the recording reference electrode and scalp resistance will be maintained below 50 kΩ. EEG results after 2 and 6 weeks of treatment will be obtained during the following tasks:

i) Emotional face perception task to examine the regulation of visual P1 amplitude by negative stimuli. Each trial consists of an emotional face stimulus that illuminates from black to blue. The time and accuracy of the participant's response to the blue fixation point is recorded. EEG signal during the entire study period will be recorded.

ii) Point probe task to identify valid and invalid cues for subsequent point stimuli with the random appearance of pairs of faces. During the task, response time, accuracy, and EEG signal will be recorded. The experimental paradigm of the point probe task will be as follows: each stimulus string starts with a picture containing a “+” word presented for 500 ms, then a picture of emotional faces, then a picture containing “+” and “*.” The “*” symbol appears either to the left of the word “+” or to the right of the word “+” for 750 ms. Participants will be asked to look at the word and determine whether the “*” symbol is on the left or right side of the word. They will respond by pressing the button as fast and accurately as possible. The time interval between stimulus strings will be 500-2000 ms (Figure 1).

Figure 1: Experimental paradigm for the electroencephalogram point probe task.

iii) Irrelevant information suppression task: in the task, a picture containing several simple gray figures will be presented. Participants must pay attention to the position of the circular pattern in a large number of diamond patterns. If the pattern appears above the diamond patterns the up arrow is pressed, and if it is below the diamond patterns, the down arrow is pressed. Color pattern interference may occur on the left or right side. The participant must eliminate interference as much as possible and concentrate on making judgments of the spatial position of the pattern (Figure 2). The stimulus presentation time will be 500 ms. During the entire task, response times and EEG data will be recorded.

Figure 2: Test image of the electroencephalogram-independent information suppression task.

p) Safety indicators

Safety indicators will be evaluated after 1, 2, 4, and 6 weeks of treatment. These include:

i) Body temperature, breathing, heart rate, blood pressure, and weight.

ii) Laboratory assessments, including a routine blood test (red blood cell count, hemoglobin concentration, white blood cell count, category percentage of neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and platelet count), routine urine test (urine protein, urine glucose, urine white blood cell count, and urine red blood cell count), blood biochemical tests of liver function (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatine kinase, γ-glutamyl transpeptidase, total bilirubin, and total protein), renal function (creatinine, urea nitrogen, and uric acid), blood lipids (high-density lipoprotein, low-density lipoprotein, total cholesterol, and triglycerides), fasting blood glucose, electrolytes (Na+, K+, and Cl-), C-reactive protein, and glycated hemoglobin, and urine pregnancy test for female patients of childbearing age.

iii) Electrocardiography will be performed with 12-lead electrocardiography (Japan Photoelectric Industry Co., Ltd., Tokyo, Japan).

q) Adverse events

Adverse events refer to adverse medical events that occur after a participant receives a test drug, which may or may not necessarily have a causal relationship with the test drug. Adverse events can include: (1) all suspected adverse drug reactions; (2) all reactions due to drug overdose, abuse, withdrawal, allergy, or toxicity; (3) obviously unrelated diseases, including exacerbations of pre-existing diseases; (4) injury or accident; (5) abnormalities found in physical examination; (6) abnormalities found in laboratory examinations.

Investigators should use simple medical terms to report any adverse events that are directly observed by the investigator or reported spontaneously by the patient. In addition, patients should be asked about the adverse events at each visit after the start of treatment. The time of action, severity, duration, and outcomes for any severe adverse events will be recorded in a Serious Adverse Events Form. These details will be reported to the relevant authorities within 24 hours. The adverse events should be recorded in the designated case report forms and will be reported to the relevant organizations within 24 hours according to Good Clinical Practice statement. Whether there is a need to break the study blinding for a serious adverse event will be determined by the principle investigator. This will be notified to the sponsor in time. The severity of the adverse events can be classified as mild, moderate, and severe.

Trial flow chart

Flow diagram of the multi-center, randomized, double-blind, sham-stimulation, parallel-control trial is shown in Figure 3.

Timing of outcome measures is shown in Table 2.

Sample size

In accordance with preliminary results and previous reports (Xiao et al., 2015), the effective rate was estimated to be 55% and 40% in the study and control groups, respectively. Assuming (1 - β) = 0.85, α = 0.05 (two-sided), a final sample size of n = 184 per group was calculated using the PASS 11.0 software (PASS, Kaysville, UT, USA). Assuming a participant loss rate of 10%, we will require a sample size of n = 203 per group.

Statistical analysis

Analysis populations

Full analysis set: Full analysis set refers to the set of subjects that receive one intervention and complete baseline evaluation according to the intention-to-treat principle. The last data of subjects who will have not completed the whole therapeutic process will be treated using the last observation carried for-ward (LOCF) method.

Table 2: Schedule for primary and outcome measures

Per protocol set: It refers to a subset of the intention-to-treat subjects who will have completed at least 4 weeks of treatment. During the 4 week of observation, subjects will not use other drugs or measures. In this study, full analysis set and per protocol set will be included.

Safety analysis set: It refers to a subset of subjects who will have completed one intervention and undergone safety recordings.

Analysis methods

All data will be statistically processed using the SAS9.4 software (SAS Institute, Inc., Cary, NC, USA). A level of P ＜ 0.05 will be considered statistically significant. Measurement data will be expressed as the means (standard deviations), medians (interquartile range), minimum, and maximum. Count data will be expressed as percentages.

Efficacy analysis

A mixed-effects model will be used to compare the scores between groups. Parametric/non-parametric tests will be used to compare measurement data between groups. The chi-square test or Fisher's exact test will be used to compare count data between groups.

Safety evaluation

Adverse events, vital signs, and abnormal values of laboratory and electrocardiographic examination results will be described in the list. The chi-square test or Fisher's exact test will be used to compare the ratios of subjects having the adverse events and side reactions between two groups. The Fisher's exact test will be used to compare the ratio of subjects who drop out of the study because of adverse events between two groups.

Data collection and management

The case report forms will be filled in by the investigators. Each included subject must complete the case report form. If no information is obtained, nothing will be entered in the boxes/space. Corrections must be made in ink by crossing out the incorrect entry with a single horizontal line, placing the correct information next to the error, and providing signature and date next to the correction. The information of dropouts should be recorded in detail, including time and cause of dropout and measures to be taken.

The completed case report forms will be reviewed by the clinical research associate and the principle investigator in charge. A data administrator will be responsible for data entry and management.

A data administrator will establish the Epidata database based on the case report forms.

All data will be input using a double-entry strategy. After accuracy check, the data administrator will determine the check contents according to the range of each index recorded in the case report form and their mutual relationship and develop computer program for data verification. All questions from the data verification will be promptly notified to the clinical research associate and answers will be made by the investigators.

After data entry and accuracy check, the original case report forms will be archived in numerical order. Electronic data will be saved as per classification and backed up regularly to prevent data loss. All file transfers will be specially recorded, signed accordingly, and kept for 5 years.

The published data will be accessible at www.figshare.com.

Audits

During the study period, relevant personnel will be arranged to regularly monitor the data to confirm that all research personnel will follow the research plan.

Case report forms will be recorded correctly. Accuracy check of original data will be made.

The clinical research associate will strictly follow the trial protocol, relevant standard operation procedure, guiding principles, and regulatory requirements throughout the study period. During the study period, the clinical research associate should keep in touch with the research center. Before the start of the study, the clinical research associate will hold a kickoff meeting at the research center to carry out training regarding research programs, standard operation procedure and Good Clinical Practice. The principle investigators and all staff participating in the study will participate in the training. At the end of the study, the clinical research associate will recheck all relevant files and archived.

All patients will receive free medication, laboratory safety examination, and follow-ups. Once serious adverse drug reactions occur, the trial will be terminated ahead of time, and an emergency response program will be initiated. The trial will provide patients with clinical trial liability insurance. The insurance company bears treatment costs and financial compensation for trial-related injuries or deaths.

Ethics and dissemination

The trial will be performed in strict accordance with the Declaration of Helsinki and applicable laws and regulations in China and approved by Hospital Ethics Committee, Beijing Anding Hospital, Capital Medical University (approval No. 2017-79-2017111-2) (Additional file 1) on December 20, 2017. This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-INR-17014075) on December 21, 2017. If trial protocol, informed consent, or other trial documents will be modified, hospital ethics committee approval must be obtained. If serious adverse events occur during the study period, they should be reported to the hospital ethics committee as required.

Prior to participation in this study, the investigators will be responsible for a complete and comprehensive introduction of the purpose, procedure, and possible benefits and risks of this study to the participants or their legal guardians. The participants or their legal guardians will sign written informed consent (Additional file 2). The participants will have the rights to withdraw from the study at any time. The informed consents will be reserved as clinical research documents.

According to relevant regulations on data protection and privacy, patients are required to authorize investigators or other relevant individuals who need to know this information for the purpose of this study to collect, use, and publish their data. The study data will be stored in a computer database and kept confidential in accordance with the applicable laws of China.

The manuscript is prepared and modified according to the CONsolidated Standards Of Reporting Trials (CONSORT) 2010 guidelines (Additional file 3). Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be published at www.figshare.com.

DISCUSSION

Previous contributions and existing problems

Attentional negativity bias is strongly correlated with depression (Eizenman et al., 2003; Gupta and Kar, 2012; Platt et al., 2015). Indeed, patients with depression show increased vigilance, rumination, and recall of negative information related to their symptoms (Hsu et al., 2015). This attentional negativity bias reflects the patient's poor ability to process information (Sanchez et al., 2015). This can lead to further worsening of work and social function in patients with depression (Culpepper, 2015). Moreover, the bias can reduce memory flexibility, leading to information extraction problems for general and specific memories, and resulting in a negativity bias for negative information and continued occurrence of depressed mood (Hitchcock et al., 2015). Furthermore, there is a continued impact on a patient's emotional regulation function, which also has direct and indirect effects on depressive symptoms (Everaert et al., 2017).

When depressive symptoms show clear improvement, there is also an improvement in the attentional negativity bias (Li et al., 2016). Therefore, if patients with depression can emphasize positive factors and change the bias of attention, then other symptoms of depression may be gradually alleviated.

When attempting to treat attentional negativity bias in depression, cortical excitability inhibition should be considered. Excitatory glutamatergic synapses are closely related to mood disorders, attention, and cognition (Treccani et al., 2016; Yi et al., 2017). TMS can increase synaptic excitability (Peng et al., 2018) and may thereby improve attentional negativity bias in depression.

Novelty of this study

This study is novel in that it focuses on suppression of negative information, and aims to establish an objective symptom assessment multivariate index system related to the attentional negativity bias in depression. Moreover, it investigates the mechanisms underlying attentional negativity bias that can contribute to developing effective treatment strategies for the bias observed in this disease.

Study limitations

In this study, severity of disease will not be assessed. In future studies, treatment effects in patients with mild, moderate, and severe depression should be further analyzed. The differential of effects of varying frequency, duration, and course of TMS are also areas of interest for future research.

Study significance

The results of our future trial will provide objective clinical evidence of whether TMS combined with duloxetine can effectively improve the attentional negativity bias in patients with depression.

Date of registration:December 21, 2017

Recruitment time:January 2018 to December 2020

Study completed:December, 2023

Trial status:Recruiting

Additional files

Additional file 1: Hospital Ethics Approval.

Additional file 2: Informed Consent Form.

Additional file 3: CONsolidated Standards Of Reporting Trials (CONSORT) 2010 checklist.

Author contributions

Concept and design of study protocol: CMW and LF; data collection: DNZ and XC; draft of manuscript: DNZ. All authors approved the final manuscript for publication.

Conflicts of interest

The authors have no conflicts of interest to declare.

Financial support

None.

Institutional review board statement

The study protocol has been approved by Ethics Committee of Beijing Anding Hospital, China Medical University, China (approval No. 2017-79-2017111-2) on December 20, 2017. This study will be performed according to the statement of the Declaration of Helsinki.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the forms, the patients or their legal guardians will give their consent for patients' images and other clinical information to be reported in the journal. The patients or their legal guardians will understand that the patients' names and initials will not be published and due efforts will be made to conceal their identity.

Reporting statement

This study followed the CONsolidated Standards Of Reporting Trials (CONSORT) 2010 guidelines.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Beijing Anding Hospital, China.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Study protocol and informed consent form will be available immediately following publication, without end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.

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