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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:136

Cordyceps sinensis combined with duloxetine improves sleep symptoms in patients with depression: a randomized, double-blind, placebo-controlled study


The National Clinical Research Center for Mental Disorder & Beijing Key Laboratory of Mental Disorder, Beijing Anding Hospital of Capital Medical University; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China

Date of Submission18-May-2018
Date of Acceptance21-May-2018
Date of Web Publication19-Nov-2018

Correspondence Address:
Lei Feng
The National Clinical Research Center for Mental Disorder & Beijing Key Laboratory of Mental Disorder, Beijing Anding Hospital of Capital Medical University; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.245217

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  Abstract 

Background and objectives: Patients with depression can experience sleep disorder. Current treatments for depression, such as duloxetine and selective serotonin reuptake inhibitors, not only have a slow onset of action but also are associated with side effects such as dizziness, blurred vision, and ataxia. The main active ingredient of cordyceps sinensis, cordycepin, may have antidepressant effects, as well as pro-immunity, anti-inflammatory, anti-tumor, anti-fatigue, and anti-viral properties. In this randomized controlled trial, we investigate the safety and effectiveness of cordyceps sinensis (containing approximately 1.0% cordycepin) in combination with duloxetine in treating sleep disorder in patients with depression.
Methods: In this randomized, double-blind, placebo-controlled, prospective trial, we plan to include 286 patients with depression receiving treatment at Beijing Anding Hospital of Capital Medical University, China. These patients are randomly assigned to undergo cordyceps sinensis combined with duloxetine or placebo combined with duloxetine. Duloxetine is assigned in an open manner, while cordyceps sinensis and placebo are assigned in a double-blind manner. Participants or their legal guardians are informed of the study protocol and medication and sign informed consent. A total of 246 patients were included in the polit study.
Results: The primary outcome measure is the proportion of patients with ≥ 50% difference in 17-item-Hamilton Depression Rating Scale total score after 6 weeks of treatment relative to baseline. The secondary outcome measures are complete remission rate after 6 weeks of treatment; effectiveness rate after 1, 2, and 4 weeks of treatment; changes in Athens Insomnia Scale score, 17-item-Hamilton Depression Rating Scale total score, Arizona Sexual Experience Scale score, Mini-International Neuropsychiatric Interview suicide score, Digit Symbol Substitution Test score, Perceived Deficits Questionnaire-Depression score, 16-item Quick Inventory of Depressive Symptomatology Self-Report Scale score, 7-item Generalized Anxiety Disorder Scale score, and Sheehan Disability Scale score after 1, 2, 4, and 6 weeks of treatment relative to baseline; changes in Insight and Treatment Attitude Questionnaire score, and time and proportion of sleep drug use during the study period after 6 weeks of treatment relative to baseline; electroencephalogram results after 2 and 6 weeks of treatment; and blood biomarkers, safety indicators, and adverse events after 6 weeks of treatment. Results of a pilot study (during 2012–2016) involving 246 patients with depression receiving duloxetine 60 mg/d or fluoxetine 20 mg/d revealed that there was a similar percentage difference in 17-item-Hamilton Depression Rating Scale total score after 6 weeks of treatment relative to baseline and a similar incidence of drug use-related adverse events for both treatments.
Discussion: We plan to perform a future study involving 286 patients to validate that cordyceps sinensis combined with duloxetine can effectively improve sleep symptoms of depression. The trial will provide data to support the clinical application of cordyceps sinensis.
Ethics and registration: This study was approved by Hospital Ethics Committee, Beijing Anding Hospital of Capital Medical University, China (approval No. 2017-79-2017111-2) on December 20, 2017. This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-INR-17014074). Protocol version: 3.0.

Keywords: cordyceps sinensis; cordycepin; duloxetine; depression; sleep disorder; Hamilton Depression Rating Scale; Athens Insomnia Scale; randomized, double-blinded, placebo-controlled study


How to cite this article:
Chen X, Zhang XL, Wang CM, Feng L, Wang G. Cordyceps sinensis combined with duloxetine improves sleep symptoms in patients with depression: a randomized, double-blind, placebo-controlled study. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:136-45

How to cite this URL:
Chen X, Zhang XL, Wang CM, Feng L, Wang G. Cordyceps sinensis combined with duloxetine improves sleep symptoms in patients with depression: a randomized, double-blind, placebo-controlled study. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Dec 16];3:136-45. Available from: http://www.actnjournal.com/text.asp?2018/3/4/136/245217


  Introduction Top


Depression is a serious mental illness that was estimated to affect approximately 3% of the world population in 2015 (GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, 2016). Depression often manifests as poor mood, decreased interest in daily activities, slow thinking, and reduced speech and movement. Patients with severe depression have an increased risk of committing suicide, while others experience a variety of somatic symptoms including sleep disorder, fatigue, loss of appetite, weight loss, constipation, painful chest tightness, nausea and vomiting, and hyposexuality (American Psychiatric Association, 2013), and long-term use of currently available drugs promoting sleep can lead to adverse reactions.

Currently prescribed antidepressants, such as duloxetine and the selective serotonin reuptake inhibitors (SSRIs), not only have a slow onset of action but also are associated with adverse reactions such as dizziness, blurred vision, and ataxia (Yang et al., 2015). Given the limitations of current medications, there is an urgent need to explore new drugs to improve the treatment of depression. Some traditional drugs that are currently available have obvious therapeutic effects in the treatment of depression [Table 1]. An electronic search of the CNKI and WanFang databases for literature describing traditional drugs for treatment of depression from 2016 to 2018 was performed using the search terms of traditional Chinese medicine, acupuncture, depression, and clinical trial [Table 1]. Results showed that some methods are effective.
Table 1: Clinical effects of traditional drugs used in China for treatment of depression

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Cordyceps sinensis (Cordyceps militaris (L.) Link), also known as cordyceps militaris, is a commonly used medicinal fungus belonging to the Ascomycota phylum in the Clavicipitaceae family and the Cordycep genus. It contains various active ingredients including cordycepic acid, cordyceps polysaccharide, adenosine, and cordycepin. Cordyceps sinensis has pro-immunity, anti-inflammatory, anti-tumor, anti-fatigue, anti-oxidative, and anti-viral properties (Liu et al., 1989; Reis et al., 2013). Moreover, cordycepin (a major biologically active ingredient of Cordyceps militaris (L.) Link) is an analog of adenosine with anti-cancer, anti-viral, immune-modulatory, sleep-promoting, cognition-promoting, and anti-oxidative effects (Mahy et al., 1973; Zhou et al., 2002, 2008; Wehbe-Janek et al., 2007; Cai et al., 2013; Wang et al., 2015).

In tail-suspension and forced swimming experiments in mice, Li et al. (2016) observed that cordycepin had antidepressant effects, with increased GluR1 S845 phosphorylation and GluR1 levels at synapses in the prefrontal cortex. Moreover, the AMPA-specific antagonist GYKI 52466 blocked the antidepressant effects of cordycepin. These results indicate that cordycepin acts as an antidepressant with potential clinical use, and its antidepressant effect is mainly achieved through regulation of the prefrontal AMPA receptor signaling pathway. However, little information is available regarding cordyceps sinensis and its main active substance cordycepin for treatment of sleep disorder in depression.

Patients with depression may experience sleep disorder as part of their symptomatology. Therefore, we will investigate the safety and effectiveness of cordyceps sinensis (containing approximately 1.0% cordycepin) in combination with duloxetine on sleep disorder in patients with depression within a randomized, double-blind, placebo-controlled, prospective trial.


  Methods/Design Top


Study design

A randomized, double-blind, placebo-controlled, prospective study.

Ethical approval and informed consent

The trial is 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 [Additional file 1]). This trial has been registered with Chinese Clinical Trial Registry (registration number: ChiCTR-INR-17014074). Protocol version: 3.0.

Participants or their legal guardians are informed of the study protocol and medication and sign informed consent (Additional file 2 [Additional file 2]).

The manuscript is prepared and modified according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines (Additional file 3 [Additional file 3]).

Study setting

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

Study population

Recruitment is performed via information dissemination in various WeChat groups. An advert informs patients about the study in clinics and wards of the Department of Psychiatrics, Beijing Anding Hospital of Beijing Capital Medical University. After being informed about the purpose of the trial and its interventions, as well as the risks and benefits, patients interested in participating or their legal guardians contact the project manager via telephone, email, or WeChat.

Eligibility criteria

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) 17-item-Hamilton Depression Rating Scale (HAMD17; Hamilton, 1960) score ≥ 17, and at least 2 out of 3 insomnia items scoring 2 points; c) Athens Insomnia Scale (AIS; Soldatos et al., 2003) score > 6; d) outpatient aged 18–65 years of either sex; and e) written informed consent from subjects and their legal representatives.

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) depressive episodes with psychotic symptoms (delusions, hallucinations); d) has previously undergone normative duloxetine treatment that was not effective; e) alcohol or drug abuse or dependence within the previous 6 months; f) 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; g) a history of epilepsy, with the exception of convulsions caused by febrile seizures in children; h) important abnormalities in laboratory examinations during the screening period, such as abnormal liver function tests (alanine aminotransferase and aspartate aminotransferase exceeding 2 times the normal value) or renal insufficiency (creatinine ≥ 2 mg/dL or ≥ 177 μM); i) clinically significant abnormalities in electrocardiogram screening, for example, male QTc interval > 450 ms, and female QTc interval > 470 ms; j) previous history of increased intraocular pressure or narrow angle glaucoma; k) a known history of allergy to cordycepin and/or duloxetine, or those who have severe allergy constitution, or those who are allergic to at least 2 drugs (including those with photoallergies); l) those receiving systematic psychotherapy (interpersonal relationship therapy, dynamic therapy, or cognitive behavioral therapy) within 3 months before screening; m) those who have used monoamine oxidase inhibitors (MAOIs) within 2 weeks before screening; n) those who have been treated with fluoxetine within a month before screening; o) those who have undergone psychiatric surgery within a year before screening; p) those who have undergone electroconvulsive, transcranial magnetic stimulation or phototherapy within 3 months before screening; q) those taking antipsychotics, antidepressants, and mood stabilizers, and those with a pre-baseline washout period of less than 5 half-lives; r) those currently taking Chinese medicine, melatonin, or hypericum perforatum, which may influence the central nervous system, or those already taking cordycepin; s) 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; t) poor medication compliance; u) those who have participated in other drug clinical trials within 3 months before screening; and v) 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. If a patient meets any of these criteria, we will obtain as much of the excluded patient’s safety and effectiveness data as possible.

Grouping and blinding

Patients are randomly assigned to a study or control group using block randomization at a 1:1 ratio. We randomize the first admitted 60 consecutive patients as described above and to avoid loss from drop out or withdrawal a further 20% will be included, such that 80 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, physicians, and evaluators are blinded to grouping. Preparation for drug blinding and emergency letters is completed by individuals unrelated to the trial. Each participant has a uniform sequence number, each serial number has its corresponding randomization, and randomized grouping is overseen by a designated person. During the drug dispensing process, drug use is recorded by a designated person. The drug manager issues the test drugs with the serial number in a random order, and each participant can only use one number.

Interventions

Two groups of patients receive oral duloxetine (enteric capsule; drug license number H20110317, H20110318, H20110319, H20110320, Eli Lilly and Company, Indianapolis, IN, USA) in a 60 mg/capsule, taking one capsule a day at breakfast for 6 successive weeks. The study group receives 1.5 g cordyceps sinensis (tablets, drug license number SC10611141617039, Beijing Guanruijin Biotechnology Co., Ltd., China), taken orally after breakfast (approximately 8:00) and dinner (approximately 20:00) for 6 successive weeks. The control group receives 1.5 g placebo (ingredients include starch and a small amount of edible pigment; Beijing Guanruijin Biotechnology Co., Ltd.) orally after breakfast (approximately 8:00) and dinner (approximately 20:00) for 6 successive weeks. The appearance, color, and smell of the placebo tablet are the same as those of cordyceps sinensis tablets.

The daily medication time is preferably be fixed (controlled within 0.5 hours), but precise medication times are not be required. If the patient still has severe sleep disturbance after 2 weeks of treatment, one of the following drugs is used in the evening: zolpidem (≤ 10 mg/d), zopiclone (≤ 7.5 mg/d), or zaleplon (≤ 10 mg/d). If one of abovementioned drugs is not invalid, another one is used. The dosage, number and duration of administrations are recorded. If the participant experiences anxiety or agitation, lorazepam 0.5 mg is administered temporarily, with a daily dosage of not more than 2 mg. It is not recommended that this be used continuously.

Use of aforementioned drugs is avoided within 8 hours before assessment. If somatic diseases exist, symptomatic treatment is given. We recommend that the type and dosage of therapeutic drugs is kept constant during the study period. However, therapeutic drugs must be withdrawn if a condition becomes serious. The type and dosage of drugs (or therapy) required for comorbid diseases, as well as the number of administrations and administration duration, are recorded.

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 is mainly used to evaluate the severity of depression among patients, with milder symptoms indicated by a lower total score and more severe symptoms indicated by a higher total score (Hamilton, 1960).

Secondary outcome measures

Several secondary outcome measures are obtained, as described below.

  1. Changes in Athens Insomnia Scale (AIS) score after 1, 2, 4, and 6 weeks of treatment relative to baseline. The AIS is a self-rating scale to assess sleep quality with subjective feelings about sleep as the main assessment index. The total assessment result is determined according to the total score, with a higher score indicating poorer sleep quality.
  2. Effectiveness rate (as defined above) after 1, 2, and 4 weeks of treatment.
  3. Complete remission rate after 6 weeks of treatment, with remission defined as a HAMD17 total score ≤ 7.
  4. Change in HAMD17 total score after 1, 2, 4, and 6 weeks of treatment relative to baseline.
  5. Time and proportion of sleep drug use during the study period after 6 weeks of treatment
  6. 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. Lower scores indicate poorer understanding of the disease and poorer attitudes toward medication.
  7. 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. Higher scores indicate more severe sexual dysfunction (McGahuey et al., 2000).
  8. Change in Mini-International Neuropsychiatric Interview (MINI) suicide score relative to baseline. Higher MINI suicide scores indicate a higher risk of suicide (Sheehan et al., 1998)
  9. 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. The test is used to evaluate attention, and sensitivity of action and thinking. Higher DSST scores indicate better functioning (Bettcher et al., 2018).
  10. 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).
  11. 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 QIDS-SR16 can intuitively reflect the subjective feelings of patients with depression. The questionnaire is mainly used for adults with depressive symptoms, including those from clinics and wards. However, this questionnaire is not easily applied to assess patients with severe delayed symptoms. Higher scores indicate more severe depressive symptoms (Rush et al., 2003).
  12. 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 an self-rating assessment of anxiety with a maximum total score of 21 points. Higher GAD7 scores indicate more severe anxiety (Mossman et al., 2017).
  13. 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).
  14. Neuroelectrophysiological parameters. Electroencephalogram 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:
    1. 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.
    2. 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.

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    3. Irrelevant information suppression task in which 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.

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  15. Blood biomarkers. Plasma levels of brain-derived nerve growth factor, interleukin-1β, interleukin-2, interleukin-6, and tumor necrosis factor-α are detected with ELISA after 6 weeks of treatment.
  16. Safety indicators. Safety indicators will be evaluated after 1, 2, 4, and 6 weeks of treatment. These include:
    1. Body temperature, breathing, heart rate, blood pressure, and weight.
    2. 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.
    3. Electrocardiography will be performed with 12-lead electrocardiography (Japan Photoelectric Industry Co., Ltd., Tokyo, Japan).
  17. 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.
    Adverse reactions occurring during the clinical trial can be rated as mild, moderate, or severe. A mild adverse reaction does not influence a patient’s normal function. A moderate adverse reaction influences a patient’s normal function to a certain degree. A severe adverse reaction greatly influences a patient’s normal function.
    Possible associations of adverse events with test drugs and concomitant drugs will be assessed and categorized as follows:
    1. Definitely related: Adverse reactions appear within a reasonable time sequence according to the medication, corresponding to the known type of reaction of the suspected drug, and the adverse reactions disappear after drug withdrawal. Patient’s clinical state or other reasons are unlikely to produce the reaction.
    2. Likely related: Adverse reactions appear within a reasonable time sequence according to the medication, corresponding to the known type of reaction of the suspected drug, and these adverse reactions disappear after drug withdrawal. Patient’s clinical state or other reasons are unlikely to produce the reaction.
    3. Possibly related: Adverse reactions appear within a reasonable time sequence according to the medication, corresponding to the known type of reaction of the suspected drug, and these adverse reactions alleviate after drug withdrawal. Patient’s clinical state or other reasons are likely to produce the reaction.
    4. Unlikely related: Adverse reactions do not appear within a reasonable time sequence according to the medication, do not correspond to the known type of reaction of the suspected drug, and these adverse reactions do not alleviate after drug withdrawal. Patient’s clinical state or other reasons are likely to produce the reaction. Adverse reactions alleviate after disease symptoms improve or other factors are eliminated.
    5. Certainly unrelated: Adverse reactions do not disappear in a reasonable time sequence according to the medication, not corresponding to the known type of reaction of the suspected drug. Patient’s clinical state or other reasons are likely to produce the reaction. Adverse reactions alleviate after disease conditions improve or other factors are eliminated.


Adverse reactions that correspond to any of the first three items (a), (b), or (c) will be considered an adverse reaction of the test drug. The 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.

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. In the case of emergency medical treatment, upon contact with the principle investigator, the emergency plan will be initiated, the trial will be immediately terminated, and appropriate medical treatment will be given. Transfer treatment will be considered in the absence of treatment in our hospital to ensure the safety of participants.

Trial flow chart

Flow diagram of the randomized, double-blind, placebo-controlled trial is shown in [Figure 3].
Figure 3: Flow diagram of the trial.

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Timing of outcome measures is shown in [Table 2].
Table 2: Schedule for primary and outcome measures

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Sample size

In accordance with preliminary results and previous reports (Du et al., 2009; Shi et al., 2016; Xu et al., 2016; Liu et al., 2017; Xu, 2017), the effective rate was estimated to be 60% and 40% in the study and control groups, respectively. Assuming (1 – β) = 0.9, α = 0.05 (two-sided), a final sample size of n = 130 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 = 143 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 forward method.

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.

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 of 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 data 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 perclassification and backed up regularly to prevent data loss. All file transfers will be specially recorded, signed accordingly, and kept for 5 years.

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 GCP. The principle investigators and all staff participating in the study will participate 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.


  Results Top


Results of a small-size-sample pilot study

We included 246 patients in a pilot study performed in 2009. These patients were administered 60 mg/d duloxetine (duloxetine group, n = 123) or 20 mg/d fluoxetine (fluoxetine group, n = 123) for 6 successive weeks. Six patients were lost to follow up during the baseline stage and did not provide efficacy data. Two were rejected because of ineligible age. Therefore, 238 patients were included in the full analysis set, with 117 patients in the duloxetine group and 121 patients in the fluoxetine group. Ten patients dropped out of the pilot study. Thus 228 patients met the per protocol set, consisting of 111 patients in the duloxetine group and 117 patients in the fluoxetine group.

Comparison of baseline information between two groups

We observed no significant differences in sex, age, course of disease, baseline HAMD17 score and Hamilton Anxiety Rating Scale score between duloxetine and fluoxetine groups (P > 0.05; [Table 3]).
Table 3: Clinical data of patients included in the pilot study

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Changes in HAMD17 total score

After 6 weeks of treatment, the proportion of patients with ≥ 50% difference in HAMD17 total score relative to baseline was similar in both the duloxetine and fluoxetine groups (P > 0.05; [Table 4]).
Table 4: Effects of duloxetine and fluoxetine on change in HAMD17 total score at 6 weeks relative to baseline

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Hamilton Anxiety Rating Scale scores

After 1, 2, 4, and 6 weeks of treatment, patients in duloxetine and fluoxetine groups had similar Hamilton Anxiety Rating Scale scores (P > 0.05, [Table 5]).
Table 5: Effects of duloxetine and fluoxetine on HAM-A scores at 6 weeks relative to baseline

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Laboratory test indicators

After 6 weeks, serum levels of alanine aminotransferase had increased in three patients, serum levels of aspartate aminotransferase increased in two patients, white cell count was abnormal in one patient, and serum glucose increased in two patients in the duloxetine group. Similarly, in the fluoxetine group, serum levels of alanine aminotransferase increased in three patients, serum levels of aspartate aminotransferase increased in two patients, white cell count was abnormal in one patient, and blood glucose level increased in one patient.

Electrocardiogram findings

After 6 weeks of treatment, one patient in each group had a prolonged QT interval and one patient in the duloxetine group had a prolonged PR interval. Abnormal patients showed no significant discomfort and returned to normal during the follow-up period.

Vital signs

After 6 weeks of treatment, heart rate, blood pressure, respiration, body mass, and physical examination results were similar between the duloxetine and fluoxetine groups (P > 0.05).

Adverse events

Adverse events occurred in 51 (42%) and 37 (30%) patients in the duloxetine and fluoxetine groups, respectively, and the difference was not significant (P > 0.05). No serious adverse events were observed. Drug-caused adverse reactions occurred in 42 (35%) and 30 (25%) patients in the duloxetine and fluoxetine groups, respectively. Common adverse reactions occurring in the duloxetine group included nausea/vomiting (8%), dry mouth (8%), abnormal liver function (4%), lethargy (4%), loss of appetite (3%), dizziness (3%), and constipation (3%). Common adverse reactions occurring in the fluoxetine group included nausea/vomiting (7%), dry mouth (6%), loss of appetite (5%), dizziness (3%), and abnormal liver function (4%). The incidence of adverse drug reactions in the two groups was close (P > 0.05).


  Discussion Top


Previous contributions and existing problems

Depressed patients taking duloxetine show significant improvements in emotional symptoms but a poor response in physical symptoms such as sleep (Greco et al., 2004). Currently, patients use a variety of traditional Chinese medicines and their preparations, which have specific actions, to treat depression and sleep disorders (Ross, 2014; Yeung et al., 2014; Shi et al., 2016; Xu et al., 2016; Liu et al., 2017; Xu, 2017). Cordycepin, the main active substance of cordyceps sinensis, has anti-cancer, anti-viral, immune-modulating, sleep- and cognitive-promoting, and anti-oxidative properties, and has been shown to have certain antidepressant effects in animal experiments (Li et al., 2016).

Novelty of this study

Severe sleep disorder exists in some depressed patients (American Psychiatric Association, 2013), and long-term use of currently available drugs promoting sleep can lead to adverse reactions. Cordyceps sinensis and its main active substance cordycepin have specific antidepressant effects. However, little information is available regarding cordyceps sinensis and its main active substance cordycepin for treatment of sleep disorder in depression.

Study limitations

Only 60 patients will be included in this trial, and the sample size will be small. More patients will be required to increase the power of the study. Because patients may have different degrees of disease severity, it is necessary to analyze specific treatment effects in patients with mild to severe depression.

Study significance

Our results suggesting that cordyceps sinensis combined with duloxetine can effectively improve sleep in patients with depression will provide objective data to support the clinical use of traditional Chinese medicine cordyceps sinensis in the treatment of depression.

Status of the study with sample size enlarged to 206 patients

Date of Registration: December 21, 2017

Recruitment time: January 2018 to December 2018

Study completed: December, 2019

Trial status: Recruiting

Additional files

Additional file 1: Hospital Ethics Approval.

Additional file 2: Informed Consent Documentation.

Additional file 3: CONSORT 2010 checklist.

Author contributions

Concept and design of study protocol: XC, CMW, LF and GW; data collection: XC and XLZ; drafting of the manuscript: XC. All authors approved the final manuscript for publication.

Conflicts of interest

The authors have no conflicts of interest to declare.

Financial support

The study was supported by Beijing Municipal Science & Technology Commission, No. Z17110000117004 (to GW). The conception, design, execution, and analysis of experiments, as well as the preparation of and decision to publish this manuscript were made independent of any funding organization.

Institutional review board statement

The study protocol was approved by Ethics Committee of Beijing Anding Hospital, China Medical University, China (approval No. 2017-79-2017111-2) on December 20, 2017. This study is performed according to the statement of the Declaration of Helsinki and applicable laws and regulations in China. Informed consent of the study procedure will be obtained from all participants or their legal guardians.

Informed consent statement

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

Reporting statement

This study follows 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.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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