Can Acupuncture Treat Post-stroke Depression?

Study Overview
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Brief Summary
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An 8-week, assessor-blind, randomized controlled trial will be conducted. A total of 138 patients with post-stroke depression (PSD) will be randomly assigned to the combination acupuncture treatment (CAI) (n = 69) or least acupuncture stimulation (LAS) (n = 69) for 3 sessions per week for 8 weeks. Treatment outcomes will be measured using the 17-item Hamilton Self-Rating Depression Scale (HAMD-17), the Montgomery-Asberg Depression Rating Scale (MADRS), and Self-Rating Depression Scale (SDS) for depression symptoms; Barthel Index (BI) for physical function, the Montreal Cognitive Assessment (MoCA) for cognitive performance. The assessment will be performed at baseline and once monthly thereafter. The study will be conducted in School of Chinese Medicine Clinics, Tung Wah Hospital, Kowloon Hospital.

Detailed Description
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Mood depression is a common and serious consequence of stroke (Paolucci, 2008). There are approximately 30% of stroke patients developing PSD, either in the early or in the late stages after stroke (Paolucci, 2008). Despite the fact that PSD is strongly associated with the poor prognosis and an increased disability, it is often neglected in the clinical management, with only a minority of PSD patients who could receive proper diagnoses and treatment (Gustafson et al., 1995; Paolucci, 2008; Williams et al., 2004). Although pharmacological treatment, represented by various types of antidepressants, are recommended as first-line drugs for PSD, the effectiveness is unsatisfactory and the clinical use is largely hampered due to apparent shortcomings. A large portion of PSD patients could not obtain satisfactory outcomes from antidepressant treatment, in particular the elderly (Bhogal et al., 2005;Paolucci, 2008). Pharmacotherapy related side effects; particularly on cardiovascular system may exacerbate stroke patients' conditions (Paolucci, 2008). Furthermore, stroke patients are often medicated with various classes of drugs, the addition of antidepressant agents may increase risk of drug-drug interactions, resulting in unexpected and unpredictable adverse events (Hemeryck and Belpaire, 2002). The development of alternative treatment strategies for PSD patients is therefore highly desired. While acupuncture is effective in reducing pain disorders, it also possesses psychotropic potential in treating psychiatric symptoms, in particular depression, anxiety and sleep disturbance. Our systematic review with meta-analysis suggests that the clinical outcomes of acupuncture is equivalent to antidepressant in treating major depression and superior to pharmacotherapy in improving clinical response and reducing the severity of PSD, with fewer incidences of adverse events (Zhang et al., 2010). Recently, the investigators have developed a novel acupuncture stimulation mode called dense cranial electroacupuncture stimulation (DCEAS), in which electrical stimulation is directly delivered on dense acupoints (6-8 pairs in general) located on the forehead innervated by the trigeminal sensory pathway. This pathway has intimate afferent fibers projecting the brainstem reticular formation, a pivotal brain region containing serotonin (5-HT) and norepinephrine (NE) neuronal cells involved in the processing of mood signals. neuroanatomic rationale for DCEAS is that electrical stimulation on dense scalp acupoints could enhance the activities of brainstem nuclei containing 5-HT and NE neuronal systems via the trigeminal sensory nucleus, and then modulate brain regions related to mood processing (Zhang et al., 2012).Our serial clinical studies have demonstrated the effectiveness of DCEAS and alike modes in patients with major depression, postpartum depression, insomnia and obsessive compulsive disorder (Chung et al., 2012; 2014; Huang et al., 2004, 2005; Qu et al., 2013; Zhang et al., 2009, 2012a). Most recently, our pilot study further confirms that DCEAS is effective in reducing stroke patients' depressive symptoms; a combination of DCEAS and body acupuncture (CAI) is more effective in reducing neuropsychiatric sequelae of stroke (Man et al., 2014). These encouraging results warrant a large-scale controlled trial. The pathogenesis of PSD is mainly associated with decreased serotonin (5-HT) and norepinephrine (NE) function in the brain (Gustafson et al., 1995). On the other hand, neuro-anatomic rationale for DCEAS is that electrical stimulation on dense scalp acupoints could enhance the activities of brainstem nuclei containing 5-HT and NE neuronal systems via the trigeminal sensory nucleus, and then modulate brain regions related to mood processing (Zhang et al., 2012b). Based on these studies, the investigators hypothesize that CAI could yield better treatment outcomes in improving PSD compared to Least acupuncture stimulation (LAS) control. An apparent advantage of TCM clinical practice is individualized or personalized treatment, i.e., treatment protocol is tailored to meet individual's current clinical manifestations and different stages of illness, termed differentiation syndromes. Previous studies have suggested a potential relationship between the therapeutic efficacy of acupuncture and TCM syndromes of PSD (Dang, 2013; Wu, 2010; Xin et al., 2005). The investigators will further determine whether there are correlates of TCM syndromes of PSD with the CAI treatment. The working hypothesis of the proposed study is that CAI is an effective intervention in improving PSD and comorbid symptoms often observed in stroke patients. To test this hypothesis, an 8-week, assessor-blind, randomized, controlled trial will be proposed to determine: (1) whether the patients treated with the CAI could produce significantly greater improvement than those treated with LAS and (2) whether there are correlates of TCM syndromes of PSD with the CAI treatment.

Official Title
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A Multisite, Assessor-blinded, Randomized Controlled Trial of Acupuncture for Post-stroke Depression

Conditions
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Stroke, Depression, Stroke Sequelae

Intervention / Treatment
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* Procedure: Dense cranial electroacupuncture stimulation
* Procedure: Body acupuncture
* Drug: Antidepressant
* Other: Rehabilitation
* Procedure: Least acupuncture stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men or women aged 35 to 80 years old; diagnosed as ischemic or haemorrhagic stroke within 18 months, confirmed with cerebral computed topographic scanning or magnetic resonance imaging; and developed significant depressive episode, with score of 16 or greater in the 17-item Hamilton Rating Scale for Depression (HAMD-17) and depression has lasted at least 2 weeks. Exclusion Criteria: presence of severe aphasia, especially fluent aphasia; presence of severe cognitive dysfunction, as indicated by the Mini-mental State Examination (MMSE) score < 18; history of psychiatric illness other than depression; presence of another chronic disorder, including severe Parkinson's disease, cardiac disease, cancers, epilepsy, or chronic alcoholism; having impaired hepatic or renal function; or (6) having bleeding tendency.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination acupuncture treatment (CAI)<br>Post stroke depression patients will receive Dense Cranial Electroacupuncture Stimulation (DCEAS) and body acupuncture. Patients will continue their existing antidepressant and rehabilitation therapy as usual. | Procedure: Dense cranial electroacupuncture stimulation<br>* DCEAS is a novel stimulation mode in which electrical stimulation is delivered on acupoints located on the forehead. Six pairs of acupoints are used: Baihui (GV20, +) and Yintang (EX-HN3, -), left Sishencong (EX-HN1, -) and Toulinqi (GB15, +), right Sishencong (EX-HN1, -) and Toulinqi (GB15, +), bilateral Shuaigu (GB8, L+, R-), bilateral Taiyang (EX-HN5, L+, R-), and bilateral Touwei (ST8, L+, R-). Disposable acupuncture needles (Hwato®, 0.30 mm in diameter and 25-40 mm in length) are inserted at a depth of 10-30 mm perpendicularly or obliquely into acupoints. Manual manipulation is then conducted to evoke needling sensation, followed by electrical stimulation (ITO ES-160, continuous waves at 2 Hz, 100 µs).<br>* Other names: DCEAS;Procedure: Body acupuncture<br>* Following acupoints are used: Shui-Gou (GV26), Shen-Men (HT7). He-Gu (LI4), Qu-Chi (LI11), Guan-Yuan (CV4), Zu-San-Li (ST36), Feng-Long (ST40) and San-Yin-Jiao (SP6). Disposable acupuncture needles (Hwato®, 0.30 mm in diameter and 25-40 mm in length) are inserted at a depth of 10-30 mm perpendicularly or obliquely into acupoints. Manual manipulation is then conducted to evoke needling sensation at 15 min. No electrical stimulation is delivered.<br>* Other names: BA;Drug: Antidepressant<br>* Patients will continue their existing antidepressant therapy as usual. Treatment regimens may be further adjusted during 8 weeks of study, depending upon physicians' discretion.<br>Other: Rehabilitation<br>* Patients will continue their existing rehabilitation therapy as usual. Treatment regimens may be further adjusted during 8 weeks of study, depending upon physicians' discretion.<br>* Other names: Rehab;|
| Sham Comparator: Least acupuncture stimulation (LAS)<br>Post stroke depression patients will receive Least acupuncture stimulation (LAS). Patients will continue their existing antidepressant and rehabilitation therapy as usual. | Drug: Antidepressant<br>* Patients will continue their existing antidepressant therapy as usual. Treatment regimens may be further adjusted during 8 weeks of study, depending upon physicians' discretion.<br>Other: Rehabilitation<br>* Patients will continue their existing rehabilitation therapy as usual. Treatment regimens may be further adjusted during 8 weeks of study, depending upon physicians' discretion.<br>* Other names: Rehab;Procedure: Least acupuncture stimulation<br>* The acupoints chosen are less related to the treated syndromes based on Traditional Chinese Medicine (TCM) theory; the number of acupoints used and the intensity of electrical stimulation are also lower than the comprehensive acupuncture regimen. The following 6 acupoints will be used in LAS control: bilateral Tong-Tian (BI7, L+, R-), bilateral Shou San-Li (LI10) and bilateral Fu-Yang (BL59). Electrical stimulation will be only performed on bilateral Tong-Tian (BI7) and the intensities are adjusted to a level at which patients just start feeling the stimulation.<br>* Other names: LAS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in depression measured by HAMD-17 | Depression will be measured using the Hamilton Rating Scale for Depression (HAMD-17). Assessments will be conducted at baseline and once monthly thereafter. | Baseline, 4 week, 8 week | 
| Changes in depression measured by MADRS | Depression will be measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). Assessments will be conducted at baseline and once monthly thereafter. | Baseline, 4 week, 8 week | 
| Changes in depression measured by SDS | Depression will be measured using the Zung Self-Rating Depression Scale (SDS). Assessments will be conducted at baseline and once monthly thereafter. | Baseline, 4 week, 8 week | 
| Changes in locomotor function measured by BI | Locomotor function will be measured using the Barthel Index of Activities of Daily Living (BI). Assessments will be conducted at baseline and once monthly thereafter. | Baseline, 4 week, 8 week | 
| Changes in cognitive function | The Montreal Cognitive Assessment (MoCA) will be used as an objective measurement for subjects' cognitive function. Assessments will be conducted at baseline and once monthly thereafter. | Baseline, 4 week, 8 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcome of treatment | It includes clinical response, defined as <50% reduction at endpoint from baseline on HAMD-17, and remission, defined as 7 points or less on HAMD-17 score. | 8 week | 
| Emergence of adverse events | Adverse events are assessed using the Treatment Emergent Symptom Scale (TESS). | Baseline, 4 week, 8 week | 
| TCM syndrome diagnosis | To determine Traditional Chinese Medicine (TCM) syndrome correlated of the treatment efficacy, the investigators will conduct TCM syndrome diagnosis. The 5 most common syndromes of PSD are listed below: Liver Depression with Qi-stagnation; Liver Depression with Spleen deficiency; Blood stasis and phlegm obstruction; Deficiency of Both Heart and Spleen; or Deficiency of Both Liver and Kidney Yin. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, depression, stroke sequelae, acupuncture, DCEAS, CAI, LAS