Li, J

Man, MSC

Ng, R

Sze, CW

Tsang, A

Wang, D

Wong, HK

Wong, M

Wong, W

Yip, K

Zhang, Z

Hong Kong Medical Journal

HKU Scholars Hub

TitleUse of electroacupuncture to accelerate the antidepressantaction   of selective serotonin reuptake inhibitors: a single-blind,randomised,   controlled studyAuthor(s) Zhang, Z; Ng, R; Man, MSC; Li, J; Wong, W; Wong, HK; Wang, D;Wong, M; Tsang, A; Yip, K; Sze, CWCitation Hong Kong Medical Journal, 2013, v. 19 n. Suppl. 9, p. 12-16Issued Date 2013URL http://hdl.handle.net/10722/195718Rights Hong Kong Medical Journal. Copyright © Hong Kong Academyof Medicine Press.HEALTH AND HEALTH SERVICES RESEARCH FUND12      Hong Kong Med J Vol 19 No 6 Supplement 9 December 2013Use of electroacupuncture to accelerate the antidepressant action of selective serotonin reuptake inhibitors: a single-blind, randomised, controlled studyZJ Zhang 張樟進R Ng 吳文建SC Man 萬帥章JTY Li 李翠妍W Wong 黃韻婷HK Wong 王熙喬D Wang 王 迪MT Wong 王萬德AWK Tsang 曾韋僑KC Yip 葉嘉池SCW Sze 施祖榮Key Messages1. Patients treated with dense cranial electroacupuncture stimulation (DCEAS) had a significantly greater reduction in the 17-item Hamilton Rating Scale for Depression scores and clinically significant response to treatment than those having sham acupuncture (19.4% vs. 8.8%). 2. Neither sham acupuncture nor DCEAS had effects on the platelet serotonin system.3. In the early phase of selective serotonin reuptake inhibitor treatment for depressed patients, DCEAS could be used as an additional therapy. 4. Neurobiological mechanisms responsible for DCEAS effects warrant further investigation using neuroimaging.School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong ZJ Zhang, SC Man, JTY Li, W Wong, HK Wong, D Wang, SCW SzeDepartment of Psychiatry, Kowloon Hospital, Hong KongR Ng, MT Wong, AWK Tsang, KC Yip HHSRF project number: 06070831Principal applicant and corresponding author:Dr Zhang-Jin ZhangSchool of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, PokfulamHong Kong SAR, ChinaTel: (852) 2589 0445Fax: (852) 2872 5476Email: zhangzj@hku.hkHong Kong Med J 2013;19(Suppl 9):S12-6IntroductionSelective serotonin reuptake inhibitors (SSRIs) are the mainstay of treatment for depressive disorders, but their outcomes are unsatisfactory.1 A large proportion of depressed patients cannot obtain a full remission and experience relapse and functional impairment. Moreover, the delay in the onset of the action of SSRIs prolongs patients’ suffering and exposes them to the risk of suicide. These shortcomings have led to the search for alternative strategies to enhance the antidepressant efficacy of SSRIs, particularly in the early phase of treatment.2 Acupuncture is efficacious for various types of depressive disorders, particularly in alleviating associated pain, autonomic dysfunction, sleepless, and low moods. This is thought to be associated with the fast, direct modulation of multiple central neurochemical systems. Adrenergic and serotonergic (5-HT) mechanisms in the brainstem, as well as neuronal and hypothalamic neuroendocrine systems play a pivotal role in the pathophysiology of major depression. We therefore hypothesised that electroacupuncture may enhance the antidepressant activity of SSRIs in the early phase of treatment.  Dense cranial electroacupuncture stimulation (DCEAS) involves electrical stimulation of dense acupoints on the forehead mainly innervated by the trigeminal nerve. Such acupoints modulates multiple central transmitter systems via the trigeminal sensory-brainstem adrenergic and 5-HT neuronal pathways.3 Pilot studies have shown that DCEAS is effective in improving refractory obsessive-compulsive disorder, major depressive disorder (MDD), post-stroke depression, and MDD-associated residual insomnia. Human platelets are terminally differentiated 5-HT-synthesising cells and are similar to 5-HT neurons in terms of synthesis, release, and receptors. Platelets have been widely used as a peripheral model for investigation of psychiatric disorders associated with the central 5-HT system. We hypothesised that DCEAS as additional treatment could produce greater clinical improvement in the early phase of SSRI treatment in patients with MDD, and that the antidepressant effects of DCEAS may be associated with changes in the platelet 5-HT system.MethodsThis single-blind, randomised, controlled trial was conducted in the Department of Psychiatry at the Kowloon Hospital of Hong Kong between May 2009 and March 2011. The study protocol was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Based on our recent meta-analysis, a sample size of 35 patients per group could provide approximately 80% power to detect an estimated difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 3 points, with an α set at 0.05 and an estimated standard deviation of 4.5 at the endpoint of 3-week treatment. Use of electroacupuncture to accelerate the antidepressant action of drugsHong Kong Med J Vol 19 No 6 Supplement 9 December 2013      13 Fluoxetine (FLX) is one of the most prescribed SSRIs for major depression worldwide.4 Unmedicated patients in both groups received orally administered FLX for 3 weeks. The dosage was initiated at 10 mg/day and escalated to an optimal dose within 1 week, based on patient response; the maximum dose was 40 mg/day. Information about the equivalent efficacy of FLX was provided to the patients.   Of 188 outpatients referred by psychiatrists, 73 were eligible and randomly assigned to receive sham acupuncture (n=35) and DCEAS (n=38). Informed consent was obtained from each patient. Each patient received nine sessions of intervention (three sessions per week) during FLX treatment. For DCEAS, acupuncture needles were inserted into six pairs of forehead acupoints and affixed with adhesive tapes to ensure allocation concealment. Electrical stimulation at a comfortable level was then delivered for 30 minutes. The acupoints were Baihui (Du-20) and Yintang (EX-HN3), left Sishencong (EX-HN1) and Toulinqi (GB15), right Sishencong (EX-HN1) and Toulinqi (GB15), bilateral Shuaigu (GB8), bilateral Taiyang (EX-HN5), and bilateral Touwei (ST8) [Fig 1]. For sham acupuncture, Streitberger non-invasive acupuncture needles were applied and affixed in the same way.5 The forehead acupoints were outside the visual field of the subjects to ensure blinding. Patients were not told about the potential response of both procedures. To ensure consistency in acupuncture procedure, the principal investigator provided a training workshop about the acupuncture protocol. Acupuncture was performed by two registered acupuncturists who had practised Chinese medicine for over 3 years. Outcome was assessed using the HAMD-17, the Clinical Global Impression-Severity (CGI-S), and the Chinese-version Self-rating Depression Scale (SDS) at baseline and at days 3, 7, 14, and 21. Secondary outcome measures included the treatment response and remission. Safety and tolerability were assessed using the Treatment Emergent Symptom Scale, in which adverse events were recorded at each visit. All assessments were completed by the same rater. A training workshop was provided to the rater. Both the patients and the rater were blind to the treatment allocation.  Two 10-ml blood samples were collected at baseline and day 14. Blood samples were also collected from age- and gender-matched healthy controls. Platelets and platelet-poor plasma were separated and the number of platelets was counted. The contents of platelet serotonin type 2A receptors and serotonin transporter were measured using Western blot. The concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid were measured using reverse-phase high-performance liquid chromatography coupled with a fluorescence detector. ResultsOf the 73 patients, 63 (86%) completed the 3-week assessment. One patient in the sham group who had a history of cocaine use and two patients in the DCEAS group who did not have post-baseline assessment were excluded from analysis (Fig. 2). The proportion of females assigned to the sham group was significantly greater (97.1% vs. 69.4%, P=0.006, Chi-square test). Other baseline variables were similar in both groups (Table 1). Compliance with treatment was nearly 95%. Changes from baseline in terms of scores of HAMD-17, CGI-S, and SDS over time revealed linear correlations (Table 2). Between-group comparisons revealed that DCEAS-treated patients had a significantly greater reduction in HAMD-17 scores at day 3 through day 21 (P≤0.025) and in SDS scores at day 3 (P=0.037) and day 21 (P=0.004). The response and remission rates were similar in both groups.  Adverse events occurred in at least 5% of the patients in both groups (Table 3). Two patients in the DCEAS group discontinued due to intolerance of acupuncture stimulation. The credibility rating in the two groups did not differ significantly. The two groups did not differ significantly at baseline and day 14 for all platelet 5-HT parameters (Table 4).DiscussionThe use of DCEAS was effective in augmenting the Fig 1. Acupoints used in dense cranial electroacupuncture stimulationBaihui(Du20)Sishencong(EX-HN1) Toulinqi(GB15)Touwei(ST8)Shuaigu(GB8)Yintang(EX-HN3)Taiyang(EX-HN5)Zhang et al14      Hong Kong Med J Vol 19 No 6 Supplement 9 December 2013antidepressant efficacy of FLX in patients with moderate to severe MDD, as indicated by the significantly greater reduction of HAMD-17 and SDS scores. The effect was observed as early as day 3 (after the first session of treatment). The frequency of adverse events in both groups was comparable, and only two DCEAS-treated patients discontinued treatment, indicating that it was well tolerated and safe.  The possibility of a placebo effect of DCEAS was also explored. There was no significant difference in the credibility of sham acupuncture and DCEAS, suggesting that non-inserted needling stimulation was valid and acceptable, so it was unlikely that the antidepressant Fig 2. Flowchart of screening and patient recruitmentScreened (n=188)Randomised (n=73)Assigned to sham acupuncture (n=35)Completed treatment (n=32, 91.4%)Included in analysis (n=34) Included in analysis (n=36)Excluded in pre-randomisation (n=115): • Refused to participate (n=71) • Did not meet the inclusion criteria (n=37) • had needle phobia (n=7)Completed treatment (n=31, 81.6%)Assigned to dense cranial electroacupuncture stimulation (n=38)Withdrew prematurely (n=3): • Lost to follow-up (n=1) • Other medical emergency (n=1) • Severe headache (n=1)Withdrew prematurely (n=7): • Lost to follow-up (n=2) • Other medical emergency (n=3) • Intolerance of acupuncture (n=2)Excluded from analysis due to cocaine use found (n=1)Excluded from analysis due to no post-baseline assessment (n=2)Table 1. Baseline characteristics of patients*Variable Sham acupuncture (n=34)Dense cranial electroacupuncture stimulation (n=36)P value (t or χ2 test)Female 33 (97.1) 25 (69.4) 0.006Age (years) 48.2±9.8 46.3±9.9 0.414Duration of major depressive disorder (years) 7.3±7.1 7.9±8.0 0.744No. of previous depressive episodes 3.6±4.4 4.9±6.1 0.332Patients with first-onset major depressive disorder 3 (8.8) 2 (5.5) 0.669Patients with previous psychiatric admission 8 (23.5) 7 (19.4) 0.901Patients with family members having mental illnesses 9 (26.5) 13 (36.1) 0.800Patients with previous acupuncture treatment 22 (64.7) 24 (66.7) 0.937Patients receiving psychotropic medications at study entry (not exceeding 1 week) 6 (17.6) 7 (19.4) 0.909Selective serotonin re-uptake inhibitors 3 3Serotonin-norepinephrine reuptake inhibitors 1 1Mood stabilisers 1 1Benzodiazepines 2 2Baseline 17-item Hamilton Rating Scale for Depression score 23.1±3.6 23.9±3.8 0.321Baseline Clinical Global Impression-Severity 4.3±0.5 4.4±0.5 0.760Baseline Self-rating Depression Scale score 40.6±14.5 41.9±14.0 0.704* Data are presented as no. (%) or mean±SDUse of electroacupuncture to accelerate the antidepressant action of drugsHong Kong Med J Vol 19 No 6 Supplement 9 December 2013      15Table 2. Changes in depression scores from baselineVariables Mean (95% CI) change in score from baseline P value (linear mixed effects model)Sham acupuncture (n=34) Dense cranial electroacupuncture stimulation (n=36) Between-group difference17-item Hamilton Rating Scale for DepressionDay 3 -3.71 (-4.34 to -3.06) -5.97 (-6.71 to -5.23) 2.27 (1.29 to 3.25) 0.000Day 7 -5.82 (-6.46 to -5.18) -6.97 (-7.71 to -6.23) 1.15 (0.17 to 2.13) 0.025Day 14 -6.41 (-7.05 to -5.77) -8.44 (-9.18 to -7.70) 2.03 (1.05 to 3.01) 0.000Day 21 -6.27 (-6.90 to -5.62) -8.66 (-9.39 to -7.91) 2.39 (1.41 to 3.37) 0.000Clinical Global Impression-SeverityDay 3 -0.32 (-0.42 to -0.22) -0.44 (-0.54 to -0.34) 0.12 (-0.03 to 0.27) 0.116Day 7 -0.65 (-0.75 to -0.55) -0.53 (-0.63 to -0.43) 0.12 (-0.03 to 0.27) 0.116Day 14 -0.71 (-0.81 to -0.61) -0.71 (-0.81 to -0.61) 0.00 (-0.15 to 0.15) 1.000Day 21 -0.74 (-0.84 to -0.64) -0.74 (-0.84 to -0.64) 0.00 (-0.15 to 0.15) 1.000Self-rating Depression ScaleDay 3 -6.44 (-8.48 to -4.40) -9.76 (-12.03 to -7.49) 3.32 (0.26 to 6.38) 0.037Day 7 -8.82 (-10.86 to -6.78) -9.12 (-11.39 to -6.85) 0.30 (-2.76 to 3.36) 0.851Day 14 -11.74 (-13.78 to -9.70) -12.38 (-14.65 to -10.11) 0.64 (-2.42 to 3.70) 0.679Day 21 -8.38 (-10.42 to -6.34) -13.06 (-15.33 to -10.79) 4.68 (1.62 to 7.74) 0.004Table 3. Adverse events during treatmentAdverse event No. (%) of patients χ2 P valueSham acupuncture (n=34) Dense cranial electroacupuncture stimulation (n=36)Dizziness 15 (44.1) 11 (30.6) 0.858 0.354Tiredness 10 (29.4) 15 (41.7) 0.672 0.412Nausea 10 (29.4) 10 (27.8) 0.013 0.910Excessive sweating 9 (26.5) 6 (16.7) 1.403 0.236Headache 8 (23.5) 10 (27.8) 0.018 0.894Transient tachycardia 8 (23.5) 9 (25.0) 0.018 0.892Insomnia 7 (20.6) 9 (25.0) 0.024 0.877Discomfort during needling sensation 7 (20.6) 14 (38.9) 1.985 0.159Vomiting 4 (11.8) 3 (8.3) - 0.706*Unsteadiness 2 (5.9) 6 (16.7) - 0.266*Somnolence 2 (5.9) 6 (16.7) - 0.266** Fisher Exact test was usedTable 4. The effects of dense cranial electroacupuncture stimulation on platelet 5-HT parameters* vs. healthy controls, P<0.01, one-way analysis of variancebenefits of DCEAS were derived from placebo effects.  There were several limitations in the present study. First, most subjects were females. There may be gender- and ethnic-differences in acceptance and credibility of acupuncture, suggesting a form of demographic bias. Single-blind treatment allocation might lead to effects mediated by the non-blind acupuncturists. Second, DCEAS only achieved a clinically meaningful (but not significant) difference in terms of the response rate (DCEAS: 19.4% vs. sham: 8.8%). This may be related to the relatively short-term (3-week) treatment. Long-term studies of antidepressant efficacy of DCEAS are warranted. Finally, no significant changes in platelet 5-HT parameters (baseline Variable Mean±SD valueHealthy controls (n=22)Sham acupuncture (n=34) Dense cranial electroacupuncture stimulation (n=36)Baseline Week 2 Baseline Week 2PlateletSerotonin type 2A receptors 1.3±0.2 2.6±1.5* 2.5±1.5 2.6±1.5* 2.5±1.5Serotonin transporter 1.6±0.2 2.3±1.5 2.0±1.5 2.2±1.8 2.1±1.85-HT (ng/109) 527.2±111.1 81.8±92.8* 81.6±91.8 84.3±62.2* 87.0±74.25-hydroxyindoleacetic acid (ng/109) 632.9±214.6 192.3±129.0* 231.7±196.1 215.2±149.5* 249.6±203.3Turnover 0.9±0.3 0.7±1.2 0.7±0.7 0.6±0.6 0.6±0.6Platelet-poor plasma5-HT (ng/ml) 9.3±1.6 4.8±1.5* 5.3±1.2 5.5±2.3* 5.4±2.45-hydroxyindoleacetic acid (ng/ml) 10.4±2.3 6.7±2.9* 7.5±3.6 7.0±3.0* 7.1±3.3Turnover 1.0±0.3 0.8±0.5 0.8±0.4 0.9±0.4 0.9±0.5Zhang et al16      Hong Kong Med J Vol 19 No 6 Supplement 9 December 2013to post-treatment) were noted in DCEAS-treated patients, suggesting that DCEAS may have minimal effects on platelet 5-HT systems. Evaluation of DCEAS effects on the brain 5-HT neuronal system may provide insight into central mechanisms responsible for the antidepressant effects of DCEAS. Several baseline 5-HT parameters of depressed patients differed significantly from those of healthy controls, and correlated significantly with the severity of depression symptoms. The platelet 5-HT indices seem to be potential biomarkers, reflecting the clinical status of major depression, although they are not directly involved in the physiopathology of major depression. ImplicationsAs patients with moderate and severe major depression have a higher risk of suicide and symptom worsening in the early phase of SSRI treatment, DCEAS can be an additional therapy. Neurobiological mechanisms responsible for DCEAS effects may warrant further investigation using neuroimaging approaches.AcknowledgementsThis study was supported by the Health and Health Services Research Fund, Food and Health Bureau, Hong Kong SAR Government (#06070831). We are grateful to Miss Lily Li for help prepare blood samples. We also thank the following colleagues at Department of Psychiatry of Kowloon Hospital for their assistance in patient recruitment: Ka-Lik Kwan, Chun-Ting Chan, Man-Lui Chan, Chi-Kwan Cheung, Janice Chik, Lung-Kit Hui, Man-Man Kwan, Chee-Kin Lee, Kwok-Chuen Ng, Yin-Ting Ng, Ting-Keung Poon, Fu-Yin Tong, Wai-Ching Yan, Kam-Hing Yeung, Tin-Yan Yeung, Frieda Shiu Mei-Kuen, Cheuk-Kin Tang, Pui-Shan Tse, Ngar-Fong Lam, See-Cheuk Fu, Carol Ching Chui-Lin, Ka-Fai Ho, Sau-Lai Tai, Sau-Ming Chan, Yiu-Kwun Law, and Yvonne Kwong Yuk-Kwan. References 1. Arroll B, Macgillivray S, Ogston S, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 2005;3:449-56.2. Adell A, Castro E, Celada P, Bortolozzi A, Pazos A, Artigas F. Strategies for producing faster acting antidepressants. Drug Discov Today 2005;10:578-85.3. Zhang ZJ, Wang XY, Tan QR, Jin GX, Yao SM. Electroacupuncture for refractory obsessive-compulsive disorder: a pilot waitlist-controlled trial. J Nerv Ment Dis 2009;197:619-22.4. Stark P, Hardison CD. A review of multicenter controlled studies of fluoxetine vs. imipramine and placebo in outpatients with major depressive disorder. J Clin Psychiatry 1985;46:53-8.5. Streitberger K, Kleinhenz J. Introducing a placebo needle into acupuncture research. Lancet 1998;352:364-5.

Use of electroacupuncture to accelerate the antidepressant action   of selective serotonin reuptake inhibitors: a single-blind, randomised,   controlled study

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Use of electroacupuncture to accelerate the antidepressant action of selective serotonin reuptake inhibitors: a single-blind, randomised, controlled study

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