Acupuncture treatment for depression A systematic review and meta-analysis

Available online at www.sciencedirect.com European Journal of Integrative Medicine 3 (2011) e259–e270 Review Acupuncture treatment for depression—A...
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European Journal of Integrative Medicine 3 (2011) e259–e270

Review

Acupuncture treatment for depression—A systematic review and meta-analysis Trine Stub a,∗ , Terje Alræk a , Jianping Liu a,b a

NAFKAM (The National Research Center for Complementary and Alternative Medicine), Department of Community Medicine, University of Tromsø, Norway b Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China Received 28 March 2011; received in revised form 13 September 2011; accepted 15 September 2011

Abstract Aim of the study: To assess the beneficial effects of acupuncture in patients with depression and to evaluate the report quality of acupuncture treatment for depression in randomized controlled trials and systematic reviews. Introduction: Acupuncture has a long history of treating illnesses which we today in a biomedical context would understand and recognize as depression. Also in contemporary China and in the West patients are trying acupuncture as a treatment for depression. Randomized controlled trials have been conducted to investigate its efficacy. Materials and methods: The following electronic databases were searched: the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, PsycINFO and PUBMED. These searches ended in January 2009. In addition new searches were completed in Asian databases in February 2010. Standard guidelines were followed when the methodological quality of the RCTs were assessed, including CONSORT and the criteria in the Cochrane Handbook. Systematic reviews were evaluated using the PRISMA checklist. Results: Four systematic reviews and 26 RCTs on acupuncture for treatment of depression were identified and included in this review. The methodological quality of the trial reports was generally low in terms of generation of the allocation sequence, allocation concealment, blinding and intention to treat. A significant beneficial effect was found for acupuncture in improvement of depression compared to pooled control measured by Hamilton Rating Scale for Depression (WMD −3.10, 95% CI −4.91 to −1.99, P = 0.0008). Subgroup analysis suggested that electro-acupuncture (WMD −0.68, 95% CI −1.49 to 0.13, P = 0.10) and TCM acupuncture (WMD 0.79, 95% CI −0.93 to 2.52, P = 0.37), were not statistically different from medication. Acupuncture was regarded as generally safe in the clinical trials included in this review. Conclusions: Current evidence from this meta-analysis of randomized trials shows that acupuncture is effective in reducing severity of depression and that TCM- and electro acupuncture may have similar effect as current usual care. More rigorous trials are needed and long-term effects should be investigated if acupuncture is to be recommended for clinical use. © 2011 Elsevier GmbH. All rights reserved. Key words: Acupuncture; Depression; Systematic review; Meta-analysis

Aim of the study To assess the beneficial effects of acupuncture in patients with depression, and to evaluate the report quality of acupuncture treatment for depression in randomized controlled trials and systematic reviews. The focused question was: Does acupuncture relieve symptoms in adults with depression? This question was analyzed according to PICO



Corresponding author. Tel.: +47 77 64 68 66; fax: +47 77 64 68 66. E-mail address: [email protected] (T. Stub).

1876-3820/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.eujim.2011.09.003

Population: Adults with depression Intervention: Acupuncture Comparison: Medication, waiting lists, non-specific acupuncture/sham or placebo Outcome: Reduction in severity of depression.

Introduction Acupuncture is an important part of Chinese medicine and Traditional Chinese medicine (TCM). Chinese medicine has a long history going back to ancient China. However, until now the most known part of the acupuncture practiced in the West originates from a part of Chinese medicine known as TCM. This

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form of medicine was a result of an institutionalized process of parts of Chinese medicine which took place in China during the early 1950s. Nevertheless and still there are many different styles of acupuncture in clinical practice which reflects the diversity of Chinese medicine. Some practices are, e.g. based on the ancient theory of five phases while others are grounded on western medical knowledge [1]. Both Chinese medicine and TCM have a unique concept of etiology, a system of diagnosis and treatment which are essential to its practice [2]. In ancient China acupuncture and Chinese medicine were used to treat mental illnesses as they were understood at that time. Both Chinese medicine and TCM approaches emotions and emotional disorders differently than the western biomedical model and still TCM accounts for a substantial part of healthcare services in mainland China [3,4]. Several studies from China are reporting the use of acupuncture, especially electro-acupuncture, for treating mild and moderate depression [17–19]. Worldwide currently supported treatment for depression is medication and different psychological interventions, such as cognitive behavioral therapy (CBT), psychotherapy and counseling [5]. However, most people with depression are only treated by their primary care provider [6]. In primary care depression is most frequently treated with antidepressants [7]. Patients often report intolerable side effects of antidepressant medications, and this may be a reason for them to explore alternative medicines such as acupuncture [8]. In the adult population in the US depression is among the 10th most frequent indications for using Complementary and Alternative Medicine (CAM) [9]. We also know from clinical experience that patients in the West are interested in acupuncture treatment for depression [10]. It is also one of the most frequently used complementary therapies in Norway [11]. Besides, many people recognize the body-mind relationship and want to approach depression holistically rather than symptomatically [12]. Acupuncture involves the insertion of fine needles into different parts of the body in order to balance the Qi within the body [1]. There are many different ways to practice acupuncture and which method to use will depend on the practitioner’s theoretical assumptions, for example as in traditional acupuncture where needles are inserted into the body in accordance with the TCM framework [13]. Neoclassical acupuncture refers to a variety of methods that have arisen over the last few decades. One example is ear acupuncture. Cookbook acupuncture is a style where the practitioner uses commonly used formula points to treat various disorders. Trigger point acupuncture is a style where the practitioner identifies and inserts needles into tender points on the body [13]. Minimalistic acupuncture is a style that favors the use of very superficial needling, where the needles are inserted just through the skin and left in for a very short time. Electroacupuncture involves passing a pulsed current through the body tissues via acupuncture needles. In China electro-acupuncture is often used to treat depression [14–16]. Previous systematic reviews found insufficient evidence for the efficacy of acupuncture on depression compared to a waiting list control and sham acupuncture [17–19]. A more recent review found promising results for acupuncture in reducing the severity of depression [20]. These current data are insufficient

to make recommendations regarding acupuncture treatment for depression, but sufficient to justify further research. We therefore undertook a review, with the aim of summarizing existing evidence from all systematic reviews and new randomized trials of acupuncture treatment for depression. Material and methods Search strategy The following electronic databases were searched: Cochrane Central Register for Controlled Trials (CENTRAL) in the Cochrane library, MEDLINE, EMBASE, AMED, PsycINFO and PUBMED. The following Journals of interest were searched: Journal of Chinese Medicine, Complementary Therapies in Medicine, and the Journal of Alternative and Complementary Medicine. In addition reference lists of identified systematic reviews and RCTs were checked in order to find additional studies not found by the electronic or manual searches. Ongoing trials were searched through the National Research Register. In order to complete this strategy, new searches were performed in Asian databases in February 2010. The following databases were searched: Korean studies Information Service System (KISS), DBPIA, Korea Institute of Science and Technology Information (KISTI), Research Information Service System (RISS) and Korea Med. Depending on the database, various combinations of both MESH terms and keywords were used. The following MESH terms were used: “Depression, depressive disorder, major, dysthymic disorder, endogenous depression, acupuncture therapy, acupuncture, ear/electro acupuncture, moxibustion”. The following keywords were used: depress, dysthymi, acupuncture, electroacupuncture, moxibustion. The search in databases with English publications was limited from 1966 to January 2009, and searching in Asian databases was completed in February 2010. The filter used was systematic reviews and randomized controlled trials. Inclusion criteria We included all published systematic reviews and metaanalyses on acupuncture for treatment of depression. We also included RCTs of acupuncture for depression whether they had been included in the reviews or not. We did not limit the type of study design (parallel or crossover) or language. The participants were adults with depression defined by clinical state description or diagnosed by the Diagnostic and Statistical manual, DSM-IV [21] or the Research Diagnostic Criteria, RCD [22] or the International Classification of Disease, ICD [23]. The interventions included TCM or electro-needling acupuncture and laser–acupuncture versus placebo (sham, minimal, electroacupuncture or non-invasive control), no treatment (waiting list), treatment as usual, standard medication or psychotherapies (cognitive behavioral therapy, psychotherapy, counseling) or other standard care as defined by the country-specific health care setting.

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Validity assessment

Data synthesis

The methodological quality of the systematic reviews was analyzed according to the following criteria included in the PRISMA checklist (reporting items for systematic reviews and meta-analyses): inclusion criteria, participants, objectives, search strategy, main findings, conclusion and recommendation for clinical practice [24,25]. Standard guidelines were followed when the methodological quality of the RCTs was assessed, including CONSORT and the criteria in the Cochrane Reviewers’ Handbook, pages 79–83 [26], describing the relationship between allocation concealment and bias. Criteria for assessing bias are: A was used to indicate an RCT with a high level of quality in which all the criteria were met. Adequate measures to conceal allocation such as central randomization were serial numbered, opaque, sealed envelopes or other descriptions that contained convincing elements of concealment. Hence, low risk of bias. B was used when the authors either did not report allocation concealment at all, or reported an approach that did not match into one of the categories in A. Hence, moderate risk of bias. C was used when the method of allocation was not concealed, such as alternation methods or the use of case record numbers. Such trials were excluded because of high risk of bias.

The effect estimate was presented according to the categories of data, i.e. dichotomous and continuous data. The effect for dichotomous data were presented as risk ratio (RR) with its 95% confidence interval (CI), whereas the continuous data were presented as weighted mean difference (WMD) with its 95% CI. Heterogeneity was tested and different statistical models were used depending on the testing for heterogeneity, which was defined as significant if the P value was less than 0.10. Studies gathering in a SR may differ. Any kind of variance between the studies in a review may be termed heterogeneity [26]. To perform a meta-analysis, data were entered directly from the data sheets into the Review Manager Software 5 (RevMan 5). Results Included trials A total of 1208 articles of interest were identified from searches performed in January 2009. This is shown in Fig. 1 Flow Chart.

Papers identified(n=1208)

Excluded: Not relative to depression (n=471) Not relevant to acupuncture (n=294) Not of interest (=353)

Studies of interest (n=90)

Systematic Review (n=19)

Randomized Controlled Trials (n=71)

Duplicated SRs (n= 15)

Not met Inclusion Criteria (n=36) Duplicated RCTs (n= 19) Mixed data (n=6)

SR (n=4 ) with RCTs (n=34) 18 duplicated RCTs RCTs (n=16)

RCTs (=10)

RCTs included (n=26)

Fig. 1. Flow Chart of the selection process of SRs and RCTs.

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A total of 1208 articles were identified and examined on the basis of titles and abstracts. Of these, 353 were clearly not relevant and 471 were excluded because they were not relevant to depression. 294 were not relevant to acupuncture, leaving 90 articles for further evaluation. 19 of these articles were systematic reviews of which 15 were duplicates. This left four reviews for this overview [17,18,27,28], with a total of 31 RCTs. Additional three trials were included in the meta-analysis [29–31] from an updated review from 2010 [19]. 18 of these studies were overlapping, leaving 16 RCTs from four SRs for this overview [15,16,29–42]. 71 publications were RCTs, 36 of these did not meet the inclusion criteria, and 19 were duplicates. We identified 16 new RCTs. Six of these trials were excluded due to mixed data [43–48], leaving 10 new identified trials for inclusion [49–58]. In the end, 26 trials were included in this overview. Methodological quality of systematic reviews The four systematic reviews were analyzed according to items included in the PRISMA checklist for author reporting a meta-analysis [25]. Inclusion criteria: There was a strong consistency among the four systematic reviews regarding the inclusion criteria. Participants: The participants were patients with depression or depression neurosis diagnosed mostly by DSMIII/IV, ICD and RCD. However, one review included patients with other psychiatric diagnoses based on clinical interviews [18]. To assess the efficacy, all four reviews used the HRSD for self-rating and clinician reported measure. In addition one review used the Beck Inventory Scale [19]. Search strategy: Three reviews [17,19,28] had searched for literature in the same six databases. They also used the same MESH and keyword terms. One review [18] only used three databases for literature searches. In addition two reviews searched in a Chinese database [20] and in a Japanese database [17] for literature. Main finding and conclusion: There were discrepancies among the reviews, as one review [19] found insufficient evidence to determine the efficacy of acupuncture compared to medication, and two reviews found that acupuncture was as effective as medication in treating depression [17,18]. These three reviews found no evidence that acupuncture was superior to sham acupuncture or a waiting list control. Two reviews found that acupuncture was an effective treatment for depression [18,20]. All four reviews found that there was poor methodological quality in the included trials. Clinical practice: Two reviews [17,19] had no recommendation for practice. One review [18] stated that between 10 and 18 acupuncture sessions were needed to treat depression. And one review [28] found that fatigue was a common side-effect after acupuncture treatment. This is shown in Table 1. Methodological quality of included trials Out of 11 trials, only two trials [53,57] were given a score of A, as the method of allocation concealment and

blinding were described and found adequate. Nine trials [47–49,51,52,54–56,58] were given a score of B, as the allocation concealment and blinding were unclear. In these nine trials participants and therapists were probably not blinded since the treatment groups received acupuncture and the control groups received medication. Whether or not the outcome assessor and analyst were blinded to the study groups were not reported. One trial [57] reported a sample size calculation, and two trials [53,59] stated that an intention to treat analysis was performed. Nine trials [47–49,51,52,54–56,58] did not report a sample size calculation or that an intention to treat analysis was performed. Losses to follow up were reported in five trials [53–57]. In seven trials [47–52,58] no losses to follow up was reported. Accordingly, two trials [53,57] had a high methodological quality, while the reminders had generally low methodological quality. Furthermore, all trials provided baseline data for the comparability among groups. See Table 2. Study Characteristics and Main Findings of Randomized Controlled Trials concerning Acupuncture Treatment separated between electro-acupuncture and TCM acupuncture. See Table 2. Meta-analysis Data from 26 trials were included in the meta-analysis which contained a total of 2173 subjects. Acupuncture versus control 1. Outcome: Improvement of depression A comparison was made between acupuncture and control. Twelve trials (892 participants) made this comparison and reported improvement of depression using the HRSD [29,30,33,35,38,39,41,42,53,57,60,61]. Significant difference was found between acupuncture and placebo on the HDRS scores (WMD −3.10, 95% CI −4.91 to −1.29, P = 0.0008). Control group was defined as medication (fluoxetine) in three trials [29,60,61], sham acupuncture in three trial [30,33,38], and sham acupuncture versus medication (fluoxetine) in two trials [53,57], massage in one trial [39], sham laser acupuncture in one trial [41] and waiting list and non-specific acupuncture control (valid acupuncture points not designed to treat depression) in two trials [35,42]. See Fig. 2. Acupuncture versus medication Electro-acupuncture TCM acupuncture 2. Outcome: Reduction in severity of depression A comparison was made between acupuncture and medication. 16 trials (1281 participants) investigated this comparison and reported reduction in severity of depression using the HRSD [53–55,16,15,31,32,34,37,49,51,52,56–58]. No significant differences were found between the two acupuncture groups and medication group at the end of

Table 1 Consistency and differences among the Systermatic Reviews. Participants

Objectives

Search Strategy

Clinical Practice

Main findings/Conclusion

Smith 2005

RCTs, acupuncture compared to sham, no treatment, medication, psychotherapy and standard care. Modes of treatment: Acupuncture, electro-acupuncture and laser-acupuncture.

Seven trials with 517 participants with depression diagnosed by DSM IV, ICD, RCD and CCMD-3-R.

RCTs, acupuncture compared to any control.

Seven trials with 509 participants with depression diagnosed by DSM III/IV and ICD.

There is insufficient evidence to determine the efficacy of acupuncture compared to medication, sham or waiting list control. The RCTs have poor study design, and high risk of bias limited the results. The evidence from RCTs is insufficient to conclude whether or not acupuncture is an effective treatment for depression. Acupuncture was as effective as medication.

Leo 2007

RCTs, no control intervention specified.

Nine trials comprising depressed stroke patients, depressed pregnant patients, adults with bipolar disorder and anxiety diagnosed by clinical interviews.

Assessed the efficacy of acupuncture using HRSD for self and clinician reported measure.

Cochrane Central Register for controlled trials, MEDLINE, EMBASE, AMED, PsycINFO, CINAHL, Wan Fang data. Terms: depression/depressive disorder, dysthymic disorder, acupuncture. Cochrane Central Register for controlled trials, MEDLINE, EMBASE, PsycINFO, Japana Centra Revuo medicina. Terms: acupuncture, electro/ laser acupuncture, depression, mental disorder, dysthymia. MEDLINE, AMED and Cochrane central register for controlled trials. Terms: Acupuncture, electro-acupuncture, depressive disorder, dysthymic disorder, depression.

No recommendation for practice, until further high quality research has been undertaken.

Mukaino 2005

Assessed the efficacy of acupuncture for depression, using HRSD and Beck Inventory Scale for self and clinician reported measure. Improvement measure as remission compared to no remission. Assessed the efficacy of acupuncture using HRSD for self and clinician reported measure.

Wang 2008

RCTs, compared acupuncture to sham acupuncture.

Eight trials comprising 477 participants with depression or depression neurosis diagnosed by DSM III/IV and ICD.

Assessed the efficacy of acupuncture using HRSD for self and clinician reported measure.

Cochrane central register for controlled trials, MEDLINE, EMBASE, BIOSIS, PsycINFO, Japana Centra Revuo medicina. Terms: acupuncture, acupressure, depression, depressive disorder.

The main side effect of acupuncture treatment was fatigue, which was transient and persisted less than 24 hours.

No data for clinical practice was reported.

The number of acupuncture treatment needed to elicit antidepressant effect is between 10-18 sessions.

The evidence for the efficacy of acupuncture in treating depression is inconclusive. The method- ological quality in the RCTs evaluated was poor. Acupuncture was as effective as medication. It is supported that acupuncture was an effective treatment that could reduce the severity of diseases in patients with depression and depressive neurosis. The quality of individual trials was poor.

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Inclusion Criteria

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Table 2 Study Characteristics, Main Findings, and Results of Randomized Controlled Trials separated between Electro- Acupuncture and TCM Acupuncture. Quality (Risk of bias)

Subjects

RxN

C×N

Electro-Acupuncture

Control

Primary Outcome

Main Findings

Fu 2003

Moderate

Depression measure by CCMD-2/HRSD

32

32

Medication: Fluoxetine 20mg daily for 8 weeks.

Reduction in severity of depression/HRSD

There was no significant difference between acupuncture and medication (p › 0.05).

Li 2007

Moderate

Depression measure by CCMD-3/HRSD

32

24

Medication, Fluoxetine or Paroxetine 20mg daily for 6 weeks.

Reduction in severity of depression/HRSD

There was no significant difference between acupuncture and medication (p › 0.05).

Zhang 2007

Moderate

Depression measure by CCMD-2/HRSD

22

20

Medication, Paroxetine 10–40 mg daily for 6 weeks.

Reduction in severity of depression/HRSD

Acupuncture combined with medication was more effective than medication alone (p › 0.05).

Duan 2008

Moderate

Depression measure by CCMD-3

23

23

Random selection of these points: LIV-3, LI-4, DU-20, EX-HN3,BL-15,BL14,HE-7,SP-6,GB-40,PC7,SP-1,KI-1,SP-4,LU-7. Ear points: Heart, Gallbladder and Shenmen. Two sessions weekly for 8 weeks. Random selection of these points: DU-20, EX-HN3, GB-20, N-HN-54, M-HN-1, HE-7, PE-5, LI-4, LIV-3, SP-6, GB-40, GB-8, ST-36, PE-6, REN-17, REN-12 and ST-25. Ear points: Heart and Shenmen. 42 session’s 6/wks for 6 weeks. Random selection of these points: DU-20, EX-HN3, PC-6, SJ-5, HE-7, LI4, LIV-3, ST-36, ST-40, Sp-6, LU-9. 36 sessions / 6wks for 6 weeks. In addition; Paroxetine 10–40 mg daily for 6 weeks. A. Electro-acupuncture group, Random selection of these points: DU-20, EX-HN3, LI-4, LIV-3, LIV-2, GB-34, N-HN-54, HE-7, PE-6, SP-6, ST-36, KID-3, and KID-6. 36 session’s 6/wks for 6 weeks.

B. Medication, group: Fluoxetine 20mg daily for 6 weeks.

Reduction in severity of depression/HRSD

Acupuncture combined with medication was more effective than medication alone (p › 0.05).

Beck scale/HRSD

There was no significant difference between acupuncture and medication (p › 0.05).

24

Huang 2004

Moderate

Depression measure by CCMD-3/HRSD

30

30

Random selection of these points: MS-5, MS-1, MS-2. 36 session’s 6/wks for 6 weeks.

C. Electro-acupuncture and medication group: Acupuncture was applied as in group A and medication as in group B. Medication: Fluoxetine 20–40 mg daily for 6 weeks.

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Study

Yan 2004

Moderate

Depression measure by CGIS /HRSD

19

11

Fu 2008

Low

Depression measure by CCMD-2

176

176

Random selection of these poins: Du-20 and EX-HN3. 42 session’s 6/wks for 6 weeks. Classical acupuncture group; Random selection of these points: LIV-4, LIV-3, DU-20 and EX-HN3. 24 sessions daily for 12 weeks. Ear points: Heart and Liver.

Zhou 2007

Moderate

Depression measure by CCMD-3/HRSD

30

28

Hou 2005

Moderate

Depression measure by CCMD-2

40

32

Fan 2005

Low risk

Depression measure by HRSD

28

24

25

Random selection of these points: BL-18, BL-23, BL-15, ST-36, SP-6, DU-24, GB-13 and M-HN-1. 36 session’s 6/wks for 6 weeks. Tiaoshen shuan acupuncture with following points: PE-6, DU-20, EX-HN3, SP-6, LIV-3 and GV-26

Classical acupuncture group; Random selection of these points: LIV-3, LI-4, DU-20 and EX-HN3. Ear points: Cowherb seeds on Heart and Liver remained for three days/one ear at the time. Twice a week for 12 weeks

Sham acupuncture group: non-acupuncture points: 0, 5cm near to LI-4, LIV-3, DU-20 and EX-HN3. Ear points: Back of Heart and Liver. Medication, Fluoxetine 20mg daily for 6 weeks.

Reduction in severity of depression/HRSD

Reduction in severity of Depression/HRSD

There was no significant difference between acupuncture and medication (p › 0.05) There was no significant difference between acupuncture and medication (p › 0.05).

Classical acupuncture was more effective than sham-acupuncture.

Reduction in severity of Depression/HRSD

There was no significant difference between acupuncture and medication (p › 0.05).

Routine acupuncture with following points: LIV-14, GB-34, HE-7 and PE-5

Depressive Severity Index (DSI)

Medication group: Medication, Prozac 20 mg daily for three months.

Reduction in severity of depression/HRSD

DSI significant decreased post- treatment compared to pre- treatment in both groups, but experimental acupuncture was more effective than routine acupuncture treatment (p < 0.05). There was no significant difference between acupuncture and medication (p › 0.05).

Sham-acupuncture group: 0.5cm near LI-4, 0, 5cm near LIV-3, 0, 5cm near DU-20 and 0,5cm near EX-HN3.Ear points: back of heart and Liver points. Twice a week for three months.

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88

Medication: Amitriptyline 250 mg for one week and after that an average dose of 130 mg daily for 6 weeks. Medication group: Prozac 20 mg daily for 12 weeks.

Classical acupuncture was more effective than sham-acupuncture.

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Fig. 2. Treatment effect of acupuncture compared to waiting list control, placebo control and active control for the outcome improvement of depression according to Hamilton Rating Scale for Depression.

the treatment (WMD −0, 23 95% CI −1.05 to 0.58, P = 0.57). To test whether different styles of acupuncture had different effects a subgroup analysis was done. We did a comparison between two subgroups, electro-acupuncture [15,16,32,49,51,52,54,55,58] and TCM acupuncture [34,37,49,53,56,57] showed no significant difference (WMD −0.68, 95% CI −1.49 to 0.13, P = 0.10) and (WMD 0.79, 95% CI −0.93 to 2.52, P = 0.37). This is shown in Fig. 3.

Treatment protocol Patients from these trials received manual acupuncture with or without electro stimulation. Patients from one trial received laser acupuncture [41]. In four trials acupuncture points were selected individually, following the principle of TCM [35,39,41,42]. Four trials described the points in detail, but the points varied significantly [33,38,41,42]. Some trials used a fixed set of points while others used points according to TCM syndromes. Ten trials used electro-acupuncture on DU20 and M-HN-3. According to the treatment protocols from this overview, a westernized medical acupuncture style was not used in any trials. Acupuncture points and TCM syndromes that were most frequently used are presented in Table 3: treatment protocol and choice of acupuncture points.

Discussion Main findings Based on this overview and meta-analysis we found no positive effect in reduction of depression by acupuncture compared to a waiting list control. However, this overview suggests significant beneficial effects for acupuncture in improving depression compared to the pooled control. The contradictory finding between a waiting list control and the pooled control may be due to the fact that there was only one trial that undertook the comparison between TCM acupuncture and a waiting list control. The trial [35] was small, which may increase the risk of underpowered results. Authors of several trials in this overview (Fig. 3) emphasized the importance of using electro-acupuncture on head points (DU-20 and EX-HN3) when treating depression. Trials presented in this overview used several points for this condition, however the most frequent points used were: LR-3, LI-4, HT-7, PC-6, SP-6, ST-36 and M-HN-1. These points are also suggested for treatment of depression in common practice [62,63]. However, there is still a great diversity in acupuncture-styles and points used with regard to treatment of depression. In order to allow for transparent reporting we recommend the use of STRICTA guidelines added to the CONSORT statement/guidelines [64].

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Fig. 3. Electro-acupuncture and classical acupuncture versus medication for the outcome of reduction in severity of depression according to Hamilton Rating Scale for Depression.

Acupuncture may work by neurological, neurohormonal and psychological mechanisms [65,66]. In relation to depression, acupuncture may affect many structures and neurotransmitters in the central nervous system including serotonin, norepinephrine, dopamine and GABA; as well as the hypothalamus, pituitary, thyroid and adrenal glands [8,65–68]. It is difficult to find a satisfactory control intervention for acupuncture, as needles inserted into the skin avoiding acupuncture points and meridians (sham acupuncture) are likely to have some effect [69,70]. In Allen [35,42] acupuncture points not designed to treat individuals’ depression were used as control intervention (nonspecific acupuncture) which was compared to specific acupuncture points for depression. The trials found no evidence to support differential efficacy of the two types of acupuncture intervention. Such results could reflect that the specific acupuncture intervention was not particularly effective, or

that the intended control was somewhat more effective than predicted, or both. The situation of blinding in acupuncture trials is highly problematic, it is (nearly) impossible to blind the provider of the treatment. Hence, a detailed description of who else is blinded is needed, e.g. the participating patients, the assessor of the outcome or both [71]. However, still scientists are engaged in developing equipment which aims to design double blind RCTs in acupuncture studies [72]. Several acupuncture studies have been published using a pragmatic design, reflecting acupuncture as it is practiced in real life. Such studies will tell us whether acupuncture as a treatment package or as a whole system work, but does not answer the question whether or not there is a specific acupuncture needle effect [70], another study design is required. The positive effect of acupuncture compared to pooled control found in this review is therefore interesting and justifies further research.

Table 3 Treatment Protocol and Choice of Acupuncture Points.

Bias consideration

Treatment Protocol

Acupuncture Points

Electro-acupuncture

DU-20 (Baihui) EX-HN3 (Yintang) LIV-3, LI-4, HE-7, PC-6, SP-6, ST-36 and M-HN-1 (Sishencong) Heart (Xin), Liver (Gan) Shenmen Deficiency of Heart and Spleen. Stagnation of Liver Qi Disharmony between Heart and Kidney

The RCTs in this overview had several methodological flaws in terms of reporting the allocation sequence, the allocation concealment and the blinding procedure of the trials. 15 trials [15,16,32,34,37,40,47–49,51,52,54–56,58] provided limited description of the study design. Most trials merely stated that patients were randomly assigned. Such information does not allow a judgment of whether or not it was properly conducted. However, 7 trials reported in detail on the conduct of randomization. One trial used stratified randomization [42]. Two trials

Classical/standard points Ear Points TCM Syndrome

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used utilized block randomization [33,38] and 4 trials reported simple randomization procedure [41,53,57,59]. In addition, two trials referred to a manual [62] in which the study design and randomization were described [35,39]. These 9 trials also used a blinded design, including blinding of subject, and outcome assessor (statistician). In addition, one trial [36] reported singleblinded design, involving patient but not therapist-blinding. Furthermore 10 trials, 6 conducted in Western countries [35,36,38,39,41,42] and 4 in China [33,53,57,59] were of high quality in terms of generation of allocation sequence, concealment of allocation, blinding and application of intention to treat analyses. They also received a high score (3–5 points) on the Jadad Scale [73] which included the following criteria: method of randomization, double blinding and reporting of withdrawals and dropouts. However, this scale has limitations as it focuses more on the quality of reporting than to the actual methodological quality [74]. This scale addresses randomization but does not assess allocation concealment. The use of an open random-numbered table would thus be considered equivalent to concealed randomization using a telephone or computer system and earn the maximum points foreseen for randomization. Therefore, relevant methodological aspects should be assessed individually and always include the key domains of concealment of treatment allocation, blinding of outcome assessment or double blinding and handling of withdrawals and dropouts [74]. Methodological issues such as poor quality in terms of randomization and blinding may be associated with exaggerated effects of acupuncture interventions due to subjected systematic bias. Potential bias may be found in selection of participants, administration of treatment and assessment of outcomes. In addition, less rigorous methodological trials demonstrate significantly larger intervention effects than trials with more rigor [24,75]. Secondly, in an intention to treat analysis participants are analyzed according to their original group assignment, whether or not this is the intervention they actually received, or whether or not they accepted or adhered to the intervention [23]. The primary analysis of an RCT should always be an intention to treat analysis, as it avoids the possibility of any bias associated with loss, miss-allocation or non-adherence of participants. Intention to treat analyses were not reported, we assume that most of the trials in this overview performed such analyses as they used all the numbers of randomization in their data analyses. 12 trials had no information on missing or drop out of participants. The insufficient report of loss to follow up makes it impossible to explore potential bias on an intention to treat basis. This may be associated with exaggerated effects for the acupuncture intervention due to systematic error (bias) [23]. Although improved reporting practice should facilitate the assessment of methodological quality in the future, incomplete reporting continues to be an important problem when assessing trial quality. Thirdly, nine trials (35%) had well defined diagnostic criteria for participants whereas 17 trials (65%) had unclear diagnostic criteria. Therefore, the included trials may have included patients with other psychiatric diseases with symptoms that overlap depression, and/or patients with different severity of

disease. This inconsistency in the application of diagnostic criteria may bias the evaluation of the acupuncture treatment due to the heterogeneous mix of participants in the included trials. We recommend transparent reporting according to STRICTA guidelines and the CONSORT statement in order to improve this issue. Fourthly, most of the included trials were small (from 23 to 352 participants). Although some data analyses did not demonstrate a statistically significant difference between acupuncture and control intervention, the results are likely to have been underpowered. Therefore, the analyses from the small trials may not establish with confidence that two interventions have equivalent effects [26]. Fifthly, many of the trials included in this overview come from China, a country that seldom publishes negative acupuncture studies [76]. Publication bias is the tendency for individuals to submit or publish trials depending on the direction or strength of the findings. Clinical trials are much more likely to be published if there is statistically significant difference among treatment groups [26,75]. This may vary across countries and cultures, but one will expect that the overall proportion of positive trials would tend to be higher in countries with the greatest publication bias. Accordingly, when interpreting the present findings, publication bias should be taken into consideration. Sixthly, another possible explanation for positive results in favor of acupuncture could be that acupuncture is more effective in countries where it is traditionally practiced. Data from this overview demonstrate that Chinese trials give an average of 33 treatment sessions for depression, with vigorous electrostimulation on head points (DU-20) and (EX-HN3), in contrast to Western trials that give an average of 12 treatment sessions and no electro-stimulation on head points at all. This may be a contributor to the positive results in favor of acupuncture in Chinese studies. The reported difference in treatments raises an interesting question whether there is a dose-response effect in acupuncture treatment of depression? It is beyond the scope of the present article to discuss this further, but we do think it is an important question which has to be raised in future research on acupuncture treatment. Limitations and strength Although strong efforts have been made to retrieve all RCTs on the subject, we cannot be absolutely certain that we have succeeded. However, findings from overviews should primarily be used as a compass for deciding what type of intervention to use for certain conditions and it is important for clinicians and policy makers not to interpret low-quality evidence of no effect. Lowquality evidence means unclear evidence, and findings should initiate more research and reviews. Implication for practice Current evidence from systematic reviews and randomized trials shows beneficial effects of acupuncture in reduction of depression compared to antidepressant medication. This emphasizes the importance of using electro-acupuncture on head points

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when treating depression. Our results are in line with a recently published meta-analysis [77], which found an overall effect of acupuncture in reducing depressive symptoms in patients with major depressive disorders (MDD) compared to the pooled control. Implication for research Randomized trials are required to evaluate the effectiveness of acupuncture in treating depression. The methodological quality of clinical trials needs to be improved. The following aspects concerning methodological quality are important: (a) reporting of the generation of the allocation sequence and allocation concealment, (b) blinding of practitioner (where appropriate), outcome assessor and analyst, (c) clear description of withdrawals/dropouts during trials. One way to improve this is to publish trial protocols, which allows researchers to learn from each other. In addition, reporting trials according to the CONSORT statement will secure methodological transparency. In non-protocol acupuncture it is essential to report according to the STRICTA guidelines in order to ensure replication and assure that the points used in trials reflects common practice. Conclusion Current evidence from this meta-analysis of randomized trials shows that acupuncture is effective in reducing depression and that TCM- and electro acupuncture may have similar effects to current routine care. Our review also emphasizes the importance of reporting the exact acupuncture treatment procedures that are under investigation. This is essential in order to be able to draw any firm conclusions on the diversity of acupuncture styles used in research which has implications for clinical recommendations. Hence, a step in the right direction is to report studies according to the STRICTA guidelines [78]. Conflict of interest There is no conflict of interest. Financial support This study had no financial support. References [1] Maciocia G. The foundation of chinese medicine. London: Churchill Livingstone; 1989. [2] Birch S, Kaptchuk T. History, nature and current practice of acupuncture: an East Asian perspective. Oxford: Butterworth-Heinmann; 1999. [3] Hesketh T, Zhu WX. Health in China: traditional Chinese medicine: one country, two systems. BMJ 1997;315:115–7. [4] Xu J, Yang Y. Traditional Chinese medicine in the Chinese health care system. Health Policy 2009;90:133–9. [5] World Health Organization. Management of mental disorders. 4th ed. Sydney: WHO Collaborating Centre for Evidence in Mental Health Policy; 2004.

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