Acupuncture for schizophrenia: a systematic ... - Wiley Online Library

META-ANALYSIS

Acupuncture for schizophrenia: a systematic review and meta-analysis M. S. Lee,1,2 B.-C. Shin,3 P. Ronan,4 E. Ernst2 Linked Comment: Samuels. Int J Clin Pract 2009; 63: 1553–5.

1

Division of Standard Research, Korea Institute of Oriental Medicine, Daejeon, South Korea 2 Complementary Medicine, Peninsula College of Medicine & Dentistry, Universities of Exeter & Plymouth, Exeter, UK 3 Department of Oriental Rehabilitation Medicine, School of Oriental Medicine, Pusan National University, Yangsan, South Korea 4 Department of Social Work, Community and Mental Health, Canterbury Christ Church University, Kent, UK Correspondence to: Myeong Soo Lee, Division of Standard Research, Korea Institute of Oriental Medicine, 461-24, Jeonmin-dong, Yuseong-gu, Daejeon 305-811, Korea Tel.: + 82 42 868 9266 Fax: + 82 42 863 9464 Email: [email protected]; [email protected] Disclosure None.

SUMMARY

Review Criteria

Background: Acupuncture is one of the most popular types of complementary ⁄ alternative medicine. It is sometimes used as a treatment for schizophrenia. Aims: The objective of this review is to assess systematically the clinical evidence for or against acupuncture as a treatment for schizophrenia. Methods: We searched 20 databases from their inception to May 2009 without language restrictions. All randomised clinical trials (RCTs) of acupuncture, with or without electrical stimulation or moxibustion for patients with schizophrenia were considered for inclusion. Results: Thirteen RCTs, all originating from China, met the inclusion criteria. One RCT reported significant effects of electroacupuncture (EA) plus drug therapy for improving auditory hallucunations and positive symptom compared with sham EA plus drug therapy. Four RCTs showed significant effects of acupuncture for response rate compared with antipsychotic drugs [n = 360, relative risk (RR): 1.18, 95% confidence interval (CI): 1.03–1.34, p = 0.01; heterogeneity: s2 = 0.00, v2 = 2.98, p = 0.39, I2 = 0%]. Seven RCTs showed significant effects of acupuncture plus antipsychotic drug therapy for response rate compared with antipsychotic drug therapy (n = 457, RR: 1.15, 95% CI: 1.04–1.28, p = 0.008, heterogeneity: s2 = 0.00, v2 = 6.56, p = 0.36, I2 = 9%). Two RCTs tested laser acupuncture against sham laser acupuncture. One RCT found beneficial effects of laser acupuncture on hallucination and the other RCT showed significant effects of laser acupuncture on response rate, Brief Psychiatric Rating Scale and clinical global index compared with sham laser. The methodological quality was generally poor and there was not a single high quality trial. Conclusion: These results provide limited evidence for the effectiveness of acupuncture in treating the symptoms of schizophrenia. However, the total number of RCTs, the total sample size and the methodological quality were too low to draw firm conclusions. As all studies originated from China, international studies are needed to test whether there is any effect.

Introduction Schizophrenia is a mental illness that is among the world’s ten most important causes of long-term disability (1). Antipsychotic medications are the mainstay for managing schizophrenia. The adverse events associated with such treatments lead patients to seek complementary and alternative medicine (CAM), usually as adjuncts to conventional medicine (2,3). The main motivation for using CAM is the hope for improvements in mood and alleviation of psychiatric symptoms (4). In many countries, the social circumstances of people with schizophrenia limit their ability to access CAM (5).

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We included all randomised clinical trials of acupuncture to treat human patients suffering from schizophrenia after searching 20 databases from their inception to May 2009, without language restrictions.

Message for the Clinic Acupuncture is one of the most popular types of CAM. It is sometimes used as a treatment for schizophrenia. The results of our systematic review and meta-analysis provided limited evidence for the effectiveness of acupuncture in treating the symptoms of schizophrenia.

Acupuncture is one of the most popular types of CAM. It is sometimes used as a treatment for schizophrenia (3) and claimed to be effective in improving mood including anxiety and depression (4,6,7). Considering these facts, it is pertinent to investigate the effectiveness of acupuncture for treating schizophrenia. Currently, two reviews of this subject are available (8,9). Unfortunately, they included only publications published before 2001 and are now out of date. The objective of this systematic review was to summarise and critically assess the evidence from randomised clinical trials (RCTs) for or against the effectiveness of acupuncture in treating schizophrenia.

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, November 2009, 63, 11, 1622–1633 doi: 10.1111/j.1742-1241.2009.02167.x

Acupuncture for schizophrenia

Methods Data sources The following electronic databases were searched from inception up to May 2009: Medline, AMED, British Nursing Index, CINAHL, EMBASE, PsycInfo, The Cochrane Library 2009 (Issue 2), six Korean Medical Databases (Korean Studies Information, DBPIA, Korea Institute of Science and Technology Information, Research Information Centre for Health Database, Korean Medline, and Korean National Assembly Library), four Chinese Medical Databases (China Academic Journal, Century Journal Project, China Doctor ⁄ Master Dissertation Full Text DB, and China Proceedings Conference Full Text DB) and three Japanese Medical Databases. The search terms used were ‘acupuncture AND schizophrenia’. We also manually searched our departmental files and relevant journal [Focus on Alternative and Complementary Therapies (FACT) and Forschende Komplementa¨rmedizin und Klassische Naturheilkunde (Research in Complementary and Classical Natural Medicine) up to May 2009]. In addition, the references in all located articles were manually searched for further relevant articles.

BCS) and if needed, by seeking the opinion of a third reviewer (EE). There were no disagreements between the three reviews about the assessment of risk of bias.

Data synthesis To summarise the effects of acupuncture on outcomes (response rate), we abstracted the risk estimates (relative risk: RR) and weighted mean differences (WMD), and 95% confidence interval (CI) was calculated using the Cochrane Collaboration’s software [Review Manager (RevMan) Version 5.0 for Windows; The Nordic Cochrane Centre, Copenhagen, Denmark]. For studies with insufficient information, we contacted the primary authors to acquire and verify data wherever possible. The variance of the change was imputed using a correlation factor of 0.4 as suggested by the Cochrane Collaboration. If appropriate, we then pooled the data across studies using random effects models (if excessive statistical heterogeneity did not exist). The v2 test, s2 and the Higgins I2 test were used to assess heterogeneity (11).

Results Study description

Study selection All articles were included that reported an RCT in which human patients with schizophrenia were treated with needle acupuncture with or without electrical stimulation. Trials were included if they employed acupuncture as the sole treatment or as an adjunct to other treatments (if the control group also received the same concomitant treatment as the acupuncture group). Trials testing other forms of acupuncture, such as laser acupuncture or moxibustion were included. Those comparing two different forms of acupuncture and those in which no clinical data were reported were excluded. Any trials with acupuncture as a part of a complex intervention were also excluded. No language restrictions were also imposed. Dissertations and abstracts were included.

Data extraction and assessment of risk of bias Hard copies of all articles were obtained and read in full. All articles were read by two independent reviewers (MSL, BCS), and data from the articles were validated and extracted according to predefined criteria. Risk of bias was assessed using the Cochrane classification in four criteria: randomisation, blinding, withdrawals and allocation concealment (10). Considering that it is very hard to blind therapists to the use of acupuncture, we assessed patient and assessor blinding separately. Discrepancies were resolved through discussions between two reviewers (MSL,

The searches identified 87 potentially relevant articles, of which 13 met our inclusion criteria (Figure 1). All of the included RCTs originated from China. The key data are summarised in Table 1 (12–23). Manual acupuncture alone was used in four trials (13,14,16) [one (13) of them included two different studies], electroacupuncture (EA) was employed in seven trials (12,15,17–21) and laser acupuncture was used in two trials (22,23). A placebo procedure was employed in three trials (12,22,23) and conventional pharmacological drug therapy in 10 trials (13–21). Seven of the included trials adopted a two-arm parallel group design (12,16–21), three adopted a three-arm parallel group design (14,22,23) and three a four-arm parallel group design (13,15). Eight trials adopted the principles of Chinese Classification of Metal Disorders (CCMD) second edition revision (13,14,17) or third edition (16,19–21), descriptive definitions of which were based on the clinical description and diagnostic guideline of ICD 10 and DSM-IV (24), for diagnosis of Schizophrenia, and another three studies diagnosed Schizophrenia according to DSM-III (18,23) and DSM-IV (12). The other RCTs did not mention the diagnostic methods employed (15,22). Subjects with type II (negative) schizophrenia, which was described as clinical poverty syndrome involving social withdrawal, poverty of content and production of thought and speech (25–27), were included in four RCTs (13,16,19,21), type I (positive) as characterised by

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, November 2009, 63, 11, 1622–1633

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Figure 1 Flow chart of trial selection process

hallucinations, delusions and formal thought disorder (25–27), in one RCT (13), paranoid type in two studies (22,23), hebetic type in one trial (14), all types in two RCTs (15,20). The other two studies did not report details about it (17,18). Most of the included studies used response rate for each intervention and it was generally divided into four categories including (1) recovery, (2) marked improvement, (3) improvement (4) and no change by practitioners. Table 2 shows the summary of treatment acupuncture points and other information related with acupuncture. The rationale for the point selection as stated was made according to Traditional Chinese Medicine theory (13,14,16–21,23), classic book (15,17), previous reports (12,22) or their clinical experience (12,14,19).

Assessment of risk of bias The included trials had high risk of bias except one recent RCT (12). Four RCTs described the methods of

randomisation (12,14,20,21). In three (12,14,20) of them, the method was appropriate, whilst in the fourth trial it was not (21). Details of drop-outs or withdrawals were described in two trials (12,21). One RCT (12) reported details about allocation concealment and ethical approval from Institutional Review Board, whilst the others failed to do so. Three RCTs adopted subject blinding (12,22,23) and three RCTs employed assessor blinding (12,16,18). Adverse events were mentioned in nine studies (12–14,18–23).

Outcomes Acupuncture plus risoperidone vs. sham acupuncture plus risoperidone One RCT (12) tested EA plus risoperidone on Psychotic Symptom Rating Scales Auditory Hallucination Subscale (PSYRATS-AH) and Positive and Negative Symptom Scale (PANSS) compared with



120 Type I§ n.r. CCMD-2-R 120 Type II§ n.r. CCMD-2-R

Zhao (2005a) (13)à

Zhao (2005b) (13)à

60 All schizophrenia with auditory hallucinations 10 ⁄ 9 (auditory hallucination) DSM-IV

Cheng (2009) (12)

First author (year) (ref)

Sample size Duration of schizophrenia (years) Diagnosis

(B) Risperidone (initial: 1 mg, reaching: 4 mg daily for 60 days, n = 30) (B) Risperidone (initial: 1 mg, reaching: 4 mg daily for 60 days, n = 30)

(A) AT (30 min, once daily for 60 days, n = 90)

Sham EA (superficial penetration, no acupuncture points without electrical current, n = 30), plus risperidone (average dose: 5.22 mg ⁄ days), concomitant lorazepam (< 4 mg) was allowed to counteract sleep problems

(A) EA (sparse dense wave, 2-10 Hz, 2–3 mA, 20 min, five times weekly over 6 weeks, total 30 session, n = 30), plus risperidone (average dos: 5.15 mg ⁄ days), concomitant lorazepam (< 4 mg) was allowed to counteract sleep problems

(A) AT (30 min, once daily for 60 days, n = 90)

Control intervention (Regimen)

Experimental intervention (Regimen)

Table 1 Summary of randomised clinical studies of acupuncture for schizophrenia*

(1) BPRS (total efficacy rate), (if, > 30% reduction in BPRS)

(1) BPRS (total efficacy rate), (if, > 30% reduction in BPRS)

(1) PSYRATS-AH (2) Response rate (if, > 20% reduction in PSYRATSAH total score) (3) PANSS

Main outcomes

(1) 90.0% vs. 70.0% (p < 0.025) in favour of AT

(1) Total score: p < 0.0167 after 4 weeks and 6 weeks in favour for real AT Physical subscale: p < 0.0167 after 4 weeks and 6 weeks in favour for real AT Emotion and cognitive subscale: NS (2) 43.3% vs. 13.3% (3) Positive symptom: p = 0.006 after 4 weeks and p = 0.004 after 6 weeks in favour for real AT; Negative symptom: NS (1) 88.9% vs. 66.7% (p < 0.025) in favour of AT

Main results Intergroup difference

(A,U,U,U,U,U)

(A,U,U,U,U,U)

(A,A,A,A,A,A)

Risk of bias

Acupuncture for schizophrenia 1625

100 n.r. 11 ⁄ 11 CCMD-2

40 n.r. 8.2 (mean) DSM-III

Zhang (1993) (17)

Zhou (1997) (18)

Luo (2006) (16)

88 All types§ n.r. n.r. 60 Type II 1.5-18 ⁄ 1.5-20 CCMD-3

48 Hebetic (occurring at puberty) schizophrenia 1.6 ⁄ 1.5 ⁄ 1.5 CCMD-2-R

Zhang (1987) (15)

Wang (2006) (14)

(B) Chlorpromazine (oral dose of 300–600 mg ⁄ days, daily for at least 20 days, n = 45) (B) Risperidone (initial: 1 mg ⁄ day, reaching 4–6 mg ⁄ days, daily for 3 months, n = 30)

(C) Sufficient antipsychotic drugs (n.r., 0.4-0.6 g daily for same duration with A, n = 16)


BPRS SAPS SANS TESS Total efficacy rate–

(1) (2) (3) (4) (5)

Total efficacy rate– BPRS SANS SAPS Antipsychotic drugs use

(1) BPRS (2) SANS (3) Total efficacy rate–

(1) Response rate–

(1) (2) (3) (4) (5)

Main outcomes

(A) EA (180 Hz, 60 mA, for 15 mn, once (B) Antipsychotic drug (1) BPRS daily, 6 days weekly for 6 weeks, total (Chlorpromazine equivalents, (2) CGI 36 sessions, n = 25), plus 40% reduced 560 mg ⁄ days, during the study, n = 15) (3) TESS dose of antipsychotics

(A) AT [30 min, once daily for 20 days after 10 days rest (1session) for 3 months (three sessions), n = 30], plus the same antipsychotic drugs as (B) (A) EA (modulation wave, 250 or 750 Hz, (B) Antipsychotic drugs 2V–9V, 45 min, once daily for 8 (n.r., n.r., n = 43) weeks, n = 57), plus the same antipsychotic drugs as (B)

(A) EA (120 Hz, two times daily for at least 20 days, n = 43)

(A) AT [3–5 min manual technique after 10 min retention, repeat for 45 min, once daily for 15 times (1session), total 2sessions, n = 16] (B) AT (same as A, n = 16), plus little dose antipsychotic drugs (chlorpromazine: £ 0.2 g ⁄ d)

Sample size Experimental Duration of First author (year) schizophrenia (years) intervention (Regimen) Diagnosis (ref)

Table 1 (continued )

Risk of bias

(1) 73.7% vs. 65.2% (p < 0.005) (2) p < 0.002 (3) p < 0.001 (4) p < 0.002 (5) NS (1) NS (2) NS (3) p < 0.01 in favour of EA

(1) p < 0.01 in favour of AT (2) p < 0.01 in favour of AT (3) 93% vs. 83% (p < 0.05) in favour of AT

(A,U,U,U,A,U)

(A,U,U,U,U,U)

(A,U,U,U,A,U)

(A,A,U,U,U,U) (1) A vs. C: p < 0.05, B vs. C: p < 0.01 (C < A < B) (2) A vs. C: NS, B vs. C: p < 0.01; (A = C < B) (3) A vs. C: p < 0.05, B vs. C: p < 0.01 (C < A < B) (4) A vs. C: p < 0.01, B vs. C: p < 0.05 (A = B < C) (5) A:B:C = 93.8% : 100.0% : 87.5% A vs. C: p < 0.05, B vs. C: p < 0.01 (1) 62.8% vs. 62.2% (NS) (A,U,U,U,U,U)


1626 Acupuncture for schizophrenia



90 All state 0.7 ⁄ 0.8 CCMD-3

62 TypeII 3-24 ⁄ 2-19 CCMD-3

60 Paranoid type 5.1 ⁄ 7.3 ⁄ 6.2 n.r.

31 Paranoid type 7.6 ⁄ 4.9 ⁄ 5.0 DSM-III

Yao (2006) (20)

Chen (2008) (21)

Liu (1986) (22)

Zhang (1991) (23)

(1) BPRS (2) CGI (3) Total efficacy rate–

(1) Severity of hallucination

(1) PANSS (2) TESS

(B) Aripiprazole [initial: 5 mg ⁄ days, 10–30 mg ⁄ days (mean: 18.4 mg ⁄ days) daily for 12 weeks, n = 30]

(B) Sham laser AT no real radiation, n = 20), plus Chlorpromazine (450 mg ⁄ days) (C) Sham laser AT (real irradiation, non-acupoint, earlobe, n = 20) (C) Sham laser AT (same procedure with A, but no real laser), plus Chlorpromazine (350–600 mg ⁄ days, daily, for 5 weeks, n = 10)

(1) Total efficacy rate (if, PANSS > 25% reduction) (2) PANSS (3) TESS

(B) Clozapine (200–300 mg ⁄ days, for 8 weeks, n = 45)

(A) EA [loose and dense wave, 30 min, once daily for 20–30 times (1session), total two sessions, n = 45], plus the same antipsychotic drugs as (B) (A) EA (45 min, once daily · 5 days per week, for 12 weeks, n = 30), plus the same antipsychotic drugs as (B)

(A) Laser AT (n.r., 6328, 4.7 hw, 6-7.5 mA, once daily, 6 days weekly for 5 weeks , total 30 sessions, n = 20) (A) Laser AT (15 min, 6328, laser fibre output > 2 milliwatts, once daily, 6 days weekly for 5 weeks, n = 11) (B) Laser AT (same with A, n = 10), plus Chlorpromazine (150–300 mg ⁄ days, daily for 5 weeks)

(1) PANSS (2) Total efficacy rate (if, PANSS > 25% reduction) (3) TESS

(B) Risperidone [initial: 1 mg ⁄ day, 3–6 mg ⁄ days (mean: 5.3 mg ⁄ days), daily for 8 weeks, n = 35]

(A) EA (interrupted wave, 20–40 Hz, 45 min, once daily, 5 days weekly for 8 weeks, n = 40), plus the same antipsychotic drugs as (B)

Main outcomes


Experimental intervention (Regimen)

(1) Total : p < 0.01 Positive symptom: NS Negative symptom: p < 0.01 (2) 65% vs. 46% (p < 0.05) (3) NS (1) 77.8% vs. 75.6%; NS (2) NS (3) Somatic complaint: p < 0.01, neurologic complaint: p < 0.01 (lower in A) (1) Total : p < 0.01 Positive symptom: NS Negative symptom: p < 0.01 in favour of EA Total efficacy rate: 73.3% vs. 40.0% (p < 0.05) (2) NS (1) A vs. C; p < 0.001 in favour of A A vs. B; p < 0.05 in favour of A (1) A vs. B: NS; A vs. C: p < 0.02 (2) NS (3) 45% vs. 60% vs. 60%; NS


(A,U,U,A,U,U)

(A,U,U,A,U,U)

(A,I,A,U,U,U)

(A,A,U,U,U,U)

(A,U,U,U,U,U)

Risk of bias

*All included RCTs were parallel design. Risk of bias (randomisation, randomisation method, drop-out or withdraw, patient blind, assessor blind, allocation concealment), A:adequate, U:unclear; I: inadequate. àTwo trials from the same one paper. §These studies were 4 arms parallel group design. We noted here the groups which fall into inclusion criteria. –It was divided to 4 categories including (1) recovery, (2) marked improvement, (3) improvement, (4) no change. There were 2 drop-outs. Usual dosage of antipsychotics for asian adults (ref: http://www.druginfo.co.kr) risperidone: 4–16 mg ⁄ days; chlorpromazine: outpatients, 200 mg ⁄ days; inpatients, 500–2000 mg ⁄ days; clozapine: 100–200 mg ⁄ days; Aripiprazole: 10–15 mg ⁄ days. DSM, diagnostic and statistical manual; EA, electroacupuncture; PSYRATS-AH, Psychotic Symptom Rating Scales Auditory Hallucination Scale; PANSS, Positive and Negative Symptom Scale; AT, acupuncture; BPRS, Brief Psychiatric Rating Scale; CCMD-2R, Chinese classification of mental disorders second edition revised, CCMD-3, Chinese classification of mental disorders third edition; CGI, clinical global impression; EKG, electrocardiogram; N ⁄ A, not applicable; n.r., not report; NS, not significant; TESS, Treatment Emergent Symptom Scale; SANS, Scale for the Assessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; WBC, white blood cell.

75 Type II 11.7 ⁄ 13.2 CCMD-3

Wang (2005) (19)

First author (year) (ref)

Sample size Duration of schizophrenia (years) Diagnosis

Table 1 (continued )

Acupuncture for schizophrenia 1627

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A

B

C

D

E

Figure 2 Forest plots of acupuncture for schizophrenia (A) response rate, AT vs. antipsychotic drugs; (B) response rate,

AT plus antipsychotic drugs vs. antipsychotic drugs; (C) SANS, AT plus antipsychotic drugs vs. antipsychotic drugs; (D) response rate, EA plus antipsychotic drugs vs. antipsychotic drugs; (E) BPRS, EA plus antipsychotic drugs vs. antipsychotic drugs. AT: needle acupuncture; EA: electro-acupuncture; SANS: Scale for the Assessment of Negative Symptoms; BPRS: Brief Psychiatric Rating Scale



Table 2 Summary of treatment acupuncture points and other information related with acupuncture

First authors (year) (ref)

Cheng (2009) (12)

Zhao (2005a) (13)

Zhao (2005b) (13)

Wang (2006) (14)

Zhang (1987) (15)

Luo (2006) (16)

Zhang (1993) (17) Zhou (1997) (18)

Wang (2005) (19)

Yao (2006) (20)

Acupuncture points used De-qi sensation

Rationale for selection of acupuncture points

SI 19, GB2, TE 17, PC7, PC6, SP6; bilaterally Considered (+) GV26, LU11, SP1, GV16, PC7, LI11, ST40; sedation n.r.()) BL15, BL18, BL20, HT7, ST40; balance tonification and sedation n.r.()) Sedation: LR3, LI4, GV26; PC6, PC7, GV14 Considered (+)

Previous reports and authors’ clinical experience TCM theory

Pain at the acupoints (real : sham = 2 : 1)

TCM theory

None (+)

TCM theory and authors’ clinical experience

Ancient books

n.r. in detail TESS scale (+): A vs. C: p < 0.01, B vs. C: p < 0.05 (A = B < C) n.r. ())

TCM theory

n.r. ())

TCM theory and Chinese medicine book TCM theory

n.r. ())

TCM theory and authors’ clinical experience

(1) Impossible sitting (A : 6; B : 9) (2) Dry mouth (A : 6; B : 4) (3) Tremor (A : 5; B : 6) (4) Insomnia (A : 4; B : 9) (5) Blurred vision (A : 4; B : 4) (6) Dizziness (A : 3; B : 3) (7) Constipation (A : 3; B : 3) (8) Weight gain (A : 3; B : 0) (9) Nausea ⁄ vomiting (0 ⁄ 3) No severe adverse events (1) Palpitation (A : 6; B : 5) (2) Old myocardial infarction in EKG (A : 1; B : 2): not related with acupuncture (3) Aminotransferase elevation (A : 2; B : 3) (4) WBC change (A : 4; B : 3)

TE17, SI19, GB18, GB15, GV20, Tou Nie (Extra point, M-HN-9) and Ding Shen (Extra point) n.r.()) GV20 (tonification), GV24 through V23 (tonification), ST36, GB34, PC6, HT7, KI1 (left: balance tonification and sedation) Sishenchong (EX: tonification), Yintang (EX) through Xinqu (facial acupuncture: tonification), ST36, GB34, PC6, HT7, KI1 (right: balance tonification and sedation) GB20, BL23 (major points) n.r. ()) Yintang (EX), GV20, GV24, GV15 n.r.()) Yintang tou xinqu (Extra point), PC7, PC6, Taiyang (Ex-HN-5), ST36, SP6, ST40 n.r.()) GV20, GV23, Yintang (EX), SP6 (both), PC6(both) n.r.())

GV20, ST40, SI3, BL18 n.r.())

TCM theory


Adverse events

None (+)

n.r. ())

1629

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Table 2 (continued ) Acupuncture points used De-qi sensation

Rationale for selection of acupuncture points

Chen (2008) (21)

GV20, PC6(both), GV26, SP6 (both) n.r.())

TCM theory

Liu (1986) (22)

TE21 (both) n.r.())

Authors’ previous study and channel theory

Zhang (1991) (23)

GV14, GV24, Taiyang (EX; both) n.r.())

TCM theory

First authors (year) (ref)

Adverse events

(1) Insomnia (A : 1; B : 5) (2) Myotonia (A : 1; B : 1) (3) Tremor (A : 2; B : 3) (4) Impossible sitting (A : 3; B : 5) (5) Blurred vision (A : 2; B : 2) (6) Sweating (A : 1; B : 0) (7) Palpitation (A : 0; B : 1) (8) Headache (A : 3; B : 1) (1) Heat sensation at the irradiated site and feeling of olugged auditory canal (A : 6; B : 0; C : 0) (2) Numbness over the ear, upper extremity and chest on the treated side (A : 1; B : 0; C : 0) Extra-pyramidal side effects (A : 0; B : 7; C : 8)

TCM, Traditional Chinese Medicine; n.r., not reported; EA, electroacupuncture; NADA, the National Acupuncture Detoxification Association.

superficial penetrating at non-acupuncture points plus risoperidone. The results showed statistically significant improvement of total score and physical subscale of PSYRATS-AH and PANSS after 4 and 6 weeks treatment.

Acupuncture vs. antipsychotic drugs Three RCTs (13,14) compared the effects of manual acupuncture with antipsychotic drug therapies, while one RCT (15) employed electroacupuncture. The meta-analysis showed a significant effect of manual acupuncture for response rate compared with antipsychotic drugs (n = 360, RR: 1.18, 95% CI: 1.03– 1.34, p = 0.01; heterogeneity: s2 = 0.00, v2 = 2.98, p = .39, I2 = 0%, Figure 2A). The other RCT, which employed EA, failed to show significant effects of EA on response rate compared with antipsychotic drug (15). One RCT (14) showed statistically significant effects of acupuncture on Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS) and Treatment Emergent Symptom Scale compared with drug therapy, but failed to show statistically significant effects of acupuncture on Scale for the Assessment of Positive Symptoms.

Acupuncture plus antipsychotic drugs vs. antipsychotic drugs Seven RCTs compared manual acupuncture or electroacupuncture with conventional antipsychotic drugs (14,16–21). The meta-analysis showed statistically significant effects of acupuncture for response rate compared with antipsychotic drug therapy (n = 457, RR: 1.15, 95% CI: 1.04–1.28, p = 0.008; v2 = 6.56, p = 0.36, heterogeneity: s2 = 0.00, 2 I = 9%, Figure 2B). Subgroup analyses also reported beneficial effects of electroacupuncture plus antipsychotic drug compared with antipsychotic drug alone (n = 365, RR: 1.19, 95% CI: 1.00–1.43, p = 0.05; heterogeneity: s2 = 0.01, v2 = 6.16, p = 0.19, I2 = 35%, Figure 2D) (17–21). There was no difference between the random effect model and the fixed effects model. Three RCTs (14,16,17) reported that BPRS significantly improved in the acupuncture plus antipsychotic drugs compared with antipsychotic drugs alone, whereas one RCT (18) found no differences between these two groups. The extent of statistical heterogeneity prevented a meaningful meta-analysis for four trials (n = 232, WMD: 9.92, 95% CI: 3.56–16.28, p = 0.002; heterogeneity: s2 = 36.70, v2 = 28.92, p < 0.00001, I2 = 90%). Subgroup



analyses also reported beneficial effects of EA plus antipsychotic drug on BPRS compared with antipsychotic drug alone (n = 140, WMD: 6.02, 95% CI: 2.53–9.51, p = 0.0007; heterogeneity: s2 = 1.18, v2 = 1.20, p = 0.27, I2 = 17%, Figure 2E) (17,18). All of the three RCTs reporting SANS found that the improvement of SANS was greater for AT plus antipsychotic drugs (14,16,17), which was confirmed by the meta-analysis (n = 192, WMD: 10.95, 95% CI: 8.22–13.69, p < 0.00001; heterogeneity: s2 = 0.00, v2 = 0.27, p = 0.87, I2 = 0%, Figure 2C). Subgroup analyses also showed beneficial effects of AT plus drug therapy on SANS compared with drug therapy alone (n = 92, WMD: 11.07, 95% CI: 8.16–13.98, p < 0.00001; heterogeneity: s2 = 0.00, v2 = 0.22, p = 0.64, I2 = 0%) (14,16).

Laser acupuncture vs. sham laser acupuncture Two RCTs (22,23) tested laser acupuncture with sham laser acupuncture. One RCT (22) found beneficial effects of laser acupuncture on the symptoms of hallucination, and the other RCT (23) showed statistically significant effects of laser acupuncture on response rate, BPRS and clinical global index compared with sham laser.

Discussion Few rigorous trials have tested the effects of acupuncture for schizophrenia. Our systematic review and meta-analysis provide suggestive evidence for the effectiveness of acupuncture alone or as an adjunct to conventional antipsychotic drug therapy in treating symptoms of schizophrenia compared with drug therapy alone. Other data suggest statistically significant effects of EA or laser acupuncture plus drug therapy compared with sham EA or laser acupuncture plus drug therapy. However, the total number of RCTs included in the analysis and the methodological quality was too low to draw firm conclusions about the effectiveness of this approach. Of the 13 RCTs, three trials were patient blind (12,22,23) and three studies were assessor blind (12,16,18). Eight further studies did not make any attempt at either subjects or assessor blinding. One RCT reported the concealment of treatment allocation (12). Trials with inadequate blinding and inadequate allocation concealment are likely to show exaggerated treatment effects (28). Most of the included trials also suffered from a lack of adequate allocation concealment and sufficient sample size to draw meaningful conclusions, with no power analysis included. Three RCTs (12,22,23) employed a sham control procedure. But the authors failed to check the success of blinding. One RCT used superficial needling

penetrating on non-acupuncture point without electrical stimulation for sham control. The other two RCTs used sham laser acupuncture without radiation for the placebo controls. If subjects experienced less electrical sensation or heat after the intervention, they may have been able to detect the sham as being different from real electric or laser acupuncture. To reliably account for the placebo effect, it is crucial for the sham procedure to be indistinguishable from the real treatment. Therefore, the success of the blinding procedures should be assessed, reported and accounted for. Needle stimulation causing a typical needle sensation has been claimed to be important for reaching maximum effects (29,30). This needle sensation (de-qi) was considered in two RCTs (12,14), whilst the others did not report such details. The interaction between antipsychotic medication and acupuncture needs further consideration. None of the trials reported on the reduction or the possibility of reduction in antipsychotic medication because of the effects of acupuncture. This is significant in light of case study evidence that illustrates the potential for this effect, especially in resistive schizophrenia (31,32). It might also be of importance in terms of co-ordination of antipsychotic dosage with acupuncture, as it is clear in the study conducted by Zhou et al. (18). Here, the dose of antipsychotic medication was reduced from the outset of the intervention for the treatment group. Results for the effect of acupuncture on positive and negative symptoms of schizophrenia were far less than in similarly conducted studies without this reduction. The dosage of antipsychotic medication was adequate and within the normal range in experimental and control group. Culture specific assessment and diagnosis of schizophrenia might continue to be an issue in these studies. Although the CCMD 2 has been found to have a reasonably high correlation with ICD10 and DSM IV, there are still discrepancies, including for schizophrenia. An obvious one might be the use of the term ‘hebetic type’ as a diagnostic category (14) which is not recognised in either DSM or ICD. An explanation for this may be found through examination of the list of the various occupations of the participants in the studies. These include farmers, teachers, government employees and manual workers (22). In many Western countries, it would be unusual for people with schizophrenia to be in employment or functioning on a professional level (33,34), which might raise some questions about assessment and diagnostic differences. Another concern is that ethical approval was not reported in any of the included trials. Considering the importance of protecting patients’ rights, Chinese


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acupuncture researchers must develop an awareness of ethical issues similar to their awareness of other aspects of research work. Moreover, their reporting of clinical trials should follow CONSORT procedures (35). All of the included RCTs originated from China. It is therefore relevant to mention that Vickers et al. (36) have shown that not a single acupuncture study from China has ever reported negative results. In our view, this phenomenon further limits the possibility of drawing reliable conclusions from this meta-analysis. Previous studies have shown that approximately a 10 ⁄ 15 points difference of the BPRS ⁄ PANSS means minimal improvement according to the CGI (37,38). The changes of BPRS ⁄ PANSS were more than 10 ⁄ 15 in acupuncture groups in all of the trials, which had data available for each scale, and this is clinically significant. Even though it is higher than that of antipsychotic drug therapy, this still needs to be confirmed in further trials with larger samples. One argument for using acupuncture for the management of schizophrenia might be that it causes fewer adverse effects than drug treatment. Nine RCTs (12–14,19–23) assessed adverse events of acupuncture treatment and four RCTs did not. No severe adverse effects of acupuncture were noted. Relative to those of standard drug treatment, adverse effects of acupuncture are not severe, infrequent and perhaps even negligible (39). Assuming that acupuncture was beneficial for treating schizophrenia, possible mechanisms of action may be of interest. These include stabilisation of autonomic and sympathetic nervous systems. It is also suggested that acupuncture can influence cortical activation and the responsiveness of the reticular activating system to stimuli and possibly reduce level of arousal (8). Others have postulated that acupuncture could normalise the release of dopamine via serotonin neurons in the hypothalamus (40). None of these theories is, however, currently fully established. Our review has a number of important limitations. Although strong efforts were made to retrieve all RCTs on the subject, we cannot be absolutely certain that we succeeded. Moreover, selective publishing and reporting are other major causes for bias, which have to be considered. It is conceivable that several negative RCTs remained unpublished and thus distorted the overall picture (41–43). Most of the included RCTs that reported positive results come from China, a country which has been shown to produce no negative acupuncture studies (36). Further limitations include the paucity and the often suboptimal methodological quality of the primary data. In

total, these facts limit the conclusiveness of this systematic review considerably. In conclusion, the results of our systematic review and meta-analysis provide limited evidence for the effectiveness of acupuncture in treating symptoms of schizophrenia. However, the total number of RCTs included in the analysis, and the total sample size and their methodological quality were too low to draw firm conclusions about the effectiveness of this approach. Further rigorous RCTs are warranted but need to overcome the many limitation of the current evidence.

Acknowledgement The authors specially thank Kate Boddy in Peninsula Medical School, Universities of Exeter & Plymouth, Exeter, UK for editing this manuscript.

Funding M. S. Lee was supported by the Acupuncture, Moxibustion and Meridian Research Project of Korea Institute of Oriental Medicine (K09050).

Author contributions Myeong Soo Lee designed the review, performed searches, appraised and selected trials, extracted data, contacted authors for additional data, carried out analysis and interpretation of the data and drafted this report. Byung-Cheul Shin performed Chinese literature searches, appraised and selected trials, extracted data, assisted interpretation of the data. Patricia Ronan reviewed and critiqued the review this report and assisted interpretation of the data. Edzard Ernst reviewed and critiqued the review protocol, the report, assisted in designing the review.

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Paper received May 15, 2009, accepted July 1, 2009


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