Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention

Journal of Affective Disorders ] (]]]]) ]]]–]]]

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Research report

Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention$ Im Quah-Smith a,n, Caroline Smith b, John D. Crawford c, Janice Russell d a

School of Psychiatry University of New South Wales, NSW 2052, Australia Centre for Complementary Medicine Research, University of Western Sydney, NSW 2751, Australia c Brain & Ageing Research Program School of Psychiatry Faculty of Medicine University of New South Wales, NSW 2052, Australia d Royal Prince Alfred Hospital School of Psychiatry Faculty of Medicine University Of Sydney, NSW 2006, Australia b

a r t i c l e i n f o

abstract

Article history: Received 4 June 2012 Received in revised form 26 November 2012 Accepted 27 November 2012

Introduction: Trials of acupuncture for the treatment of depression have produced mixed results. We examined the effectiveness of laser acupuncture compared with placebo acupuncture for the treatment of major depression. Methods: A randomised, double blinded, placebo controlled trial was conducted in Sydney, Australia. Participants aged 18–50 years with DSM-IV major depressive disorder were eligible to join the study. Forty-seven participants were randomised to receive laser acupuncture or placebo laser at acupoints LR14, CV14, LR8, HT7 and KI3. The intervention was administered twice a week for 4 weeks and once a week for another four weeks, for a total of 12 sessions. The primary outcome assessed the change in severity of depression using the Hamilton-Depression Rating Scale (HAM-D), and secondary outcomes assessed the change in severity of depression using the Quick Inventory for Depression-Self Reporting (QID-SR), the Quick Inventory for Depression-Clinician (QIDS-CL), with outcomes assessed at eight weeks. The treatment response (greater than 50% improvement in HAM-D) and remission (HAM-D o 8) were analysed. Results: At eight weeks participants showed greater improvement in the active laser group on the primary and clinician-rated secondary outcome measures (HAM-D (mean 9.28 (SD 6.55) vs. mean 14.14 (SD 4.78 p o 0.001); QIDS-CL (mean 8.12 (SD 6.61 versus 12.68 (mean SD 3.77)) po 0.001). The selfreport QIDS-SR scores improved in both groups but did not differ significantly between the groups. In the active laser group, QIDS-SR scores remained significantly lower than baseline at 3 months followup. Response rates (active laser, placebo laser) on ITT (intention to treat) analyses were 72.0% and 18.2% (p o 0.001), respectively. Remission rates on ITT analyses (active laser, placebo laser) were 56.0% and 4.5% (po 0.001). Transient fatigue was the only adverse effect reported. Limitations: There was no follow-up for the placebo group at one and 3 months. Conclusion: Laser acupuncture showed a clinically and statistically significant benefit with reducing symptoms of depression on objective measures. & 2012 Elsevier B.V. All rights reserved.

Keywords: Laser acupuncture Depression Randomised controlled trial

1. Introduction Clinical depression has been identified as one of the top health priorities worldwide. The World Health Organization quantifies unipolar depression as the fourth leading cause of total disease burden worldwide (Lopez, 2005). In addition to lost productivity, depression has a major impact on the quality of life of the sufferer. In spite of growing community awareness and attempts to destigmatise depression, 60% of the depressed population avoids professional help, seeking only symptomatic relief. Of the $ Trial registration: Australian New Zealand Clinical Trials Registry ANZCTR #12610000340033. n Corresponding author. Tel.: þ61 2 94174772; fax: þ61 2 94755035. E-mail address: [email protected] (I. Quah-Smith).

remainder, less than half receive evidence-based care (Ellis and Smith, 2002). Many patients with depression either refuse antidepressant drugs or discontinue them owing to side-effects, and turn to complementary and alternative medicines (CAMs) (MacPherson et al., 2006). The latter are perceived as being ‘‘natural’’, holistic, free of adverse effects and more nurturing than standard medical therapies. Amongst CAMs, herbal remedies such as St John’s Wort and acupuncture are two of the most popular therapies (Kessler et al., 2001; Jorm et al., 2002). Recent evaluation of the use of pharmacotherapy in depression found that only 7% of patients remitted on antidepressants (Pigott et al., 2010). The majority discontinued due to adverse effects. There was also concern that, for those who continued pharmacotherapy, the adverse effects actually increased the placebo response (Pigott et al., 2010). This sobering report raises concerns for the future

0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2012.11.058

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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management of major depression in the community. There is therefore some urgency to evaluating non-drug treatments of depression. There been much clinical interest in acupuncture for the treatment of depression over the last decade, with the current scientific evidence base being inconclusive. Four systematic reviews (Mukaino et al., 2005; Leo and Ligot, 2007; Halbreich, 2008; Smith et al., 2010) found acupuncture to be no more effective than sham or waitlist control strategies. The efficacy of acupuncture as an adjunct to standard treatment is also unclear. Methodological issues have plagued many of these investigations. There are many acupuncture techniques, most of which traditionally use needle puncture. However there are other modalities utilised such as acupressure and low intensity laser. Laser acupuncture (LA) has emerged as a well-accepted technique due to its ease of application, and being both needle and painfree, it is non-invasive and presents no risk of infection. Laser is an acronym for Light Amplification by Stimulated Emission of Radiation. In brief, the chosen lasing medium (in this study, this is a semiconductor made from gallium–aluminiumarsenide or GaAlAs) is excited by an external energy source (battery pack consisting of AA alkaline batteries) to a higher energy state and a portion of this is released as the laser output from the laser unit (Baxter, 1994). The laser output is usually measured in milliwatts in low intensity laser acupuncture units. Being pain-free and non-invasive, low intensity laser lends itself to clinical applications in paediatrics. LA in the treatment of children with headaches significantly reduced the number of headache days (p o0.001) with active laser compared to placebo laser (p o0.22) (Gottschling et al., 2008). LA to acupoint PC 6 also significantly reduced postoperative vomiting in children undergoing strabismus surgery (Schlager et al., 1998) and when this modality was used in school age children with asthma, there were significantly less days of febrile infections and reduction in bronchial hypersensitivity (Stockert et al., 2007). An earlier study on low intensity laser (with lasing medium GalAlAs) described the relationship between pain attenuation and significant change (po0.001) in serotonin plasma ratios after laser application (Mizokami et al., 1993). Endogenous opiate like peptides and serotonin plasma levels were found to increase with laser puncture analgesia (Zhong et al., 1989). There has been one pilot laser acupuncture study (Quah-Smith et al., 2005) that reported LA as efficacious compared to placebo laser (PA) (p o0.001) in the treatment of mild to moderate depression in a primary care setting, and the treatment response persisted for 3 months following laser intervention (p o0.01). This improvement in mood was more significant at the end of the series of LA, with data showing only a trend for improvement at 4 weeks post LA and then was very significant again at 12 weeks post LA. This fluctuation may be attributable to, possibly, a delay before the longer- term effect of acupuncture (in this case, mood improvement) was evident (Quah-Smith et al., 2012). There were no significant adverse effects. It has also been shown, using functional magnetic resonance imaging (fMRI), that LA produces significant activation and deactivation in fronto-limbic-striatal brain regions compared to placebo (Quah-Smith et al., 2010). In this study, we examined the efficacy of acupuncture with reducing the symptoms of depression compared with a placebo control Fig. 1.

2. Methods A double blinded, randomised, placebo controlled clinical trial was undertaken at the Black Dog Institute and a private acupuncture clinic in Sydney, Australia. Participants were recruited from

the media and online advertising. Individuals aged 18–50 years were eligible to join the trial if they were diagnosed with major depressive disorder meeting DSM-IV (American Psychiatric Association, 1993) criteria for current major depression, a score of Z14 on the Hamilton Depression Rating Scale (HAM-D17) (Hamilton, 1960), and a score 4 10 on the Quick Inventory of Depressive Symptomatology – Clinician (QIDS-CL) and Quick Inventory of Depressive Symptomatology – Self Reporting (QIDS-SR) (Rush et al., 2003). Participants needed to be free of psychotropic drugs and herbal remedies for at least four weeks prior to trial entry, and no co-interventions were permitted during the trial. Participants were not eligible if the duration of depression was greater than two years, or there was a history of hypomania or mania, substance abuse disorders, known central nervous system lesions, known uncontrolled endocrine disorders, pregnancy or potential pregnancy, or active suicidal tendencies. Suitability was confirmed by clinician screening. Participants provided written informed consent and the study was approved by the Human Research Ethics Committee of the University of New South Wales (HREC No. 07258). Following recruitment, participants were randomised to either laser acupuncture (LA) or placebo acupuncture (PA). Randomisation was computer-generated. Only the project manager (JAH) was privy to this sequence to allow allocation of participants to LA or PA. Switch ‘A’ or ‘B’ was identified for each participant and this was kept in an envelope in each participant’s folder (identifiable by the recruitment code alone of initials and recruitment number). The medical acupuncturist was not allowed access to each participant’s folder. All participants received treatment at selected putative ‘depression’ acupoints (unilateral right sided Qimen LR14, Juque Ren14, left sided Ququan LR8, left sided Shenmen HT7) and unilateral (right side) Taixi KI3. Twelve sessions of the intervention were performed: twice weekly for four weeks and once a week for another four weeks. The choice of acupoints administered to both groups included – Qimen LR14, Ququan LR8, Juque CV14, Shenmen HT7 and Taixi KI3 – was based on the principles of TCM (Macioca, 1994; Aung and Chen, 2007), No TCM differential diagnosis was undertaken as the selected acupoints have been trialled successfully in our pilot study (Quah-Smith et al., 2005). Qimen LR14 and Juque CV14 are ‘‘alarm points’’ empirically known to act rapidly. LR14 and LR8 are useful in mood disorders and stressful states. CV14 is useful where somatic changes occur including pectoral pain, headaches, epigastric pain and nausea. HT7 is a classical acupoint used to calm the individual and help in insomnia. KI3 is useful for addressing fatigue and reducing anxiety. KI3 replaced CV15 in the pilot study, for the purposes of treating the anxiety component found in 85% of depressives (Tiller, 2012). Empirically, CV14 is used more frequently than CV15 and the former is the ‘‘alarm point’’ as previously mentioned on the Heart meridian (Aung and Chen, 2007). This clinical study is part of a series of clinical and biological investigations into LA in depression: KI3 on the right had side was treated and LR8 on the left hand side so laterality could be tested (whether acupoint stimulation with LA activates ipsilateral or contralateral brain regions) in our associated functional magnetic resonance (fMRI) investigations mentioned above (Quah-Smith et al., 2010, 2012). Acupoint location followed the guidelines documented by the World Health Organisation were applied (World Health Organization, 2008). IQS administered the LA: she is a Fellow of the Australian Medical Acupuncture College and has been teaching and practising acupuncture for 21 years. For those receiving LA, 100 mW low intensity infra red (808 nm) units were produced, based on the MoxlaR protocol, by Advantage Health Care, Victoria, Australia for this study. The

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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Assessed for eligibility n=306

Excluded Did not meet inclusion criteria n=259

Randomised n=47

Allocated to laser acupuncture n=25 Received acupuncture n=25

Allocated to placebo laser n=22

Discontinued intervention n=3

Discontinued intervention n=1

Expectancy and Belief, QID-SR at baseline 2 x week for 4 weeks Repeat QID-SR 1 x week for 4 weeks Post LA QID-SR, QIDCL, HAM-D, adverse effects questionnaire HAM-D, QID-CL, QIDSR Completed the study n=22

Expectancy and Belief QID SR at baseline 2 x week for 4 weeks Repeat QID-SR 1 x week for 4 weeks Post LA QID-SR, QIDCL, HAM-D, adverse effects questionnaire HAM-D, QID-CL, QIDSR Completed the study n=21

Fig. 1. Recruitment and participant flow through the trial.

laser beam is infra-red in frequency range (808 nm) and is not visible to the naked eye. The laser probe is fully in contact (perpendicular to the skin surface) to avoid scatter of the laser beam. Both laser units had a concealed section with a flick switch numbered by the manufacturer as ‘A’ and ‘B’, one of which was the placebo option, known only to the project manager (JAH) and the manufacturer. The control panel of the laser units beeped and a red light flashed when the laser probe button was on either A or B. Each unit was separately set up for placebo or laser options. None of the participants reported any sensation apart from a light touch of the laser probe when it was applied to the skin. The flick switches were concealed with wide fabric strip (velcrose)

bands. The prepared unit was handed to the medical acupuncturist at the time of treatment and retrieved immediately after. The laser was applied to each acupoint for 10 s to deliver one joule of laser energy at each acupoint, giving a total of 5 J for 5 acupoints per session. For those in the placebo group the laser infra- red beam did not come on when the switch was pressed. Each participant wore black lensed laser protective glasses supplied by the manufacturer and was treated in a brightly lit environment. The laser probe was in direct contact with the participant’s skin surface perpendicularly before commencement of laser delivery. The participants and acupuncturist were blind to group allocation.

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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The primary endpoint was measured at the 2 months mark after the last treatment (HAM-D). Secondary endpoints were measured at the one month mark (QID-SR), at the two months mark after the last treatment (QID-SR, QID-CL), one month post treatment (QID-SR) and three months post treatment (QID-SR). The primary outcome measured a reduction in the severity of depression defined as a 450% reduction in score, of the 17-item HAM-D. The secondary outcome measured remission at the end of treatment defined as a score of r7 on HAM-D or r5 on QIDSCL and QIDS-SR. The structured interviews for rating were conducted by trained clinicians blind to group allocation. Inter-rater reliability of the rating clinicians was high prior to trial commencement. Practice ratings were conducted to ensure reliability. The raters were (MH designated main rater), IQS (for emergencies) and for screening only, JAH.) We evaluated the baseline expectations and beliefs of the participants and whether there might be any contributory bias (positive effect) to their scores, using a self report 6-item Expectancy and Belief scale, adapted from the University of Michigan study on acupuncture and fibromyalgia (Harris et al., 2005). Upon completion of the 12 sessions of acupuncture, JH asked all participants to complete a 6-item scale with score range of 0 to 6 (6 being maximum intensity) to assess any adverse effects:1. dizziness, 2.aches, 3.transient fatigue, 4.prolonged fatigue, 5.vagueness, and 6.nausea). An assessment of blinding was made from each participant and the medical acupuncturist. The results of the pilot study showed a large effect size (Cohen’s d) of approximately 0.90, based on differences between the placebo and active groups in the change in the Beck Depression Inventory (BDI) scores (Beck et al., 1961). To detect a similar effect size for measures used in the present study, with power of 80% and a ¼ 0.05, we estimated that a total sample of 44 participants would be required, assuming approximately equal number of participants in placebo and active groups. The analysis was carried out by JC. Repeated measures ANCOVA was used to examine differences between the active and placebo groups in changes in the HAM-D, QIDS-CL and QIDSSR measures. Control variables were age, sex and expectancy. The Expectancy variable was calculated as the first principal component (Question1: ‘‘In general, do you think acupuncture works?’’) of the six expectancy items and was rated from 1 (very negative) to 7 (very positive). The remaining 5 questions in the Expectancy and Beliefs Questionnaire were rated 0% to 100% by the participants: (Questions 2: Do you want LA to improve your mood and help your depression; Question 3: Do you want LA to help your general wellbeing: Question 4: How confident are you that LA will improve your mood; Question 5: How confident are you that it will improve your fatigue; Question 6: How confident are you LA will alleviate your other symptoms for (physical complaints).). Mean values were calculated for Questions 2 to Question 6. Per-protocol analyses were performed using only those participants with both pre- and post-treatment ratings, as well as Intention to Treat (ITT) analyses in which last observed value carried forward for missing post-treatment ratings. In order to better understand which domain of depression was most affected by the laser acupuncture intervention, the repeated measures ANCOVA was also performed with each of the items in HAM-D and QIDS-CL as dependent variables. Only the clinician based assessments were selected for the latter analysis in order to better evaluate items such as somatic symptoms, psychomotor agitation and retardation, as well as general interaction. Response and remission rates based on HAM-D and QIDS scores at post-test were calculated. Remission was at HAM-Do8 or QIDS-CLo6 and QID-SR o6 (Insel, 2006). The statistical significance of differences between active and placebo groups in response and remission rates were investigated using the chi-squared test. Number-

needed-to-treat (NNT) values were calculated for remission rates. An assessment of blinding was examined using the Chisquare test.

3. Results Recruitment commenced in mid-August 2007 and continued until the end of August 2009. In total, 306 potential participants were assessed for eligibility. The majority of those excluded had chronic depression of more than 2 years or were on antidepressant therapy and did not wish to stop their medication. Fortyseven were randomised. Twenty-two recruited subjects completed laser acupuncture (LA) and 21 completed the placebo acupuncture (PA). There were four dropouts (LA 3; PA 1). The reasons for dropout were: LA group—one participant withdrew after 2 weeks LA, the subject felt her mood was not improving and may be deteriorating and chose to return to pharmacotherapy, one was unable to keep up attendance and withdrew, and the last completed the series of LA but was too unwell to continue with post LA QID-SR. The dropout in the PA group withdrew for personal reasons after completing the treatment series. The baseline characteristics are presented in Table 1. Thirtyfour participants were female (72%), thirty-five were working (74%). Twenty-six (55%) had previously sought needle acupuncture treatment. Participants had clinically significant depression with a DSM-IV diagnosis of major depressive disorder and were drug free or drug naive at the time of their entry into the trial. Clinical depression scores included mean scores on the HAM-D of 20.03 (SD 4.2), QIDS-CL 20.6 (SD 4.3), and QIDS-SR 18.40 (SD 4.6). Twenty-seven participants reported duration of depression of greater than three months (57%), and thirty-two reported a previous episode of depression (68%). No statistically significant differences between LA and PA were found at baseline. There was no statistical difference between groups for expectancy (p ¼0.412). All participants completed all scheduled intervention sessions. In addition to the baseline characteristics, mean values for the remaining questions in the expectancy and belief questionnaire were: wanting LA to help their depression (92.0%), wanting LA to help their general wellbeing (42.7%), confident that LA will improve their mood (30.5%), confident that LA will alleviate their fatigue (28.8%) and confident that LA will alleviate all their other physical complaints (28.0%). 3.1. Treatment effects Table 2 Statistically significant group by occasion interactions were found with both per-protocol and ITT analyses for HAM-D (P¼ 0.001 and 0.013, respectively) and for QIDS-CL (P¼ o0.001 and 0.016). For QIDS-SR, although there was an overall statistically significant decrease in depression scores over time (F1, 39¼4.63, p¼ 0.038 and F1, 42 ¼0.013, respectively), there were no differences between groups (P¼0.571 and 0.390). In these analyses, no statistically significant interactions with occasion were observed with any of the control variables, sex, age or expectancy, except for the per-protocol analysis for changes in QIDS-CL, in which greater reductions in scores were found for those with higher expectancy scores (F1, 38¼ 5.61, p¼ 0.023). 3.2. Ancillary analyses In the analyses of depression symptoms HAM-D item-by-item analyses, five items showed statistically significant group by occasion interactions, after controlling for age, sex and expectancy. These were: depressed mood (P¼0.044), late insomnia

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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Table 1 Baseline characteristics of participants. Laser acupuncture group

Placebo laser group

N

N

Mean (SD)

Mean (SD)

t

p

Age in years

25

40.08 (9.37)

22

36.27 (10.13)

1.34

.187

Expectancy

25

 0.11 (1.19)

22

0.13 (0.74)

0.82

.412

N

n (%)

w2 (d.f.)

pa

1.566 (1)

.328

3.623(2)

1.000

0.011 (1)

1.000

1.103 (2)

1.000

5.294 (3)

1.000

1.607 (1)

.230

0.341 (3)

1.000

0.899 (1) 0.563 (1)

1.000 .710

2.520 (2)

1.000

N Sex (female)

25

Marital status: Never married Married Divorced/separated

25

Career status (active)

25

Education Completed secondary Completed tertiary Currently studying

25

Employment status Full time Part time Home duties Unemployed

25

Depressions diagnosis

25

How long depressed this time? Less than 3 months 3 to 6 months 6 to 12 months More than 12 months

23

Medication for depression Herbs for depression Other medications

25 25 25

Type of previous acupuncture Needle Laser Both needle and laser

12

a

n (%) 20 (80.0%)

22

14 (63.6%)

22 12 (48.0%) 11 (44.0%) 2 (8.0%)

15 (68.2%) 4 (18.2%) 3 (13.6%)

19 (76.0%)

22

17 (77.3%)

22 5 (20.0%) 17 (68.0%) 3 (12.0%)

3 (13.6%) 14 (63.6%) 5 (22.7%) 22

10 9 2 4

(40.0%) (36.0%) (8.0%) (16.0%)

14 2 3 3

15 (60.0%)

22

(63.6%) (9.1%) (13.6%) (13.6%)

17 (77.3%)

22 9 4 4 6

(39.1%) (17.4%) (17.4%) (26.1%)

9 3 3 7

1 (4.0%) 0 (0.0%) 6 (24.0%)

22 22 20

(40.9%) (13.6%) (13.6%) (31.8%)

0 (0.0%) 0 (0.0%) 3 (15.0%)

16 12 (100.0%) 0 (0.0%) 0 (0.0%)

13 (81.3%) 2 (12.5%) 1 (6.3%)

p values derived from Fisher’s Exact test.

Table 2 Baseline and post-treatment values on HAM-D and QID measures by treatment group. Placebo laser N

Baseline mean (SD)

Laser acupuncture

F(df1, df2))

p

.001 .0003 .571

Post-treatment mean (SD)

N

Baseline mean (SD)

Post-treatment mean (SD)

Per-protocol analyses HAM-D 21 20.71 (3.38) QID-CL 21 20.57 (4.87) QID-SR 21 18.57 (5.26)

13.48 (3.74) 12.24 (3.22) 10.67 (4.48)

22 22 23

20.98 (3.62) 20.68 (4.03) 17.91 (4.35)

7.64 (4.94) 6.55 (5.27) 11.22 (6.67)

14.44 (1.38) 15.78 (1.38) 0.33 (1.39)

ITT analyses HAM-D 22 QID-CL 22 QID-SR 22

14.14 (4.78) 12.68 (3.77) 10.55 (4.41)

25 25 25

21.02 (3.51) 20.56 (3.84) 18.20 (4.28)

9.28 (6.55) 8.12 (6.61) 12.04 (7.00)

6.69 (1.42) 6.25 (1.42) 0.75 (1.42)

21.05 (3.65) 20.64 (4.77) 18.64 (5.14)

.013 .016 .390

F and p values are for statistical tests for interactions between group and occasion, with control variables age, sex and Expectancy. 17-item Hamilton-Depression Rating Scale HAM-D; Quick Inventory for Depression-Self Reporting QIDS-SR; Quick Inventory for Depression-Clinician QIDS-CL.

(P¼0.014), anorexia (P ¼ 0.035), somatic symptoms (P ¼0.00021), somatic anxiety (P ¼ 0.013) and agitation (P ¼0.035). [Supplementary Table 1]. In the QIDS-CL, five items with significant group by occasion interactions. These were: waking up too early (p ¼0.002), increased or decreased appetite (p ¼0.002), view of self (p ¼0.042), general interest (p ¼0.007) and energy level (p ¼0.021). After Bonferroni’s correction for multiple comparison, somatic symptoms (heaviness in limbs, back and head; backache, headache and muscle aches; loss of energy and

fatigability) were still highly significant (p ¼0.00021). [Supplementary Table 1]. Statistical analyses were undertaken to ensure there was no significant difference between raters. Statistical analyses were undertaken on pre- and post-LA-treatment scores only. In the rater comparisons, there was a constant trend for MH to rate lower than QS but the only statistically significant difference was for pre treatment QID-CL (means 18.17 and 21.13, p ¼0.041) [Supplementary Table 2].

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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Table 3 Response and remission rates, and numbers needed to treat (NNT) for per-protocol and intention to treat (ITT) analyses by treatment group. Placebo laser n/N (%)

Laser acupuncture n/N (%)

w2 (df¼ 1)

P

NNT

Per-protocol analyses HAM-D 450% reduction HAM-D o8 at post-test QID-CL o 6 at post-test QID_SR o6 at post-test

4/21 1/21 0/21 1/21

(19.0%) (4.8%) (0.0%) (4.8%)

18/22 14/22 12/22 5/23

(81.8%) (63.7%) (54.5%) (21.7%)

18.94 16.40 15.89 2.69

.00005 .00005 .00006 .188

1.59 1.70 1.83 5.89

ITT analyses HAM-D 450% reduction HAM-D o8 at post-test QID-CL o 6 at post-test QID_SR o6 at post-test

4/22 1/22 0/22 1/22

(18.2%) (4.5%) (0.0%) (4.5%)

18/25 14/25 12/25 5/25

(72.0%) (56.0%) (48.0%) (20.0%)

13.61 14.26 14.18 2.51

.0004 .0001 .0001 .194

1.86 1.94 2.08 6.47

Hamilton-Depression Rating Scale (HAM-D17); Quick Inventory for Depression-Self Reporting (QIDS-SR); Quick Inventory for Depression-Clinician (QIDS-CL).

3.3. Treatment response rate, treatment Effects on remission Rates, and Numbers needed to treat (Table 3) Response rates ( 450% reduction in HAM-D scores) were 81.8% in the active group and 19.0% in the placebo group (p o0.001) for the per-protocol analysis, and for the ITT analyses these were 72.0% and 18.2% (po0.001), respectively. The numbers needed to treat (NNT) to achieve a response over 8 weeks of LA were 1.59 for per-protocol analysis and 1.86 for the ITT analysis. Remission rates were significantly different between the two groups based on a criteria of HAM-D o8 or QIDS-CLo6, for both per-protocol and ITT analyses (p o0.001), but not based on a criteria of QIDSSR o6 (p ¼0.188 and 0.194). For HAM-Do8 criteria, remission rates in the active group were 63.7% and 56.0% for the two types of analyses, and for the placebo group, 4.8% and 4.5%. Based on the criterion of QIDS-SR o6, remission rates in the active group were 21.7% and 20.0%, and in the placebo group 4.8% and 4.5%, respectively. NNT for remission based on the HAM-Do8, QIDSCLo6 and QIDS-SR o6 criteria were 1.70. 1.83 and 5.89, respectively, for the per-protocol analyses, and 1.94, 2.08 and 6.47, for the ITT analyses, respectively Table 3.

3.4. Follow up at one and three Months post treatment for laser acupuncture group QIDS-SR follow-up scores were obtained for the laser acupuncture group at one month (n ¼18), and at 3 months after study completion (n ¼16). Repeated measures ANCOVA, controlling for age, sex and expectancy, showed statistically significant differences between pre-test scores and each of end of LA, and 1-month post LA and 3 months post LA follow-up scores (all P¼0.001). No statistically significant differences were found between the post-test and 1 and 3 months QID-SR scores.

3.5. Integrity of blinding The percentage of participants in the active group that offered guesses ‘active’, ‘placebo’ and ‘unsure’ were 65.2%, 30.4% and 4.3%. For participants in the placebo group, the corresponding percentages were 60.0%, 30.0% and 10.0%. These differences were not statistically significant between groups (Chi-square¼0.537, df ¼2, p ¼0.765). Overall, the acupuncturist’s patterns of response for the three options (active vs. placebo vs. unsure) were evenly distributed with no significant difference in proportion of guesses (Chi-squared¼ 0.125, df ¼1; p ¼0.723).

3.6. Adverse effects There were no significant inter-group differences in adverse effects. Out of a maximum score of 6, the only adverse effects with mean scores 40.50 were: in the LA group, minimal transient fatigue (0.67); and in the PA group, aches (0.11), transient fatigue (1.0), days of fatigue (0.71) and vagueness (0.52).

4. Discussion This is the first adequately sized double blind controlled trial of LA in depression. LA was associated with a clinically and statistically significant reduction in HAM-D scores, and a significant number of patients with major depression responded or remitted on this measure after 8 weeks of treatment. This result was supported by analysis of the secondary clinician-rated measure, but not by the self-rated measure. Although this positive effect was found in the earlier pilot study at 3 months post LA compared to PA (as recorded using the self reporting Beck Depression Inventory Scale (BDI)), we cannot make any conclusive comments that this was the case in this study. In the LA group, the positive effect was still measurable at the third month post treatment (QID-SR po0.001 compared to baseline) but we did not follow up the QID-SR in the PA group after completion of intervention due to our ethical responsibility (a condition of our ethical approval) to break the blinding and offer the PA group active laser upon completion of intervention. Clinician ratings at the 3-month post treatment mark, which were not carried out due to resource limitations, would have overcome this limitation. There were no significant adverse effects of LA. The results of this trial must be examined in light of the accumulating literature on acupuncture in depression. A recent Cochrane Review (Smith et al., 2010) examined 30 trials of acupuncture in depression and concluded that the evidence of the effectiveness of acupuncture in depression, relative to sham acupuncture, was inconclusive. The majority of trials compared acupuncture with drug treatment and found no group differences. Two trials found acupuncture to have an additional beneficial effect when co-administered with medication. Most studies used either manual acupuncture or electro-acupuncture, with the exception of one small study that examined laser acupuncture (Quah-Smith et al., 2005), the latter finding LA to be superior to placebo in its anti-depressant effect. There are three possible explanations to justify the large clinical effect observed in this trial. First, the double blind study design allowed an evaluation of the efficacy of laser acupuncture compared with a placebo and therefore reduced the potential for effects arising from the use of

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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active sham points seen in manual acupuncture studies. Our findings have been supported by our fMRI study (Quah-Smith et al., 2005) on healthy subjects where we demonstrated significant brain activation patterns greater than rest or placebo with active laser. Second, there was a significant improvement in the debilitating somatic changes that accompany depression including somatic symptoms (muscle aches and pains, headaches, digestive changes), and sleep patterns. Consequently participants’ quality of life improved. Third, there were little or no adverse effects using the low intensity laser. This clinical study returned a transient mild fatigue (for only a few minutes after each laser session which appeared and resolved within the couple of hours after the laser intervention). The lack of significant inter-group difference in the self-report measure in our study is worthy of comment. The high expectancy of being in the LA group by all subjects (60% in both LA and PA groups thought they were in the LA group when asked by JH which group they were in upon completion of the intervention) may be a factor. Also at baseline, the mean Expectancy Score for wanting LA to improve their mood and help their depression (Question 2) by all the subjects was very high (mean score of 92%). This desire for LA to work did not, however, carry through to wanting LA to help their wellbeing (42.7%), confidence their mood will improve (30.5%), confidence their fatigue will get better (28.8%) nor alleviate other physical symptoms they might also have (28.0%). Another factor may be that the HAM-D and QID-CL rated different items of depression to the QID-SR and the acupuncture effect in depression is better measured by the first two scales. We did not foresee that changing the self-rating instrument from BDI in our pilot study to the QID-SR in this study would be of concern. Unfortunately, this was not the case. The BDI correlated well with the HAM-D in the assessment of depression (Schotte et al., 1997; Hotopf et al., 1998; Kim et al., 2009). For this reason, we used the BDI as the primary measure in the pilot study as we did not then have the resources to use the HAM-D. Our finding in the pilot study that the change in score for BDI from baseline was significant (p o0.001) in the LA group has been replicated in this study with the change in score of the HAMD (p o0.001). Our secondary measure in the pilot study, the Hospital Anxiety and Depression Scale (HADS) did not record this significant improvement at all (Zigmund and Snaith, 1983). Upon further evaluation at the item-by-item level, we examined items of depression in the HAM-D, the BDI (as it was our primary measure in the pilot study) and the QID-SR: the HAM-D measured somatic changes (Questions 8, 9, 13) and the QID-SR had no clearly defined somatic symptoms questioning. Irritability is measured in the HAM-D (Question 12) and interestingly, also by the BDI (Question 11) in the pilot study, but does not feature as an item in the QID-SR. Although psychomotor agitation is measured by all three instruments, psychomotor retardation is only measured by the HAM-D (Question 16). Furthermore, the QIDS-SR did not correlate well with its sister scale the QIDS-CL in this study and the primary measure the HAM-D, while the latter two correlated well. The somatic items (Q 3,Q 6,Q 7,Q 14 in QIDS-CL) (Supplementary Table 1) were found to show a significant change in LA; these items were measures of pain, appetite, speech and agitation, which are possibly better assessed by a clinician. In the QIDS-CL, improvement in sleep (Q 1) and appetite (Q 7) were greater in the LA group. These differences may be attributed to laser acupuncture induced somatisation effects as described previously, including autonomic modulation (Haker et al., 2000; Agelink et al., 2003; Wu et al., 2009; Napadow et al., 2012; QuahSmith et al., 2012). After correction for multiple comparisons, the HAM-D item on change in somatic symptomatology was still highly significant (p ¼0.00021) reflecting the most important positive physical changes from active laser acupuncture resulting

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in improved quality of life. In spite of the participants’ lack of confidence in LA alleviating their fatigue or their physical symptoms such as headaches and back aches, those who received active laser certainly benefited as measured by the HAM-D item on somatic changes. It is apparent now that the choice of primary and secondary measures including the self-reporting measure is important if we want to better measure the acupuncture effect. In this study, not being able to follow up at one and three months post intervention with the QID-SR in the PA group imposes a limitation- if there was a delayed or prolonged effect of LA we have missed the opportunity to measure this effect compared to the PA group. However there is emerging evidence of this prolonged or delayed effect as measured by fMRI (Rheu et al., 2011; Quah-Smith et al., 2012). An important strength of the trial was that blinding was successfully maintained for study participants. Not only does LA lend itself to blinding easily because of the lack of skin sensation from laser stimulation, the allocation, administration and evaluation aspects of the trial were kept separate. Unforeseen circumstances necessitated IQS to be a rater as well. However analysis of the ratings by MH and IQS did not show any significant difference between the two raters for the post treatment scores, only a tendency for MH to overall rate a lower baseline QID-CL compared to IQS. This lower baseline QID-CL would have exerted a conservative effect by lowering post treatment scores. Posttreatment questioning of participants and IQS did not suggest that blinding had been compromised. We therefore explain the discrepancy between objective and subjective ratings to be due two possibilities: (a) the objective measures of depression improved to a greater extent than the subjective measures. An item-analysis of HAM-D revealed 5 items as being significantly affected by treatment: depressed mood, late insomnia, anorexia, somatic symptoms, somatic anxiety and agitation, partially supporting this possibility; (Supplementary Table 1). (b) our choice of self rating scale the QID-SR in this study did not measure some of the items of depression which improve with LA (for example, irritability and psychomotor retardation). In addition, the somatic symptoms changes with LA were also highly significant (p¼0.00021) in the HAM-D item-by-item analysis. In studies of major depression, it has been found that the placebo response is significant regardless of the treatment type being tested and is related to the study design and study population (Brunoni et al., 2009). The frequent visits for treatment and the contact with the supportive research team are likely to have exaggerated the placebo effect, especially at a subjective level. JAH also recorded the relatively long periods of time (20– 30 min) some of the subjects would stay on in her office to chat (unsolicited by JAH) or arrange appointment times. The conditioning effects of repeated visits leading to increased learning and increased placebo response have previously been described (Colloca et al., 2010). The mechanism of action of LA, and indeed all acupuncture as a potential anti-depressant treatment, is poorly understood. Various mechanisms have been suggested for needle acupuncture, which include stimulation of large peripheral nerves, neurovascular bundles, mechanoreceptors, or free nerve endings, but no neuroanatomical structure or pathway has been clearly established as mediating the therapeutic effect (Napadow et al., 2008). More recent attention has been on the intermuscular/intramuscular loose connective tissue, as many meridians and acupuncture points align with this (Langevin and Yandow, 2002). Acupuncture meridians have also been reported to have lower electrical impedance and higher capacitance compared to adjacent controls, which may justify the use of electroacupuncture, although the data on this are not conclusive (Ahn et al., 2008). In relation to the use of laser, the mechanisms are poorly understood.

Please cite this article as: Quah-Smith, I., et al., Laser acupuncture for depression: A randomised double blind controlled trial using low intensity laser intervention. Journal of Affective Disorders (2013), http://dx.doi.org/10.1016/j.jad.2012.11.058i

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The choice of acupoints for this trial was based on recommendations in TCM for the treatment of depression (Macioca, 1994; Aung and Chen, 2007), the highly significant results of our pilot study and the neuroimaging evidence we have gathered with regards to this suite of acupoints in depression (Quah-Smith et al., 2012). In practice, acupoint efficacy is not specific, and one acupoint can be used for several different conditions, just as one medical condition can be managed with several acupoint locations. Empirical basis for the choice of acupoints is therefore weak and requires further evaluation. There is however some emerging evidence for acupoint specificity (Jin et al., 2004; Yan et al., 2005; Campbell, 2006). For example, in a functional magnetic resonance imaging (fMRI) investigation of acupoints considered to be useful in depression performed in a healthy sample, HT7, considered to be an anti-anxiety acupoint in TCM, did not have any significant brain response (Quah-Smith et al., 2010). The neuroanatomical pathways by which laser stimulation produces its effect are also not known, although a role has been postulated for unmyelinated C fibres (Olausson et al., 2002). There is further evidence that acupuncture produces brain changes that are consistent with a potential therapeutic effect. Some neuroimaging and neuroendocrine studies have suggested that needle acupuncture affects hypothalamic as well as extrahypothalamic functions and modulates mood (Hsieh et al., 2001; Napadow et al., 2007). Laser acupuncture of a foot acupoint, classically used for treating visual problems, was demonstrated to cause activation of the occipital cortex (Siedentopf et al., 2002). More recently, our group showed in an fMRI study that LA stimulation of the acupoints used in the current study lead to activation of frontal-limbic-striatal brain regions, with the pattern of neural activity being somewhat different for each acupuncture point (Quah-Smith et al., 2010). This argued for the plausibility of LA as an anti-depressant treatment, although the relative merits of the various acupoints, or their combinations, are unknown. The promise of improved efficacy, in particular, the clinically and statistically significant improvement of somatic symptomatology and lack of adverse effects is a potent combination for improving the quality of life for the depressed. The efficacy of LA relative to established treatments is not known, and it is therefore difficult to suggest a place for it in today’s repertoire of antidepressant treatments. A recent study did however use acupuncture as augmentation therapy in antidepressant partial and nonresponders (Yeung et al., 2011). Our study also does not further our understanding of potential mechanisms by which the response occurs.

5. Conclusion Low intensity laser acupuncture was associated with objective improvement in depression. Further studies are needed to replicate this finding, and larger trials will help determine the predictors of good response. It is also important to examine longer-term effects, and whether repeated applications are necessary to maintain such benefit.

Role of funding source This study was funded by the Black Dog Foundation and a grant from a private philanthropist.

Conflict of interest The authors have no conflict of interest to declare.

Acknowledgements We wish to thank Scientia Professor Gordon Parker, the Black Dog Foundation and Mr Charles Scarf for their support and generosity, Scientia Professor Perminder Sachdev for his support, Associate Professor Vijaya Manicavasagar for her counsel, Julie Ann Ho (JAH) for her role as the research project manager, Dr. Mark Horowitz for his role in pre and post acupuncture assessments, Matthew Hyett (BDI) for his role in helping establish inter-rater reliability for the project, BDI staff for their kind support and enthusiasm always and the staff at Albert Medical Acupuncture for their support. Thanks also to Professor Rick Harris (University of Michigan) for his permission to modify his expectancy and belief measures for acupuncture in pain for our study.

Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.jad.2012.11.058.

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