Acupuncture for Major Depressive Disorder

Introduction

Major depressive disorder (MDD) is a prevalent condition associated with significant burden in terms of reduced quality of life, lower productivity, increased prevalence of other conditions, and increased health care costs. Several evidence-based treatments for MDD exist, but these interventions vary in their effectiveness, safety, and acceptability to different patient populations (Tylee and Jones, 2005). Individuals with depression sometimes use complementary and alternative medicine therapies, including acupuncture. Monotherapy acupuncture refers to its use instead of or as an alternative to conventional therapies, such as antidepressants and psychotherapy. Acupuncture may also be used adjunctively with conventional therapies as a complementary medicine. When used as adjunctive therapy, patients may obtain acupuncture separately from other treatments for depression with no communication between health care providers, or acupuncture may be part of integrative health care when its use is planned and coordinated with conventional therapies. This systematic review summarizes the evidence from randomized controlled trials (RCTs) testing the efficacy and safety of acupuncture to treat adults with MDD. Specifically, this systematic review aimed to answer the following primary key questions (KQs) and subquestions:

• KQ 1: Is needle acupuncture, as a monotherapy, more effective than sham acupuncture, treatment as usual, waitlists, no treatment, or other active treatments in reducing depressive symptoms in adults with MDD?
  • KQ 1a: Among publications that address monotherapy acupuncture as a treatment for adults with MDD, how common and severe are adverse events?
• KQ 2: Is needle acupuncture, as an adjunctive therapy, more effective than sham acupuncture, treatment as usual, waitlists, no treatment, or other active treatments in reducing depressive symptoms in adults with MDD?
  • KQ 2a: Among publications that address adjunctive acupuncture for adults with MDD, how common and severe are adverse events?
• KQ 3: Is needle acupuncture, as a monotherapy, more effective than sham acupuncture, treatment as usual, waitlists, no treatment, or other active treatments in decreasing relapse rates in adults with MDD?^[1]
• KQ 4: Is needle acupuncture, as an adjunctive therapy, more effective than sham acupuncture, treatment as usual, waitlists, no treatment, or other active treatments in decreasing relapse rates in adults with MDD?

In addition, the review aimed to answer the following secondary questions:

• KQ 5: Is needle acupuncture, as a monotherapy, more effective than sham acupuncture, treatment as usual, waitlists, no treatment, or other active treatments in improving health-related quality of life in adults with MDD?
• KQ 6: Is needle acupuncture, as an adjunctive therapy, more effective than sham acupuncture, treatment as usual, waitlists, no treatment, or other active treatments in improving health-related quality of life in adults with MDD?

Methods

We conducted a systematic search of databases—PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), clinicaltrials.gov, DARE (Database of Abstracts of Reviews of Effects), and PILOTS (Published International Literature on Traumatic Stress)—for English-language studies published through January 2015 to identify RCTs testing the effectiveness and safety of acupuncture either as monotherapy or as adjunctive therapy to treat adults with MDD. In addition, we screened bibliographies of prior systematic reviews and included studies.

Two independent reviewers used pre-established eligibility criteria to screen identified studies, abstract study-level information, and assess the quality of included studies. Outcomes of interest included depressive symptoms, response to treatment, remission, relapse, health-related quality of life, and adverse events. Study details were documented in detailed evidence tables and summarized in a narrative synthesis. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (or GRADE) approach.

Results

We identified 18 RCTs that examined acupuncture in the treatment of MDD. Eleven of these studies focused on acupuncture as a monotherapy, and seven examined its use as an adjunctive therapy to antidepressants or treatment as usual. Assessment of the literature is complicated by a variety of factors, including variation in comparators (e.g., sham acupuncture with nonpenetrating needles, acupuncture at nonacupoints, waitlist). We found that the methodological quality of the studies was generally poor, with limited blinding, high attrition, and limited use of intention-to-treat analysis. Study samples were small and ranged from 20 to 160 participants.

Key Question 1

We identified 11 RCTs assessing treatment effects of acupuncture as monotherapy on depressive symptoms in patients diagnosed with MDD. Studies used a variety of acupuncture schedules. Eight studies compared acupuncture at acupoints specifically targeting depression with nonspecific acupuncture.

There was low quality of evidence that acupuncture is superior to waitlist in reducing depression scale scores, but the size of the treatment effect could not be determined and only two RCTs contributed to the finding.

There is very low quality of evidence that acupuncture is not statistically significantly different from sham acupuncture using nonpenetrating needles in reducing depression scale scores, but this result is based on one small RCT only and the true effect may be substantially different.

Eight RCTs assessed the effect of depression-specific acupuncture on depression scale scores compared with acupuncture targeting acupoints not specific to depression. The direction of effects varied, sometimes favoring depression-specific acupuncture, sometimes the nonspecific acupuncture, and some studies showed no statistically significant difference between study arms. The quality of the evidence is very low, and it is not possible to determine with confidence whether depression-specific acupuncture is superior to control acupuncture targeting nonspecific points.

There was low quality evidence that acupuncture is not statistically significantly different from massage in reducing depression scale scores, but the statistical power to detect differences between study arms was unclear and the result is based on one fair and one poor quality RCT.

Four fair and poor quality RCTs compared acupuncture and antidepressants. Differences in depression scale scores varied somewhat across arms. Two studies reported no statistically significant differences between study arms, but none of the RCTs reported a statistical power calculation to determine whether the studies were sufficiently powered to detect differences; hence, it is difficult to draw conclusions from the very low quality of evidence.

Results for an alternative measure of depression improvement, the number of patients showing a treatment response (usually defined as a 50-percent reduction in depression scale scores), showed inconclusive findings. Effect estimates for the rate of treatment responders comparing acupuncture with waitlist, sham acupuncture using nonpenetrating needles or using nonspecific acupoints, massage, or antidepressants were hampered by inconsistent results across individual studies, or results were based on only one or two RCTs reporting on the outcome. Hence, all results were graded as very low quality evidence.

Four studies reported on the outcome remission. Acupuncture arms reported a higher remission rate than waitlist in two RCTs, but the one study that tested the statistical significance of the results did not find results different from chance. Acupuncture versus sham acupuncture with nonpenetrating needles reported a higher, but not statistically significantly different, remission rate in the sham acupuncture group, but the result is based on a single RCT. Remission rates varied comparing depression-specific acupuncture and control acupuncture using nonspecific acupoints and sometimes favored the targeted acupuncture, sometimes the nonspecific arm across four RCTs. Two RCTs comparing acupuncture and massage showed inconsistent results. All evidence statements for the outcome remission were determined to be very low quality of evidence due to the methodological quality, inconsistency in or lack of replication, or the imprecision and lack of statistical power to detect a difference between alternative interventions.

Key Question 1a

Six RCTs of monotherapy acupuncture reported on adverse events, five of which systematically assessed adverse events by using a structured instrument or by systematically asking participants about side effects. Three studies compared the rate of adverse events between acupuncture and control groups.

Among the monotherapy studies that reported on adverse events, there were few events and most were mild, such as pain, bruises, or discomfort at acupuncture sites. Severe adverse events either occurred in the comparator group or were deemed unrelated to the acupuncture intervention. Two RCTs reported no statistically significant differences between arms in the rate of adverse events; one study reported that milder side effects were more common among those receiving acupuncture than massage.

Key Question 2

Seven RCTs assessed acupuncture as an adjunctive therapy. Five studies compared acupuncture adjunctive to antidepressants with antidepressants alone. One study compared acupuncture plus usual care with sham acupuncture at nonacupoints plus usual care, and one study compared acupuncture plus usual care with sham acupuncture using nonpenetrating needles plus usual care.

The combination of acupuncture and antidepressants tended to show lower depression scale scores or reported a greater reduction in scores than antidepressant arms alone, but the size of the effect varied and the difference was only statistically significant in three of five studies.

The RCT comparing acupuncture with minimal pricking at nonacupoints showed no difference between arms; both arms also received treatment as usual. The RCT comparing acupuncture with sham acupuncture using nonpenetrating needles also showed no statistically significant differences; both arms received treatment as usual. One RCT reported a comparison with nonspecific acupoints and found no statistically significant differences. A comparison of acupuncture plus antidepressants with sham acupuncture using nonpenetrating needles plus antidepressants showed a statistically significant difference between arms in favor of true acupuncture, but the result is based on one, poor quality RCT and the quality of evidence is very low.

Three RCTs that compared acupuncture plus antidepressants with antidepressants alone reported the rate of treatment responders. All three favored the combination groups, but only one RCT reported a statistically significant difference. All three studies contributing to this result were of poor quality; hence, our confidence in the finding is limited. One RCT comparing acupuncture plus antidepressants with sham acupuncture using nonpenetrating needles plus antidepressants found a higher response rate in the true acupuncture group, but the difference was not statistically significant and the study was a poor quality RCT.

Effects on remission rates showed no differences between acupuncture plus antidepressants with antidepressants alone, acupuncture plus treatment as usual with sham acupuncture using nonpenetrating needles plus treatment as usual, or acupuncture plus antidepressants with sham acupuncture using nonpenetrating needles plus antidepressants. The rate of patients achieving remission was low and the quality of the evidence was very low for all findings because of the methodological quality and the inconsistency and imprecision of the effect estimates.

Key Question 2a

Five studies reported on the occurrence of adverse events during the course of the study, but only two studies systematically assessed adverse events for adjunctive acupuncture with a structured instrument and compared the frequency of events between groups.

For participants who received acupuncture, most recorded adverse events were mild in nature, such as discomfort and mild bleeding or bruising at the needling site. Among participants in both acupuncture and sham acupuncture interventions, more-severe adverse events were occasionally reported, such as heart attack (cranial electroacupuncture plus body acupuncture plus fluoxetine group), but, in general, studies were too small to adequately assess rare adverse events. Both RCTs with systematic assessments compared acupuncture and antidepressants with antidepressants alone and found no significant differences between any of the groups in the rate of adverse events.

Key Question 3

We identified no RCTs of acupuncture as monotherapy that examined depression relapse rates; the review is not able to answer this question.

Key Question 4

We identified no RCTs of acupuncture as adjunctive therapy that examined depression relapse rates; the review is not able to answer this question.

Key Question 5

There was only one, poor quality study that examined the effect of monotherapy acupuncture on health-related quality of life. The study did not find a statistically significant difference in quality of life between the electroacupuncture group and the control group, which used nonspecific acupoints, but the finding is based on very low quality of evidence.

Key Question 6

We identified no RCTs of acupuncture as adjunctive therapy that examined health-related quality of life; the review is not able to answer this question.

Conclusions

This review systematically documents the available evidence for the effectiveness and safety of acupuncture in treating MDD. Evidence on the effectiveness and comparative effectiveness of acupuncture to treat depression for the outcomes depression improvement (measured as scale score differences) and the number of responders is very weak. Acupuncture may be superior to waitlist (low quality of evidence). The limited evidence suggests a higher rate of responders with adjunctive acupuncture plus antidepressants than with antidepressants alone, but the studies were of poor quality (low quality of evidence). Findings for effect estimates of acupuncture compared with other comparators are inconclusive. Few studies reported on patients achieving remission. The effect of acupuncture on relapse rates could not be determined. Too few studies assessed quality of life to estimate treatment effects. Reported adverse events were typically mild in nature, but the assessment lacked rigor and studies were not designed to detect rare events. See Table 1 for a summary of findings.

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Note

^[1] A relapse occurs when a patient previously in remission experiences another episode of MDD less than a year after the previous episode; a recurrence occurs when a patient experiences a subsequent episode of major depression at least a year after the previous episode. Here, we use the term relapse to include both relapses and recurrences.

This research was sponsored by the Office of the Secretary of Defense and the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury and conducted within the Forces and Resources Policy Center of the RAND National Defense Research Institute, a federally funded research and development center sponsored by the Office of the Secretary of Defense, the Joint Staff, the Unified Combatant Commands, the Navy, the Marine Corps, the defense agencies, and the defense Intelligence Community.