Original Research March 13, 2013

Randomized Controlled Trial of Mindfulness Meditation for Generalized Anxiety Disorder: Effects on Anxiety and Stress Reactivity

Elizabeth A. Hoge, MD; Eric Bui, MD; Luana Marques, PhD; Christina A. Metcalf, BA; Laura K. Morris, BA; Donald J. Robinaugh, MA; John J. Worthington, MD; Mark H. Pollack, MD; Naomi M. Simon, MD

J Clin Psychiatry 2013;74(8):786-792

Article Abstract

Objective: Mindfulness meditation has met increasing interest as a therapeutic strategy for anxiety disorders, but prior studies have been limited by methodological concerns, including a lack of an active comparison group. This is the first randomized, controlled trial comparing the manualized Mindfulness-Based Stress Reduction (MBSR) program with an active control for generalized anxiety disorder (GAD), a disorder characterized by chronic worry and physiologic hyperarousal symptoms.

Method: Ninety-three individuals with DSM-IV-diagnosed GAD were randomly assigned to an 8-week group intervention with MBSR or to an attention control, Stress Management Education (SME), between 2009 and 2011. Anxiety symptoms were measured with the Hamilton Anxiety Rating Scale (HAMA; primary outcome measure), the Clinical Global Impressions-Severity of Illness and -Improvement scales (CGI-S and CGI-I), and the Beck Anxiety Inventory (BAI). Stress reactivity was assessed by comparing anxiety and distress during pretreatment and posttreatment administration of the Trier Social Stress Test (TSST).

Results: A modified intent-to-treat analysis including participants who completed at least 1 session of MBSR (n = 48) or SME (n = 41) showed that both interventions led to significant (P < .0001) reductions in HAMA scores at endpoint, but did not significantly differ. MBSR, however, was associated with a significantly greater reduction in anxiety as measured by the CGI-S, the CGI-I, and the BAI (all P values < .05). MBSR was also associated with greater reductions than SME in anxiety and distress ratings in response to the TSST stress challenge (P < .05) and a greater increase in positive self-statements (P = .004).

Conclusions: These results suggest that MBSR may have a beneficial effect on anxiety symptoms in GAD and may also improve stress reactivity and coping as measured in a laboratory stress challenge.

Trial Registration: ClinicalTrials.gov identifier: NCT01033851

J Clin Psychiatry 2013;74(00):000-000

Submitted: August 7, 2012; accepted February 11, 2013.

Online ahead of print: March 13, 2013 (doi:10.4088/JCP.12m08083)

Corresponding author: Elizabeth A. Hoge, MD, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, One Bowdoin Sq, 6th Floor, Boston, MA 02114 ([email protected]).

Randomized Controlled Trial of Mindfulness Meditation for Generalized Anxiety Disorder: Effects on Anxiety and Stress Reactivity

Vertical divider

ABSTRACT

Objective: Mindfulness meditation has met increasing interest as a therapeutic strategy for anxiety disorders, but prior studies have been limited by methodological concerns, including a lack of an active comparison group. This is the first randomized, controlled trial comparing the manualized Mindfulness-Based Stress Reduction (MBSR) program with an active control for generalized anxiety disorder (GAD), a disorder characterized by chronic worry and physiologic hyperarousal symptoms.

Method: Ninety-three individuals with DSM-IV-diagnosed GAD were randomly assigned to an 8-week group intervention with MBSR or to an attention control, Stress Management Education (SME), between 2009 and 2011. Anxiety symptoms were measured with the Hamilton Anxiety Rating Scale (HAMA; primary outcome measure), the Clinical Global Impressions-Severity of Illness and -Improvement scales (CGI-S and CGI-I), and the Beck Anxiety Inventory (BAI). Stress reactivity was assessed by comparing anxiety and distress during pretreatment and posttreatment administration of the Trier Social Stress Test (TSST).

Results: A modified intent-to-treat analysis including participants who completed at least 1 session of MBSR (n = 48) or SME (n = 41) showed that both interventions led to significant (P < .0001) reductions in HAMA scores at endpoint, but did not significantly differ. MBSR, however, was associated with a significantly greater reduction in anxiety as measured by the CGI-S, the CGI-I, and the BAI (all P values < .05). MBSR was also associated with greater reductions than SME in anxiety and distress ratings in response to the TSST stress challenge (P < .05) and a greater increase in positive self-statements (P = .004).

Conclusions: These results suggest that MBSR may have a beneficial effect on anxiety symptoms in GAD and may also improve stress reactivity and coping as measured in a laboratory stress challenge.

Trial Registration: ClinicalTrials.gov identifier: NCT01033851

J Clin Psychiatry 2013;74(08):786-792

Submitted: August 7, 2012; accepted February 11, 2013.

Online ahead of print: March 13, 2013 (doi:10.4088/JCP.12m08083)

Corresponding author: Elizabeth A. Hoge, MD, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, One Bowdoin Sq, 6th Floor, Boston, MA 02114 ([email protected]).

Generalized anxiety disorder (GAD), characterized by worry that is difficult to control and symptoms such as poor sleep, muscle tension, and irritability, is relatively common, with a lifetime prevalence rate of 5.7%.1 While pharmacotherapy and psychotherapy are common treatment strategies, 30% to 60% of patients do not achieve remission after treatment.2-6 In one early naturalistic study7 of 164 patients with GAD predominantly treated with pharmacotherapy, remission was as low as 15%. Further, individuals with GAD may not seek care in psychiatric settings due to perceived stigma.

Recently, mindfulness-based interventions have been of increasing interest as a cost-effective, low-stigma, accessible treatment option for a variety of psychological and medical symptoms, including anxiety.8 Mindfulness training teaches participants meditation techniques that increase awareness of present-moment experiences, including thoughts, emotions, and bodily sensations, with a gentle and accepting attitude toward oneself.9 Roemer et al10 found that patients with GAD have lower levels of trait mindfulness and more difficulties with emotion regulation than healthy controls and suggested that mindfulness training may be helpful.

Although several studies have examined the effect of mindfulness meditation on GAD, most are small or lack an attention control group to control for nonspecific effects of treatment, such as group support effects, expectancy bias, and attention from an instructor or experimenter. Early research by Kabat-Zinn et al11 found a decrease in anxiety symptoms after Mindfulness-Based Stress Reduction (MBSR) in patients with GAD, although there was no comparison group. V׸llestad et al12 used MBSR in patients with panic disorder, GAD, and social anxiety disorder, but utilized a wait-list comparison group that could not control for expectancy and attention effects. Mindfulness has also been combined with cognitive therapy in Mindfulness-Based Cognitive Therapy (MBCT) treatment13,14; however, since cognitive therapy alone has been shown to decrease anxiety in some studies, the combination of mindfulness meditation training and cognitive therapy makes it difficult to ascertain the proportion of effect due to each strategy.

Although a recent meta-analysis8 found a moderate effect size for mindfulness-based interventions for anxiety, other reviews and meta-analyses have noted significant deficits in methodology in meditation studies, including a Cochrane review cautioning implementation prior to more randomized, controlled data confirming efficacy.15-18 To our knowledge, this is the first randomized, controlled trial (RCT) of mindfulness meditation without added cognitive therapy, compared to an active control condition (incorporating elements of group treatment including attention from instructor, group support, and education, but not meditation training) for GAD.

In addition, we assessed the effect of meditation training on stress reactivity by employing a laboratory stress task, the Trier Social Stress Test (TSST). We hypothesized that MBSR training would result in greater reduction in anxiety symptoms and greater reduction in stress reactivity to the TSST than Stress Management Education (SME).

METHOD

Participants

Participants were recruited by referral and media advertisement between December 2008 and February 2011 for a study on “stress reduction.” After telephone screening, outpatients who completed the informed consent process received the Structured Clinical Interview for DSM-IV (SCID),19 administered by a trained graduate or higher level psychologist or psychiatrist independent evaluator at the Center for Anxiety and Traumatic Stress Disorders at Massachusetts General Hospital (MGH). Training in the use of the SCID was done using corated recorded and live interviews until a diagnostic concordance of 100% was reached. Individuals 18 years or older were eligible if they (1) met DSM-IV criteria for current primary GAD and designated GAD as the primary problem and (2) scored 20 or above on the Hamilton Anxiety Rating Scale (HAMA).20

clinical points
  • Mindfulness-Based Stress Reduction appears to be an effective tool to reduce anxiety in patients with generalized anxiety disorder.
  • Patients who learned mindfulness meditation had less stress reactivity, and were more resilient, to a laboratory stress task.

Exclusion criteria included the following: (1) a lifetime history of schizophrenia or any other psychosis, mental retardation, organic medical disorders, bipolar disorder, posttraumatic stress disorder, or obsessive-compulsive disorder; (2) alcohol or substance abuse or dependence within the past 6 months; (3) significant suicidal ideation or behaviors within the past 6 months; (4) if on medication, on a stable dose for less than 4 weeks or unwilling to remain on that dose throughout the study; (5) serious medical illness or instability; (6) concurrent psychotherapy directed toward GAD; (7) more than 4 classes of meditation training and practice (including yoga and tai chi) in the past 2 years; (8) pregnancy or lactation; and (9) significant personality disorder likely to interfere with study participation. A CONSORT flowchart provides information about participants (Figure 1), and Table 1 provides descriptive information on the study sample.

Figure 1

Click figure to enlarge

Table 1

Click figure to enlarge

Measures

Anxiety symptoms. Symptoms of anxiety were assessed at baseline and week 8 (endpoint) with the Structured Interview Guide for the HAMA, an adaptation of the 14-item HAMA designed to standardize clinician assessment,20 and the Clinical Global Impressions-Severity of Illness and -Improvement scales (CGI-S and CGI-I).21 Self-reported anxiety was measured with the 21-item Beck Anxiety Inventory (BAI).22 Sleep was assessed at baseline and endpoint with the 24-item self-report Pittsburgh Sleep Quality Index (PSQI).23 Independent evaluators, blinded to treatment assignment, completed the assessments.

Ratings used during TSST. Anxiety during the stress task was assessed with the “state anxiety” section of the State-Trait Anxiety Inventory (STAI),24 a widely used 40-item, multiple-choice questionnaire. The Subjective Units of Distress Scale (SUDS) assessed overall distress during the task; this widely used, highly reliable single-item question measures the intensity of current distress on a scale from 0 to 100.25-28

To assess the participants’ evaluation of their speech, we used the 10-item self-report Self-Statements During Public Speaking (SSPS) scale,29 which consists of two 5-item subscales, the positive self-statements subscale (SSPS-P, eg, “I can handle everything”) and the negative self-statements subscale (SSPS-N, eg, “I’ ll probably ‘ bomb out’ anyway”). Subjects rated their agreement with several statements about their performance to measure negative and positive self-perceptions and perceived negative or positive evaluation by others.

Procedure

Study procedures were approved by the MGH institutional review board. The study is registered with ClinicalTrials.gov (identifier: NCT01033851). All diagnostic screens and baseline clinician ratings, self-report questionnaires, and TSSTs were completed before treatment initiation. Patients underwent group randomization to either MBSR or SME. To prevent loss of independent evaluator blinding, participants were instructed not to discuss any details about their class with the evaluators.

Trier Social Stress Test. Participants arrived between 1:00 and 3:00 pm for the TSST. The TSST has been well described elsewhere30; in summary, it consists of an 8-minute public speaking task and a subsequent 5-minute mental arithmetic task (serial subtraction) performed in front of a panel of 2 strangers dressed in white laboratory coats and holding clipboards, introduced as “the evaluators,” and a large, conspicuous video camera. The TSST procedure followed a detailed script to ensure its systematic and controlled delivery.

Because the TSST was administered before and at the end of the trial, several measures were taken to lower the potential for stress habituation and to improve methodological rigor for the second TSST: (1) the evaluators were switched so that they would be strangers, (2) the TSST was moved to a different room, (3) a different arithmetic task was employed to avoid practice effects, and (4) participants were told that their performance on the first speech was in the low range and that this was their chance to improve their score (method 4 used by T. W. W. Pace, PhD, and C. L. Raison, MD; oral communication, April 27, 2012).

Interventions

Mindfulness-Based Stress Reduction. The MBSR program has been described previously.11 In brief, this intervention is composed of 8 weekly group classes with a single weekend “retreat” day and daily home practice guided by audio recordings. In-class practices (breath-awareness, a body-scan, and gentle Hatha yoga) are used to cultivate awareness of internal present-moment experiences with an accepting, nonjudgmental stance. For example, breath-awareness practice starts with the awareness of the sensations of breathing, then expands to other body sensations, thoughts, and emotions, all of which are treated with acceptance and nonjudgment and are allowed to “pass by” in order to return mental focus to the breath. The body-scan exercise guides the attention sequentially through the body, focusing on sensations of each area, and the yoga practices contain gentle stretching and slow movements, focusing on present experience and treating the body kindly. Participants were also instructed in “informal” home mindfulness practice (eg, present-focused awareness during eating, bathing, or cleaning).

For this protocol, some small adjustments were made to improve adherence and practicality: classes were shortened from 2.5 to 2 hours, the day-long retreat to 4 hours, and the homework from 45 to 20 minutes. In addition, metta (loving-kindness) was introduced in the first class, and a metta CD for home practice was included. The class was taught by an MBSR instructor with over 8 years of experience.

Stress Management Education. The SME course was designed as an active control, for comparison with MBSR, and did not contain any mindfulness components. It also consisted of an 8-week 2-hour class, with 20-minute homework exercises, and a 4-hour weekend “special class,” such that the total number of minutes of both class and home activities were exactly matched with MBSR. The SME course was taught in a didactic format, covering topics relevant to stress, stress physiology, effect of stress on body systems, time management techniques, sleep physiology, insomnia, optimal nutrition, effects of stress on diet, caffeine, exercise, stress hardiness, and factors that can buffer the impact of stress, such as humor, altruism, and volunteering. The course content was based on the control condition used by Dusek et al31 but delivered in a group lecture format. To more closely match the yoga portion of MBSR, SME included gentle strength and posture exercises with a physical therapist for the same total number of minutes. Extra resistance bands were provided for assigned home exercises. There was no aerobic exercise in the course.

The weekend special class included stability ball exercise instruction, a lecture on functional movement and individual postural assessments with a fitness instructor, a short massage, and a lecture from a licensed dietician. Similar to the MBSR class, 20-minute audiobook recordings were provided for SME participants to listen to at home (same total number of minutes). The SME class was taught by an instructor with 9 years of experience in providing health and wellness courses in a hospital-based clinic to groups of patients with physical health conditions and a physical therapist with 22 years of experience.

All the MBSR and SME classes were audiotaped, and 20% of the classes were randomly reviewed by one of the authors not involved in assessments (E.A.H.) for content, using a classes’ weekly content checklist to assess fidelity.

Statistical Analysis

Data analysis was performed using STATA version 11.1 (College Station, Texas). Analyses were conducted for a modified intent-to-treat (ITT) sample defined as all participants who had at least 1 treatment session (n = 48, MBSR vs n = 41, SME), with last observation carried forward (LOCF). The HAMA was defined a priori as the primary outcome variable, and the CGI-S, as the secondary outcome variable. A mean imputation method for measures with 15% or fewer missing items was employed.

Demographic data were examined using independent samples t tests, and Fisher exact tests were used for dichotomous variables. Independent samples t tests and repeated-measures analyses of variance (ANOVAs) were employed to compare changes in clinical symptoms and other psychometric ratings. Primary univariate analyses consisted of t tests for continuous outcome variables (ie, HAMA, BAI, and PSQI scores) and Fisher exact test for binary variables (responder status). The level of statistical significance was set to .05 (2-tailed).

RESULTS

Study Population

The 89 subjects who enrolled in the study and attended at least 1 class were included in the modified ITT analysis. Sociodemographic and clinical characteristics are reported in Table 1. Three participants in the SME group discontinued before any treatment, and 1 was removed due to later discovery of lack of eligibility. BAI scores were not available for the first 7 participants, and the CGI-S score was missing for 1 subject. Adverse events were 2% for MBSR (n = 1, “muscle soreness”) and 2% for SME (n = 1, “sleep disruption”).

Anxiety Symptom Outcomes

A repeated-measures ANOVA with time (baseline and endpoint) as the repeated measure, treatment arm as between-subjects factor, and HAMA score as the dependent variable was significant (F1,87 = 2.86, P < .001). The analyses revealed a main effect of time (F1,87 = 66.93, P < .001) but no significant treatment arm ×— time interaction (F1,87 = 1.38, P = .244). To further examine the main effect of time, we conducted 2 dependent samples t tests examining changes from baseline to endpoint within the MBSR and SME groups (Table 2). HAMA scores decreased significantly for both groups (see Table 2).

Table 2

Click figure to enlarge

A repeated-measures ANOVA with time (baseline and endpoint) as the repeated measure, treatment arm as between-subjects factor, and BAI score as the dependent variable found a main effect of time (F1,79 = 28.52, P < .001) and a significant treatment arm ×— time interaction (F1,79 = 4.31, P = .041). Mean BAI scores decreased for the MBSR group and for the SME group but showed a significantly greater decrease in the MBSR group. Similarly, a repeated-measures ANOVA with time as the repeated measure, treatment arm as between-subjects factor, and CGI-S score as the dependent variable found a main effect of time (F1,84 = 62.19, P < .001) and a significant treatment arm ×— time interaction (F1,84 = 4.51, P = .0366). Change scores for symptom measures appear in Figure 2.

Figure 2

Click figure to enlarge

Responder status was defined as a CGI-I rating of 1 (very much improved) or 2 (much improved) at endpoint. Response rate was greater for MBSR (29/44; 66%) than for SME (14/35; 40%); (P = .025) (Figure 3). The risk ratio for response to MBSR was 1.65 (95% CI, 1.04-2.60), and the number needed to treat was 3.9 (95% CI, 2.23-26.19).

Figure 3

Click figure to enlarge

Sleep quality. Because the allowed psychiatric medications (selective serotonin reuptake inhibitors and benzodiazepines) affect sleep and can potentially obscure treatment-related effects, the measurement of sleep changes was restricted to participants not taking psychiatric medications (n = 61). A repeated-measures ANOVA with time (baseline and endpoint) as the repeated measure, treatment arm as between-subjects factor, and PSQI score as the dependent variable found a main effect of time (F1,59 = 24.55, P < .001) and a significant treatment arm ×— time interaction (F1,59 = 4.69, P = .035). Although PSQI scores improved from baseline to endpoint in both treatment groups, the MBSR group had a greater reduction (mean change score [SD] for MBSR = 2.6 [3.6], SME = 1.0 [1.9]).

Stress Reactivity

Ratings of distress, anxiety, and self-judgment were assessed during each of the 2 TSSTs, and the changes were compared between groups as a measure of how “resilient” individuals were to subsequent stress. Scores of the participants who completed the protocol were compared. Although study participants were asked to avoid starting new treatments during the study, 3 individuals initiated antidepressant or benzodiazepine medications, all in MBSR. These 3 subjects were included in the modified ITT analysis of clinical outcome measures above but were not included in the TSST stress reactivity analyses due to the known effects of these medications on the TSST response.32 Removing these 3 subjects from the clinical outcome measure analyses above did not change the direction, magnitude, or significance of the results.

A repeated-measures ANOVA with time (baseline and endpoint) as the repeated measure, treatment arm as between-subjects factor, and state STAI (STAI-S) score as the dependent variable found a main effect of time (F1,73 = 47.11, P < .001) and a significant treatment arm ×— time interaction (F1,73 = 4.37, P = .040). STAI-S scores dropped from 53.9 to 40.8 in the MBSR group and 52.2 to 45.2 in the SME group (Figure 4). Similarly, a repeated-measures ANOVA with time as the repeated measure, treatment arm as between-subjects factor, and SUDS score as the dependent variable found a main effect of time (F1,68 = 37.10, P < .001) and a significant treatment arm ×— time interaction (F1,68 = 5.25, P = .025). SUDS scores dropped from 53.2 to 28.7 in the MBSR group and 50.5 to 39.4 in the SME group.

Figure 4

Click figure to enlarge

Self-Evaluation

Participants completed the SSPS, indicating their amount of agreement with the provided positive (SSPS-P) and negative self-statements (SSPS-N). A repeated-measures ANOVA with time as the repeated measure, treatment arm as between-subjects factor, and SSPS-P score as the dependent variable found a main effect of time (F1,72 = 4.49, P = .038) and a significant treatment arm ×— time interaction (F1,72 = 8.64, P = .004). There was a greater increase in agreement with the positive statements with MBSR (15.9 to 18.6) compared to SME (16.9 to 16.5).

The mean score for negative statements decreased in both groups, but did not differ between groups. Specifically, a repeated-measures ANOVA with time as the repeated measure, treatment arm as between-subjects factor, and SSPS-N score as the dependent variable found a main effect of time (F1,72 = 11.5, P = .001) but a nonsignificant treatment arm ×— time interaction (F1,72 = 1.32, P = .26).

DISCUSSION

This is the first RCT employing an active control group to examine the effect of MBSR on GAD. We found significantly larger reductions in most (CGI-S, CGI-I, BAI, PSQI) but not all (HAMA) of our clinical outcome measures. One possible explanation is that the HAMA, which heavily weighs somatic symptoms, was not sensitive to the change in psychological symptoms; indeed, the HAMA has been reported to be “dominated by the somatic correlates of anxiety.”33(p16) This possibility was suggested by post hoc analyses that showed a greater (although nonsignificant) drop (4.8 vs 3.9) in the psychological symptom HAMA subscale in the MBSR group compared to the SME group and a greater drop in the BAI psychological symptom subscale in the MBSR group compared to the SME group (3.12 vs 1.51, t79 = −1.81, P = .07). Given greater differences in self-report and global improvement ratings than in HAMA scores, it is also possible that the MBSR participants experienced a decrease in overall distress and impairment that was not reflected in GAD symptom change as measured by the HAMA. This distinction between symptom severity and symptom distress has been made in the pain literature, in which mindfulness meditation training was associated with a decrease in “pain unpleasantness.”34,35

Using the standard outcome measure of the HAMA to calculate effect sizes of the active treatment, the MBSR group’s effect size (pretreatment to posttreatment, Cohen d) was 1.06, which is similar to other psychosocial treatment studies (Cohen d of 0.73 to 1.37 in studies of cognitive-behavioral therapy [CBT]36,37; for review, also see meta-analysis by Stewart and Chambless38 that reports a Hedges g overall effect size of 0.92 for CBT).

Resilience is defined in the Oxford English Dictionary as “the ability of a substance or object to spring back into shape; the capacity to recover quickly from difficulties”; given that this term measures a reaction to something, the use of a paper questionnaire to measure resilience seems wanting. Indeed, the TSST has been used as a measure of resilience in many different populations, including healthy controls, as it gives scientists an opportunity to systematically measure how well an individual copes with and recovers from a well-recognized significant stress.39-41 We found a greater reduction in ratings of distress and anxiety after the TSST with MBSR than SME, suggesting that meditation training may have improved coping or “resilience” to this performance stress task. Our findings are consistent with those of Britton and colleagues,42 who found that participants with partially remitted depression had a greater reduction in STAI scores after the TSST with MBCT compared to a wait-list control.

Because mindfulness meditation teaches participants to let thoughts pass by without judgment,9 it is possible that participants who learned MBSR were less likely to ruminate over negative thoughts about the speech and their performance and treated themselves with more kindness and less self-judgment, an inherent part of the practice. This hypothesis is supported by the significant increase in positive self-statement agreement in the SSPS, which occurred with MBSR but not SME, and represents a possible growth in positive self-regard that is distinct from the decrease in anxiety symptoms overall. Indeed, lower positive emotion associated with the TSST has been shown to predict increased depression symptoms over the following year.43

The study has several limitations. First, our sample was relatively small, and large-scale replications are needed. Second, although comorbidity rates of depression and anxiety disorders in our sample are consistent with other treatment-seeking GAD populations,44,45 large epidemiologic studies have reported higher comorbidity rates among GAD patients, suggesting that our results might not be completely generalizable. Third, the study included some participants taking psychiatric medication. While our meditation training had a significant effect (despite the fact that the sample comprised a mixed clinical population), the small numbers of participants on medication, balanced between groups, precluded the examination of the effects of medication on response. Last, our study lacked a clinical diagnostic assessment at endpoint.

In conclusion, our findings suggest that mindfulness meditation training, in the form of MBSR, can reduce anxiety symptoms in patients with GAD even when compared to an active control condition and is a treatment option worth pursuing in larger investigational trials. We also observed that patients who learned mindfulness meditation had improved coping during a laboratory stress paradigm, raising the possibility that mindfulness may imbue some resilience to stressful psychological challenges.

Author affiliations: Department of Psychiatry, Massachusetts General Hospital, Boston (Drs Hoge, Bui, Marques, Worthington, and Simon, Mss Metcalf and Morris, and Mr Robinaugh); and Department of Psychiatry, Rush University Medical Center, Chicago, Illinois (Dr Pollack).

Potential conflicts of interest: Dr Pollack has been an advisory board member or consultant for Eli Lilly, Medavante, Otsuka, and Transcept; has equity in Medavante, Mensante Corporation, Mindsite, and Targa; has received royalties from/holds patents on the SIGH-A and SAFER interviews; and has received research grants from the National Institute on Drug Abuse and National Institute of Mental Health. Drs Hoge, Bui, Marques, Worthington, and Simon; Mss Metcalf and Morris; and Mr Robinaugh report no potential conflict of interest.

Funding/support: This study was primarily supported by grant K23AT4432 from the National Center on Complementary and Alternative Medicine, National Institutes of Health (Dr Hoge, principal investigator). The Highland Street Foundation provided additional support, including to Drs Bui, Marques, Pollack, and Simon and Ms Metcalf.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, National Center for Research Resources, or National Institutes of Health.

Previous presentations: Parts of the data have previously been reported at the Annual Meeting of the Anxiety Disorders Association of America, April 15, 2012, Crystal City, Virginia, and the Annual Meeting of the Consortium of Academic Health Centers for Integrative Medicine, May 17, 2012, Portland, Oregon.

Acknowledgments: The authors thank Zayda Vallejo, MLitt, and Jennifer Johnston, LMHC, PhD, for their work in teaching the study courses. Ms Vallejo and Dr Johnston report no potential conflict of interest. The authors also acknowledge the Massachusetts General Hospital volunteers who assisted in this study and the nursing support from the Harvard Clinical and Translational Science Center (National Institutes of Health award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers).

REFERENCES

1. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602. PubMed doi:10.1001/archpsyc.62.6.593

2. Zinbarg RE, Lee JE, Yoon KL. Dyadic predictors of outcome in a cognitive-behavioral program for patients with generalized anxiety disorder in committed relationships: a “spoonful of sugar” and a dose of non-hostile criticism may help. Behav Res Ther. 2007;45(4):699-713. PubMed doi:10.1016/j.brat.2006.06.005

3. Dugas MJ, Brillon P, Savard P, et al. A randomized clinical trial of cognitive-behavioral therapy and applied relaxation for adults with generalized anxiety disorder. Behav Ther. 2010;41(1):46-58. PubMed doi:10.1016/j.beth.2008.12.004

4. Bandelow B, Chouinard G, Bobes J, et al. Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder: data from a randomized, double-blind, placebo- and active-controlled study. Int J Neuropsychopharmacol. 2010;13(3):305-320. PubMed doi:10.1017/S1461145709990423

5. Rickels K, Rynn M, Iyengar M, et al. Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database. J Clin Psychiatry. 2006;67(1):41-47. PubMed doi:10.4088/JCP.v67n0107

6. Simon NM, Worthington JJ, Moshier SJ, et al. Duloxetine for the treatment of generalized social anxiety disorder: a preliminary randomized trial of increased dose to optimize response. CNS Spectr. 2010;15(7):367-373. PubMed

7. Yonkers KA, Warshaw MG, Massion AO, et al. Phenomenology and course of generalised anxiety disorder. Br J Psychiatry. 1996;168(3):308-313. PubMed doi:10.1192/bjp.168.3.308

8. Hofmann SG, Sawyer AT, Witt AA, et al. The effect of mindfulness-based therapy on anxiety and depression: a meta-analytic review. J Consult Clin Psychol. 2010;78(2):169-183. PubMed doi:10.1037/a0018555

9. Bishop SRB, Lau M, Shapiro S, et al. Mindfulness: a proposed operational definition. Clin Psychol Sci Pract. 2004;11(3):230-241. doi:10.1093/clipsy.bph077

10. Roemer L, Lee JK, Salters-Pedneault K, et al. Mindfulness and emotion regulation difficulties in generalized anxiety disorder: preliminary evidence for independent and overlapping contributions. Behav Ther. 2009;40(2):142-154. PubMed doi:10.1016/j.beth.2008.04.001

11. Kabat-Zinn J, Massion AO, Kristeller J, et al. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. Am J Psychiatry. 1992;149(7):936-943. PubMed

12. V׸llestad J, Sivertsen B, Nielsen GH. Mindfulness-based stress reduction for patients with anxiety disorders: evaluation in a randomized controlled trial. Behav Res Ther. 2011;49(4):281-288. PubMed doi:10.1016/j.brat.2011.01.007

13. Evans S, Ferrando S, Findler M, et al. Mindfulness-based cognitive therapy for generalized anxiety disorder. J Anxiety Disord. 2008;22(4):716-721. PubMed doi:10.1016/j.janxdis.2007.07.005

14. Kim YW, Lee SH, Choi TK, et al. Effectiveness of mindfulness-based cognitive therapy as an adjuvant to pharmacotherapy in patients with panic disorder or generalized anxiety disorder. Depress Anxiety. 2009;26(7):601-606. PubMed doi:10.1002/da.20552

15. Krisanaprakornkit T, Krisanaprakornkit W, Piyavhatkul N, et al. Meditation therapy for anxiety disorders. Cochrane Database Syst Rev. 2006;(1):CD004998. PubMed

16. Ospina MB, Bond K, Karkhaneh M, et al. Clinical trials of meditation practices in health care: characteristics and quality. J Altern Complement Med. 2008;14(10):1199-1213. PubMed doi:10.1089/acm.2008.0307

17. Ospina MB, Bond K, Karkhaneh M, et al. Meditation practices for health: state of the research. Evid Rep Technol Assess (Full Rep). 2007;(155):1-263. PubMed

18. Chiesa A, Serretti A. A systematic review of neurobiological and clinical features of mindfulness meditations. Psychol Med. 2010;40(8):1239-1252. PubMed doi:10.1017/S0033291709991747

19. First MB, Gibbon M, Spitzer RL, et al. Structured Clinical Interview for Axis I DSM-IV Disorders—Non-Patient Edition (SCID-I/NP, Version 2.0). New York, NY: New York State Psychiatric Institute; 1996.

20. Shear MK, Vander Bilt J, Rucci P, et al. Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH-A). Depress Anxiety. 2001;13(4):166-178. PubMed doi:10.1002/da.1033

21. Guy W. Clinical global impression. In: Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health; 1976:218-221.

22. Beck AT, Epstein N, Brown G, et al. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56(6):893-897. PubMed doi:10.1037/0022-006X.56.6.893

23. Buysse DJ, Reynolds CF 3rd, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213. PubMed doi:10.1016/0165-1781(89)90047-4

24. Spielberger CD. Manual for the State-Trait Anxiety Inventory for Children. Palo Alto, CA: Consulting Psychologists Press; 1973.

25. Wolpe J. The Practice of Behavior Therapy. New York, NY: Pergamon; 1969.

26. Eifert GH, Zvolensky MJ, Sorrell JT, et al. Predictors of self-reported anxiety and panic symptoms: an evaluation of anxiety sensitivity, suffocation fear, heart-focused anxiety, and breath-holding duration. J Psychopathol Behav Assess. 1999;21(4):293-305. doi:10.1023/A:1022116731279

27. Spira AP, Zvolensky MJ, Eifert GH, et al. Avoidance-oriented coping as a predictor of panic-related distress: a test using biological challenge. J Anxiety Disord. 2004;18(3):309-323. PubMed doi:10.1016/S0887-6185(02)00249-9

28. Tanner BA. Validity of global physical and emotional SUDS. Appl Psychophysiol Biofeedback. 2012;37(1):31-34. PubMed doi:10.1007/s10484-011-9174-x

29. Hofmann SG, Dibartolo PM. An instrument to assess self-statements during public speaking: scale development and preliminary psychometric properties. Behav Ther. 2000;31(3):499-515. PubMed doi:10.1016/S0005-7894(00)80027-1

30. Kirschbaum C, Pirke KM, Hellhammer DH. The “Trier Social Stress Test”—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28(1-2):76-81. PubMed doi:10.1159/000119004

31. Dusek JA, Chang BH, Zaki J, et al. Association between oxygen consumption and nitric oxide production during the relaxation response. Med Sci Monit. 2006;12(1):CR1-CR10. PubMed

32. Fries E, Hellhammer DH, Hellhammer J. Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam. Psychoneuroendocrinology. 2006;31(10):1278-1288. PubMed doi:10.1016/j.psyneuen.2006.09.009

33. Emilien G, Durlach C, Lepola U, et al. Anxiety Disorders: Pathophysiology and Pharmacological Treatment. Williston, VT: Birkhauser; 2002.

34. Perlman DM, Salomons TV, Davidson RJ, et al. Differential effects on pain intensity and unpleasantness of two meditation practices. Emotion. 2010;10(1):65-71. PubMed doi:10.1037/a0018440

35. Gard T, Holzel BK, Sack AT, et al. Pain attenuation through mindfulness is associated with decreased cognitive control and increased sensory processing in the brain. Cereb Cortex. 2012;22(11):2692-2702. PubMed doi: 10.1093/cercor/bhr352

36. Reinecke A, Rinck M, Becker ES, et al. Cognitive-behavior therapy resolves implicit fear associations in generalized anxiety disorder. Behav Res Ther. 2013;51(1):15-23. PubMed doi:10.1016/j.brat.2012.10.004

37. Stanley MA, Beck JG, Glassco JD. Treatment of generalized anxiety in older adults: a preliminary comparison of cognitive-behavioral and supportive approaches. Behav Ther. 1996;27(4):565-581. doi:10.1016/S0005-7894(96)80044-X

38. Stewart RE, Chambless DL. Cognitive-behavioral therapy for adult anxiety disorders in clinical practice: a meta-analysis of effectiveness studies. J Consult Clin Psychol. 2009;77(4):595-606. PubMed doi:10.1037/a0016032

39. Armbruster D, Mueller A, Strobel A, et al. Children under stress—COMT genotype and stressful life events predict cortisol increase in an acute social stress paradigm. Int J Neuropsychopharmacol. 2012;15(9):1229-1239. PubMed doi:10.1017/S1461145711001763

40. Kudielka BM, Schmidt-Reinwald AK, Hellhammer DH, et al. Psychosocial stress and HPA functioning: no evidence for a reduced resilience in healthy elderly men. Stress. 2000;3(3):229-240. PubMed doi:10.3109/10253890009001127

41. Smeets T. Autonomic and hypothalamic-pituitary-adrenal stress resilience: impact of cardiac vagal tone. Biol Psychol. 2010;84(2):290-295. PubMed doi:10.1016/j.biopsycho.2010.02.015

42. Britton WB, Haynes PL, Fridel KW, et al. Mindfulness-based cognitive therapy improves polysomnographic and subjective sleep profiles in antidepressant users with sleep complaints. Psychother Psychosom. 2012;81(5):296-304. PubMed doi:10.1159/000332755

43. Aschbacher K, Epel E, Wolkowitz OM, et al. Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms. Brain Behav Immun. 2012;26(2):346-352. PubMed doi:10.1016/j.bbi.2011.10.010

44. Lenze EJ, Rollman BL, Shear MK, et al. Escitalopram for older adults with generalized anxiety disorder: a randomized controlled trial. JAMA. 2009;301(3):295-303. PubMed doi:10.1001/jama.2008.977

45. Wetherell JL, Gatz M, Craske MG. Treatment of generalized anxiety disorder in older adults. J Consult Clin Psychol. 2003;71(1):31-40. PubMed doi:10.1037/0022-006X.71.1.31