Research

JAMA Psychiatry | Original Investigation

Mindfulness-Based Stress Reduction vs Escitalopram

for the Treatment of Adults With Anxiety Disorders
A Randomized Clinical Trial
Elizabeth A. Hoge, MD; Eric Bui, MD, PhD; Mihriye Mete, PhD; Mary Ann Dutton, PhD;
Amanda W. Baker, PhD; Naomi M. Simon, MD, MSc

Visual Abstract
IMPORTANCE Anxiety disorders are common, highly distressing, and impairing conditions. Supplemental content
Effective treatments exist, but many patients do not access or respond to them.
Mindfulness-based interventions, such as mindfulness-based stress reduction (MBSR) are
popular and can decrease anxiety, but it is unknown how they compare to standard first-line
treatments.

OBJECTIVE To determine whether MBSR is noninferior to escitalopram, a commonly used

first-line psychopharmacological treatment for anxiety disorders.

DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial (Treatments for Anxiety:
Meditation and Escitalopram [TAME]) included a noninferiority design with a prespecified
noninferiority margin. Patients were recruited between June 2018 and February 2020. The
outcome assessments were performed by blinded clinical interviewer at baseline, week 8
end point, and follow-up visits at 12 and 24 weeks. Of 430 individuals assessed for inclusion,
276 adults with a diagnosed anxiety disorder from 3 urban academic medical centers in the
US were recruited for the trial, and 208 completed the trial.

INTERVENTIONS Participants were 1:1 randomized to 8 weeks of the weekly MBSR course or
the antidepressant escitalopram, flexibly dosed from 10 to 20 mg.

MAIN OUTCOMES AND MEASURES The primary outcome measure was anxiety levels as
assessed with the Clinical Global Impression of Severity scale (CGI-S), with a predetermined
noninferiority margin of −0.495 points.

RESULTS The primary noninferiority sample consisted of 208 patients (102 in MBSR and
106 in escitalopram), with a mean (SD) age of 33 (13) years; 156 participants (75%) were
female; 32 participants (15%) were African American, 41 (20%) were Asian, 18 (9%) were
Hispanic/Latino, 122 (59%) were White, and 13 (6%) were of another race or ethnicity
(including Native American or Alaska Native, more than one race, or other, consolidated
owing to low numbers). Baseline mean (SD) CGI-S score was 4.44 (0.79) for the MBSR group
and 4.51 (0.78) for the escitalopram group in the per-protocol sample and 4.49 (0.77) vs
4.54 (0.83), respectively, in the randomized sample. At end point, the mean (SD) CGI-S score
was reduced by 1.35 (1.06) for MBSR and 1.43 (1.17) for escitalopram. The difference between
groups was −0.07 (0.16; 95% CI, −0.38 to 0.23; P = .65), where the lower bound of the Author Affiliations: Department of
interval fell within the predefined noninferiority margin of −0.495, indicating noninferiority Psychiatry, Georgetown University
Medical Center, Washington, DC
of MBSR compared with escitalopram. Secondary intent-to-treat analyses using imputed
(Hoge, Dutton); Caen University
data also showed the noninferiority of MBSR compared with escitalopram based on the Hospital & UNICAEN, INSERM, U1237,
improvement in CGI-S score. Of patients who started treatment, 10 (8%) dropped out of PhIND, NEUROPRESAGE Team, Caen,
the escitalopram group and none from the MBSR group due to adverse events. At least France (Bui); Medstar Health
Research Institute, Hyattsville,
1 study-related adverse event occurred for 110 participants randomized to escitalopram Maryland (Mete); Massachusetts
(78.6%) and 21 participants randomized to MBSR (15.4%). General Hospital, Department of
Psychiatry, Harvard Medical School,
CONCLUSIONS AND RELEVANCE The results from this randomized clinical trial comparing Boston (Baker); Department of
a standardized evidence-based mindfulness-based intervention with pharmacotherapy for Psychiatry, New York University
the treatment of anxiety disorders found that MBSR was noninferior to escitalopram. Grossman School of Medicine,
New York (Simon).
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03522844 Corresponding Author: Elizabeth A.
Hoge, MD, Department of Psychiatry,
Georgetown University Medical
Center, 2115 Wisconsin Ave NW,
JAMA Psychiatry. 2023;80(1):13-21. doi:10.1001/jamapsychiatry.2022.3679 Ste 200, Washington, DC 20007
Published online November 9, 2022. ([email protected]).

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 Research Original Investigation Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders

A
nxiety disorders are the most common type of mental
disorder, currently affecting an estimated 301 million Key Points
people globally.1 Generalized anxiety disorder, social
Question Is mindfulness-based stress reduction noninferior
anxiety disorder, panic disorder, and agoraphobia are anxi- to escitalopram for the treatment of anxiety disorders?
ety disorders associated with considerable distress, impair-
Findings In this randomized clinical trial of 276 adults with anxiety
ment in functioning, and increased risk for suicide.2,3
disorders, 8-week treatment with mindfulness-based stress
Effective treatments for anxiety disorders exist and in-
reduction was noninferior to escitalopram.
clude medications and cognitive behavioral therapy, but not
all patients have access to them, respond to them, or are com- Meaning In this study, mindfulness-based stress reduction was
a well-tolerated treatment option with comparable effectiveness
fortable seeking care in a psychiatric setting. For example,
to a first-line medication for patients with anxiety disorders.
nearly one-third of people surveyed in 1 study4 believed that
psychiatric medication would interfere with daily activities,
and about one-fourth believed it is harmful to the body. Fur- and safety monitoring board. All participants provided writ-
ther, roughly two-thirds of patients who do start taking an an- ten informed consent. The study followed the Consolidated
tidepressant discontinue it.5 While cognitive behavioral therapy Standards of Reporting Trials (CONSORT) reporting guideline.
is also effective, it can be difficult for patients to access due to
a lack of health care professionals trained in this technique.6 Participants
These challenges support a need for additional evidence- Eligible participants were aged 18 to 75 years with a current pri-
based treatment options for patients with anxiety disorders mary diagnosis of generalized anxiety disorder, social anxi-
with broad acceptability. ety disorder, panic disorder, or agoraphobia, as determined
Mindfulness-based interventions (MBIs) may be seen as by structured psychiatric diagnostic interviews performed by
a more acceptable option given that mindfulness meditation trained clinicians.14 A diagnosis was determined primary (using
has recently become more popular. For example, in the US, ap- clinical judgment with participant input) as the condition with
proximately 15% of the population has tried meditation.7 Mind- the most severe symptoms and that caused the greatest amount
fulness meditation has been found to help reduce anxiety; of interference and distress for the patient in their daily life.
a recent meta-analysis8 of trials with anxiety disorders found Eligibility criteria have been described elsewhere13 and were
a significant benefit with mindfulness meditation compared selected to include a generalizable population of adults with
with treatment as usual. While MBIs have been shown to de- anxiety disorders. Briefly, major exclusion criteria included life-
crease anxiety,9,10 the need to assess the relative effective- time bipolar disorder, psychotic disorders, or obsessive com-
ness of MBIs compared with standard therapies for anxiety dis- pulsive disorder as well as current anorexia or bulimia ner-
orders has been emphasized. 11 Mindfulness-based stress vosa, posttraumatic stress disorder, substance use disorders,
reduction (MBSR) is the most widely researched MBI (over 1000 or significant active suicidal ideation or behaviors. Partici-
citations in PubMed) and is available internationally.12 pants must not have completed MBSR or equivalent training
To our knowledge, no clinical trial comparing an evidence- in the past year or had an ongoing daily meditation practice.
based MBI, such as MBSR, with a first-line pharmacological Patients taking psychiatric medications were excluded ex-
treatment for anxiety disorders has been published. To clarify cept for trazodone (if 100 mg or less), sleep medications (zol-
whether MBSR should be considered an alternative first-line pidem and eszopiclone), and benzodiazepines, if at stable dose
intervention comparable to a gold-standard pharmaco- 4 weeks prior to baseline. Recruitment included online, print,
therapy used in primary care, our aim was to compare MBSR and radio advertisements.
with escitalopram, an European Medicines Agency– and
US Food and Drug Administration–approved pharmaco- Randomization and Blinding
therapy for the treatment of anxiety and hypothesized that Potential participants deemed eligible on phone screening were
MBSR would be noninferior to escitalopram. scheduled for an in-person consent and structured interview
with a study clinician. The study statistician (M.M.) made a
computer-generated concealed block randomization sched-
ule that was stratified by site and baseline anxiety severity
Methods (low = Clinical Global Impression of Severity [CGI-S]15 score
Study Design ≤4; high = CGI-S >4). The randomization schedule was pro-
Our study protocol and analysis plan are published in full else- grammed into the study electronic data capture software
where and in Supplement 1.13 Treatments for Anxiety: Medi- (Research Electronic Data Capture [REDCap] version 12.4.12).
tation and Escitalopram (TAME) is a prospective randomized The baseline CGI-S score for each participant was entered into
2-arm parallel-group controlled single-blinded (blinded rat- REDCap, which then assigned the treatment group. In this
ers, with unblinded providers and participants) trial to evalu- single-blinded trial, the computer-generated randomization
ate the relative effectiveness of 8 weeks of MBSR vs escitalo- assignment was revealed through REDCap to the research
pram. Recruitment and enrollment occurred at 3 US hospital assistant, who then relayed the assignment to the site study
sites in Boston, Massachusetts, New York, New York, and Wash- clinician, but all symptom severity ratings for the primary out-
ington, DC. The study was approved by each institution’s in- come were performed by independent evaluators who were
stitutional review board and overseen by an independent data blinded to treatment allocation.

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 Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders Original Investigation Research

Procedures estimation, we reduced the margin to −0.33, which generated

The CGI-S is a widely used treatment-sensitive instrument that a target randomized sample size of 368 providing 80% power
assesses overall severity of symptoms on a scale from 1 (not with a 1-sided type I error of 0.025 (or equivalently with 95%
at all ill) to 7 (among the most extremely ill).15 Independent CI) for a noninferiority test. However, due to the SARS-Cov-2
evaluator ratings were performed at baseline (week 0), pandemic, we had to stop enrollment at 276. After discussion
midtreatment (week 4), end point (posttreatment week 8), and with the data and safety monitoring board and trial sponsor, it
follow-up (weeks 12 and 24). Study participants were in- was determined that since 276 randomized participants (with
structed and reminded not to disclose their treatment group 208 participants who completed the trial) still provided 80%
to the independent evaluator. A random 5% of independent power to determine noninferiority with our clinically accept-
evaluator sessions were corated, yielding a CGI-S interrater re- able a priori margin of −0.495, we thus confirmed this margin,
liability of κ = 0.80. Participants also met at weeks 1, 2, 4, 6, clarified the sample size and margin on ClinicalTrials.gov,
and 8 (end point) and follow-up visits (weeks 12 and 24) with agreed not to attempt to reopen enrollment after the pan-
an unblinded study clinician for safety monitoring, including demic, and moved forward with data analysis.
assessment of adverse events, clinical worsening, and emerg- The per-protocol analysis was prespecified as primary, and
ing suicidality, with referral if needed to the most appropri- the intent-to-treat (ITT) sample as secondary, as is typical for
ate level of medical care based on clinician judgment. noninferiority trials, to account for the increased chance of evi-
dence in favor of noninferiority in ITT analyses.18 Partici-
Interventions pants completing at least 6 of the 9 MBSR sessions19 or at least
MBSR 6 weeks of escitalopram use with nonmissing end point CGI-S
MBSR is a manualized 8-week protocol with weekly 2.5-hour data were considered to have completed the trial.
long classes, a day-long retreat weekend class during the fifth Baseline characteristics of the participants were summa-
or sixth week, and 45-minute daily home practice exercises.16 rized using descriptive statistics for all randomized partici-
Study participants received MBSR classes at clinic and com- pants as well as for those who completed the trial by treat-
munity sites. Qualified instructors taught the theory and prac- ment groups and are presented in Table 1. We collected data
tice of several forms of mindfulness meditation, such as breath on race and ethnicity as required by our trial sponsor; these
awareness (focusing attention on the breath and other physi- data were collected using a multiple-choice self-report form
cal sensations), a body scan (directing attention to one body based on the National Institutes of Health standard enroll-
part at a time and observing how that body part feels), and ment table. Treatment group differences at baseline were tested
mindful movement (stretching and movements designed to using 2-sample t tests, χ2, and Fisher exact tests as appropri-
bring awareness to the body and increase interoceptive aware- ate. Baseline characteristics were also compared between those
ness). A qualified MBSR instructor (M.A.D.) reviewed audio who completed the trial and those who did not using similar
recordings from a representative session from every MBSR bivariate statistical tests (eTable 1 in Supplement 2) to evalu-
teacher to ensure treatment fidelity. Participants’ class atten- ate whether characteristics of those who did not complete the
dance was recorded by the MBSR teacher or through self- trial were significantly different at baseline compared with
report to the unblinded study clinician. those of participants who did complete the trial.
Primary outcome assessment at end point was first con-
Escitalopram ducted for the sample of participants who completed the trial
Escitalopram was initiated at 10 mg daily orally and in- consistent with the primary preplanned analysis and then as
creased to 20 mg daily at week 2 if well tolerated or delayed if planned for all randomized participants (ITT sample) by im-
not. Adherence was measured by pill count and patient re- puting end point scores for those who did not complete the
port. Medication management visits with a study clinician trial and were without week-8 data. The change in the out-
(M.D. or N.P.) occurred at weeks 1, 2, 4, 6, and 8 (end point). come indicating the amount of improvement was computed
After end point, patients wishing to continue taking escitalo- by subtracting the end point score from the baseline score. End-
pram were assisted in doing so. point CGI-S data were imputed using multiple imputation with
multivariate normal regression methods combining 50 im-
Outcomes puted samples after establishing that missingness was at ran-
The primary outcome measure was the CGI-S15 scale for anxi- dom. The multivariate normal regression model for imputa-
ety, assessed by trained clinicians. Our primary patient- tion included age, employment status, race, sex, site, use of
reported outcome was the Overall Anxiety Severity and Im- benzodiazepines, primary diagnosis, total number of second-
pairment Scale (OASIS).17 ary diagnoses, baseline CGI-S score, and high vs low severity
used in stratification. Secondary analyses of the primary out-
Sample Size and Statistical Analysis Plan come were conducted using linear mixed models to further ex-
The sample size was determined using a noninferiority mar- amine the trends in CGI-S in the ITT sample, including data for
gin based on previous similar studies.13 Following published baseline and weeks 4, 8, 12, and 24. The mixed models with
guidelines and taking into account the minimal clinically im- random effects at participant level were adjusted by age, race,
portant difference change score for the CGI-S, we adopted a non- sex, site, baseline severity variable used for stratification, and
inferiority margin of −0.495 as the largest clinically accept- the number of secondary diagnoses and included interac-
able margin.13 To be more conservative for the sample size tions between treatment group and time indicators entered as

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 Research Original Investigation Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders

Table 1. Baseline Characteristics for All Randomized Participants and Those Who Completed Protocol at 8 Weeks

Randomized Completed protocol

No (%) No. (%)
Variablea MBSR Escitalopram P value MBSR Escitalopram P value
No. 136 140 NA 102 106 NA
Site
Georgetown University Medical Center 61 (45) 63 (45) 50 (49) 50 (47)
New York University Langone 32 (24) 35 (25) NA 18 (18) 27 (25) .38
Massachusetts General Hospital 43 (32) 42 (30) 34 (33) 30 (28)
Disorder severity
Low 68 (50) 70 (50) 54 (53) 55 (51)
NA .82
High 68 (50) 70 (50) 48 (47) 52 (49)
Sex .78 .40
Female 101(74) 106 (76) 74 (73) 83 (78)
Male 35 (26) 34 (24) 28 (28) 24 (22)
Age, mean (SD), y 33 (12) 33 (13) .67 33 (12) 34 (14) .92
Raceb
Asian 27 (20) 24 (17) 23 (23) 18 (17)
Black 19 (14) 21 (15) 15 (15) 17 (16)
.67 .68
White 83 (61) 83 (59) 59 (58) 64 (60)
Otherc 7 (5) 12 (9) 5 (5) 8 (8)
Ethnicityb
Hispanic/Latino 7 (5) 18 (13) .02 4 (4) 14 (13) .02
Education
≤High school 5 (4) 4 (3) 4(4) 3 (3)
Some college 25 (18) 26 (19) 18 (18) 22 (21)
.32 .23
College degree 43 (32) 59 (42) 30 (29) 44 (41)
Graduate school degree 63 (46) 51 (36) 50 (49) 38 (36)
Marital status
Single 82 (60) 86 (61) 63 (62) 64 (60)
Living with partner/married 47 (35) 43 (31) .58 34 (33) 37 (35) .95
Divorced/widowed/separated 7 (5) 11 (8) 5 (5) 6 (6)
Employment status
Not applicable 17 (13) 11 (8) 13 (13) 8 (8)
Full-time 73 (54) 88 (63) 56 (55) 63 (59)
.20 .43
Part-time 16 (12) 20 (14) 10 (10) 15 (14)
Student/dependent on spouse 30 (22) 21 (15) 23 (23) 20 (19)
Primary diagnosis
Panic disorder 2 (1.5) 9 (6) 0 9 (8)
Agoraphobia 2 (1.5) 2 (1.4) 2 (2) 1 (1)
.20 .01
Social anxiety disorder 48 (35) 44 (31) 35 (34) 37 (35)
Generalized anxiety disorder 84 (62) 85 (61) 65 (64) 59 (56)
Comorbid conditions
Major depressive disorder 12 (9) 17 (12) .24 8 (8) 12 (11) .41
Panic disorder 22 (16) 27 (19) .30 17 (17) 23 (22) .38
Agoraphobia 12 (9) 16 (11.4) .30 7 (7) 11 (10) .38
Social anxiety disorder 29 (21) 45 (32) .03 24 (24) 34 (32) .18
Generalized anxiety disorder 16 (12) 27 (19.3) .06 12 (12) 26 (24) .02
Comorbid conditions, No.
0 46 (35) 40 (29) 30 (29) 32 (30)
1 49 (36) 44 (31) 40 (39) 28 (26)
2 27 (20) 35 (25) .15 24 (24) 28 (26) .08
3 14 (10) 16 (11) 8 (8) 15 (14)
4 0 5 (4) 0 4 (4)

(continued)

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 Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders Original Investigation Research

Table 1. Baseline Characteristics for All Randomized Participants and Those Who Completed Protocol at 8 Weeks (continued)

Randomized Completed protocol

No (%) No. (%)
Variablea MBSR Escitalopram P value MBSR Escitalopram P value
Comorbid conditions, mean (SD) 1.1 (1.0) 1.3 (1.1) .06 1.1 (0.9) 1.4 (1.2) .08
Baseline CGI-S score, mean (SD) 4.49 (0.77) 4.54 (0.83) .60 4.44 (0.79) 4.51 (0.78) .53
Concurrent benzodiazepine use 4 (3) 7 (5) .29 2 (2) 6 (6) .17
Sleep medication 2 (2) 6 (4) .28 2 (2) 3 (3) >.99
Abbreviations: CGI-S, Clinical Global Impression of Severity scale; National Institutes of Health standard enrollment table.
MBSR, mindfulness-based stress reduction; NA, not applicable. c
Other included Native American or Alaska Native, more than one race, or
a
Group means were compared using 2-sample t tests. Percentages for other, consolidated because of low numbers in these groups and because test
categorical variables were compared using χ2 test or Fisher exact test. results based on percentages become misleading when the distribution of
b
We collected data on race and ethnicity as required by our trial sponsor; these observations across categories is highly disproportionate.
data were collected using a multiple-choice self-report form based on the

dummy variables with baseline as the reference category. Pre- and the escitalopram group by 1.43 (1.17) points. The differ-
dicted margins were computed at each time point for both treat- ence between the groups in the primary CGI-S outcome at week
ment groups. The patient-reported outcome measure OASIS 8 (change in MBSR minus change in escitalopram) was −0.07
was described and analyzed using similar methods. Safety out- (95% CI, −0.38 to 0.23; P = .65). The confidence interval crossed
comes were assessed for all randomized participants. All analy- zero, suggesting that the change was not significantly differ-
ses were conducted in Stata version 15 (StataCorp; com- ent between groups. The lower end of this 97.5% (−0.38) was
mands: mi impute, mi estimate, xtmixed, margins, contrasts, smaller than the prespecified noninferiority margin of −0.495,
marginsplot) by coinvestigator statistician M.M. indicating noninferiority of MBSR compared with escitalo-
pram (Figure 2). CGI-S outcomes for each time point by treat-
ment are reported in Table 2.
Sensitivity analyses in the ITT sample at week 8 using im-
Results puted data also showed a noninferiority of MBSR compared
Of 430 adults who consented and were assessed by study cli- with escitalopram based on the improvement in CGI-S score
nicians, 276 met study criteria (mean [SD] age, 33 [13] years; (eTable 3 in Supplement 2). We had 222 observations for CGI-S
156 [75%] female; 32 (15%) African American, 41 (20%) Asian, at week 8 regardless of participants’ completion status. Sen-
18 (9%) Hispanic/Latino, 122 (59%) White, and 13 (6%) of an- sitivity analyses comparing baseline characteristics between
other race or ethnicity, including Native American or Alaska participants with and without week 8 data suggested no sys-
Native, more than one race, or other, consolidated because of tematic differences in missingness patterns (eTable 2 in Supple-
low numbers in these groups and because test results based ment 2). Multiple imputation was thus performed to impute
on percentages become misleading when the distribution of CGI-S score for participants with no end point assessment. Re-
observations across categories is highly disproportionate). Par- sults summarized over 50 imputed samples generated a mean
ticipants were randomized to MBSR (n = 136) or escitalopram (SE) of 3.16 (0.11) for MBSR and 3.12 (0.11) for escitalopram at
(n = 140). In the escitalopram group, 33 participants either did week 8. The difference between groups was estimated using
not begin or only partially received treatment, and 1 missed a linear regression model of CGI-S score on treatment group
the end point study visit, and in the MBSR group, 34 partici- indicator using imputed samples with no other covariates. The
pants either did not begin or only partially received treat- CGI-S score was smaller on average by 0.04 points for the
ment, resulting in a final sample of 208 participants. See Table 1 ESC group, but the difference was not statistically significant
for participant characteristics and Figure 1 for the CONSORT (95% CI, −0.33 to 0.26, P = .81). The mean (SE) improvement
diagram. Participants were enrolled between June 6, 2018, in the MBSR group was 1.34 (0.10) and 1.43 (0.11) in the escit-
and February 11, 2020. alopram group. The difference between the groups was esti-
Baseline demographic characteristics were similar be- mated to be −0.09 (95% CI, −0.39 to 0.20). The confidence in-
tween the per-protocol and ITT samples (eTable 1 in Supple- terval crossed zero, indicating no difference between the
ment 2) and by treatment group within each sample (Table 1). groups. In addition, the lower end of this 97.5% CI (−0.39) was
Clinical severity at baseline was in the moderate to markedly smaller than the prespecified noninferiority margin of −0.495,
ill range and did not differ by treatment group. Baseline mean showing that MBSR was noninferior to escitalopram.
(SD) CGI-S score was 4.44 (0.79) for MBSR and 4.51 (0.78) for Next, we examined the primary outcome at follow-up and
escitalopram in the per-protocol sample and 4.49 (0.77) vs 4.54 found that both the MBSR and escitalopram groups contin-
(0.83) in the randomized sample. ued to improve in the follow-up period (Table 2). The mean (SD)
Primary outcome analyses in those who completed the trial CGI-S score for those who completed treatment was 2.89 (1.09)
at week 8 showed noninferiority for CGI-S score improve- in MBSR and 2.95 (1.07) in escitalopram (difference = −0.07;
ment with MBSR compared with escitalopram. Specifically, at P = .67) at week 12, and 2.92 (1.17) in MBSR and 2.92 (1.03) in
week 8, the MBSR group improved by a mean (SD) 1.35 (1.06) escitalopram (difference = 0.00; P > .99) at week 24.

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 Research Original Investigation Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders

Figure 1. CONSORT Diagram

430 Assessed for eligibility

154 Excluded
118 Did not meet inclusion criteria
49 Had an excluded psychiatric diagnosis
35 No anxiety disorder
12 Medical conditions
11 Not willing to follow or unable to
understand study procedures
4 High risk for suicidality
3 Currently taking disallowed medication
3 Recently initiated psychotherapy
1 Already completed MBSR training
or equivalent
18 Declined to participate
14 Lost contact
2 Became ineligible
2 COVID-19–related reasons

276 Randomized

140 Assigned to receive escitalopram 136 Assigned to MBSR

125 Received intervention as assigned 117 Received intervention as assigned
15 Did not receive assigned intervention 19 Did not receive assigned intervention
4 Unwilling to take medication 12 Time commitment challenges
3 Time commitment challenges 1 Traveling/moving during study
2 Traveling/moving during study 2 COVID-19–related reasons
3 Changed mind about study 1 Worsening depression, desire to seek
3 Lost contact other treatment
3 Lost contact or unknown reasons

5 Lost to follow-up (due to lost contact or unknown reason) 3 Lost to follow-up (due to lost contact or unknown reason)
13 Discontinued intervention 12 Discontinued intervention
10 Adverse events 2 Time commitment challenges
1 Time commitment challenges 2 Dissatisfaction with treatment
1 Dissatisfaction with treatment 1 Religious conflict
1 Declined to comply with procedures 7 Did not attend sufficient number of MBSR sessions
1 Missed end point study visit

106 Included in per-protocol treatment 102 Included in per-protocol treatment

106 Analyzed for week 12 105 Analyzed for week 12

98 Analyzed for week 24 104 Analyzed for week 24

140 Analyzed for intent-to-treat 136 Analyzed for intent-to-treat

MBSR indicates mindfulness-based
stress reduction.

Longitudinal data were analyzed using a linear mixed ences between the groups at week 4 show that participants in
model of CGI-S in the ITT sample with random effects at par- the escitalopram group experienced larger improvements
ticipant level, pooling data across 5 time points: baseline in the short term by OASIS score (mean, 1.2; 95% CI, −2.02 to
(n = 276), week 4 (n = 226), week 8 (n = 222), week 12 (n = 211), −0.35; P = .01) in escitalopram. The treatment groups were not
and week 24 (n = 202). The model estimates are presented in significantly different at end point on OASIS score (−0.7; 95%
eTable 4 in Supplement 2 showing the predicted mean differ- CI, −1.51 to 0.17; P = .12).
ences with 95% CIs between groups at each time point. Group No serious adverse events occurred during the study across
trajectories over time, based on predicted means, are illus- the 2 arms. At least 1 study-related adverse event occurred for
trated in Figure 3. Results show that the adjusted mean dif- 110 participants randomized to escitalopram (78.6%) and 21
ference between the groups was −0.07 points (95% CI, −0.31 participants randomized to MBSR (15.4%) (P < .001). Adverse
to 0.17; P = .55) at week 8, further confirming the noninferi- events (considered possibly or definitely related to study treat-
ority of MBSR to escitalopram. Baseline mean (SD) scores for ment) that occurred in 5% or more of participants in the esci-
OASIS were 9.2 (2.9) in MBSR and 9.5 (3.0) in escitalopram with talopram group were insomnia or sleep disturbance (n = 51;
no statistically significant difference (P = .48). At the primary 41%), nausea (n = 44; 35%), fatigue (n = 33; 26%), headache
end point (week 8), treatment groups were not significantly (n = 23; 18%), somnolence (n = 18; 14%), anorgasmia or de-
different either (5.8 [3.8] in MBSR vs 5.2 [3.5]; P = .21). layed orgasm (n = 14; 11%), abnormal dreaming (n = 11; 9%),
The results of the linear mixed models for outcomes are decreased appetite (n = 11; 9%), jitteriness (n = 11; 9%), de-
presented in eTable 4 in Supplement 2. The predicted differ- creased libido (n = 9; 7%), dizziness/lightheaded/faint (n = 8;

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 Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders Original Investigation Research

6%), increased sweating (n = 8; 6%), and anxiety (n = 7; 5%). with generalized anxiety disorder and failed to show nonin-
The only adverse event (possibly or definitely related to treat- feriority. Compared with our MBI, the dropout rate in Costa
ment) that occurred in 5% or more of participants in the MBSR et al22 was higher (nearly 40% vs 25%), the sample size was
group was increased anxiety (n = 13; 11%). A full list of ad- smaller (165 vs 276), the intervention length was shorter (16
verse events across treatment arms is reported in eTables 5 and hours vs 27 hours), and the intervention structure and con-
6 in Supplement 2. tent were fundamentall different. We are unaware of other
No participants discontinued due to clinical worsening or noninferiority studies comparing MBIs with medications in
emerging suicidality. The completion rate (completing at least anxiety disorders. Strengths of our study include a carefully
6 of the 9 MBSR sessions or at least 6 weeks of escitalopram) diagnosed and well-characterized patient sample, trained
for participants was 75% for MBSR (n = 102) and 76.5% (n = 106) clinical raters blinded to treatment allocation doing assess-
for escitalopram. At 12-week follow-up, 75 (78%) of the escit- ments, and a prespecified clinically meaningful noninferior-
alopram group reported continued treatment, and 48 (49%) ity margin.
in MBSR had continued meditating (defined as at least 4 days
a week). By 24-week follow-up, 53 (52%) were still taking Limitations
escitalopram while 27 (28%) in MBSR were still doing regular This study has limitations. Treatments in this study were not
mindfulness meditation. matched for time and attention, as participants in the MBSR
group spent more time engaged in treatment-related activi-
ties than those in the escitalopram group, and this design
allowed only for single-blinding procedures. However, this
Discussion comparative effectiveness trial was designed to inform clini-
cal decision-making in the real world rather than test the
Our prospective randomized clinical trial found that MBSR was
theoretical efficacy of 2 time-matched arms, and contact
noninferior to escitalopram for the treatment of anxiety dis-
orders. In addition, MBSR was safe and well tolerated, with Figure 2. Noninferiority Diagram
fewer adverse events associated with treatment compared
with escitalopram. The magnitude of symptom reduction in Noninferiority margin = –0.496
the escitalopram group (mean of 1.4 points on the CGI-S) was Effect size and 95% CI for the MBSR MBSR
comparable to published studies that established escitalo- difference in the PP sample inferior noninferior
pram as more effective than placebo. For example, Davidson –0.07 (–0.38 to 0.23)

et al20 compared escitalopram with placebo for generalized Effect size and 95% CI for the
difference in the ITT sample
anxiety disorder and found a decrease of 1.4 points on the
–0.09 (–0.39 to 0.20)
CGI-S. In another example, Asakura et al21 reported a de-
crease of 1.1 points on the CGI-S in a randomized clinical trial –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8
Difference (95% CI)
using escitalopram for social anxiety disorder.
To our knowledge, this is the first study comparing a
Effect sizes and noninferiority confidence intervals of primary outcome for
standardized evidence-based MBI with a first-line medica- mindfulness-based stress reduction (MBSR) vs escitalopram (week 8 end
tion for anxiety disorders. Costa et al22 compared an experi- point). Difference is the improvement in MBSR minus improvement in
mental MBI based on movement exercises rather than the escitalopram. Shaded region indicates region of noninferiority. ITT indicates
intent-to-treat; PP, per-protocol.
traditional sitting meditation, with fluoxetine in patients

Table 2. Primary Outcome Assessment Clinical Global Impression of Severity for Mindfulness-Based Stress
Reduction (MBSR) vs Escitalopram

Mean (SD)
Mean P
CGI-S score MBSR Escitalopram difference (SE) value
No. 102 106
Baseline 4.44 (0.79) 4.51 (0.78) −0.07 (0.11) .53
No. 136 140
Week 4 3.42 (1.01) 3.34 (1.04) 0.09 (0.14) .55
No. 101 106
Primary end point (week 8) 3.09 (1.09) 3.09 (1.07) 0.00 (0.15) .98
No. 102 106
Change from baseline to end 1.35 (1.06) [1.15 to 1.43 (1.17) [1.20 to −0.07 (0.16) [−0.38 to .65
point, mean (SD) [95% CI] 1.56] 1.65] 0.23]
Follow-up (week 12) 2.89 (1.09) 2.95 (1.07) −0.07 (0.15) .67
No. 96 102
Follow-up (week 24) 2.92 (1.17) 2.92 (1.03) 0.00 (0.16) 1
Abbreviation: CGI-S, Clinical Global
No. 95 95
Impression of Severity.

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 Research Original Investigation Mindfulness-Based Stress Reduction vs Escitalopram for the Treatment of Anxiety Disorders

ment at 3 urban academic medical centers, which may limit

Figure 3. Longitudinal Data
the generalizability of the findings.
5.0

MBSR
4.5
Escitalopram
4.0
Conclusions
Predicted CGI-S score

In this trial, an MBSR was shown to be a well-tolerated treatment

3.5
option with comparable effectiveness to a first-line medication
3.0 for patients with anxiety disorders. Problematic habitual thought
2.5 patterns characterize anxiety disorders, and mindfulness train-
ing specifically focuses the mind on the present moment; thus,
2.0
individuals practice seeing thoughts and sensations as merely
1.5 transient mental phenomena and not necessarily accurate reflec-
1.0
tions of reality.23 This reappraisal process improves emotion
Baseline Week 4 Week 8 Week 12 Week 24 regulation, and individuals become less reactive to thoughts
Time
and sensations.24 In addition, mindfulness is practiced with a
nonjudgmental, accepting attitude, which over time appears to
Predicted Clinical Global Impression Severity scale (CGI-S) score based on
a linear mixed model adjusted by age, sex, race, site, and total number of increase self-acceptance and self-compassion.25
secondary diagnoses. MBSR indicates mindfulness-based stress reduction. Of note, MBSR in this trial was delivered in person, with
trained meditation teachers available weekly to answer questions
with the research study team was matched between the and guide practices, limiting any extrapolation in support of mind-
groups, with the clinical safety and assessment visits using fulness apps or programs that are delivered over the internet.
the same procedures and carried out by the same members Future studies should assess the clinical effectiveness of virtual
of the study staff. Sleep medications and benzodiazepines delivery of MBSR, other MBIs, and of mindfulness apps.
were also allowed if stable for at least 4 weeks prior to entry; Although replication in different settings is warranted, this
however, the rate of use was minimal (<5%) and did not vary study’s finding of the noninferiority of MBSR to a first-line phar-
by group (Table 1). Other limitations include a sample that macotherapy for treatment of anxiety provides support for
was predominantly female with a relatively high education mindfulness meditation as an evidence-based treatment
level, the lack of data on disorder chronicity, and recruit- option for adults with anxiety disorders.

ARTICLE INFORMATION consulting fees from Engrail Therapeutics, 2022;9(2):137-150. doi:10.1016/S2215-0366(21)

Accepted for Publication: September 21, 2022. Bionomics Limited, BehavR LLC, Vanda 00395-3
Pharmaceuticals, Praxis Therapeutics, Cerevel, 2. Nepon J, Belik SL, Bolton J, Sareen J.
Published Online: November 9, 2022. Genomind, and Wiley (deputy editor Depression
doi:10.1001/jamapsychiatry.2022.3679 The relationship between anxiety disorders and
and Anxiety); royalty fees from Wolters Kluwer suicide attempts: findings from the National
Author Contributions: Drs Hoge and Mete had full (UpToDate), APA Publishing (Textbook of Anxiety, Epidemiologic Survey on Alcohol and Related
access to all the data in the study and take Trauma and OCD Related Disorders, 2020); and Conditions. Depress Anxiety. 2010;27(9):791-798.
responsibility for the integrity of the data and the spousal equity in G1 Therapeutics and Zentalis doi:10.1002/da.20674
accuracy of the data analysis. outside the submitted work. No other disclosures
Concept and design: Hoge, Bui, Mete, Dutton, were reported. 3. Ormel J, VonKorff M, Ustun TB, Pini S, Korten A,
Simon. Oldehinkel T. Common mental disorders and
Funding/Support: This research was supported by disability across cultures. results from the WHO
Acquisition, analysis, or interpretation of data: the Patient-Centered Outcomes Research Institute
All authors. Collaborative Study on Psychological Problems in
(PCORI; CER-2017C1–6522). General Health Care. JAMA. 1994;272(22):1741-1748.
Drafting of the manuscript: Hoge, Bui, Mete, Simon.
Critical revision of the manuscript for important Role of the Funder/Sponsor: The funder had no doi:10.1001/jama.1994.03520220035028
intellectual content: All authors. role in the design and conduct of the study; 4. Croghan TW, Tomlin M, Pescosolido BA, et al.
Statistical analysis: Mete. collection, management, analysis, and American attitudes toward and willingness to use
Obtained funding: Hoge, Bui, Dutton, Simon. interpretation of the data; preparation, review, psychiatric medications. J Nerv Ment Dis. 2003;191
Administrative, technical, or material support: Hoge, or approval of the manuscript; and decision to (3):166-174. doi:10.1097/01.NMD.0000054933.
Bui, Baker, Simon. submit the manuscript for publication. 52571.CA
Supervision: Hoge, Bui, Dutton, Baker, Simon. Data Sharing Statement: See Supplement 3. 5. Mullins CD, Shaya FT, Meng F, Wang J, Bron MS.
Conflict of Interest Disclosures: Dr Bui reports Additional Contributions: We thank the study Comparison of first refill rates among users of
grants from the National Institutes of Health and participants, the mindfulness-based stress sertraline, paroxetine, and citalopram. Clin Ther.
the US Department of Defense, licenses or reduction teachers, and the research staff and 2006;28(2):297-305. doi:10.1016/j.clinthera.2006.
royalties from Springer and Wolters Kluwyer, and the New York University Innovation Fund for 02.006
consulting fees from Cereval Therapeutics. In the partial support for study treatments. 6. Shafran R, Clark DM, Fairburn CG, et al. Mind the
past 3 years, Dr Simon reports grants from the gap: improving the dissemination of CBT. Behav Res
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