BRIEF REPORT
Does Bupropion Increase Anxiety?
A Naturalistic Study Over 12 Weeks
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Zachary Poliacoff, MD,1 Heather G. Belanger, PhD,1,2 and Mirène Winsberg, MD2
Abstract:
Purpose/Background: There has long been a clinical belief that bupropion
exacerbates anxiety. The purpose of the current retrospective study is to
compare anxiety severity over time in those prescribed selective serotonin
reuptake inhibitors (SSRIs) versus bupropion.
Methods/Procedures: Archival data (N = 8457) from patients receiv-
ing psychiatric care from a national tele-mental health company were used.
Propensity matching was used to create SSRI and bupropion groups using
17 covariates. These samples were then compared using repeated measures
analysis of variance on Generalized Anxiety Disorder Scale 7 scores at start
of treatment, 6 weeks, and 12 weeks.
Findings/Results: The SSRI and bupropion groups were significantly
different across a number of variables. In the entire sample, the bupropion
group had significantly greater anxiety levels. However, for propensity-
matched comparisons, there were no significant interactions between group
and time (ie, groups did not differ and improved comparably over time).
Implications/Conclusions: Using propensity matching, there were no
differences in anxiety outcome between those prescribed selective seroto-
nin reuptake inhibitor versus bupropion across 12 weeks of treatment.
Key Words: bupropion, antidepressant, anxiety, depression, selective
serotonin reuptake inhibitors
(J Clin Psychopharmacol 2023;43: 152–156)
T he only medications currently Food and Drug Administration–
approved for generalized anxiety disorder (GAD) are the se-
lective serotonin reuptake inhibitors (SSRIs) paroxetine and
escitalopram, and the selective serotonin-norepinephrine reuptake
inhibitors (SNRIs) duloxetine and venlafaxine. In clinical prac-
tice, virtually all SSRIs, SNRIs, tricyclic antidepressants, and
“atypical” antidepressants are used to treat GAD and other anxiety
disorders.1 One exception is the norepinephrine-dopamine reup-
take inhibitor bupropion, which has several advantages over other
antidepressants: it is less likely to cause weight gain or sexual dys-
function, is not sedating, and is less likely to induce mania.2 How-
ever, many clinicians believe that it will exacerbate anxiety3 and
avoid it for patients with comorbid depression and anxiety.4
In an analysis of 10 pooled studies, Papakostas et al5 found a
small advantage for SSRIs versus bupropion in treating anxious
From the 1Department of Psychiatry and Behavioral Neurosciences, University
of South Florida, Tampa, FL; and 2Brightside Health, Inc, Oakland, CA.
Received November 8, 2022; accepted after revision December 8, 2022.
Address correspondence to: Heather Belanger, PhD, 5214F Diamond Heights
Blvd #3422, San Francisco, CA 94131 (e‐mail: heather.belanger@
brightside.com).
Funding for the current research was provided by Brightside Health, Inc, and the
University of South Florida. H.G.B. and M.W. are employees of and own
stock in Brightside Health.
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the work
provided it is properly cited. The work cannot be changed in any way or
used commercially without permission from the journal.
ISSN: 0271-0749
DOI: 10.1097/JCP.0000000000001658
152 www.psychopharmacology.com Journal of Clinical Psychopharmacology • Volume 43, Number 2, March/April 2023
depression (ie, depressed individuals with high concurrent anxi-
ety) for response rates, but not for remission. However, various
meta-analyses and studies comparing SSRIs with bupropion have
found comparable rates of improvement in anxiety.6,7 The largest
relevant meta-analysis to date, which included 2890 patients across
10 studies, found that bupropion provided comparable improve-
ment in anxiety symptoms compared with SSRIs6; all included
studies used the Hamilton Depression Rating Scale (HDRS)
Anxiety-Somatization Factor.
This article attempts to confirm earlier findings that bupropion
is an effective treatment for anxiety using a larger and more ho-
mogenous dataset with outcomes measured by the GAD Scale 7
(GAD-7),8 a self-report scale that is more commonly used in
clinical practice and which has high validity, sensitivity, and
specificity for detecting GAD.9 The goal of this study was to com-
pare anxiety over time in those prescribed SSRIs versus bupropion.
Our hypothesis is that both groups will provide similar reductions
in anxiety.
MATERIALS AND METHODS
Participants
Participant data used in the current investigation were obtained
from a national mental health telehealth company (ie, Brightside
Health) and consisted of 8457 US-based adult patients, aged 18
to 82 (mean age, 32.52; SD, 8.75) receiving psychiatric care for
anxiety or depression between November 2018 and January 2022.
Participants were eligible if they (a) were prescribed either a single
SSRI or bupropion and maintained on that same medication for
12 weeks, (b) had complete outcome data, and (c) were not pre-
scribed any other psychiatric medications during the 12-week study
period. Patients at high risk for suicide, patients with primary sub-
stance use disorder, and patients with psychosis or in need of emer-
gency psychiatric services at the initial evaluation were not eligible.
Procedure
All study procedures were approved by the WCG Institutional
Review Board for the retrospective analysis of patient data obtained
by Brightside Health as part of routine clinical care. Enrolled
Brightside Health patients complete an initial digital intake that
includes clinically validated measures of depression and anxiety,
as well as questions about clinical presentation, medical history,
and demographics. All Brightside Health patients are required to
complete baseline and intake questionnaires. During a patient's
first session, a licensed professional prescribed psychiatric medi-
cation(s) for each patient. Over the course of treatment, patients
communicated with their provider both asynchronously via mes-
saging and synchronously via video telehealth sessions. Assess-
ments were completed at baseline/intake and periodically thereaf-
ter. Surveys were administered digitally through an email prompt.
Survey completion at baseline, 6 weeks, and 12 weeks were re-
quired for participation.
 Journal of Clinical Psychopharmacology • Volume 43, Number 2, March/April 2023 Does Bupropion Increase Anxiety

TABLE 1. Characteristics of SSRI and Bupropion Groups

Propensity-Matched
Overall Cohort Cohort
Characteristic SSRI (n = 6528) Bupropion (n = 1,929) d* SSRI (n = 346) Bupropion (n = 346) d*
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Age 32.1 (8.6) 33.8 (8.9) 0.19 32.3 (8.7) 33.0 (8.5) 0.08
Baseline PHQ-9 16.5 (5.5) 17.3 (4.7) 0.14 17.7 (5.3) 17.4 (5.0) 0.06
Baseline GAD-7 14.9 (4.5) 11.5 (5.1) 0.75 14.9 (4.1) 14.8 (4.2) 0.03
No. chronic medical conditions 0.5 (0.8) 0.5 (0.8) 0.06 0.5 (0.8) 0.6 (0.8) 0.09
Frequency (%) Frequency (%)
Sex 0.04 0.00
Male 2032 (31.1) 690 (35.8) 114 (32.9) 114 (32.9)
Female 4496 (68.9) 1239 (64.2) 232 (67.1) 232 (67.1)
Region of the country 0.0 0.08
Midwest 1219 (18.7) 366 (19.0) 66 (19.1) 55 (15.9)
Northeast 1348 (20.6) 419 (21.7) 80 (23.1) 66 (19.1)
South 2212 (33.9) 661 (34.3) 116 (33.5) 128 (37.0)
West 1749 (26.8) 483 (25.0) 84 (24.3) 97 (28.0)
Prior antidepressant treatment 3734 (57.2) 981 (50.9) 0.1 144 (41.6) 170 (49.1) 0.08
Prior depressive 0.01 0.04
Episodes
None 478 (7.3) 135 (7.0) 27 (7.8) 20 (5.8)
One 760 (11.6) 234 (12.1) 36 (10.4) 36 (10.4)
>One 3222 (49.4) 932 (48.3) 179 (51.7) 187 (54.0)
Nonepisodic 2068 (31.7) 628 (32.6) 104 (30.1) 103 (29.8)
Education: 0.05 0.05
No high school 89 (1.4) 18 (0.9) 4 (1.1) 6 (1.7)
High school 1972 (30.2) 503 (26.1) 107 (30.9) 105 (30.3)
Some college 837 (12.8) 241 (12.5) 47 (13.6) 41 (11.8)
College degree 2473 (37.9) 776 (40.2) 132 (38.2) 128 (37.0)
Graduate degree 1157 (17.7) 391 (20.3) 56 (16.2) 66 (19.1)
Race/ethnicity 0.05 0.1
White/Caucasian 5070 (77.7) 1534 (79.5) 257 (74.3) 274 (79.2)
Asian 280 (4.3) 67 (3.5) 18 (5.2) 11 (3.2)
Hispanic 541 (8.3) 131 (6.8) 26 (7.5) 20 (5.8)
Black/African American 297 (4.5) 75 (3.9) 16 (4.6) 16 (4.6)
6 (1.7) 0 (0.0)
Native American/Pacific Islander 38 (0.6) 17 (0.9) 1 (0.3) 4 (1.2)
Other 302 (4.6) 105 (5.4) 22 (6.4) 21 (6.1)
Employed 0.01 0.06
Full time 4512 (69.1) 1357 (70.3) 240 (69.4) 247 (71.4)
Part time 758 (11.6) 209 (10.8) 34 (9.8) 41 (11.8)
Unemployed 1258 (19.3) 363 (18.8) 72 (20.8) 58 (16.8)
Annual income 0.06 0.06
<$30,000 1965 (30.1) 511 (26.5) 103 (29.8) 100 (28.9)
$30–60,000 2015 (30.9) 537 (27.8) 115 (33.2) 103 (29.8)
$60–100,000 1318 (20.2) 449 (23.3) 60 (17.3) 75 (21.7)
>$100,000 1230 (18.8) 432 (22.4) 68 (19.7) 68 (19.7)
Depression diagnosis 6204 (95.0) 1889 (97.9) 0.06 339 (98.0) 334 (96.5) 0.04
Anxiety diagnosis 5422 (83.1) 1086 (56.3) 0.27 297 (85.8) 288 (83.2) 0.34
Duration of illness 0.04 0.07
<2 wk 71 (1.1) 13 (0.7) 5 (1.4) 5 (1.4)
2 wk to 2 mo 715 (11.0) 203 (10.5) 31 (9.0) 32 (9.2)
2 mo to 1 y 1789 (27.4) 570 (29.5) 90 (26.0) 104 (30.1)
1 to 2 y 1140 (17.5) 369 (19.1) 62 (17.9) 71 (20.5)
>2 y 2813 (43.1) 774 (40.1) 158 (45.7) 134 (38.7)

Continued next page

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 Poliacoff et al Journal of Clinical Psychopharmacology • Volume 43, Number 2, March/April 2023

TABLE 1. (Continued)

Propensity-Matched
Overall Cohort Cohort
Characteristic SSRI (n = 6528) Bupropion (n = 1,929) d* SSRI (n = 346) Bupropion (n = 346) d*
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Current smoker 749 (11.5) 203 (10.5) 0.01 35 (10.1) 40 (11.6) 0.02
Current treatment 0.04 0.01
Medication 5226 (80.1) 1613 (83.6) 283 (81.8) 286 (82.7)
Medication + therapy 1302 (19.9) 316 (16.4) 63 (18.2) 60 (17.3)
Frequency of technology use, 0–4 0.01 0.08
Seldom, never 141 (2.2) 38 (2.0) 10 (2.9) 4 (1.2)
Rarely 570 (8.7) 183 (9.5) 32 (9.2) 34 (9.8)
Few times/week 1192 (18.3) 348 (18.0) 64 (18.5) 71 (20.5)
Once/day 1347 (20.6) 398 (20.6) 66 (19.1) 76 (22.0)
Multiple times/day 3278 (50.2) 962 (49.9) 174 (50.3) 161 (46.5)
Depression and anxiety diagnoses are based on PHQ-9 and GAD-7 criteria, respectively.
*d = standardized difference.

Measures Patients were not prescribed any other psychiatric medications

The Patient Health Questionnaire 9 (PHQ-9)10 is a 9-item
self-report measure used to assess the severity of depressive symp-
toms present within the prior 2 weeks as outlined by Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
criteria. Respondents rate items on a 4-point Likert scale (0–3) and
total scores range from 0 to 27, with scores of 10 or above falling into
the clinical range.11 Because provider diagnoses were not available
for most participants, criteria for major depressive disorder was con-
sidered met if 5 or more of the 9 items were endorsed at least “more
than half the days” in the past 2 weeks and one of the symptoms
was depressed mood or anhedonia.10 This approach was intended
to approximate DSM criteria—that is, at least 5 or more symptoms
and at least one of the symptoms must be either depressed mood or
loss of interest/pleasure.
The GAD-78 is a 7-item self-report instrument used to assess
the severity of anxiety symptoms present within the prior 2 weeks
as outlined by DSM-5 criteria. Respondents rate items on a 4-point
Likert scale (0–3) and total scores range from 1 to 21, with scores
of 10 and above falling into the clinical range.11 The GAD-7 has
shown strong reliability and validity, demonstrating 89% sensitiv-
ity and 82% specificity for GAD at a score of 10 or greater.9
Other variables measured at baseline included self-reported
age, sex, education, race/ethnicity, employment status, income, prior
episodes of depression (zero, one, or multiple), duration of the current
episode, prior antidepressant use (yes/no), comorbid anxiety disor-
ders (to include anxiety disorder unspecified, generalized anxiety dis-
order, obsessive compulsive disorder, social anxiety disorder, panic
disorder, acute stress disorder, or posttraumatic stress disorder), and
total number of chronic health conditions endorsed (including ar-
rhythmia, asthma, cancer, hypercholesterolemia, diabetes, heart con-
dition, irritable bowel syndrome or Crohn disease, lung disease,
obesity, thyroid disease, seizures, and chronic pain/fibromyalgia).
Interventions
Participants in the SSRI group were prescribed one of several
SSRIs (47.0% escitalopram, 32.8% sertraline, 16.8% fluoxetine,
3.5% other). Dosage adjustments were made based on participant
responses to the GAD-7, PHQ-9, and other assessments, as well as
virtual visits between patients and providers, and remained within
standard therapeutic ranges. Because this was a naturalistic study,
dosages were not controlled and varied to meet individual needs.
during the 12-week study period.
Data Analyses
Data analyses were performed via SPSS, Version 28. Anxiety
severity as measured by the GAD-7 at baseline, 6 weeks, and
12 weeks were compared between the SSRI group and the
bupropion group using repeated measures analysis of variance
(ANOVA) in the overall sample. Comparisons between groups were
made using t tests for continuous variables and χ2 analyses for cat-
egorical and evaluated at P < 0.01, two-tailed. Then, propensity
matching was done based on a priori variables collected at baseline
that might potentially affect outcome.12 This approach attempts to
replicate a randomized trial by obtaining treatment groups with sim-
ilar distributions of known covariates.13 Propensity score matching
was done using nearest neighbor pair matching without replace-
ment with a 0.00001 caliper, which is effective at reducing system-
atic differences between groups.14 Included variables were as fol-
lows: age, sex, race/ethnicity, education level, employment status,
income level, census-defined region of the country, past antidepres-
sant use (yes/no), number of chronic medical conditions, current
smoker (yes/no), duration of current psychiatric illness, baseline de-
pression and anxiety symptom severity, current participation in psy-
chotherapy, frequency of nonwork use of digital technology on a
scale from 0 to 4, and current depression and/or anxiety diagnosis.
Standardized mean differences were examined to examine balance
after matching, with differences of 10% or less indicative of suc-
cessful matching.15 Mauchly test was used to test the sphericity
assumption, with the Greenhouse-Geisser correction16 used for
violations.
RESULTS
There were 6528 (77.2%) individuals in the SSRI group and
1929 (22.8%) in the bupropion group. As can be seen in Table 1,
these groups differed significantly on several variables, including
age, baseline PHQ-9 and GAD-7 scores, sex, prior antidepressant
use, education level, race/ethnicity, annual income, depression and
anxiety diagnoses, and concurrent psychotherapy treatment. A re-
peated measures ANOVA comparing the groups on anxiety sever-
ity across time revealed that GAD-7 scores significantly decreased
over time within each treatment group, F (2, 8454) = 4209.22,
P < 0.000, η2 = 0.50. As can be seen in Figure 1, the bupropion

154 www.psychopharmacology.com © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
 Journal of Clinical Psychopharmacology • Volume 43, Number 2, March/April 2023 Does Bupropion Increase Anxiety
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FIGURE 1. Anxiety severity over time for each group, entire sample (N = 8457).

group had significantly lower anxiety severity at each time point,
P < 0.001, F (2, 8454) = 191.21, P < 0.001, η2 = 0.04.
Because of the differences between groups at baseline, par-
ticularly in terms of significantly different baseline GAD-7 scores,
propensity matching was used to create matched groups (Fig. 2).
Each had 346 participants that did not significantly differ on any
of the variables in Table 1. Repeated measures ANOVA comparing
the groups on anxiety severity across time revealed that GAD-7
scores decreased significantly over time in both groups, F (2,
689) = 684.61, P < 0.001, η2 = 0.67. There was no significant dif-
ference in anxiety at any time point, F (2, 689) = 1.20, P = 0.30,
η2 = 0.00.
DISCUSSION
To confirm earlier findings that bupropion provides similar
relief of anxiety symptoms to SSRIs, we conducted an iterative
analysis of 8457 adult patients receiving psychiatric care through
a national mental telehealth company for depression and/or anxi-
ety who were engaged with treatment and prescribed the same
agent for 12 consecutive weeks. Symptoms were monitored with
the GAD-7, a self-report scale of anxiety symptoms with high di-
agnostic validity for generalized anxiety disorder and numerous
advantages over the HDRS Anxiety-Somatization Factor used in
earlier studies. We performed 2 analyses:

FIGURE 2. Anxiety severity over time for each group, propensity-matched sample (N = 692).

© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. www.psychopharmacology.com 155
 Poliacoff et al Journal of Clinical Psychopharmacology • Volume 43, Number 2, March/April 2023
1) the entire 8,457 participant sample,
2) propensity-matched groups from the whole sample, with 346
participants in both the bupropion and SSRI treatment groups,
In each analysis, both bupropion and pooled SSRIs were asso-
ciated with a statistically significant reduction in self-reported anx-
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iety symptoms as measured by the GAD-7 over the 12-week period.
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In the propensity-matched groups, there was no statistically sig-
nificant difference in symptom reduction between the SSRI and
bupropion group.
In the whole sample analysis, the bupropion group had a lower
GAD-7 score than the SSRI group at each time point, which is most
likely due to selection bias; prescribers tend to avoid prescribing
bupropion for patients with anxiety, which is reflected in the pro-
nounced difference in initial GAD-7 scores between the 2 groups.
There were also likely numerous other reasons for each prescriber's
clinical gestalt when choosing what agent to prescribe, as reflected
in the demographic differences between the bupropion and SSRI
groups as reported in Table 1.
Strengths and Limitations
This study has several notable strengths. The sample size ex-
amined here is far larger than the largest meta-analysis to date
comparing the effect of bupropion to SSRIs on anxiety.6,17 Our
propensity-matched sample is also far larger than any individual
study included in the analysis. All patients were followed using
the same protocol, which minimizes potential differences caused
by different methods of measurement and provides a more accurate
assessment. Finally, the present analysis extends over 12 weeks,
whereas most previously reported studies end at 8 weeks, about
the amount of time SSRIs take to reach their full effect. Ending at
12 weeks minimizes the risk of bias in favor of bupropion due to
lagging medication responses.
The primary unresolved limitation of this study is selection
bias—patients were not randomly assigned to treatment. This
analysis also excluded patients who either changed agents or were
lost to follow-up. Therefore, we can only conclude that bupropion
is as effective as SSRIs for the treatment of anxiety in patients who
are able to tolerate treatment. The meta-analysis by Papakostas
et al6 found that bupropion, SSRIs, and placebos all had similar
discontinuation rates of about one quarter of participants, although
there was no analysis reported to indicate whether bupropion's ad-
vantage in this respect was statistically significant. In addition, the
analyses with propensity-matched groups excluded a large number
of patients, thereby limiting the generalizability of the findings. Be-
cause there was no control group, this study was unable to separate
the benefit of medication from the benefit of being “in treatment.”
This question is beyond the scope of this particular study, but given
the controversy in recent years over whether antidepressants are
overprescribed or even effective, it is an important question to in-
vestigate systematically.18 Another limitation is that there was no
examination of other interventions besides SSRI or bupropion for
treating depression, which again limits generalizability. Finally,
the lack of statistical difference in anxiety scores between groups
does not mean they do not exist; in other words, type II error can-
not be ruled out.
CONCLUSIONS
Bupropion is just as effective a treatment as SSRIs for anxi-
ety symptoms in patients with comorbid major depressive disor-
der. The common concern among clinicians that bupropion will
worsen anxiety in this population is unfounded. Given the many
advantages in terms of tolerability bupropion has over SSRIs, cli-
nicians should consider using bupropion more often.
156 www.psychopharmacology.com
AUTHOR DISCLOSURE INFORMATION
Z. Poliacoff has no conflicts of interest. H.G. Belanger and M.
Winsberg are employees and stockholders of Brightside Health.
DATA AVAILABILITY STATEMENT
The data set analyzed during the current study is not available.
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© 2023 The Author(s). Published by Wolters Kluwer Health, Inc.