Depression and Anxiety - 2021 - Courtney - Forks in The Road Definitions of Response Remission Recovery and Other 1

Received: 23 October 2020 | Revised: 18 June 2021 | Accepted: 24 June 2021
DOI: 10.1002/da.23200
REVIEW
Forks in the road: Definitions of response, remission,

recovery, and other dichotomized outcomes in randomized
controlled trials for adolescent depression. A scoping review
Darren B. Courtney1 | Priya Watson1 | Benjamin WC Chan2 |

Kathryn Bennett3 | Karolin R. Krause4 | Martin Offringa5 | Nancy J Butcher1 |
1 6 7 4
Suneeta Monga | Kirsten Neprily | Tabitha Zentner | Terri Rodak |
Peter Szatmari1
1
Department of Psychiatry, Child and Youth
Mental Health, University of Toronto, Abstract
Toronto, Ontario
Background: Definitions of dichotomous outcome terms, such as “response,” “re-
2
Independent practitioner, Toronto, Ontario
mission,” and “recovery” are central to the design, interpretation, and clinical ap-
3
Department of Health Research Methods,
Evidence and Impact (formerly Clinical plication of randomized controlled trials of adolescent depression interventions.
Epidemiology and Biostatistics), McMaster Accordingly, this scoping review was conducted to document how these terms have
Univeristy, Toronto, Ontario
4
been defined and justified in clinical trials.
Centre for Addiction and Mental Health,
Toronto, Ontario Method: Bibliographic databases MEDLINE, Embase, APA PsycInfo, and CINAHL
5
Department of Pediatrics, Neonatology, were searched from inception to February 2020 for randomized controlled trials
University of Toronto, Toronto, Ontario
evaluating treatments for adolescent depression. Ninety‐eight trials were included
6
Department of Psychology, School and
for data extraction and analysis.
Applied Child Psychology, University of
Calgary, Calgary, Alberta Results: Assessment of outcome measurement instruments, metric strategies,
7
Margaret and Wallace McCain Centre for methods of aggregation, and measurement timing, yielded 53 unique outcome de-
Child, Youth and Family Mental Health,
Centre for Addiction and Mental Health,
finitions of “response” across 45 trials that assessed response, 47 unique definitions
Toronto, Ontario of “remission” in 29 trials that assessed remission, and 19 unique definitions of
“recovery” across 11 trials that assessed recovery. A minority of trials (N = 35)
Correspondence
Darren B. Courtney, Department of provided a rationale for dichotomous outcomes definitions, often by citing other
Psychiatry at the University of Toronto, Staff studies that used a similar definition (N = 11). No rationale included input from
Psychiatrist at the Centre for Addiction and
Mental Health, Toronto M6J 1H4, Canada. youth or families with lived experience.
Email: dr.courtney.research@gmail.com Conclusion: Our review revealed that definitions of “response,” “remission,” “re-
Funding information covery,” and related terms are highly variable, lack clear rationales, and are not
Cundill Centre for Child and Youth informed by key stakeholder input. These limitations impair pooling of trial results
Depression
and the incorporation of trial findings into pragmatic treatment decisions in clinical
practice. Systematic approaches to establishing outcome definitions are needed to
enhance the impact of trials examining adolescent depression treatment.
KEYWORDS
adolescent, antidepressants, child/adolescent, clinical trials, depression, evidence‐based
medicine, empirical supported treatments, humans, measurement/psychometrics, outcome
assessment (health care), randomized controlled trials as topic, treatment, treatment
resistance
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COURTNEY ET AL. | 1153
1 | BACKGROUND highlighted in a review where 19 different outcome measurement

instruments were used to assess depression symptom severity in 30
Major Depressive Disorder in adolescents (MDD‐A) is prevalent recent RCTs of MDD‐A (Mew et al., 2020). Furthermore, standar-
(Mojtabai et al., 2016) and associated with significant morbidity dized definitions of these terms set out a priori can protect against
(Gore et al.,) and mortality (Renaud et al., 2008). Multiple rando- selective analysis and reporting of findings that may introduce bias
mized controlled trials (RCTs) have contributed to an evidence base into study conclusions.
for treatments of MDD‐A (Brent et al., 2008; March et al., 2004); Moreover, these demarcations of important change used in
however, optimal use of this evidence in clinical decision‐making and RCTs need to be scientifically justified (Butcher et al., 2020) and
research synthesis relies on widely‐recognized, empirically sup- should represent outcomes that are important to patients or have
ported, and clinically‐relevant definitions of desired treatment out- some predictive validity (e.g., predict reduced chance of further im-
comes representing important change, such as “response,” provement, relapse, or recurrence), ideally both (Zimmerman
“remission,” or “recovery” (Mew et al., 2020; Monga, Offring et al., 2008). A gap here has been underlined by another review by
et al., 2020). Definitions of outcomes that describe lack of change, the same group, where 11 of 18 recent RCTs on MDD‐A dichot-
like “treatment resistance,” are also important to consider as ado- omously defined a “clinical significant change” in their primary out-
lescents who do not recover fully pose a great challenge for clinicians come measurement instrument, and only three provided a rationale
trying to decide which next steps to recommend. The extent of for the respective definition (Monsour et al., 2020).
standardization of these outcome terms impacts the quality of in- With the intent of supporting clinical decisions and consistency
dividual patient care as well as the quality of information within the in research, historical attempts have been made to define these
broader research field. important change anchor points in the course of MDD (see Table 1
At the individual patient level, the absence of clear treatment for commonly cited and more recent examples). In their 1991 review
goals that can be mapped onto the evidence provided by rigorous of treatment trials of adult MDD, Prien and colleagues found high
randomized trials renders clinical decisions about changes in treat- variability in labeling and defining such dichotomous outcomes (Prien
ment vulnerable to arbitrariness. The promise of measurement‐ et al., 1991). Labels included, but were not limited to, “response,”
based care as a means of improving the effectiveness of treatment “remission,” and “recovery.” In response to this finding, Frank et al.
for individual patients is based on this principle (Fortney et al., 2016). (1991) set out to operationalize these terms and were later involved
Some clinical practice guidelines use precise definitions of these in an effort to further specify definitions carried out by the American
terms to make treatment recommendations with respect to starting, College of Neuropsychopharmacology Task Force (Rush et al., 2006).
intensifying, switching, augmenting, or discontinuing specific inter- Moreover, the DSM‐5 lays out its own definition of “remission”
ventions (e.g., Kennedy et al., 2016). Although it is increasingly re- (American Psychiatric Association, 2013). The American Academy of
cognized that mental disorders in youth are realistically captured on Child and Adolescent Psychiatry practice parameters for the man-
a continuum of symptom severity, rather than a dichotomous state of agement of child and adolescent depression paraphrase the terms
well/unwell (Haltigan et al., 2018), much clinical decision‐making used by Frank et al. (Birmaher & Brent, 2007). In their recent nar-
involves a choice between categorical options. Without clear and rative review of pediatric treatment‐resistant depression, Dwyer
consistent outcome anchor points being reported in clinical trials, et al. (2020) describe other proposed definitions of response and
clinicians will not know whether or not findings from the trials can remission.
apply to decisions about particular patients. Although recent reviews on outcomes take a broad look at
Furthermore, true evidence‐based decision‐making gives em- outcome selection, measurement, and reporting in recent RCTs of
phasis to patient values, in addition to the family's perspective, MDD‐A (Krause et al., 2019; Mew et al., 2020; Monsour et al., 2020),
clinician expertise, and the research literature (Sackett et al., 1996). there are currently no published comprehensive examinations of
In order for patients to make informed decisions in this process, the dichotomized outcomes demarcating clinically important change in
outcome needs to be meaningful to the people engaging in treat- MDD‐A treatment. Moreover, we do not know if, or how commonly
ment. There are increasing calls to prioritize the experience of used clinical definitions of “response,” “remission,” and “recovery”
people affected by the illness when conducting outcome measure- (i.e., Table 1) have been converted into consistent operationalizations
ment (Coulter, 2017); however, most recent trials on treatment ef- in clinical trials.
fectiveness for MDD‐A have focused instead on the clinician's The objective of this current scoping review was to describe how
assessment of change, to the exclusion of the adolescent's perspec- RCTs of treatment for MDD‐A have operationally defined “re-
tive, as well as the perspective of families and caregivers (Krause sponse,” “remission,” “recovery” and related dichotomized outcomes
et al., 2019). of change in depressive symptoms. More specifically, the review
At the research level, inconsistencies in definitions of “response,” assesses variability with respect to four key elements of a defined
“remission,” and “recovery” across trials impede data synthesis ef- trial outcome (Mayo‐Wilson et al., 2017; Zarin et al., 2011) with
forts needed for high‐quality meta‐analyses (Mayo‐Wilson respect to the outcome domain of depression symptom severity;
et al., 2017) and, as a result, the formulation of high‐quality clinical namely, (1) outcome measurement instrument (e.g., Childhood De-
practice guidelines (Courtney et al., 2019). This issue has been pression Rating Scale‐Revised (Poznanski et al., 1985)), (2) analysis
1154 | COURTNEY ET AL.
metric strategy (e.g., percent reduction on a scale score from base-

line to endpoint), (3) method of aggregation (e.g., proportion with at
depression for ≥2 months

least 50% reduction) and (4) time point (e.g., measured and analyzed
≤2 significant symptoms of
Extended period without
8 weeks after starting treatment). This study also aims to explore the
4 months of remission
extent of scientific justification of demarcations and the degree of
input of adolescents with lived experience and their families in es-
symptoms
tablishing these definitions.
Recovery
N/A
N/A
≥2 weeks and <2 months with no or
2 | ME THO D S
The methods are detailed in a published protocol (Courtney et al., 2020)

3 weeks of no core symptoms and
minimal associated symptoms
Minimal symptoms of depression

≥2 or more months with ≤2 mild
Brief period without symptoms
and registration (https://osf.io/ubtcm). In summary, we used the Joanna

few depressive symptoms
Briggs Institute scoping review guidelines (Peters et al., 2020) and Pre-
ferred Reporting Items for Systematic Reviews and Meta‐Analyses ex-
tension for Scoping Reviews (Tricco et al., 2018) to guide our methods
and reporting, respectively. We applied the planned search strategy (see
symptoms
Figure S1) to the following databases: MEDLINE, Embase, APA PsycInfo,

Remission
and Cumulative Index to Nursing and Allied Health Literature. The dates
of the search were from inception of the respective database to February
6th, 2020. Inclusion criteria for the current review were: English lan-
guage RCTs that assess the treatment of adolescent depression, where:
“Partial response”: 25%–40% improvement in symptoms.“Response”:
(a) adolescent was defined as ages 13–17, inclusive, for ≥80% of the
≥2 weeks of no symptoms or a significant reduction in depressive
Clinical definitions of response, remission, and recovery from frequently used selected sources
sample; and (b) depression was defined as diagnoses of major depressive

disorder, dysthymia/persistent depressive disorder or depressive symp-
Not fully symptomatic, but more than minimal symptoms
3 weeks of ≥50% reduction in symptoms from baseline
toms above an established cut‐off on a measure. Exclusion criteria were

(1) protocol papers; (2) trials evaluating depression in the context of
≥50% improvement in depressive symptoms.
bipolar disorder, the peripartum period, premenstrual dysphoria, minor

depression, or seasonal affective disorder; (3) trials aimed at preventing
depression or depression relapse; (4) trials focusing on cost‐effectiveness.
If RCTs included study participants outside the adolescent age range (e.g.,
7–17), we only included them if they conducted a separate subgroup
analysis of a depression symptom severity score was reported for the
adolescent age group. We did not include studies on children less than
13 years old in the current review as the nature of measurement of
depression symptoms in children is likely distinct from adolescents
symptoms
(Stallwood et al., 2020).

Response
As a deviation of the published protocol, we also excluded

N/A
conference abstracts (as they did not provide the detail required for
Note: N/A, not applicable as no definitions provided.
this review) and dissertations (as the quality of the reporting in these
American Psychiatric Association, 2013, p. 165.
documents was found to be a limiting factor).

Dwyer et al., 2020
Frank et al., 1991
JAACAP practice
Rush et al., 2006
parameters
2.1 | Title and abstract screening

DSM‐5a
Source
After the initial search strategy was executed, the two lead authors (PW
and DBC) independently evaluated a sample of 100 titles and abstracts
against the a priori defined inclusion and exclusion criteria. The lead
adolescent only
authors then reviewed and resolved any disagreements regarding study

Across lifespan
eligibility criteria. The sample of 100 citations was then used to train two
TABLE 1
Child and
raters (KN, TZ), achieving greater than 85% sensitivity in their screening
with respect to the lead authors' ratings. The two trained raters then
Age
independently screened titles and abstracts.

a
F I G U R E 1 Study selection. RCT,

randomized controlled trial
2.2 | Full‐text screening of patients had an endpoint score of less than “Y” on scale “Z”). These
outcomes were equally relevant to the rationale for our objectives
Inter‐rater reliability for eligibility was established among three in- and would not be captured had we limited our extraction to “re-
vestigators (PW, DBC, and BC) on 50 articles. Kappa with two values sponse” and “remission” only. As a result, we adjusted our extraction
(include/exclude), and multiple raters was calculated as 0.93. The process to look for how depressive symptom scales were dichot-
remaining citations were reviewed by one of these three in- omized. Apart from what has been described above, the protocol was
vestigators through the Covidence software (“Covidence systematic followed without deviation.
review software, Veritas Health Innovation. Melbourne, Australia”) Data sharing is not applicable to this article as no new data were
and classified thereafter. created or analyzed in this study.
2.3 | Data extraction 3 | RES ULTS
For each paper, two of three investigators (PW, DBC, BC) in- 3.1 | Study characteristics
dependently extracted data using a form to capture the information
sought. Two investigators then met to compare the extraction, dis- Ninety‐eight trials were included for analysis in this review (see
cuss discrepancies and establish consensus on each variable of in- Figure 1 for the study selection flow diagram). The earliest paper was
terest. If a consensus was not obtained, the third investigator would from 1981 (Kramer & Feiguine, 1981). The vast majority (N = 82;
make the final decision on how the data were extracted. Rationales 84%) were published from the year 2000 onward. Table 2 sum-
for specific metric strategies and methods of aggregation used in marizes further study characteristics.
dichotomized outcomes were extracted if investigators noted any
explanation for selection. If a citation was listed immediately fol-
lowing the definition, we considered this as a rationale as well. Ra- 3.2 | Measurement and analysis of depression
tionales for outcome measurement instrument selection or time outcomes
point selection were not extracted. These have already been found
to be poorly reported in the literature (Monsour et al., 2020). The majority of trials (N = 72; 73%) reported at least one dichot-
omous depression symptom severity outcome; some with just one
dichotomized outcome (N = 28; 28%), some with two (N = 30; 30%),
2.4 | Data synthesis and a handful with three or more dichotomized outcomes (N = 14;
14%). There were 6 metric strategies trials used to dichotomize
The initial intention of the review was to organize the information outcomes:
around the terms, “response” and “remission.” As Prien et al. (1991)
discussed above, it soon became apparent that similar definitions (1) percent reduction in continuous scale score from baseline to a
were used to describe other terms, including “recovery.” Often, there time point (N = 24),
was no specific term used, rather the authors described a dichot- (2) rating of global improvement from baseline (N = 23),
omization of the measure to describe depression and reported pro- (3) endpoint cut‐off on a continuous scale score (N = 39),
portions of participants who were categorized accordingly (e.g., “X”% (4) diagnostic status at endpoint (N = 21),
T A B L E 2 Study Characteristics of included adolescent TABLE 2 (Continued)

depression clinical trials
Variable N = 98
Variable N = 98
3 days to <8 weeks 19
Region where the first author is based
8 weeks to 12 weeks 60
North America 58
>12 weeks to 16 weeks 12
Europe 17
>16 weeks to 104 weeks 6
Oceania 10
Not reported 1
Eastern Asia 4
Method of Identifying depression as inclusion
Middle East 3 criteria
Caribbean 3 DSM or ICD criteria only 24
South America 2 Cut‐off on a scale score only 20
Africa 1 Both of the above 53
Gender distribution Either of the above 1
Female > Male 73
Male > Female 13 (5) reduction of an absolute number on a scale score from baseline
Female = Male 1 to endpoint (N = 4),

(6) a composite outcome combining two of the above strategies
Not reported 11
with “AND” or “OR” logic (N = 8). An example of a composite
Sample size outcome is requiring both a 50% percent reduction on a scale
≤25 12 score over 12 weeks AND a CGI‐I rating of ≤2 at the endpoint to
26–50 32 be considered a “response” (Brent et al., 2008).
51–100 18
(see Figure 2, Tables 3, 4, S1, S2, and S3 for a breakdown of
101–200 19 these metric strategies).
201–400 14
>400 3
3.3 | Measurement and definitions of response,
Funding
remission, recovery, and resistance
Government 59
Industry 20 3.3.1 | Response

Mixed 6
Table 3 describes the 45 trials (46% of the set) that used the term
Philanthropy 3
“response,” “responder,” or “responded” explicitly to refer to at least one
Not reported 10
dichotomous treatment outcome. Sometimes, a single trial dichotomized
Recruitment setting “response” in two different ways (N = 9); for example, one trial (Findling
Outpatient only 25 et al., 2009) referred both to CDRS‐R responders (≥40% reduction on the
CDRS‐R over 8 weeks) and CGI‐I responders (score of ≤2 on the CGI‐I
Community only 15
over 8 weeks), analyzing each outcome separately.
School only 12
Overall, 12 different outcome measurement instruments (OMIs)
Inpatient only 8 were used. Five different metrics strategies were used. The most com-
Primary care only 3 mon metric strategy used to define “response” was by a percent re-
duction in scale score from baseline to endpoint (N = 21 trials). The
Combination 21
percent reduction used to define response ranged from 20% to 50%. The
Not reported 14
childhood depression rating scale‐revised (CDRS‐R) (Poznanski
Experimental Intervention type et al., 1985) scale was the most commonly used OMI for this metric
Biological only 40 strategy (N = 13). The second most common metric strategy (N = 19) for
Psychosocial only 48
defining “response” was by a rating on the Clinical Global Impression –
Global Improvement Scale (CGI‐I) (Guy, 1976). The CGI‐I is a seven‐point
Combination 10
scale rated by an evaluator with respect to the clinician's impression of
Duration of randomized component of trial the extent of improvement. The vast majority of trials (N = 18) using this
F I G U R E 2 Metric strategies used for

dichotomous outcomes. RCT, randomized
controlled trial
approach classified the rating of ≤2 (“much improved” (score of 2) or When taking into account OMI, metric strategy, method of ag-
“very much improved” (score of 1)) as “responders” to aggregate parti- gregation, and the time point at which the outcome was measured
cipants; while in the remaining study (Simeon et al., 1990), it was unclear there were 47 unique definitions of “remission.”
as to what the parameters for the method of aggregation were. These
trials were predominantly testing medications (N = 16 of the 19). The use
of a composite outcome was the third most common metrics strategy, 3.3.3 | Recovery
used by six trials. Importantly, no two trials used the same definition of
“response” for this strategy. Time interval length where the change was Eleven of the 98 trials (11%) used the term “recovery,” all but one
defined was also highly variable (median = 10; interquartile range of these were psychotherapy trials. Table S1 reports details, in-
[IQR] = 8–12, range = 1 week to 104 weeks). cluding the 7 different OMIs that were used. Three metric stra-
Taking into account OMI, metric strategy, method of aggrega- tegies were used (percent reduction on an OMI, endpoint cut‐off,
tion, and the time point at which the outcome was measured, there and diagnostic status). With respect to the method of aggrega-
were 53 unique definitions of “response” across the 45 trials that tion, six of these trials required a sustained period of low
used the “response” term. symptom severity, consistent with Frank and colleagues' con-
ceptualization of recovery; five trials did not include such a re-
quirement in their definition. Variability in the time point of the
3.3.2 | Remission measure was also high (median = 12 weeks, IQR = 9–52 weeks,
range = 6–104). Nineteen unique definitions of recovery were
“Remission” was explicitly used as a term to represent a dichot- found across the 11 studies.
omized outcome in 29 of the 98 trials (30%), described in Table 4.
One trial defined and analyzed as “remission” in two separate ways:
(a) an endpoint CDRS‐R score of ≤28 and (b) an endpoint CGI‐I score 3.3.4 | Other terms used to represent dichotomized
≤2 over 2 assessments 1 week apart (Emslie et al., 1997). outcomes
Remission was defined using 12 different OMIs. Four different
metric strategies were used, where the use of an endpoint cut‐off Multiple trials (N = 15, 15%) dichotomized outcomes in similar ways
score on a measurement scale was the most frequent (N = 21). The to those that defined “response,” “remission” and “recovery,” but
CDRS‐R was the most commonly used OMI for this purpose (N = 12), used different terms to represent the dichotomization (see Table S2).
often with a cut‐off score of ≤28 (N = 9). This cut‐off was commonly “Reliable change” was a concept used in four papers as re-
used in North American trials testing medications (N = 8). Diagnostic commended by Jacobson and colleagues (Jacobson & Truax, 1991;
status at trial endpoint was the metric strategy defining remission in Jacobson et al., 1999). This strategy defines important change as a
seven trials. For this approach, the Kiddie Schedule for Affective function of pre‐ and post‐mean scores and the standard error of the
Disorders and Schizophrenia (Chambers et al., ) was the most com- difference between pre‐and post‐scores. The resulting value is an
monly used OMI to assess diagnostic status; and as a method of absolute number that is the threshold for which an individual par-
aggregation, remission was most commonly defined as “no longer ticipant's pre‐post change in symptoms scores need to have sur-
meeting criteria for Major Depressive Disorder.” Time intervals from passed to be considered outside the realm of chance and due to
baseline also varied highly (median = 12, IQR = 8–26, range = 2–64). random measurement error.
TABLE 3 Definitions of “response” used in 45 randomized clinical trials in adolescent MDD
Time points
Authors and year Intervention of interest Country N OMI Method of aggregation (weeks)
Metric strategy: percent reduction in scale score (n = 21)
Stasiak K. et al., 2014 C‐CBT New Zealand 34 CDRS‐R ≥30%Δa 4 to 10; 8 to 14
Merry et al., 2012 C‐CBT New Zealand 187 CDRS‐R ≥ 30%Δ a

4 to 7; 16 to 19
Findling et al., 2009 Fluoxetine USA 34 CDRS‐R ≥ 30%Δ a

8
Emslie et al., 2002 Fluoxetine USA 97 CDRS‐R ≥ 30%Δ b

9
Heiligenstein et al., 2006 Fluoxetine USA 15 CDRS‐R ≥ 30%Δ c

10
Findling et al., 2009 Escitalopram USA 311 CDRS‐R ≥ 40%Δ b

both at 8
CDRS‐R post hoc: ≥50% a
Durgam et al., 2018 Vilazodone USA 529 CDRS‐R ≥ 40%Δc 8
Wagner et al., 2003 Sertraline USA 199 CDRS‐R ≥ 40%Δa 10
Emslie et al., 2014 Duloxetine USA 271 CDRS‐R ≥ 50%Δa 10
Atkinson et al., 2014 Duloxetine USA 202 CDRS‐R ≥ 50%Δa 10
Clarke et al., 2016 CBT USA 198 CDRS‐R ≥ 50%Δc 6; 12; 26; 52;
78; 104
Richardson et al., 2014 Collaborative care USA 101 CDRS‐R ≥ 50%Δc 26; 52
Emslie et al., 2007 Venlafaxine USA 197 CDRS‐R ≥ 35%Δ a

all at 8
MADRS ≥ 50%Δ
HDRS ≥ 50%Δ
Sallee et al., 1997 Pulse IV clomipramine USA 16 HDRS ≥ 50%Δ 1
Boulos et al., 1991 Desipramine Canada 30 HDRS ≥ 50%Δ 6
Deas et al., 2000 Sertraline USA 10 HDRS ≥ 50%Δ 12
Gunlicks‐Stoessel Fluoxetine/IPT USA 40 HDRS‐R ≥ 20%Δ 4

et al., 2019
HDRS‐R ≥ 40%Δ 8
Braconnier et al., 2003 Paroxetine/ France 121 MADRS ≥ 50%Δ 8

Clomipramine
Berard et al., 2006 Paroxetine South Africa 275 MADRS ≥ 50%Δ 12
Parhiala et al., 2019 Interpersonal Finland 55 BDI‐I ¶

≥ 50%Δ both at 6 to 12
Counselling
ADRSc ≥50%Δ
Topooco et al., 2018 C‐CBT Sweden 70 BDI‐II ≥ 30%Δ 8
Metric strategy: rating of global improvement (n = 19)
Simeon et al., 1990 Fluoxetine Canada 40 CGI‐I unclear 7
Emslie et al., 1997 Fluoxetine USA 48 CGI‐I ≤ 2 (much or very much 8

improved)
Wagner et al., 2006 Escitalopram USA 160 CGI‐I ≤2 8
Findling et al., 2009 Escitalopram USA 311 CGI‐I ≤2 8
Emslie et al., 2006 Paroxetine USA 107 CGI‐I ≤2 8
Emslie et al., 2007 Venlafaxine XR USA 197 CGI‐I ≤2 8

TABLE 3 (Continued)
Time points
Atkinson et al., 2018 Desvenlafaxine USA 254 CGI‐I ≤2 8
Weihs et al., 2018 Desvenlafaxine US 207 CGI‐I ≤2 8
Braconnier et al., 2003 Paroxetine/ France 121 CGI‐I ≤2 8

clomipramine
Bangs et al., 2007 Atomoxetine USA 142 CGI‐I ≤2 9
Atkinson et al., 2014 Duloxetine USA 202 CGI‐I ≤2 10
Wagner et al., 2003 Sertraline USA 199 CGI‐I ≤2 10
Gabbay et al., 2018 Omega‐3 fatty acids USA 48 CGI‐I ≤2 10
McCauley et al., 2016 Behavioural activation USA 60 CGI‐I ≤2 12
Clarke et al., 2015 CBT USA 41 CGI‐I ≤2 12; 26
Davey et al., 2019 Fluoxetine Australia 49 CGI‐I ≤2 12
March et al., 2004 Fluoxetine/CBT USA 439 CGI‐I ≤2 12
Berard et al., 2006 Paroxetine South Africa 275 CGI‐I ≤2 12
DelBello et al., 2014 Selegiline transdermal USA 304 CGI‐I ≤2 12
Metric strategy: endpoint cut‐off on a scale score (n = 4)
Wagner et al., 2006 Escitalopram USA 160 CDRS‐R ≤ 28 8
Diamond et al., 2010 ABFT USA 66 BDI‐II ≤9 6;12;24
Iftene et al., 2015 Sertraline, REBT, CBT Canada 88 CDI < 19 16
Bangs et al., 2007 Atomoxetine USA 142 CGI‐S ≤ 2 (normal or borderline) 9
Metric strategy: use of diagnostic status (n = 1)
Melvin et al., 2006 Sertraline + CBT Australia 73 KSADS unclear ("full remission or 12; 36
partial remission")
Metric strategy: composite (n = 6)
Geller et al., 1990 Nortriptyline USA 31 CDRS (original) ≤25 8
and
KSADS ≤ 2 DSM‐III MDD criteria

(≤3 items if
concentration impaired)
Brent et al., 2008 Venlafaxine, SSRI, CBT USA 334 CGI‐I ≤2 12
and
CDRS‐R ≥ 50%Δa
Hughes et al., 2013 Exercise USA 26 CGI‐I ≤2 12; 26; 52
and
CDRS‐R ≥ 50%Δa
Von Knorring et al., 2006 Citalopram Sweden 244 KSADS ≤ 2 on both depression and 12
anhedonia items
or
MADRS ≥ 50%Δ
Gabbay et al., 2018 Omega‐3 Fatty Acids USA 48 CDRS‐R ≥ 50%Δa 10
or
CDRS‐R ≤ 28
(Continues)
TABLE 3 (Continued)
Time points
Keller et al., 2001 Paroxetine USA 275 HDRS ≤8 8
or
HDRS ≥ 50%Δ
Note: B: “Response” is the term listed here if the cited paper used any of the following terms: “Responder,” “Responded,” “Response.” Δ = reduction in
score from baseline to endpoint.
Abbreviations: ABFT, attachment‐based family therapy; ADRS, adolescent depression rating scale; BDI‐I, Beck depression inventory (original); BDI‐II,
Beck epression inventory‐II; CBT, cognitive behaviour therapy; C‐CBT, computerized cognitive behaviour therapy; CDI, Children's depression inventory;
CDRS‐R, childhood depression rating scale‐revised; CGI‐I, clinical global impression scale–global improvement item; CGI‐S, clinical global impression
scale–global severity item; HDRS, Hamilton depression rating scale; HDRS‐R, Hamilton depression rating scale‐revised; IPT, interpersonal therapy;
KSADS, Kiddie schedule for affective disorders and schizophrenia; MADRS, Montgomery Asberg depression rating scale; OMI, outcome measurement
instrument; REBT, rational emotive behavioral therapy; SSRI, selective serotonin reuptake inhibitor.
a
Adjusted for a minimum score of 17 on the CDRS‐R.
b
Adjusted for a minimum score of 17 on the CDRS‐R, reported as post hoc.
c
Not reported whether score was adjusted for the minimum score of 17 on the CDRS‐R.
d
Finnish version of the scale.
Six trials represented dichotomized outcomes with the term “nonresponse” (Clarke et al., 1999; Clarke et al., 2016; Deas
“clinically significant change,” two trials used the term “caseness,” et al., 2000; DelBello et al., 2014; Gabbay et al., 2018; Geller
one trial used the term “improved,” one trial use the term “normalcy.” et al., 1990; Klein et al., 1998; Sallee et al., 1997; von Knorring et al.,
2006) with respect to reference to the counterpart of aforemen-
tioned dichotomized outcomes.
3.3.5 | Descriptive approach
Several trials (N = 14; 14%) presented dichotomized outcomes by simply 3.3.8 | Rationale for metric strategies and methods
describing outcomes, rather than using an associated term like “re- of aggregation used in dichotomized outcomes
sponse,” “remission,” or “recovery” (see Table S3). These outcomes were
defined in similar ways to the terms listed above. For example, one trial A minority of trials (N = 34 of 98 trials, 35%) provided a rationale for
(Clarke et al., 2015) reported that a third of the participants in each of the metric strategies and methods of aggregation for outcome di-
the experimental and comparison groups had a reduction of greater than chotomization, listed in Table S4. Of these, about a third (N = 11;
50% on the CDRS‐R at week 12 but did not associate this result with the 32%) solely pointed to various other RCTs which used a similar
term “response” as others have done. strategy to dichotomize outcomes.
Only six trials (18%) referred to a discriminatory validity
study to justify the criteria used for dichotomization. For ex-
3.3.6 | Treatment resistance ample, one trial (Hughes et al., 2013) cited a paper by others (Tao
et al., 2009) wherea greater than 50% reduction in the CDRS‐R at
Outcomes were reported in terms of “resistance” in 2 of the 98 trials 4 weeks predicted remission (defined as CDRS‐R ≤ 28) at
(2%). One trial (Emslie et al., 1997) defined resistance as the coun- 12‐week endpoint on ROC curve analysis in the context of a
terpart to the definition of “response” (which was defined as ≤2 on fluoxetine trial spanning ages 7–18 years.
the CGI‐I), implied as ≥3 on the CGI‐I. Another trial (Goodyer Ten out of 35 trials referred to conceptual papers (29%),
et al., 2017) defined “resistance” as the secondary outcome of in- including the Frank et al.'s paper (1991) previously discussed. Six
terest in an RCT comparing various psychotherapies. Here it was of these ten refer to papers by Jacobson (Jacobson &
defined as a Mood and Feelings Questionnaire score of greater than Truax, 1991; Jacobson et al., 1999). Eight of the 35 trials (23%)
26 at the 86‐week follow‐up time point. provided unique justifications for their specific metric strategy.
Six of the 35 trials (17%) referred to studies in adults or pre‐
pubescent children with depression to justify definitions. Apart
3.3.7 | Other terms and definitions used to describe from situations where “nonresponse” or “treatment resistance”
lack of important change over time was defined as the counterpart to “response” or “remission,” we
did not observe any rationale for definitions related to lack of
Other trials used alternative terms to represent the lack of im- change. Table S4 also highlights how no rationale included input
portant change. Ten of the 98 trials (10%) used the term from youth or families with lived experience.
TABLE 4 Definitions of “Remission” used in 29 randomized clinical trials in adolescent MDD
Time point
Authors and year Intervention Country N OMI Method of aggregation (weeks)
Metric strategy: rating of global improvement (n = 2)
Emslie et al., 1997 Fluoxetine USA 48 CGI‐I ≤ 2 over two assessments 1 week apart 8
(much or very much improved)
Emslie et al., 2006 Paroxetine USA 107 CGI‐I = 1 (very much improved) 8
Metric strategy: endpoint cut‐off on a scale score (n = 21)
Emslie et al., 1997 Fluoxetine USA 48 CDRS‐R ≤ 28 8
Findling et al., 2009 Fluoxetine USA 34 CDRS‐R ≤ 28 8
Emslie et al., 2002 Fluoxetine USA 97 CDRS‐R ≤ 28 9
Findling et al., 2009 Escitalopram USA 311 CDRS‐R ≤ 28 8
Emslie et al., 2006 Paroxetine USA 107 CDRS‐R ≤ 28 8
Durgam et al., 2018 Vilazodone USA 529 CDRS‐R ≤ 28 8
Emslie et al., 2014 Duloxetine USA 271 CDRS‐R ≤ 28 10
Atkinson et al., 2014 Desvenlafaxine USA 202 CDRS‐R ≤ 28 10
Bernal et al., CBT + parent education Puerto Rico 121 CDRS‐R ≤ 28 12;26; 36;52;64
Fleming et al., 2012 C‐CBT New Zealand 30 CDRS‐R < 30 5
Merry et al., 2012 C‐CBT New Zealand 187 CDRS‐R < 30 4 to 7; 16 to 19
Stasiak et al., 2014 C‐CBT New Zealand 34 CDRS‐R ≤ 29 4 to 10; 8 to 14
Martinez et al., 2019 C‐CBT Chile 216 BDI‐I < 10 16; 26
Brent et al., 1997 CBT, SBFT, supportive USA 107 BDI‐I ≤ 9 on 3 consecutive assessments 6;12 to 16
therapy through remaining sessions
Diamond et al., 2019 ABFT USA 129 BDI‐II <9 4;8;12;16
Bogen et al., 2016 Bright Light Therapy Germany 57 BDI‐II < 10 2;5
Von Knorring Citalopram Sweden 244 MADRS ≤ 12 12

et al., 2006
Davey et al., 2019 Fluoxetine Australia 49 MADRS ≤7 12
Wunram et al., 2017 Whole Body Vibration Germany 35 DIKJ < 18 6;14;26
Richardson Collaborative Care USA 101 PHQ‐9 <5 26;52

et al., 2014
Bolton et al., 2007 Group IPT USA 314 APAI ≤ 15.6 16
Metric strategy: use of diagnostic status (n = 8)
Sanford et al., 2006 Parent Psychoeducation Canada 31 KSADS Not meeting MDD‐A criteria 26;36
Shirk et al., 2014 Mindfulness‐CBT USA 43 KSADS Not meeting MDD‐A criteria 16
McCauley Behavioural Activation USA 60 KSADS Not meeting MDD‐A criteria 12;26
et al., 2016
Parhiala et al., 2019 Interpersonal Counselling Finland 55 KSADS Not meeting MDD‐A criteria 12;26
Melvin et al., 2006 Sertraline + CBT Australia 73 KSADS 8 weeks of no MDD‐A symptoms 12;36
Topooco et al., 2018 Internet supported CBT Sweden 70 MINI Not meeting MDD‐A criteria 8
Poole et al., 2018 “BEST MOOD” Family Australia 64 KID‐SCID Unclear unclear
Therapy
Bernal et al., CBT + parent education Puerto Rico 121 DISC‐IV Not meeting MDD‐A criteria (implied) 12;36;64
(Continues)
TABLE 4 (Continued)
Time point
Authors and year Intervention Country N OMI Method of aggregation (weeks)
Metric strategy: composite (n = 1)
Hughes et al., 2013 Exercise USA 26 CGI‐I ≤2 12;26;52
and
CDRS‐R ≤ 28
Note: NB: “Remission” is the term listed here if the paper used any of the following terms: “Remitter,” “Remitted,” “Remission.”
Abbreviations: ABFT, attachment‐based family therapy; ADRS, adolescent depression rating scale; APAI, Acholi psychosocial assessment instrument;
BDI‐I, Beck depression inventory (original); BDI‐II, Beck epression inventory‐II; CBT, cognitive behaviour therapy; C‐CBT, computerized cognitive
behaviour therapy; CDI, Children's depression inventory; CDRS‐R, childhood depression rating scale‐revised; CGI‐I, clinical global impression
scale–global improvement item; CGI‐S, clinical global impression scale–global severity item; DIKJ, depressions Inventar fur Kinder und Jugendliche;
HDRS, Hamilton depression rating scale; HDRS‐R, Hamilton depression rating scale‐revised; IPT, interpersonal therapy; KSADS, Kiddie schedule for
affective disorders and schizophrenia; MADRS, Montgomery Asberg depression rating scale; MINI, mini international neuropsychiatric interview; OMI,
outcome measurement instrument; PHQ‐9, patient health questionnaire–9 item version; REBT, rational emotive behavioral therapy; SBFT, systemic
behaviour family therapy; SSRI, selective serotonin reuptake inhibitor.
4 | DI SCUSSION medication more quickly than to psychotherapy. The extent of

variability we have observed, however, far exceeds this justification.
In this comprehensive scoping review of RCTs evaluating the effec- In fact, our results are similar to those found in Prien et al.'s study
tiveness of treatments for MDD‐A, we found that the key dichot- (1991) published on depressed adults almost 30 years ago, indicating
omous outcomes, “response,” “remission,” and “recovery” were: (a) a need for more precision of definitions than what Frank et al. (1991)
defined with high variability across studies, (b) for the most part, had to offer. The extent of variability is not helpful to researchers,
lacked scientific rationale and (c) lacked input from patients and clinicians, and other stakeholders including policymakers.
families with lived experience. Even when there is some relative consistency in definition, we
Variability was evident in our finding of 53 different definitions did not find evidence of the dichotomized outcome being driven by
of “response,” 47 definitions of “remission” and 19 definitions of empirical findings. Ideally, cut‐offs should be derived from rigorous
“recovery.” In keeping with consensus‐based broad concepts for scientific approaches (e.g., receiver operating characteristic curve
these terms outlined by various groups (i.e., Table 1), there does analyses) involving adolescent study participants with depression. In
appear to be some consistency in which metric strategies are used to contrast, rationales often cited simple precedent or literature fo-
define these terms; that is, “response” is often defined by a percent cused on a different age group. For example, the endpoint cut‐off
reduction in scale score, or rating of global improvement at the score of ≤28 on the CDRS‐R was used to define “remission” in nine
endpoint, whereas remission and recovery appear to be generally trials. This threshold was first used in an MDD‐A RCT in 1997
defined by an endpoint scale score below a particular cut‐off or di- (Emslie et al., 1997); though the rationale for this cut‐off was not
agnostic criteria status. At the same time, there is a lot of variability cited in this paper. Nor does the manual for the CDRS‐R (Poznanski
in how these definitions are more precisely operationalized with the et al., 1985) describe this cut‐off for scoring purposes. Furthermore,
combined four elements of a dichotomized outcome; namely, OMI, the CDRS‐R was initially developed for prepubescent children and to
metric strategy, method of aggregation, and time point. These dif- date has limited to insufficient psychometric support for use in
fering definitions are not interchangeable. For example, a secondary adolescents with MDD, despite it being the most commonly used
analysis of the treatment for adolescents with depression study trial OMI to assess depression in adolescent research studies (Stallwood
(N = 439) noted that of the 271 participants who no longer met di- et al., 2020). Many trials referred to studies with limited general-
agnostic criteria for depression at the 12‐week endpoint (commonly izability, including studies conducted in adults or pre‐pubescent
defined as “remission” in other trials), only 97 (35.7%) met their children, to justify the cut‐offs.
definition of “remission,” which was a CDRS‐R score of ≤28 (Kennard In a minority of trials, we observed some attempts towards di-
et al., 2006). With respect to lack of change, the only two trials to chotomized outcomes being driven by the use of data and statistical
specifically define the term “resistance” used two disparate defini- analysis. Jacobson and Truax (1991) described an approach to de-
tions. Results regarding variability expand upon results demon- termine “clinical significance” with respect to change scores; that is,
strating variability in broader aspects of outcome measurement and observing a participant move from the clinical range on a scale score
reporting in RCTs for MDD‐A (Mew et al., 2020; Monsour to the normative range. This approach was intended to be used
et al., 2020). Some variability may be justified as different inter- alongside calculation of the RCI, which takes into account the risk of
ventions may have different expected response timelines given their measurement error in interpreting a change score. In our review,
proposed mechanisms of action; for example, youth may respond to three trials analysed Jacobson and Truax' concept of “clinical
significance” (Clarke et al., 2005; Hayes et al., 2011; Rossello & underway, aims to develop a COS related to adolescent depression
Bernal, 1999), and four calculated the RCI (Bernal et al.,; Diamond that could generalize to any intervention. Previous efforts to develop
et al., 2019; Hayes et al., 2011; Israel & Diamond 2013). Although a pediatric COS' have taken about 2 years (e.g., Kelly et al., 2020;
handful of trials had some convincing justification for their dichot- Knaapen et al 2020). Although we await results from the IN‐ROADS
omization, the majority of definitions of dichotomized outcomes did study, trialists can follow established guidance on good trial design
not report any empirical support for their use. and measurement using some of the information from this paper.
Regardless of whether the dichotomization of an outcome is More specifically, investigators can take multiple steps to address the
empirically grounded, the relevance of whether a study participant is gap identified in this review, such as: (1) codesign trials with patient
considered to have “responded,” “remitted,” or “recovered” is of and family input (see Darnay et al., for guidance on this), (2) involve a
prime importance to adolescents with MDD‐A and their family broad array of stakeholders (e.g., patients, families, researchers,
members in the clinic. It is notable that none of the 98 trials prior- clinicians, journal editors, research funders) in outcome prioritization
itized the perspectives of patients and families in the outcome defi- and measurement selection; (3) choose measures with measurement
nitions. More specifically, no trials implemented the concept of a properties that meet specified standards (e.g., www.cosmin.nl); (4) use
minimal clinically important difference (MCID) to define outcomes, credible and empirically‐grounded MCIDs on selected scales where
where continuous scale scores are mapped onto anchor points from available; (5) transparently report the rationale for decisions made,
various perspectives (Revicki et al., 2008). For example, ROC analyses even in the absence of consensus and evidence; (6) incorporate re-
can be applied to explore the relationship between changes in scale search methods regarding validity, reliability, responsiveness and in-
scores and the patient's subjective experience of meaningful im- terpretability of outcome measures and definitions into trials to
provement based on a patient rating of perceived global change further advance this science; and (7) share data from trials that
(DeVet et al., 2011). This gap is consistent with findings across other permit future pooling between studies and/or prospective meta‐
pediatric health research outcomes (Sinha et al., 2008). This is an analyses studies with respect to outcome definitions. Trialists may
important concern to address, as arguably the adolescent's own also benefit from the work of the Delta‐2 guidance group, a collective
perception of benefit is an essential outcome in the treatment of of statisticians and epidemiologists based in the UK (Cook
MDD‐A (The Lancet Psychiatry, 2020). et al., 2018). They aim to take a systematic approach to establish a
Our findings and other calls in the literature show a clear need to “target difference” in clinical trials that take into account consistency,
establish a standard for dichotomized outcomes that are applicable empiricism, and patient perspectives.
across trials, are driven by empirical findings and are perceived as
important by an array of stakeholders. In establishing definitions of
response, remission, and recovery, there is an inherent tension be- 4.1 | Strengths and limitations
tween tailoring the definitions to the needs of specific study objec-
tives, the needs of specific stakeholders (e.g., regulators, researchers, Our scoping review was completed with rigor as the protocol followed
clinicians, patients, policy‐makers), and the need to standardize out- established methods (Peters et al., 2020) and reporting (see Table S5 for
comes to facilitate inter‐study comparisons. To reduce current un- the PRISMA extension for scoping reviews fillable checklist; Tricco
certainty surrounding treatment effects and to reduce research et al., 2018). This includes using duplicate reviewers for data extraction to
waste, our study informs the next steps in navigating this tension. minimize susceptibility to bias. We have also used broad inclusion criteria
When the early RCTs were being designed in child and youth mental and conducted our literature search across multiple databases, with
health, there was very little other research to draw upon to de- publication dates starting at the inception of the databases, to achieve a
termine the best methods. After nearly 100 RCTs having been con- comprehensive examination of the literature. There are limitations in-
ducted in adolescent depression, researchers can now use established cluding that we did not examine studies published in non‐English lan-
consensus and evidence‐based methods that have been developed to guages, grey literature, or trial protocols. With the intention of capturing a
select, define, and measure trial outcomes that reflect the perspec- comprehensive set of RCTs for the treatment of adolescent depression,
tives of a wide variety of stakeholders. we included studies with variable definitions of depression. Some used
One such method is through the development of core outcome diagnostic status, some used established cut‐offs on a scale (mostly psy-
sets (COS). A COS is a minimum set of outcome domains and OMIs chotherapy trials) and some used both approaches. Although this may be
intended to promote the use of quality measures with consistency a source of variability in our results; it cannot account for its full extent
between trials for the purposes of comparability and to enhance given the number of unique definitions for “response,” “remission,” and
appropriate interpretation of trial results. There is an established “recovery.”
method to systematically develop COS' (https://www.comet-
initiative.org) through examination of the evidence and consensus‐
building procedures designed to minimize bias (i.e., Delphi surveys). 5 | C O N CL U S I O N
Once a COS is chosen, metrics strategies, methods of aggregation,
and time points at which these are measured also need to be stan- The establishment of harmonized and empirically supported defini-
dardized, merging the scientific literature and the patient perspective. tions of “response,” “remission,” and “recovery” in MDD‐A treatment
The IN‐ROADS project (Monga, Monsour, et al., 2020), already is overdue. Definitions that specify valid OMIs, metric strategies,
methods of aggregation, and key time points to be used across stu- atomoxetine in adolescents with attention‐deficit/ hyperactivity
dies and in the clinic will enable clinicians, youth, and their caregivers disorder and major depression. Journal of Child and Adolescent
Psychopharmacology, 17(4), 407–419. https://doi.org/10.1089/cap.
to make optimal use of existing and future trial findings in treatment
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the Canadian Institute of Health Research. Kathryn Bennett, Karolin
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R. Krause, and Martin Offringa recieved financial support from the
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Received: 23 October 2020 | Revised: 18 June 2021 | Accepted: 24 June 2021

Forks in the road: Definitions of response, remission,

Darren B. Courtney1 | Priya Watson1 | Benjamin WC Chan2 |

1152 | © 2021 Wiley Periodicals LLC wileyonlinelibrary.com/journal/da Depression Anxiety. 2021;38:1152–1168.

1 | BACKGROUND highlighted in a review where 19 different outcome measurement

metric strategy (e.g., percent reduction on a scale score from base-

depression for ≥2 months

The methods are detailed in a published protocol (Courtney et al., 2020)

Minimal symptoms of depression

Brief period without symptoms

and registration (https://osf.io/ubtcm). In summary, we used the Joanna

Figure S1) to the following databases: MEDLINE, Embase, APA PsycInfo,

sample; and (b) depression was defined as diagnoses of major depressive

3 weeks of ≥50% reduction in symptoms from baseline

toms above an established cut‐off on a measure. Exclusion criteria were

bipolar disorder, the peripartum period, premenstrual dysphoria, minor

(Stallwood et al., 2020).

As a deviation of the published protocol, we also excluded

documents was found to be a limiting factor).

2.1 | Title and abstract screening

authors then reviewed and resolved any disagreements regarding study

independently screened titles and abstracts.

F I G U R E 1 Study selection. RCT,

2.3 | Data extraction 3 | RES ULTS

T A B L E 2 Study Characteristics of included adolescent TABLE 2 (Continued)

Caribbean 3 DSM or ICD criteria only 24

South America 2 Cut‐off on a scale score only 20

Africa 1 Both of the above 53

Gender distribution Either of the above 1

Female > Male 73

Female = Male 1 to endpoint (N = 4),

26–50 32 be considered a “response” (Brent et al., 2008).

Industry 20 3.3.1 | Response

F I G U R E 2 Metric strategies used for

TABLE 3 Definitions of “response” used in 45 randomized clinical trials in adolescent MDD

Metric strategy: percent reduction in scale score (n = 21)

Stasiak K. et al., 2014 C‐CBT New Zealand 34 CDRS‐R ≥30%Δa 4 to 10; 8 to 14

Merry et al., 2012 C‐CBT New Zealand 187 CDRS‐R ≥ 30%Δ a

Findling et al., 2009 Fluoxetine USA 34 CDRS‐R ≥ 30%Δ a

Emslie et al., 2002 Fluoxetine USA 97 CDRS‐R ≥ 30%Δ b

Heiligenstein et al., 2006 Fluoxetine USA 15 CDRS‐R ≥ 30%Δ c

Findling et al., 2009 Escitalopram USA 311 CDRS‐R ≥ 40%Δ b

CDRS‐R post hoc: ≥50% a

Durgam et al., 2018 Vilazodone USA 529 CDRS‐R ≥ 40%Δc 8

Wagner et al., 2003 Sertraline USA 199 CDRS‐R ≥ 40%Δa 10

Emslie et al., 2014 Duloxetine USA 271 CDRS‐R ≥ 50%Δa 10

Atkinson et al., 2014 Duloxetine USA 202 CDRS‐R ≥ 50%Δa 10

Emslie et al., 2007 Venlafaxine USA 197 CDRS‐R ≥ 35%Δ a

Sallee et al., 1997 Pulse IV clomipramine USA 16 HDRS ≥ 50%Δ 1

Boulos et al., 1991 Desipramine Canada 30 HDRS ≥ 50%Δ 6

Deas et al., 2000 Sertraline USA 10 HDRS ≥ 50%Δ 12

Gunlicks‐Stoessel Fluoxetine/IPT USA 40 HDRS‐R ≥ 20%Δ 4

Braconnier et al., 2003 Paroxetine/ France 121 MADRS ≥ 50%Δ 8

Berard et al., 2006 Paroxetine South Africa 275 MADRS ≥ 50%Δ 12

Parhiala et al., 2019 Interpersonal Finland 55 BDI‐I ¶

Topooco et al., 2018 C‐CBT Sweden 70 BDI‐II ≥ 30%Δ 8

Metric strategy: rating of global improvement (n = 19)

Simeon et al., 1990 Fluoxetine Canada 40 CGI‐I unclear 7