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Psychological Medicine
cambridge.org/psm
Review Article
*These authors share last authorship.
Cite this article: van Bronswijk S, Moopen N,
Beijers L, Ruhe HG, Peeters F (2018).
Effectiveness of psychotherapy for
treatment-resistant depression: a
meta-analysis and meta-regression.
Psychological Medicine 1–14. https://doi.org/
10.1017/S003329171800199X
Received: 5 November 2017
Revised: 19 June 2018
Accepted: 15 July 2018
Key words:
Meta-analysis; meta-regression;
psychotherapy; treatment resistant depression
Author for correspondence:
Frenk Peeters, E-mail: f.peeters@
maastrichtuniversity.nl
© Cambridge University Press 2018
Effectiveness of psychotherapy for
treatment-resistant depression: a meta-analysis
and meta-regression
Suzanne van Bronswijk1, Neha Moopen2, Lian Beijers3, Henricus G. Ruhe4,5,*
and Frenk Peeters1,*
1
Department of Psychiatry and Psychology, University Hospital Maastricht, School for Mental Health and
Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, P.O. Box 5800, 6202 AZ
Maastricht, The Netherlands;
2
School of Social and Behavioral Sciences, Tilburg University, Tilburg, The
Netherlands;
3
Department of Psychiatry, University of Groningen, University Medical Center Groningen,
Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Groningen, The Netherlands;
4
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK and
5
Department of Psychiatry,
Radboudumc Nijmegen, The Netherlands
Abstract
Despite substantial advances in treatment and management strategies for major depression,
less than 50% of patients respond to first-line antidepressant treatment or psychotherapy.
Given the growing number of controlled studies of psychotherapy for treatment-resistant
depression (TRD) and the preference for psychotherapy of depressed subjects as a treatment
option, we conducted a meta-analysis and meta-regression analysis to investigate the effective-
ness of psychotherapy for TRD. Seven different psychotherapies were studied in 21 trials that
included a total of 25 comparisons. In three comparisons of psychotherapy v. treatment as
usual (TAU) we found no evidence to conclude that there is a significant benefit of psycho-
therapy as compared with TAU. In 22 comparisons of add-on psychotherapy plus TAU v.
TAU only, we found a moderate general effect size of 0.42 (95% CI 0.29–0.54) in favor of psy-
chotherapy plus TAU. The meta-regression provided evidence for a positive association
between baseline severity as well as group v. individual therapy format with the treatment
effect. There was no evidence for publication bias. Most frequent investigated treatments
were cognitive behavior therapy, interpersonal psychotherapy, mindfulness-based cognitive
therapy, and cognitive behavioral analysis system of psychotherapy. Our meta-analysis pro-
vides evidence that, in addition to pharmacological and neurostimulatory treatments, the
inclusion of add-on of psychotherapy to TAU in guidelines for the treatment of TRD is jus-
tified and will provide better outcomes for this difficult-to-treat population.
Introduction
Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition.
Despite substantial advances in treatment and management strategies for MDD, less than
50% of patients respond to first-line antidepressant treatment or psychotherapy (Cuijpers
et al.,2013; Kolovos et al., 2016). MDD that is treatment refractory, mostly described as
treatment-resistant depression (TRD), is characterized by marked functional impairment, a
large burden on patients and families, and is associated with great direct and indirect health-
care costs (Greden, 2001; Moussavi et al., 2007).
Clinical reviews suggest a prevailing inclination to manage TRD (solely) by pharmacother-
apy or other somatic treatments while scarcely mentioning studies into psychotherapy for
TRD with little or no discussion of the findings and prospects (e.g. Carvalho et al., 2014;
Dold and Kasper, 2016). This may be imprudent because (i) the likelihood of remission is con-
siderably reduced for individuals who require third or fourth-line antidepressant treatment
due to non-response in prior steps (Rush et al., 2006), (ii) a majority of depressed individuals
seems to prefer psychotherapy over medication (McHugh et al., 2013), and (iii) patients receiv-
ing their preferred treatment show better outcomes (Gelhorn et al., 2011; Mergl et al., 2011;
Swift et al., 2011; McHugh et al., 2013). Given these considerations, there is a need to thor-
oughly evaluate psychotherapy as a treatment option for TRD and accordingly formulate
recommendations for clinical practice.
High-quality studies that specifically sought to examine the effectiveness of psychothera-
peutic treatments for TRD are scarce and virtually absent until the beginning of this millen-
nium. In 2002, Stimpson, Agrawal, and Lewis conducted a systematic review of randomized
controlled trials (RCTs) for TRD but no psychotherapy studies met their minimal inclusion
criteria at that point. Two more recent reviews, based on seven RCTs and eight uncontrolled
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studies, concluded that psychotherapy either as augmentation or
substitute therapy could be an effective and reasonable treatment
for TRD (McPherson et al., 2005; Trivedi et al., 2011). The
authors emphasized the need for more high-quality, controlled
trials to effectively judge the utility of psychotherapy for TRD
and guide clinical practice.
Moreover, there is considerable variation in and confusion
about definitions of TRD and chronic depression (cMDD) in
the literature (Ruhe et al., 2012). As a result, many studies into
the psychotherapeutic treatment of cMDD appear to be carried
out in clinical samples that in the majority consist of participants
that already received one or more failed treatments for the index
episode, thereby qualifying them, in fact, as studies of psychother-
apy for TRD.
Given the considerations above and a growing database of ran-
domized controlled studies treating TRD with psychotherapy, we
decided to conduct a meta-analysis and meta-regression. For
these analyses, we collected all randomized controlled studies of
psychotherapy for adult patients with TRD and/or unsuccessfully
treated cMDD in which the effectiveness of psychotherapy was
examined as either a substitute for or add-on to treatment as
usual (TAU; routine treatments such as clinical management
and/or the continuation, optimization or next step pharmacother-
apy). We hypothesized (i) that switching to psychotherapy is
more effective than TAU, and (ii) psychotherapy as an add-on
to TAU to be more effective than TAU only.
Methods
Search strategy and study selection
Two authors (SB and NM) independently performed a compre-
hensive search through PubMed, Embase and PsychINFO elec-
tronic databases combining terms regarding psychotherapy, and
TRD/cMDD (online Supplementary Methods I). Publications
up until and including 19 December 2016 were reviewed. The
search was limited to articles published in English, describing
studies with a controlled design in samples of adult participants.
References of the selected articles were checked, as well as refer-
ences of earlier systematic reviews and meta-analyses
(McPherson et al., 2005; Cuijpers et al., 2010c; Trivedi et al.,
2011; Spijker et al., 2013; Kriston et al., 2014; Negt et al., 2016).
The same authors independently assessed articles for inclusion
by screening titles and abstracts followed by detailed full-text
evaluation if necessary. Disagreements between the reviewers
were solved through discussion with a third independent reviewer
(FP). We included (i) RCTs that examined the effectiveness of
psychotherapy for (ii) adults (⩾18 years of age) with TRD by
comparing (iii) psychotherapy v. TAU or (iv) add-on psychother-
apy and TAU v. TAU only. For this meta-analysis, we defined
TRD in line with previous reviews (Stimpson et al., 2002;
McPherson et al., 2005; Trivedi et al., 2011), as an individual’s
failure to respond to at least one adequate trial of antidepressants
for the current episode irrespective of duration of the current epi-
sode. We decided to apply this broad definition to enable compar-
isons with previous literature and to include a large body of
evidence. A failed response was assumed when study sample
descriptions mentioned the inclusion of participants not meeting
the criteria for clinically significant response or remission to the
previous treatment. For the current meta-analyses, we included
cMDD studies if the majority of the sample fulfilled our criterion
for TRD. Psychotherapy was defined as a face-to-face interaction
with a therapist, which was allowed to be delivered either in a
group or individual format in both out- and inpatient settings.
TAU was defined as treatments that individuals would normally
receive in routine (mental) health care, such as clinical manage-
ment and pharmacotherapy. Pharmacotherapy included continu-
ation, optimization, switching or starting of antidepressant
medication. Studies were excluded if they had a maintenance
treatment study design or if treatment-resistance was undefined
or remained unclear based on the reported information on previ-
ously failed response to antidepressant medication.
Quality assessment and data extraction
Two authors (SB and FP) independently evaluated the validity of
the studies eligible for the qualitative synthesis. Following recent
meta-analyses (Cuijpers et al., 2014,2015), we examined all
included studies on four criteria of the ‘Risk of bias’assessment
tool, developed by the Cochrane Collaboration (Higgins and
Green, 2011): (1) adequate random sequence generation, (2) allo-
cation to treatments by an independent (third) party, (3) blinding
of the outcome assessment and (4) the quantity, nature and man-
agement of incomplete outcome data. Disagreements between the
reviewers were resolved through discussion.
Two authors (NM and LB) independently extracted the data
from the included studies. Data extraction was checked and dis-
agreements were resolved by two other reviewers (FP and SB).
For the outcome variable, means and standard deviations (S.D.)
of change in depression severity scales from pre- to post-
intervention were extracted for both the treatment and TAU con-
dition. Our research questions addressed outcomes of acute-phase
treatment specifically. Therefore, the post-treatment endpoint was
set a maximum of 16 weeks with a minimum session frequency of
once a week. Follow-up measurements were excluded from our
analyses. Although the treatment endpoint was set at 16 weeks
to target the acute phase, for some studies outcome data were
not available at this time point. As a result, the post-intervention
depression severity score was assessed at 12.8 weeks on average,
varying between 5 and 26 weeks. In addition, we extracted clinical
variables, treatment variables and study variables for background
information input for sensitivity analyses, and meta-regressions
(as described in the ‘Statistical Analyses’section). Clinical vari-
ables included the male/female ratio, the mean age of the sample,
mean depression severity at baseline, prior history (number of
previous episodes and mean illness duration in months), mean
duration of the current episode and the percentage of participants
that did not respond to antidepressants or psychotherapy for the
current episode prior to the study. Treatment variables included
the type of psychotherapy, treatment duration (number of months
and number of treatment sessions), individual or group setting,
attrition rates, and treatment integrity. Study variables included
the year the study was conducted, the clinical setting (inpatient
or outpatient), and an intention to treat approach for the
extracted outcome measures.
For each study, we coded the type of comparison: (1) psycho-
therapy v. TAU or (2) add-on psychotherapy plus TAU v. TAU.
In addition, we specified the type of interventions that were con-
sidered TAU. For a few studies comparing the ‘add-on psycho-
therapy plus TAU v. TAU’, the TAU interventions were slightly
different between the two groups. If so, this was coded during
our data extraction.
All corresponding authors were contacted to check the data
retrieved during our data extraction and were asked to provide
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missing data. If those attempts failed and the incomplete data
made the calculation of an effect size impossible, studies were
excluded from the quantitative but not the qualitative synthesis
of evidence.
Statistical analyses
All analyses were done with Stata version 13.1. The primary out-
come was the difference between the average depression severity
change of treatment and control condition, calculated as
Hedges’geffect sizes. If multiple instruments were available to
assess symptomatic change, the mean effect size was calculated
(Borenstein et al., 2009). To test whether studies with multiple
depression severity scales affected the overall results of the
meta-analyses, sensitivity analyses were performed with only
studies using one measurement scale. Since most studies had a
small sample size, effects sizes were corrected for small sample
bias (Hedges’g). If average change scores were not reported,
they were calculated using the average pre and post-intervention
depression severity score. When unavailable, S.D. of the change
scores were calculated using the S.D. of the average pre- and post-
intervention depression scores and the correlation coefficient
between these scores (calculations were based on the formula pre-
sented in online Supplementary Methods II). If this correlation
coefficient was not reported, we assumed a correlation of r=
0.5, which was based on data from a recent RCT comparing cog-
nitive therapy and interpersonal psychotherapy for MDD
(Lemmens et al., 2015). To examine the impact of this assump-
tion, a sensitivity analyses were performed to test whether a
reduced (r= 0.2) or increased (r= 0.8) correlation would change
the overall results of the meta-analysis.
Summary effect sizes were pooled using a random-effects
model for (i) psychotherapy v. TAU or (ii) add-on psychotherapy
plus TAU v. TAU comparison. To test the homogeneity of the
effect sizes, the I
2
statistic was estimated with 95% confidence
intervals (Ioannidis et al., 2007). An I
2
value of >50% was
assumed to be indicative of heterogeneity. When multiple com-
parisons of one trial were included, sensitivity analyses were per-
formed to test whether this affected the pooled results by only
including the comparison with the smallest effect size. In add-
ition, sensitivity analyses on study quality were conducted by lim-
iting the analyses to the studies meeting all four quality criteria
with a low-risk score. For the second comparison, studies with
slightly different TAU interventions between the two groups
were excluded to see whether this affected the pooled effect size
(additional sensitivity analysis). A similar sensitivity analysis
was computed for studies with the inclusion of psychotherapy
in the TAU interventions. We assessed publication bias by
inspecting funnel plots and examining plot asymmetry using
the Egger’s test (Egger et al., 1997).
A meta-regression was conducted in order to relate specific
study-level variables to the statistical heterogeneity between the
results of the studies (Thompson and Higgins, 2002). First, we
conducted univariate meta-regressions for each of the following
a priori selected variables: mean depression severity at baseline,
mean illness duration (number of months and number of previous
episodes), mean duration of the current episode, the percentage of
participants that did not respond to antidepressants for the cur-
rent episode, mean treatment duration (number of months and
number of treatment sessions), attrition rates, the clinical setting
(inpatient or outpatient), individual or group format, clinician-
rated or self-reported outcomes (or a combination), and whether
the extracted outcomes were based on intention to treat data.
When variables had at least a pvalue <0.10, they were included
in a multivariate meta-regression. Correlations between the vari-
ables that were included in the multivariate meta-regression
were examined to check if collinearity could influence the results.
Results
Selection and inclusion of trials
We identified 1044 potentially relevant citations through database
searching and 16 additional records through other sources. After
removing duplicates and excluding non-relevant citations based
on abstract examination, we retrieved 32 full-text papers for fur-
ther consideration. Finally, 22 trials met our inclusion criteria
for the meta-analysis, however, 1 trial was only included in the
qualitative analysis as a result of reporting incomplete data. The
PRISMA flow chart describing the inclusion process and exclu-
sion reasons is presented in Fig. 1.
Characteristics of included trials
The 21 trials included in the meta-analyses provided a total of 25
comparisons; three comparisons (three studies) pertained to psy-
chotherapy v. TAU (Table 1), and 22 (20 studies) to a comparison
of add-on psychotherapy plus TAU v. TAU only (Table 2). A total
of 3539 patients were enrolled (293 in psychotherapy only, 1588
in add-on psychotherapy plus TAU and 1638 in TAU). Sample
sizes varied between 11 and 235 participants per treatment arm.
All trials (22 with the inclusion of the one study that was
retained in the qualitative analysis only) recruited participants
in secondary or tertiary care facilities except for one that was con-
ducted in primary care (Wiles et al., 2013). Two trials were con-
ducted in an inpatient setting. Eight trials were conducted in
North- and South America, nine in the UK, four in other
European countries, and one in East Asia.
In total, 11 different psychotherapeutic treatments were inves-
tigated. In the 25 comparisons, six examined cognitive behavior
therapy (CBT), six cognitive behavioral-analysis system of psy-
chotherapy (CBASP), two interpersonal psychotherapy (IPT),
four mindfulness-based cognitive therapy (MBCT). The number
of treatment sessions varied from 8 to 60 (although treatment
endpoint for further analyses was set at 16 weeks to target the
acute phase which restricted the range between treatments, see
method section). Fourteen comparisons used an individual for-
mat, 10 employed a group format, and one utilized a mixed indi-
vidual and group approach.
In the psychotherapy v. TAU comparison, TAU conditions
included starting of (Keller et al., 2000;Schrammet al., 2015)
and switching to (Thase et al., 2007) different types of antidepres-
sant medication. TAU interventions in the add-on psychotherapy
plus TAU v. TAU comparison included clinical management,
and starting, augmenting, optimizing, and continuing pharmaco-
therapy. Changes in antidepressant medication (starting, augment-
ing and optimizing) were guided by a study protocol (Barker et al.,
1987;Kelleret al., 2000;Kennedyet al., 2003; Schramm et al., 2007;
Thase et al., 2007;Kocsiset al., 2009) or left to the decision of clin-
icians (Murray et al., 2010; Wiles et al., 2013;Wiersmaet al., 2014;
Fonagy et al., 2015;Michalaket al., 2015; Eisendrath et al., 2016;
Souza et al., 2016). For a few studies comparing add-on psychother-
apy plus TAU v. TAU, TAU conditions involved psychotherapy
options (not for all participants) (Murray et al., 2010; Watkins
Psychological Medicine 3
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et al., 2011; Wiles et al., 2013;Wiersmaet al., 2014; Fonagy et al.,
2015; Michalak et al., 2015), psycho-education (Chiesa et al., 2015),
a health enhancement program (Eisendrath et al., 2016)orother
health care services (Harley et al., 2008;Barnhoferet al., 2009;
Wiersma et al., 2014). In nine of 22 ‘psychotherapy plus TAU v.
TAU’comparisons, the TAU interventions were slightly differ-
ent between the two groups (Kennedy et al., 2003;Schramm
et al., 2007;Thaseet al., 2007; Murray et al., 2010;Watkins
et al., 2011;Wiersmaet al., 2014;Chiesaet al., 2015;Fonagy
et al., 2015; Eisendrath et al., 2016).
Studies used various instruments to examine depression severity,
including clinician-rated measures (Hamilton Rating Scale for
Depression Scale, Montgomery-Asberg Depression Rating Scale,
Quick Inventory of Depressive Symptomatology) and self-report mea-
sures (Inventory of Depressive Symptomatology, Beck Depression
Inventory, Quick Inventory of Depressive Symptomatology).
Quality of included trials
Thirteen of the 22 studies met all four quality criteria with a ‘low
risk’score. A total of 18 studies reported an adequate random
sequence generation. In 19 studies, it was reported that the
treatment allocation was done by an independent party. In 23
studies, the outcome assessors were blinded to the treatment allo-
cation. A total of 15 studies used intention-to-treat analyses and
had a balanced number of missing outcome data across
interventions.
Treatment integrity
Two of the 22 studies did not report information on the thera-
pist’s competence in and adherence to the specific treatment
type (Barker et al., 1987; Kennedy et al., 2003). Of the remaining
20 studies, seven trials provided extra training for the therapists
prior to the study. Therapists received supervision (individual
and/or group) in 17 studies, and sessions were video or audio
recorded in 13 studies. Adherence was systematically rated in
eight studies, of which two used ‘checklists’and the remaining
six used standardized instruments. Competence was systematic-
ally assessed in five studies with standardized instruments.
Detailed information about treatment integrity for each study is
provided in online Supplementary Results I.
Fig. 1. Study selection process.
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Table 1. Psychotherapy for TRD when substituted for TAU; study and treatment variables
Author,
year
Treatment resistance
Psychotherapy TAU
No. of
sessions,
duration
Sample size
(treatment,
control)
Measurement
scales Setting
Group or
individual
therapy
Study
quality
a
Definition of
treatment resistance
or chronicity
Rates of
non-response
to ADM or
other
treatments
Keller
et al.
(2000)
Chronic forms of
major depressive
disorder
ADM: 60.2%;
PT: 65.2%;
ADM + PT:
45.1%.
CBASP Starting NFN
treatment + CM
16–20
sessions;
12 weeks
228, 226 HAM-D
24
Outpatient Individual 1: +
2: +
3: +
4: +
Thase
et al.
(2007)
Inadequate benefit
from an initial CTM
treatment (level 1 of
the STAR-D trial).
ADM: 100% CBT Switching to BUP, SER
or VLX treatment
16 sessions;
12 weeks
36, 86 HAM-D
17
;
QIDS-C
Outpatient Individual 1: −
2: +
3: +
4: −
Schramm
et al.
(2015)
Chronic major
depressive disorder
ADM:56.9%
PT: 67.80%
ADM + PT:
47.0%
CBASP Starting ECM
treatment
12 sessions;
8 weeks
29, 31 MADRS;
IDS-SR
Outpatient Individual 1: +
2: +
3: +
4: +
TRD, treatment-resistant depression; TAU, treatment as usual; ADM, antidepressant medication; PT, psychotherapy; CBASP, Cognitive Behavioral Analysis System of Psychotherapy; NFN, Nefazodon; CM, clinical management; HAM-D
24
, 24-item Hamilton
Rating Scale for Depression; CTM, Citalopram; CBT, cognitive behavioral therapy; BUP, bupropion; SER, sertraline; VLX, venlafaxine; HAM-D
17
, 17-item Hamilton Rating Scale for Depression; QIDS-C, clinician-administered version of the 16-item Quick
Inventory of Depressive Symptomatology; ECM, Escitalopram; MADRS, Montgomery-Asberg Depression Rating Scale; IDS-SR, self-report version of the Inventory of Depressive Symptomatology.
a
Study quality was examined using four criteria of the ‘‘Risk of bias’’ assessment tool, developed by the Cochrane Collaboration (Collaboration 2015). A positive (low risk) or negative sign (high risk or unclear) is given to each of the criteria respectively:
(1) adequate random sequence generation, (2) allocation to treatments by an independent (third) party, (3) blinding of the outcome assessment and (4) the quantity, nature and management of incomplete outcome data.
Psychological Medicine 5
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Table 2. Add-on psychotherapy plus TAU v. TAU; study and treatment variables
Author,
year
Treatment resistance
Psychotherapy plus
TAU TAU No. of sessions; duration
Sample size
(treatment,
control)
Measurement
scales Setting
Group or
individual
therapy
Study
quality
a
Definition of
treatment resistance
or chronicity
Rates of
non-response to
ADM or other
treatments
Barker
et al.(1987)
Depression for at
least 2 years with
failure to respond to
recognized
treatment regimes.
Recognized
treatment
regimes: 100%
CBT + starting 5-HT
cocktail + low
vanadium regime
5-HT cocktail + starting
low vanadium regime
15 sessions, 12 weeks Unclear HAM-D, BDI Outpatient Individual 1: −
2: −
3: −
4: −
Paykel
et al.
(1999);
Scott et al.
(2000)
Residual depression
symptoms lasting
2–18 months (after a
depressive episode
within the last
18 months), despite
ADM for at least the
8 weeks prior to the
study, with at least
4 weeks at an
adequate dose (a
minimum equivalent
to 125 mg per day of
AMI), or to have
refused explicitly to
increase the dosage.
ADM:100% CBT + continuation of
PHT + CM
Continuation of
PHT + CM
16 sessions; 20 weeks 80, 78 HAM-D
17
; BDI Outpatient Individual 1: +
2: +
3: +
4: +
Keller et al.
(2000)
Chronic forms of
major depressive
disorder
ADM: 60.2%;
PT: 65.2%;
ADM + PT: 45.1%.
CBASP + starting NFN
treatment + CM
Starting NFN treatment
+CM
16–20 sessions;12 weeks 227, 226 HAM-D
24
Outpatient Individual 1: +
2: +
3: +
4: +
Kennedy
et al.(2003)
Partial response
after receiving 1 of 4
standard ADM (MOC,
PAR, SER, VLX) to
maximum tolerated
doses for 8 to
14 weeks.
ADM: 100% CBT+ continuation of
PHT
Lithium augmentation +
continuation of PHT
12 session; 8 weeks 23, 21 HAM-D
17
; BDI Outpatient Individual 1: −
2: −
3: +
4: +
Thase et al.
(2007)
Inadequate benefit
from an initial CTM
treatment (level 1 of
the STAR-D trial).
ADM: 100% CBT+ continuation of
CTM
Augmentation
medication (BUP, BUS)
+ continuation of CTM
16 sessions;12 weeks 65, 117 HAM-D
17
;
QIDS-SR
Outpatient Individual 1: −
2: +
3: +
4: −
Schramm
et al.(2007)
Not defined. ADM: 50,8%
Outpatient
treatment: 83.0%
Previous
hospitalization:
44%
IPT + starting PHT Starting PHT + CM 23 sessions; 5 weeks 65, 65 HAM-D
17
; BDI Inpatient Individual
and group
1: +
2: +
3: +
4: +
Wong,
(2008)
Ongoing major
depressive disorder
despite ADM with
mild to severe
depressive
symptoms despite
ADM treatment
ADM:100% CBT + continuation of
PHT
Continuation of PHT 10 sessions; 10 weeks 48, 48 BDI Outpatient Group 1: −
2: −
3: +
4: −
Harley
et al.(2008)
Ongoing major
depressive disorder
despite ADM
ADM: 100% DBTST+ continuation
of PHT and other
Continuation of PHT and
other mental health
treatments as usual
16 sessions;16 weeks 13, 11 HAM-D
17
,
BDI-II
Outpatient Group 1: +
2: −
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treatment (i.e. at
least the standard
effective dosage of a
given antidepressant
defined in the
consensus of
2 senior
psychiatrists, and no
change in dosage for
at least 6 weeks prior
to the study)
mental health
treatments as usual
3: +
4: −
Kocsis
et al.(2009)
Chronic forms of the
major depressive
disorder. Inadequate
benefit (less than
remission) from an
initial standardized
PHT (phase 1 of the
REVAMP trial).
ADM: 100% A: BSP + switching PHT
+CM
B: CBASP + switching
PHT + CM
Switching PHT + CM A. 16–20 session; 12
weeks
B:16 sessions;12 weeks
BSP: 195
CBASP: 200
TAU:96
HAM-D
24
;
QIDS-C
Outpatient Individual 1: +
2: +
3: +
4: +
Barnhofer
et al.(2009)
Chronic major
depressive disorder
ADM: 60% at the
start of the trial
(80% previously)
PT: >2/3 had
received PT or
counselling, more
than half of them
had received CBT
MBCT + continuation of
PHT and other mental
health treatments as
usual (except
individual PT)
Continuation of PHT and
other mental health
treatments as usual
(except individual PT or
meditation practice)
8 sessions; 8 weeks 16, 15 BDI-II Outpatient Group 1: +
2: +
3: +
4: +
Murray
et al.(2010)
Chronic forms of
major depressive
disorder
ADM: on average
3 failed
medication trials
PT: 85.7%
ECT: 28.1%
Re-ChORD: optimizing
PHT, IPT and
occupational therapy
Treated with available
services based on a
detailed
recommendations on
optimizing PHT and PT
interventions
26–28 sessions; 4 months 34, 30 BDI-II Outpatient Group 1: +
2: +
3: +
4: −
Watkins
et al.(2011)
Residual depression
symptoms despite
ADM treatment (at a
therapeutic dose as
recommended by
the British National
Formulary and/or
equivalent to 125 mg
of AMI) for at least 8
weeks continuously
during the current
episode and within
the 2 months prior to
the study
ADM:100% IRCBT + continuation
of PHT + CM
Continuation of PHT
+ CM + PT (for n = 7)
12 sessions; 6 months 21, 21 HAM-D
17
,
BDI-II
Outpatient Individual 1: +
2: +
3: +
4: +
Strauss
et al.(2012)
Chronic forms of
major depressive
disorder
ADM:88%
PT: 84%
PBCT + continuation
of PHT + CM
Continuation of
PHT + CM
12 sessions; 12 weeks 14, 14 BDI-II Outpatient Group 1: −
2: −
3: +
4: +
Wiles et al.
(2013)
Ongoing depressive
symptoms despite at
least 6 weeks of ADM
treatment at an
adequate dose
ADM:100% CBT + optimizing PHT +
CM by a general
practitioner (no
restrictions on referring
to other mental health
services including PT)
Optimizing PHT + CM by
a general practitioner
(no restrictions on
referring to other
mental health services
including PT)
12–18 sessions; 6 months 234, 235 BDI-II Outpatient Individual 1: +
2: +
3: +
4: +
Rohricht
et al.(2013)
Chronic forms of the
major depressive
disorder
ADM: 100%; an
average of 4 ADM
trials at an
adequate dose
(range 2–7)
GBOPT + continuation
of PHT + CM by
community psychiatric
services
Continuation of PHT +
CM by community
psychiatric services
20 sessions; 10 weeks 16,15 HAM-D
21
Outpatient Group 1: +
2: +
3: +
4: −
(Continued)
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Table 2. (Continued.)
Author,
year
Treatment resistance
Psychotherapy plus
TAU TAU No. of sessions; duration
Sample size
(treatment,
control)
Measurement
scales Setting
Group or
individual
therapy
Study
quality
a
Definition of
treatment resistance
or chronicity
Rates of
non-response to
ADM or other
treatments
PT: 100%; one or
two courses of
individual
psychotherapy
(CBT, PDP)
Wiersma
et al.(2014)
Chronic forms of the
major depressive
disorder
ADM: 64.1%
Previous mental
health treatment
(secondary or
tertiary care):
82.3%
CBASP + optimizing
PHT + CM
Optimizing PHT + CM +
psychotherapy (CBT,
IPT, short
psycho-analytic
supportive therapy and
supported/structured
therapy)
24 sessions: 12 months
b
69, 73 IDS Outpatient Individual 1: +
2: +
3: +
4: +
Michalak
et al.(2015)
Chronic forms of the
major depressive
disorder
ADM:53.8%
PT: 29.2%
A. MBCT + continuation
and starting PHT +
CM/PT
B. CBASP +
continuation and
starting PHT + CM/PT
Continuation and
starting PHT + CM/PT
MBCT: 8 sessions;
8 weeks
CBASP: 10 sessions;
8 weeks
MBCT:36
CBASP:35
TAU:35
HAM-D
24
BDI-II
Outpatient Group 1: +
2: +
3: +
4: +
Fonagy
et al.(2015)
Ongoing major
depressive disorder
despite at least two
antidepressant
treatments, one of
which must have
included ADM
treatment and the
other with
either ADM or
a psychological
intervention.
ADM:100% PDP + optimizing PHT +
CM
Optimizing PHT +
CM + PT
60 sessions; 18 months
c
67, 62 HAM-D
17
;
BDI
Outpatient Individual 1: +
2: +
3: +
4: +
Chiesa
et al.(2015)
Ongoing major
depressive disorder
(failure to achieve
remission) despite
ADM treatment at
adequate dosages
for at least 8 weeks
prior to the study
ADM: 100% MBCT+ continuation of
PHT
Psycho-education
program + continuation
of PHT
8 sessions; 8 weeks 26, 24 HAM-D
21
BDI-II
Outpatient Group 1: +
2: +
3: +
4: +
Eisendrath
et al.(2016)
Ongoing major
depressive disorder
despite at least two
adequate trials of
antidepressant
medication during
the current episode
ADM:100% MBCT + continuation or
optimizing of PHT
Health Enhancement
Program (comparator
condition for MBCT)+
continuation or
optimizing of PHT
8 sessions; 8 weeks 87, 86 HAM-D
17
Outpatient Group 1: +
2: +
3: +
4: −
8 Suzanne van Bronswijk et al.
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Psychotherapy v. TAU
We examined three studies consisting of three comparisons (see
Table 1). Interventions were CBT and CBASP. The TAUs as
described in the trials were mainly a continuation of ongoing
pharmacotherapy.
The mean pooled effect size was g=−0.13 (95% CI −0.30 to
0.05), heterogeneity was low with a high level of uncertainty
given the wide 95% CI interval (I
2
= 0.00: 95% CI 0.00–89.60).
The effect sizes of the individual trials are plotted in Fig. 2, show-
ing that none of the interventions had significantly higher depres-
sion severity change scores on average than TAU. Given the small
number of studies, we did not perform an Egger’s test (Higgins
and Green, 2011). Separate sensitivity analyses (1) examining dif-
ferent correlations between pre- and post-intervention depression
scores, (2) excluding studies that used multiple outcome mea-
sures, (3) including only the comparison with the smallest effect
size, did not change the results, and (4) including only studies
meeting all four quality criteria with a low risk score. Given the
small number of included studies, we were not able to conduct
a meta-regression.
Add-on psychotherapy plus TAU v. TAU
We examined 20 studies consisting of 22 comparisons for the
effectiveness of psychotherapy added to TAU v. TAU alone.
The psychotherapeutic interventions were IPT, CBASP, CBT,
psychodynamic therapy (PDT), body-oriented therapy (BOT),
dialectic behavior therapy (DBT) and brief supportive psycho-
therapy (BSP). The TAUs as described in the trials were mainly
a continuation of ongoing pharmacotherapy. Study characteristics
are shown in Table 2.
The mean pooled effect size was g= 0.42 (95% CI 0.29–0.54),
indicating that adding psychotherapy to TAU resulted in higher
average depression severity change as compared with treatment
with TAU alone (Fig. 3). We found an indication for heterogen-
eity between studies, with again large uncertainty around this esti-
mate (I
2
= 52.96; 95% CI 23.6–71.04). When grouped together by
type of treatment, IPT (g= 0.33; 95% CI 0.02–0.64), CBASP (g=
0.42; 95% CI 0.08–0.76), CBT (g= 0.26; 95% CI 0.01–0.51), and
MBCT (g= 0.55; 95% CI 0.31–0.79) show moderate but signifi-
cant pooled effect sizes. Within the group of other therapies,
BOT, PDT, individual rumination-focused cognitive behavioral
therapy, and person-based cognitive therapy showed significant
effect sizes (Fig. 3). The funnel plot (Fig. 4) did not indicate pub-
lication bias and Egger’s test did not indicate asymmetry of the
funnel plot (intercept: 0.78; 95% CI −0.79 to 2.35; p= 0.31).
Separate sensitivity analyses (1) examining alternative correla-
tions between pre- and post-intervention depression scores, (2)
excluding studies that used multiple outcome measures, (3)
including only the comparison with the smallest effect size, (4)
excluding trials where the TAU in the control group was different
from the TAU in the intervention arm, (5) excluding trials where
TAU included psychotherapy options, and (6) including only
studies meeting all four quality criteria with a low-risk score,
did not change the results.
In the univariate meta-regression analyses regarding the set of
a priori selected variables, baseline severity (β= 0.16; S.E. = 0.09;
p= 0.079); divided into four categories between mild and very
severe (Rush et al., 2003), number of sessions (β=−0.12; S.E.=
0.06; p= 0.073), and individual v. group format (β= 0.32; S.E.=
0.14; p= 0.027) met our criterion of p< 0.10. In a final multivariate
Souza et al.
(2016)
Ongoing major
depressive disorder
despite at least one
trial of ADM in an
adequate dose
(equivalent to
⩾75 mg of AMI) and
adequate duration
(⩾4 weeks)
ADM: 100% IPT+ optimizing PHT +
CM
Optimizing PHT + CM 16 sessions; 16–19 weeks, 17, 23 HAM-D
17
;
BDI
Outpatient Individual 1: +
2: +
3: +
4: −
TRD, treatment resistant depression; TAU, treatment as usual; CBT, Cognitive Behavior Therapy; 5-HT cocktail, combination of phenelzine, L-tryptophan and lithium carbonate; low vanadium regime, a diet low in vanadium and sodium calcium edetat;
HAM-D, Hamilton Rating Scale for Depression; BDI, Beck Depression Inventory; AMI, amitriptyline; ADM, antidepressant medication; PHT, Pharmacotherapy; CM, clinical management; HAM-D
17
, 17-item Hamilton Rating Scale for Depression; CBASP,
Cognitive Behavioral Analysis System of Psychotherapy; NFN, Nefazodon; HAM-D
24
, 24-item Hamilton Rating Scale for Depression; MOC, moclobemide; PAR, paroxetine; SER, sertraline; VLX, venlafaxine; CTM, Citalopram; BUP, bupropion; BUS,
buspirone; QIDS-SR, self-report version of the Inventory of Depressive Symptomatology; DBTST, Dialectic Behaviour Therapy Skills Training; BDI-II, Beck Depression Inventory, second edition; BSP, Brief supportive psychotherapy; QIDS-C,
clinician-administered version of the 16-item Quick Inventory of Depressive Symptomatology; MBCT, Mindfulness Based Cognitive Therapy; ECT, electroconvulsive therapy; PDP, Psycho-dynamic psychotherapy; GBOPT, Group body oriented
psychological therapy; HAM-D
21
,21-item Hamilton Rating Scale for Depression; IPT, Interpersonal Therapy; IDS, Self-report version of the Inventory for Depressive Symptomatology.
a
Study quality was examined using four criteria of the ‘‘Risk of bias’’ assessment tool, developed by the Cochrane Collaboration (Collaboration 2015). A positive (low risk) or negative sign (high risk or unclear) is given to each of the criteria, respectively:
(1) adequate random sequence generation, (2) allocation to treatments by an independent (third) party, (3) blinding of the outcome assessment and (4) the quantity, nature and management of incomplete outcome data.
b
For reasons of adequate comparison results at 12 weeks of acute treatment were used in the analyses.
c
For reasons of adequate comparison results at 16 weeks of acute treatment were used in the analyses.
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meta-regression higher baseline severity (β= 0.81; S.E. = 0.07;
p= 0.032), and group therapy-format (β= 0.38; S.E. = 0.20;
p= 0.079) were associated with a larger effect size. Their correl-
ation was 0.23, indicative of low collinearity.
Discussion
In the present meta-analysis, we investigated the effectiveness of
psychotherapy for adult patients with TRD and/or unsuccessfully
treated cMDD either as a substitute or as an add-on to TAU. We
identified 22 trials of which 21 could be included in the
meta-analyses, yielding a total of 25 comparisons. In three com-
parisons of psychotherapy v. TAU we found no significant advan-
tage of psychotherapy over TAU, while in 22 comparisons of
add-on psychotherapy plus TAU v. TAU only, we found a signifi-
cant improvement of patients due to psychotherapy with a mod-
erate general effect size of 0.42 (95% CI 0.29–0.55).
Psychotherapy v. TAU
Our hypothesis that for acute-phase treatment psychotherapy is
more effective than TAU in TRD was not confirmed. Compared
with ongoing TAU, psychotherapy, as a substitute for ongoing
or recently started TAU, psychotherapy appeared not more effect-
ive in TRD (Hedges’g=−0.02). We found no indication for pub-
lication bias and the heterogeneity between studies was small
although this should be interpreted with caution because CI inter-
vals were wide. In a previous meta-analysis (Cuijpers et al.,
2010c), addressing the effectiveness of psychotherapy for cMDD
and dysthymia, the authors reported that pharmacotherapy was
more effective than psychotherapy, which seems at odds with
our finding. However, it should be kept in mind that our inclusion
criteria (aimed at TRD and exclusion of dysthymia) resulted in a
selection of different studies. The vast majority of participants in
our study selection had not responded to at least one previous
trial with an antidepressant that is known to be associated with
a less favorable response to subsequent treatments with pharma-
cotherapy (Ruhe et al., 2006).
Add-on psychotherapy plus TAU v. TAU
We found that psychotherapy added to ongoing TAU has a mod-
erate and significant effect size (Hedges’g= 0.42) in comparison
with TAU alone in TRD. Again, there was no evidence for publi-
cation bias, however there was some indication of heterogeneity
between studies with wide CI intervals. The results from this
meta-analysis suggest that, in line with a previous meta-analysis
(Cuijpers et al., 2010c) and recent clinical recommendations
(Jobst et al., 2016) about the treatment of cMDD, several psycho-
therapeutic approaches may be of value in the treatment of TRD
when added to TAU, with some evidence for more effectiveness in
patients with more severe depressive symptomatology. However,
some considerations may apply. First, studies of the effectiveness
of CBT were done in samples with relatively low levels of TRD
(mostly one unsuccessful trial with an antidepressant), which
may restrict its applicability in patients with more advanced
TRD. Second, some studies (e.g. Keller et al., 2010) excluded par-
ticipants displaying high levels of TRD, like non-response to three
previous adequate trials of different classes of antidepressants or
electroconvulsive therapy, again limiting generalizability to
patients with more advanced levels of TRD. Third, based on
these findings one cannot rule out that TAU and psychotherapy
interfere and that the combination of the two interventions
leads to a greater impact than the sum of each treatment effect
separately. However, a recent meta-analysis on combination ther-
apy (pharmacotherapy and psychotherapy) for depression and
anxiety disorders has shown equal and independent effects of
pharmacotherapy and psychotherapy (Cuijpers et al., 2014).
Fig. 2. Effects of psychotherapy for TRD when substituted for TAU. g = Hedges’g effect sizes, 95% CI = 95% confidence interval, DL = DerSimonian-Laird method:
between study variation was estimated using the DerSimonian-Laird method.
10 Suzanne van Bronswijk et al.
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Fourth, since no active and structural equivalent placebo condi-
tion was included, the current design is insufficient to examine
if the specific components of psychotherapy are responsible for
the moderate effect size (Baskin et al., 2003).
Meta-analyses of psychotherapy for non-TRD typically report
effect-sizes, that are comparable with the overall effect-size of g=
0.42 for psychotherapy as an add-on to TAU for TRD that we
have found (Cuijpers et al., 2008,2010b). This is also commensur-
ate with the results from a meta-analysis that examined the effect-
iveness of psychotherapy for cMDD and dysthymia (Cuijpers
et al., 2010c).
In the current meta-analysis, the most frequently investigated
treatments are CBT, CBASP, MBCT, and to a lesser extent IPT,
all with small to moderate overall effect sizes. No significant dif-
ferences in the efficacy between the treatments emerged from the
meta-regression. This result should be interpreted with caution
since for each therapy a different number of comparisons was
included (ranging between one and five studies). In addition,
one could argue that aggregated results from RCTs are not suited
to isolate effects of specific psychotherapies (Budd and Hughes,
2009).
Clinical features and study characteristics
In our meta-regression we found no evidence, other than baseline
severity and group of individual treatment format, for an associ-
ation between variables such as mean duration of the current epi-
sode, mean treatment duration (number of months and number
of treatment sessions), attrition rates, clinician-rated or self-
reported outcomes, and an intention to treat approach for the
outcome measures. The lack of an association between effect
size and treatment duration or a number of sessions should be
interpreted with caution since we used results from acute-phase
treatment with an endpoint at approximately 16 weeks treatment
for sake of comparison and absence of long-term follow-up data
in many studies. Therefore, in the current study, we did not dem-
onstrate that more treatment sessions would result in significant
larger effect sizes like previously reported in a meta-analysis
examining the effectiveness of psychotherapy for cMDD and dys-
thymia (Cuijpers et al., 2010c). However, we found comparable
effects sizes between recent studies of MBCT and treatments of
longer duration, suggesting that the reported association between
a number of sessions and effect size may be not as strong as
Fig. 3. Effects of add-on psychotherapy plus TAU v. TAU for TRD. g = Hedges’g effect sizes, 95% CI = 95% confidence interval, DL = DerSimonian-Laird method:
between study variation was estimated using the DerSimoni an-Laird method, MBCT = Mindfulnes s Based Cognitive Therapy, CBASP = Cognitive Behavioral
Analysis System of Psychotherapy, BSP = Brief supportive psychotherapy.
Psychological Medicine 11
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previously reported. It cannot be ruled out that some elements of
MBCT (e.g. daily application of exercises after treatment termin-
ation) have enduring effects beyond the typically 8 weeks duration
of training. In contrast to previous findings (Cuijpers et al.,
2010a), we did not find an effect of clinician-rated v. self-reported
instruments on our results. This result should also be interpreted
with caution since we used a combination of clinician-rated and
self-reported outcomes (average effect size) for 11 of the included
comparisons.
Studies that included participants with more baseline depres-
sion severity showed a larger effect-size. This is in line with pre-
vious findings that reported more efficacy of antidepressants in
more severely depressed subjects (Turner et al., 2008; Fournier
et al., 2010). An unexpected finding from the meta-regression
was the larger effect-size in studies that employed a group instead
of an individual treatment format. Several speculative explana-
tions can be put forward. First, group formats consist of longer
sessions than typical for individual treatment thereby increasing
therapy exposure, although the literature does not support this
speculation as there is no indication for greater efficacy of group
format compared with individual therapy (Huntley et al., 2012).
Additionally, one of the group therapies (MBCT) consists of
daily exercises outside of the strict session context thereby increas-
ing exposure to therapeutic interventions. Another explanation
may be that the group format also provides additional peer support
in subjects demoralized after unsuccessful previous treatment.
In the last decade, both the number and quality of psycho-
therapeutic trials in the field have increased considerably. The for-
mer is illustrated by the small number of studies that were
included in previous reviews and meta-analyses (Stimpson
et al., 2002; McPherson et al., 2005; Trivedi et al., 2011).
Quality improved because recent studies relied on solid random-
ization procedures, well-described treatments, and well-trained
therapists, used blinded outcome assessments, and reported
intention-to-treat instead of completers-only analyses. We con-
sider this a positive development given the preference for psycho-
therapy of many patients and the association between receiving a
preferred treatment and clinical outcome.
Generally, one of the problems in interpreting study results of
treatments for TRD is the lack of a uniform definition of TRD
which may range from non-response to only one treatment
trial, mostly with an antidepressant, to non-response following
intensive consecutive treatments including ECT (Ruhe et al.,
2012). Subsequently, non-response to only one treatment trial
might not be considered as a relevant level of TRD in clinical
practice. These different levels of treatment resistance impede
interpretation of the results from this meta-analysis and its applic-
ability in daily practice. A recommendation for future studies
would be to include detailed information on previous failed treat-
ments and include this in data-analysis. This can facilitate clinical
decision-making based on the level of treatment resistance.
Strengths and limitations
To our knowledge, this is the largest meta-analysis to date of stud-
ies into the effectiveness of psychotherapeutic treatments when
applied for the treatment of individuals with TRD. Although
studies specifically aimed at this clinically very important popula-
tion have been carried out in recent years, we were able to enlarge
the database by adding studies in cMMD that in fact included a
majority of patients with TRD. This enabled us to address the
clinically relevant question whether psychotherapy for TRD is
indeed effective. In addition, we extended this meta-analysis
with a meta-regression to relate specific study-level variables to
the statistical heterogeneity between the study results.
Some limitations apply to this meta-analysis. First, one of the
problems in interpreting study results of treatments for TRD is
the lack of a uniform definition of TRD which may range from
non-response to only one treatment trial (mostly with an anti-
depressant) to non-response following intensive consecutive treat-
ments including ECT (Ruhe et al., 2012). This is also illustrated by
the fact that the majority of the studies included participants that
were resistant to pharmacotherapy, no studies investigated specif-
ically the efficacy of psychotherapy after previous treatment with
some other form of psychotherapy. This impedes interpretation of
the results from this meta-analysis and its applicability in daily
practice. A recommendation for future studies would be to
include more detailed information on previous failed treatments
and include this in data-analysis and/or use validated tools to
quantify TRD (Peeters et al., 2016). Second, although effect-sizes
were roughly of equal magnitude, differences in content between
experimental interventions were large, which may limit guidance
for daily clinical practice; clinicians are confronted with many
remaining options. Third, the impact of treatment integrity and
therapists effects on the effectiveness of psychotherapy was not
evaluated, since standardized instruments to assess therapy adher-
ence and therapist’s competence were often lacking and informa-
tion of therapists effect was not included. Fourth, the number of
studies in the comparison between psychotherapy and TAU was
limited. Fifth, type and quality of the TAU conditions (mostly
pharmacotherapy and clinical management) were variable,
which may affect their validity as comparison intervention
resulting in an overestimation of effect sizes of the experimental
conditions. However, given their presumed reflection of common
clinical practice in these patients, this variability might improve
the generalizability of the results. Sixth, although we performed
meta-regression analyses to address the impact of potentially rele-
vant variables on outcome differences between studies, we did not
find significant results apart from baseline depression severity and
group/individual format. It should be noted that meta-regression
is an analysis of the influence at the level of differences between
and not within studies. Therefore, including variables at this
level, has its limitations because only sample means are used,
while ignoring the range in scores in the individual study popula-
tions (i.e. ecological bias; Thompson and Higgins, 2002). This
Fig. 4. Add-on psychotherapy plus TAU v. TAU for TRD: Funnel plot.
12 Suzanne van Bronswijk et al.
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limits adequate subgroup analyses and better examination of het-
erogeneity between subjects for which individual patient data
would be needed. Another limitation of our meta-regression is
the missing information on some variables, limiting the power
of our analyses. Eighth, we included studies of cMDD when a
majority of the participants were reported to have failed to
respond to at least one treatment trial for the current episode.
This might have resulted in the inclusion of some subjects who
were, in fact, true cMDD patients without qualifying for TRD,
which may have influenced the results. However, it should be
kept in mind that the majorities of non-responding patients in
the included studies were large. Additionally, we examined this
potential bias in the meta-regressions; the percentage of partici-
pants that did not respond to antidepressants for the current epi-
sode was not significantly associated with effect sizes. We,
therefore, feel that our results represent an accurate approxima-
tion of the effect size in TRD. Finally, as outlined earlier, we
were not able to pool long-term data from the few studies that
relied on treatments with longer duration and/or more treatment
sessions which may obscure additional beneficial results.
Conclusion
Our meta-analysis provides evidence that, in addition to pharma-
cological and neurostimulatory treatments, add-on of psychother-
apy to TAU in guidelines for the treatment of TRD is justified and
will provide better outcomes for this difficult-to-treat population.
Supplementary material. The supplementary material for this article can
be found at https://doi.org/10.1017/S003329171800199X.
Conflict of interest. None.
References
Barker WA, Scott J and Eccleston D (1987) The Newcastle chronic depres-
sion study: results of a treatment regime. International Clinical
Psychopharmacology 2, 261–272.
Barnhofer T, Crane C, Hargus E, Amarasinghe M, Winder R and
Williams JM (2009) Mindfulness-based cognitive therapy as a treatment
for chronic depression: a preliminary study. Behaviour Research and
Therapy 47, 366–373.
Baskin TW, Tierney SC, Minami T and Wampold BE (2003) Establishing
specificity in psychotherapy: a meta-analysis of structural equivalence of
placebo controls. Journal of Consulting and Clinical Psychology 71, 973.
Borenstein M, Hedges LV, Higgins JPT and Rothstein HR (2009)
Introduction to Meta-Analysis. Wiley: NYC.
Budd R and Hughes I (2009) The Dodo Bird Verdict –controversial, inevit-
able and important: a commentary on 30 years of meta‐analyses. Clinical
Psychology & Psychotherapy 16, 510–522.
Carvalho AF, Berk M, Hyphantis TN and McIntyre RS (2014) The integra-
tive management of treatment-resistant depression: a comprehensive review
and perspectives. Psychotherapy and Psychosomatics 83,70–88.
Chiesa A, Castagner V, Andrisano C, Serretti A, Mandelli L, Porcelli S and
Giommi F (2015) Mindfulness-based cognitive therapy vs. psycho-education
for patients with major depression who did not achieve remission following
antidepressant treatment. Psychiatry Research 226,474–483.
Cuijpers P, van Straten A, Andersson G and van Oppen P (2008)
Psychotherapy for depression in adults: a meta-analysis of comparative out-
come studies. Journal of Consulting and Clinical Psychology 76, 909–922.
Cuijpers P, Li J, Hofmann SG and Andersson G (2010a) Self-reported versus
clinician-rated symptoms of depression as outcome measures in psycho-
therapy research on depression: a meta-analysis. Clinical Psychology
Review 30, 768–778.
Cuijpers P, Smit F, Bohlmeijer E, Hollon SD and Andersson G (2010b)
Efficacy of cognitive-behavioural therapy and other psychological treat-
ments for adult depression: meta-analytic study of publication bias. The
British Journal of Psychiatry 196, 173–178.
Cuijpers P, van Straten A, Schuurmans J, van Oppen P, Hollon SD and
Andersson G (2010c) Psychotherapy for chronic major depression and dys-
thymia: a meta-analysis. Clinical Psychology Review 30,51–62.
Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AT and
Reynolds 3rd CF (2013) The efficacy of psychotherapy and pharmacother-
apy in treating depressive and anxiety disorders: a meta-analysis of direct
comparisons. World Psychiatry 12, 137–148.
Cuijpers P, Sijbrandij M, Koole SL, Andersson G, Beekman AT and
Reynolds CF (2014) Adding psychotherapy to antidepressant medication
in depression and anxiety disorders: a meta‐analysis. World Psychiatry
13,56–67.
Cuijpers P, Karyotaki E, Andersson G, Li J, Mergl R and Hegerl U (2015)
The effects of blinding on the outcomes of psychotherapy and pharmaco-
therapy for adult depression: a meta-analysis. European Psychiatry 30,
685–693.
Dold M and Kasper S (2016) Evidence-based pharmacotherapy of
treatment-resistant unipolar depression. International Journal of
Psychiatry in Clinical Practice 21,13–23.
Egger M, Davey Smith G, Schneider M and Minder C (1997) Bias in
meta-analysis detected by a simple, graphical test. BMJ 315, 629–634.
Eisendrath SJ, Gillung E, Delucchi KL, Segal ZV, Nelson JC, McInnes LA,
Mathalon DH and Feldman MD (2016) A randomized controlled trial of
mindfulness-based cognitive therapy for treatment-resistant depression.
Psychotherapy and Psychosomatics 85,99–110.
Fonagy P, Rost F, Carlyle JA, McPherson S, Thomas R, Pasco Fearon RM,
Goldberg D and Taylor D (2015) Pragmatic randomized controlled trial of
long-term psychoanalytic psychotherapy for treatment-resistant depression:
the Tavistock Adult Depression Study (TADS). World Psychiatry 14,
312–321.
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD,
Shelton RC and Fawcett J (2010) Antidepressant drug effects and depres-
sion severity: a patient-level meta-analysis. Jama 303,47–53.
Gelhorn HL, Sexton CC and Classi PM (2011) Patient preferences for
treatment of major depressive disorder and the impact on health out-
comes: a systematic review. The Primary Care Companion to CNS
Disorders 13,5.
Greden JF (2001) The burden of disease for treatment-resistant depression.
The Journal of Clinical Psychiatry 62(suppl. 16), 26–31.
Harley R, Sprich S, Safren S, Jacobo M and Fava M (2008) Adaptation of
dialectical behavior therapy skills training group for treatment-resistant
depression. The Journal of Nervous and Mental Disease 196, 136–143.
Higgins JPT and Green S (2011) Cochrane Handbook for Systematic Reviews
of Interventions Version 5.1.0 [updated March 2011]; http://www.cochrane-
handbook.org.
Huntley AL, Araya R and Salisbury C (2012) Group psychological therapies
for depression in the community: systematic review and meta-analysis. The
British Journal of Psychiatry 200, 184–190.
Ioannidis JP, Patsopoulos NA and Evangelou E (2007) Uncertainty in het-
erogeneity estimates in meta-analyses. BMJ 335, 914–916.
Jobst A, Brakemeier EL, Buchheim A, Caspar F, Cuijpers P, Ebmeier KP,
Falkai P, Jan van der Gaag R, Gaebel W, Herpertz S, Kurimay T,
Sabass L, Schnell K, Schramm E, Torrent C, Wasserman D, Wiersma J
and Padberg F (2016) European psychiatric association guidance on psy-
chotherapy in chronic depression across Europe. European Psychiatry 33,
18–36.
Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ,
Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH and
Zajecka J (2000) A comparison of nefazodone, the cognitive behavioral-
analysis system of psychotherapy, and their combination for the treatment
of chronic depression. New England Journal of Medicine 342, 1462–1470.
Kennedy SH, Segal ZV, Cohen NL, Levitan RD, Gemar M and Bagby RM
(2003) Lithium carbonate versus cognitive therapy as sequential combin-
ation treatment strategies in partial responders to antidepressant medica-
tion: an exploratory trial. The Journal of Clinical Psychiatry 64, 439–444.
Psychological Medicine 13
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S003329171800199X
Downloaded from https://www.cambridge.org/core. Uni bibliotheek Maastricht, on 29 Aug 2018 at 19:42:58, subject to the Cambridge Core terms of use, available at
Kocsis JH, Gelenberg AJ, Rothbaum BO, Klein DN, Trivedi MH,
Manber R, Keller MB, Leon AC, Wisniewski SR, Arnow BA,
Markowitz JC and Thase ME (2009) Cognitive behavioral analysis system
of psychotherapy and brief supportive psychotherapy for augmentation of
antidepressant nonresponse in chronic depression: the REVAMP Trial.
Archives of General Psychiatry 66, 1178–1188.
Kolovos S, van Tulder MW, Cuijpers P, Prigent A, Chevreul K, Riper H and
Bosmans JE (2016) The effect of treatment as usual on major depressive
disorder: a meta-analysis. Journal of Affective Disorders 210,72–81.
Kriston L, von Wolff A, Westphal A, Holzel LP and Harter M (2014)
Efficacy and acceptability of acute treatments for persistent depressive dis-
order: a network meta-analysis. Depression and Anxiety 31, 621–630.
Lemmens LH, Arntz A, Peeters F, Hollon SD, Roefs A and Huibers MJ
(2015) Clinical effectiveness of cognitive therapy v. interpersonal psycho-
therapy for depression: results of a randomized controlled trial.
Psychological Medicine 45, 2095–2110.
McHugh RK, Whitton SW, Peckham AD, Welge JA and Otto MW (2013)
Patient preference for psychological vs pharmacologic treatment of psychi-
atric disorders: a meta-analytic review. The Journal of Clinical Psychiatry 74,
595–602.
McPherson S, Cairns P, Carlyle J, Shapiro DA, Richardson P and Taylor D
(2005) The effectiveness of psychological treatments for treatment-resistant
depression: a systematic review. Acta Psychiatrica Scandinavica 111,
331–340.
Mergl R, Henkel V, Allgaier AK, Kramer D, Hautzinger M, Kohnen R,
Coyne J and Hegerl U (2011) Are treatment preferences relevant in response
to serotonergic antidepressants and cognitive-behavioral therapy in depressed
primary care patients? Results from a randomized controlled trial including a
patients’choice arm. Psychotherapy and Psychosomatics 80,39–47.
Michalak J, Schultze M, Heidenreich T and Schramm E (2015) A rando-
mized controlled trial on the efficacy of mindfulness-based cognitive ther-
apy and a group version of cognitive behavioral analysis system of
psychotherapy for chronically depressed patients. Journal of Consulting
and Clinical Psychology 83, 951–963.
Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V and Ustun B (2007)
Depression, chronic diseases, and decrements in health: results from the
World Health Surveys. Lancet 370, 851–858.
Murray G, Michalak EE, Axler A, Yaxley D, Hayashi B, Westrin A,
Ogrodniczuk JS, Tam EM, Yatham LN and Lam RW (2010) Relief of
chronic or resistant depression (Re-ChORD): a pragmatic, randomized,
open-treatment trial of an integrative program intervention for chronic
depression. Journal of Affective Disorders 123, 243–248.
Negt P, Brakemeier EL, Michalak J, Winter L, Bleich S and Kahl KG (2016)
The treatment of chronic depression with cognitive behavioral analysis sys-
tem of psychotherapy: a systematic review and meta-analysis of
randomized-controlled clinical trials. Brain and Behavior 6, e00486.
Paykel ES, Scott J, Teasdale JD, Johnson AL, Garland A, Moore R,
Jenaway A, Cornwall PL, Hayhurst H, Abbott R and Pope M (1999)
Prevention of relapse in residual depression by cognitive therapy. Archives
of General Psychiatry 56, 829–835.
Peeters FP, Ruhe HG, Wichers M, Abidi L, Kaub K, van der Lande HJ,
Spijker J, Huibers MJ and Schene AH (2016) The Dutch Measure for
quantification of Treatment Resistance in Depression (DM-TRD): an exten-
sion of the Maudsley Staging Method. Journal of Affective Disorders 205,
365–371.
Rohricht F, Papadopoulos N and Priebe S (2013) An exploratory randomized
controlled trial of body psychotherapy for patients with chronic depression.
Journal of Affective Disorders 151,85–91.
Ruhe HG, Huyser J, Swinkels JA and Schene AH (2006) Switching antidepres-
sants after a first selective serotonin reuptake inhibitor in major depressive
disorder: a systematic review. JournalofClinicalPsychiatry67,1836–1855.
Ruhe HG, van Rooijen G, Spijker J, Peeters FP and Schene AH (2012)
Staging methods for treatment resistant depression. A systematic review.
Journal of Affective Disorders 137,35–45.
Rush AJ, Thase ME and Dube S (2003) Research issues in the study of
difficult-to-treat depression. Biological Psychiatry 53, 743–753.
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW,
Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD,
McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J and
Fava M (2006). Acute and longer-term outcomes in depressed outpatients
requiring one or several treatment steps: a STAR*D report. Am J Psychiatry,
163, 1905–1917.
Schramm E, van Calker D, Dykierek P, Lieb K, Kech S, Zobel I, Leonhart R
and Berger M (2007) An intensive treatment program of interpersonal psy-
chotherapy plus pharmacotherapy for depressed inpatients: acute and long-
term results. American Journal of Psychiatry 164, 768–777.
Schramm E, Zobel I, Schoepf D, Fangmeier T, Schnell K, Walter H, Drost S,
Schmidt P, Brakemeier EL, Berger M and Normann C (2015) Cognitive
behavioral analysis system of psychotherapy versus escitalopram in chronic
major depression. Psychotherapy and Psychosomatics 84, 227–240.
Scott J, Teasdale JD, Paykel ES, Johnson AL, Abbott R, Hayhurst H,
Moore R and Garland A (2000) Effects of cognitive therapy on psycho-
logical symptoms and social functioning in residual depression. The
British Journal of Psychiatry 177, 440–446.
Souza LH, Salum GA, Mosqueiro BP, Caldieraro MA, Guerra TA and
Fleck MP (2016) Interpersonal psychotherapy as add-on for
treatment-resistant depression: a pragmatic randomized controlled trial.
Journal of Affective Disorders 193, 373–380.
Spijker J, van Straten A, Bockting CL, Meeuwissen JA and van Balkom AJ
(2013) Psychotherapy, antidepressants, and their combination for chronic
major depressive disorder: a systematic review. The Canadian Journal of
Psychiatry 58, 386–392.
Stimpson N, Agrawal N and Lewis G (2002) Randomised controlled trials
investigating pharmacological and psychological interventions for
treatment-refractory depression. Systematic review. The British Journal of
Psychiatry 181, 284–294.
Strauss C, Hayward M and Chadwick P (2012) Group person-based cognitive
therapy for chronic depression: a pilot randomized controlled trial. The
British Journal of Psychiatry 51, 345–350.
Swift JK, Callahan JL and Vollmer BM (2011) Preferences. Journal of Clinical
Psychology 67, 155–165.
Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH,
Luther JF, Fava M, Nierenberg AA, McGrath PJ, Warden D,
Niederehe G, Hollon SD and Rush AJ (2007) Cognitive therapy versus
medication in augmentation and switch strategies as second-step treat-
ments: a STAR*D report. American Journal of Psychiatry 164, 739–752.
Thompson SG and Higgins JP (2002) How should meta-regression analyses
be undertaken and interpreted? Statistics in Medicine 21, 1559–1573.
Trivedi RB, Nieuwsma JA and Williams Jr. JW (2011) Examination of the
utility of psychotherapy for patients with treatment resistant depression: a
systematic review. Journal of General Internal Medicine 26, 643–650.
Turner EH, Matthews AM, Linardatos E, Tell RA and Rosenthal R (2008)
Selective publication of antidepressant trials and its influence on apparent
efficacy. New England Journal of Medicine 358, 252–260.
Watkins ER, Mullan E, Wingrove J, Rimes K, Steiner H, Bathurst N,
Eastman R and Scott J (2011) Rumination-focused cognitive-behavioural
therapy for residual depression: phase II randomised controlled trial. The
British Journal of Psychiatry 199, 317–322.
Wiersma JE, Van Schaik DJ, Hoogendorn AW, Dekker JJ, Van HL,
Schoevers RA, Blom MB, Maas K, Smit JH, McCullough Jr. JP,
Beekman AT and Van Oppen P (2014) The effectiveness of the cognitive
behavioral analysis system of psychotherapy for chronic depression: a ran-
domized controlled trial. Psychotherapy and Psychosomatics 83, 263–269.
Wiles N, Thomas L, Abel A, Ridgway N, Turner N, Campbell J, Garland A,
Hollinghurst S, Jerrom B, Kessler D, Kuyken W, Morrison J, Turner K,
Williams C, Peters T and Lewis G (2013) Cognitive behavioural therapy as
an adjunct to pharmacotherapy for primary care based patients with treat-
ment resistant depression: results of the CoBalT randomised controlled
trial. Lancet 381, 375–384.
Wong DF (2008) Cognitive behavioral treatment groups for people with
chronic depression in Hong Kong: a randomized wait-list control design.
Depression and Anxiety 25, 142–148.
14 Suzanne van Bronswijk et al.
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S003329171800199X
Downloaded from https://www.cambridge.org/core. Uni bibliotheek Maastricht, on 29 Aug 2018 at 19:42:58, subject to the Cambridge Core terms of use, available at
