Psychiatry Research 291 (2020) 113262

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Treatment of double depression: A meta-analysis T

⁎
David G. May , Victoria N. Shaffer, K. Lira Yoon
University of Notre Dame, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Double depression (DD), the co-existence of DSM-IV major depressive disorder (MDD) and dys-
Double depression thymia, is a poorly known and sparsely studied phenomenon. Nevertheless, it is prevalent in clinical samples of
Major depressive disorder patients with depression. Thus, it is important to understand the efficacy of its treatment.
Dysthymia Methods: We conducted a meta-analysis of studies in which antidepressant medication was used to treat de-
Persistent depressive disorder
pression. Systematic searches in bibliographical databases resulted in 11 samples, including 775 patients that
Meta-analysis
met inclusion criteria.
Pharmacotherapy
Results: The overall effect size indicating the differences in depressive symptoms before and after pharma-
cotherapy was 1.81 (95% CI: 1.47, 2.16), suggesting that individuals with depression exhibited a significant
reduction in their depressive symptoms following treatment. Importantly, a moderation analysis indicated that a
higher proportion of individuals with DD within a sample was associated with lower effect sizes. Publication bias
did not pose a major threat to the stability of the findings.
Limitations: High observed heterogeneity indicated substantial variability in effect sizes and elucidation of the
potential moderators of treatment outcome was limited due to a paucity of relevant data.
Conclusions: Pharmacotherapy seems to be effective in treating DD, but DD may be more difficult to treat than
either MDD or dysthymia alone. More research specifically focusing on the treatment of DD with larger sample
sizes using randomized control trials is needed to make a firm conclusion.

1. Introduction et al., 1988). For example, DD has an increased likelihood of the

Keller and Shapiro (1982) first coined the term double depression
(DD). In the previous version of the Diagnostic and Statistical Manual for
Mental Disorders (4th ed.; DSM-IV, American Psychological Association
[APA], 1994), DD was indicated when major depressive disorder
(MDD) is present during the course of dysthymia. In the current DSM
(5th ed.; DSM-5, APA, 2013), persistent depressive disorder (PDD) was
introduced as “a consolidation of DSM-IV-defined chronic major de-
pressive disorder and dysthymic disorder” (p. 168). Therefore, in DSM-
5, DD is a sub-type of PDD in which afflicted individuals also experience
persistent (PDD with persistent major depressive episode) or inter-
mittent major depressive episodes (PDD with intermittent major de-
pressive episode, with[out] current episode). Importantly, DD is pre-
valent in clinical samples of patients with depression, with at least one-
fifth of individuals with MDD meeting the criteria for DD
(Friedman et al., 1999; Keller and Shapiro, 1982; Kocsis et al., 1988;
Rabkin et al., 1999; Thase et al., 2002).
Considering that DD is, in essence, two disorders in one, it is not
particularly surprising that its clinical presentation tends to be more
serious than either MDD or dysthymia alone (Joiner et al., 2007; Klein
manifestation of manic tendencies and other comorbid mental disorders
(Klein et al., 1988), elevated rates of both remission and relapse (Keller
et al., 1997; Keller and Shapiro, 1982; Miller et al., 1999), greater al-
cohol dependence (Diaz et al., 2012), and greater procurement of
medical attention (Goldney and Fisher, 2004) compared to either MDD
or dysthymia alone. In addition, DD is associated with increased social
impairment (Leader and Klein, 1996; but see McCullough et al., 2000;
Miller et al., 1986, for null findings). Thus, DD could present substantial
barriers to effective treatment and may require a more tailored ap-
proach. Yet, no comprehensive analysis of the efficacy of DD treatment
is available.
There is a paucity of studies that focus exclusively on the treatment
of DD. Instead, most individuals with DD were included in studies that
were designed to examine the efficacy of pharmacotherapy for de-
pression in general. An abundance of evidence suggests that pharma-
cotherapy can significantly reduce symptoms in patients with depres-
sion (e.g., Fournier et al., 2010; Khan et al., 2002; Kirsch et al., 2008).
In patients with moderate to severe depression, pharmacotherapy sig-
nificantly outperforms placebo (e.g., DeRubeis et al., 2005), and con-
tinuation of antidepressant treatment appears to protect them from

⁎
Corresponding author at: Teachers College, Columbia University, 525W. 120th Street, New York, NY 10027.
E-mail address: dmay@alumni.nd.edu (D.G. May).

https://doi.org/10.1016/j.psychres.2020.113262
Received 17 November 2019; Received in revised form 18 June 2020; Accepted 27 June 2020
Available online 08 July 2020
0165-1781/ © 2020 Elsevier B.V. All rights reserved.
D.G. May, et al.
relapse (e.g., Hollon et al., 2005). Similarly, pharmacotherapy sig-
nificantly outperformed placebo in a randomized controlled trial in
patients with mild depression or dysthymia (e.g., Williams et al., 2000).
At the same time, given significant variability in treatment responses
and the degree of efficacy of pharmacotherapy over placebo across
studies, identifying factors that moderate treatment outcomes is critical
in fully understanding which treatments are effective and why
(Kraemer et al., 2002). The variability in the proportion of patients with
DD in the samples may be one such moderating factor, especially
considering that DD is associated with elevated rates of both remission
and relapse (e.g., Miller et al., 1999).
To examine if DD affects efficacy of pharmacotherapy, we con-
ducted a meta-analysis of studies that examined the efficacy of phar-
macotherapy for depression in samples in which at least some patients
were diagnosed with DD. We predicted that pharmacotherapy will
significantly reduce the severity of depressive symptoms. More im-
portantly, we predicted that the presence of individuals with DD would
moderate treatment outcome. Specifically, we expected that a higher
proportion of individuals with DD in a sample would be associated with
less reduction in depressive symptoms.
2. Methods
2.1. Inclusion/Exclusion criteria
Inclusion criteria for studies were: adult participants, inclusion of at
least some participants with DD, assessments of depressive symptoms
before and after treatment, the use of antidepressant medications as the
main form of treatment, and depression as the treatment target. Studies
were excluded if they precluded the use of medication to treat de-
pression, focused on mental disorders other than depression, failed to
discuss DD, and/or treated children or adolescents. We also excluded
maintenance studies with people who had already recovered or partly
recovered after an earlier treatment and studies examining the effects of
medications other than antidepressants (e.g., amisulpride). Only studies
published in English were considered for inclusion.
2.2. Identification and selection of studies
Medline, PsycINFO, and Web of Science were used to search for
published peer-reviewed studies. The following search terms were used:
double depression, depression, dysthymia, persistent depressive dis-
order, CBT, cognitive-behavioral therapy, treatment, and adult. We also
conducted a title search with the phrase ‘double-depression’ to find
studies that focused on DD; the dash was used to differentiate between
studies that assessed DD and studies that happened to include both the
words ‘double’ and ‘depression’ in their titles. In addition, we checked
the references of the studies that were ultimately included and also
searched for any publications that cited these studies to ensure inclu-
sion of all relevant studies.
The electronic search resulted in 306 papers, 54 of which were
duplicates. Of the 252 articles screened, 232 were excluded due to
failure to meet one or more of the main inclusion criteria. Of the 20 full-
text articles evaluated, 11 were removed for various reasons: in-
sufficient data, such as not reporting adequate pre- and/or post- mean
and/or standard deviation data (n = 5); failure to assess treatment
outcome (n = 5); and a continuation phase of treatment (n = 1). As a
result, nine papers with 11 independent samples were included in the
current study. Fig. 1 illustrates our process through the different phases.
2.3. Coding
Identified papers were evaluated and coded based on the following
variables: the type of antidepressant used (e.g., SSRI, TCA), the measure
used to assess depressive symptoms (e.g., Hamilton Depression Rating
Scale; Hamilton, 1960), initial and post-treatment levels of depressive
2
Psychiatry Research 291 (2020) 113262
symptoms, the number of individuals in treatment and control groups,
length of treatment, and the proportion of patients with DD in the
treatment group. Two independent raters coded all the studies and
demonstrated perfect agreement for the variables included in the meta-
analysis.
2.4. Data analytic plan
Meta-Essentials (Suurmond and Hak, 2017) was used to compute
effect sizes and to conduct a random-effects meta-analysis. Hedges’ g
(Hedges, 1981) was calculated based on the differences between the
pre-treatment and post-treatment scores on the depression measures,
which all of the included studies provided. Most studies did not report
the correlation between pre- and post-scores. Thus, we followed
Rosenthal (1993)’s recommendation and used r = 0.70.
Marin et al. (1994) was the sole publication that reported a correlation
coefficient between pre- and post-scores (r = 0.31), which was used for
its effect size computation. If a paper reported results using multiple
measures of depressive symptoms, we first computed an effect size for
each measure. We then computed an average effect size, which was
used for the analyses. Thus, a single effect size for each sample was
included in the meta-analysis to not violate the assumption of in-
dependence (Lipsey and Wilson, 2001). If a paper reported a study with
multiple independent treatment groups, an effect size for each treat-
ment group was computed and included separately in the meta-ana-
lysis. That is, every independent sample contributed one effect size to
the meta-analysis.
I2 was calculated in order to assess heterogeneity. A value of 0%
indicates no observed heterogeneity, 25% as low, 50% as moderate, and
75% as high heterogeneity. To better understand observed hetero-
geneity in the data, we conducted a sub-group analysis in which studies
within sub-groups were pooled with the random effects model. Most
importantly, a moderation analysis was conducted to determine if the
proportion of individuals with DD within a sample contributed to the
differences in treatment outcome across different studies.
To assess publication biases, a fixed-effect model was used to create
a funnel plot with the trim-and-fill method to determine the difference
between observed and adjusted effect sizes. We also calculated
Rosenthal (1979)’s Failsafe-N and conducted Egger's regression test
(Egger et al., 1997) to quantify the publication bias captured by the
funnel plot and to test whether the publication bias was significant.
3. Results
3.1. Characteristics of included studies
A summary of all of the included studies is reported in Table 1. In
the 11 samples, a total of 775 patients received treatment. The anti-
depressants that were examined in the studies included SSRI's (n = 6),
SNRI's (n = 1), and TCA's (n = 4). The proportion of patients with DD
in the sample ranged from 8% to 100%.
3.2. Treatment effects
Effect sizes for each independent sample and the overall effect size
are presented in Table 2 and Fig. 2. The overall mean effect size was
1.81, 95% CI [1.47, 2.16], which is considered a large effect
(Cohen, 1988). Thus, patients with depression exhibited significant
improvement over time following pharmacotherapy, supporting the
first hypothesis. However, there was significant heterogeneity
(I2 = 90.90%), indicating substantial variability across the studies.
A sub-group analysis was conducted to elucidate possible factors
that accounted for the heterogeneity. To this end, two sub-groups based
on treatment duration were created. The first group consisted of studies
whose duration of treatment lasted for three months or longer (i.e., long
treatment; n = 6), and the second group consisted of studies whose
D.G. May, et al.
Fig. 1. Study Selection and Data Acquisition.
duration of treatment lasted less than three months (i.e., short treat-
ment; n = 5). The difference between the effect sizes between the short
(g = 2.00, 95% CI [1.63, 2.36]) and the long (g = 1.68, 95% CI [1.23,
2.14]) treatment sub-groups was not significant (Q = 1.18, p = 0.278),
suggesting that the treatment duration did not significantly impact
treatment outcome.
To address the main research question, the moderator analysis ex-
amined whether the proportion of patients with DD within each sample
modulated the magnitude of treatment effects. The analysis yielded a
significant result (β = −0.09, p < 0.001, Q = 107.81, p < 0.001);
effect sizes decreased significantly as the proportion of individuals with
DD within a sample increased. Thus, a larger proportion of patients
with DD in a sample was associated with significantly lower effect sizes,
suggesting that DD may be more resistant to treatment.
Possible publication bias was first examined by inspecting the
funnel plot, which indicated a relatively symmetrical spread of the es-
timates (Fig. 2). Consistent with the funnel plot, the Egger's regression
test was not significant (intercept estimate = 2.85, 95% CI [−1.47,
7.17], t = 1.47, p = 0.175). Lastly, Rosenthal's Failsafe-N indicated
4809 studies would be needed to render the current finding insignif-
icant. Overall, we found insufficient evidence for publication bias.
4. Discussion
In this meta-analysis, we found a significant reduction in depressive
symptoms following pharmacotherapy. Importantly, the proportion of
patients with DD within a sample significantly moderated the treatment
3
Psychiatry Research 291 (2020) 113262
outcome. Specifically, as the proportion of patients with DD within a
sample increased, the observed effect size decreased significantly. That
is, pharmacotherapy efficacy was lower in samples with a larger (versus
smaller) proportion of patients with DD.
The current finding suggests that individuals with DD may not
benefit from antidepressants as much as individuals with MDD or
dysthymia alone. Certain characteristics that are unique to DD might
make it more difficult to be treated compared to MDD or dysthymia. In
particular, the fact that DD is characterized by higher comorbidity rates
than MDD (Klein et al., 1988) and the fact that DD itself is a comorbid
condition (i.e., comorbid MDD and dysthymia) might have contributed
to lower treatment efficacy. Indeed, the presence of comorbid mental
disorders has been identified as one of the key predictors of treatment
response (Hirschfield et al., 1998; Klein et al., 2008; Levitt et al., 1991).
The current findings are notable given the large overall effect size
and the lack of evidence for publication bias. However, the current
meta-analysis is fairly limited by the quantity and quality of the original
studies included in the analyses. For example, only one study
(Rabkin et al., 1999) included a placebo control group and reported
information on that group. As a result, treatment effects were examined
by comparing pre- and post-treatment symptom levels in the treatment
group. Thus, despite the large overall effect size, we cannot entirely
eliminate the possibility that the changes might be due to other factors,
such as spontaneous recovery. In addition, the number of studies in-
cluded in the meta-analysis was small. Our findings also need to be
interpreted with caution given the fact that the original studies in-
cluded in the current meta-analysis were not designed to examine
D.G. May, et al. Psychiatry Research 291 (2020) 113262

Note. Superscript letters denote the depression measure used in the study; B = Beck Depression Inventory; C = Cornell Dysthymia Rating Scale; H = Hamilton Depression Rating Scale; I = Inventory for Depressive
Symptomatology; M = Montgomery-Åsberg Depression Rating Scale. Superscript numbers denote independent treatment groups reported in a single paper. The arrow is used to indicate which medications was
Table 2
Post-treatment Mean (SD) Differences in Depressive Symptoms Between Pre- and Post-Treatment.
95% CI
Author Hedges' g LL UL Weight

12.2 (10.2)

21.9 (14.1)

15.3 (10.9)
14.9 (11.0)
25.3 (15.5)
11.9 (8.7)
11.1 (8.4)

12.8 (8.4)

13.1 (9.3)

15.3 (9.4)
Amore & Jori, 2001 1.96 1.75 2.16 9.52%
6.1 (6.2)
7.3 (7.9)
4.8 (3.4)
8.0 (4.9)
7.8 (7.4)

7.6 (6.9)
9.1 (7.1)
6.5 (5.6)
Friedman et al., 1999 2.10 1.69 2.50 8.54%
Hellerstein et al., 1994 1.93 1.29 2.57 7.29%
Koran et al., 2007 2.70 2.00 3.40 6.84%
Marin et al., 1994 1.38 0.88 1.89 7.95%
Pre-treatment Mean (SD)

McCullough et al., 2000 1.65 1.49 1.81 9.69%

Piazza et al., 1997 - Men 1.86 1.03 2.69 6.40%
Piazza et al., 1997 - Women 2.04 1.27 2.81 6.62%
(10.0) Rabkin et al., 1999 2.47 2.12 2.81 8.89%

(11.2)
Thase et al., 2002 - SSRI 1.25 0.96 1.54 9.17%
(3.8)
(5.3)
(7.5)
(4.1)
(6.3)
(8.0)
(4.7)
(6.3)
(5.9)
(4.7)
(6.0)

(7.4)
(9.5)
(6.4)
(8.9)
(8.4)
Thase et al., 2002 - TCA 1.00 0.83 1.18 9.65%
Overall 1.81 1.47 2.16 –
17.6
21.4
20.4
17.3
27.3
23.7
24.2
21.1
23.6
19.6
25.0
22.3
25.8
39.7
24.6
22.8
24.8
38.7
Note. CI = Confidence Interval; LL = Lower Limit; UL = Upper Limit;
SSRI = Selective Serotonin Reuptake Inhibitor; TCA = Tricyclic
% of participants with DD

Antidepressant.

whether the presence of DD affected treatment responses.

In spite of the large overall effect size and insufficient evidence of
publication bias, the observed level of heterogeneity in the current
100.0

100.0
100.0

study indicates that effect size varied substantially across the studies.
12.0
12.0
61.0

60.0
50.0
50.0
50.0
50.0
50.0
50.0
50.0
50.0
8.0

Moderation and/or sub-group analyses could shed a light on the source

–
–

of heterogeneity; we planned and coded several additional variables for

% of female participants

moderation and sub-group analyses, including class of medication,

educational attainment, proportion of female participants, and re-
lationship status. However, because many studies did not report re-
levant information and/or there were an insufficient number of studies
in each sub-group, we were unable to conduct these analyses. Our at-
100.0

tempts to contact the authors of these studies did not produce any
64.0
64.0
48.0
77.8
54.0

60.0

66.7
66.7
66.7
66.7
66.7
66.7
66.7
66.7
0.0

2.5
–

additional data. Thus, we were unable to examine factors that may

contribute to differential treatment responses in DD.
Mean age

Baseline depression severity could also moderate treatment out-

48.3
48.3
37.4
37.9
47.3

40.2
49.3
40.6

39.6
40.9
39.6
40.9
39.6
40.9
39.6
40.9

come (Blom et al., 2007). The studies included in the current meta-
–

analysis used different measures to assess the severity of depressive

symptoms; using the raw scores for a moderation analysis was, thus,
Duration of Treatment (in months)

inappropriate. Because all but two studies’ mean scores could be con-
Descriptive Information for the Nine Studies of Medication for Patients with Double Depression.

sidered as moderate for a given measure, the large heterogeneity was

administered successively over the course of a switch protocol. – indicates missing data.

unlikely to be due to the differences in depression severity across the

study samples. Nevertheless, it would be crucial for future studies to
examine whether the severity of depressive symptoms moderates
treatment responses in DD.
Importantly, we had to rely on the moderation analysis to examine
the effects of DD on treatment efficacy due to a lack of studies ex-
clusively focusing on treatment of DD. Given the current finding,
3.0
3.0
2.5
3.0
3.0
2.0
3.0
1.5
1.5
2.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0

however, future treatment outcome research should, at a minimum,

Medication(s) administered

assess the presence of DD in their samples and clearly indicate the

Sertraline → imipramine
Sertraline → imipramine
Sertraline → imipramine
Sertraline → imipramine
Imipramine → sertraline
Imipramine → sertraline
Imipramine → sertraline
Imipramine → sertraline

proportion of individuals meeting DD (or PDD with persistent/inter-

Imipramine, sertraline
Fluoxetine, trazodone

Paroxetine, sertraline
Paroxetine, sertraline

mittent major depressive episode). An increased attention to the

chronicity of depression could provide better understanding of the
factors that affect treatment responses. Along this line, it would also be
Desipramine

Desipramine
Duloxetine

Fluoxetine
Sertraline
Sertraline

critical for future research to comparatively assess treatment outcomes

in different sub-types of PDD while assessing and providing more
comprehensive information on patient characteristics and treatment-
related variables. It would also be important for future research to ex-
156
156

216

117

117

117

117
46
18
24
42

11
14
81
50

50

50

50

amine whether treatment responses of DD differ from MDD of equal

N

severity. Given greater social impairment (Leader and Klein, 1996) and
McCullough et al., 2000H

alcohol use (Diaz et al., 2012) in DD, more behaviorally- or inter-

Hellerstein et al., 1994H
Friedman et al., 1999H

Piazza et al., 1997H, 1

Piazza et al., 1997H, 2

Thase et al., 2002M, 1

Thase et al., 2002M, 2
Amore & Jori, 2001M

Thase et al., 2002H, 1

Thase et al., 2002H, 2

personally-oriented therapies could be particularly useful in addressing

Amore & Jori, 2001H

Thase et al., 2002C, 1

Thase et al., 2002B, 1
Thase et al., 2002B, 2
Rabkin et al., 1999H

Thase et al., 2002C,2

Marin et al., 1994H
Koran et al., 2007I

DD's profile of functional impairment. We, thus, originally planned to

compare treatment efficacy of pharmacotherapy and CBT; this plan,
however, had to be abandoned after searches yielded only one CBT
Authors
Table 1

study (Miller et al., 1999) that met our inclusion criteria. Therefore,
research assessing the effects of psychotherapy for DD is in great need.

4
D.G. May, et al.
Fig. 2. Funnel Plot of Published and Unpublished Studies.
These endeavors would promote a more comprehensive understanding
of depression in general, and DD in particular, and help us provide a
more individualized treatment.
Despite notable limitations, this represents the first attempt to
quantify the effect of the pharmaceutical treatment of DD, using strict
inclusion criteria to ensure that all of the included studies differentiated
DD from other forms of depressive disorders in their treatment samples.
The effects of pharmacotherapy depended on the presence of DD in the
sample: Samples with higher proportion of patients with DD exhibited
less reduction in depressive symptoms. Thus, future treatment studies
will benefit from close attention to the presence of DD in their samples.
Funding source
This work was partly supported by the Undergraduate Research
Opportunity Program from the Institute for Scholarship in the Liberal
Arts at the University of Notre Dame.
Contributors
DGM and KLY conceptualized the study and conducted analyses.
DGM and VNS identified and coded studies included in the meta-ana-
lysis. All authors contributed to writing and editing the manuscript. All
authors have approved the final manuscript.
Declaration of Competing Interest
All authors declare that they have no conflicts of interest.
Acknowledgment
N/A
5
Psychiatry Research 291 (2020) 113262
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