Journal of Psychiatric Research 141 (2021) 167–175

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Journal of Psychiatric Research

journal homepage: www.elsevier.com/locate/jpsychires

Combining psychopharmacotherapy and psychotherapy is not associated

with better treatment outcome in major depressive disorder - evidence from
the European Group for the Study of Resistant Depression
Lucie Bartova a, b, 1, Gernot Fugger a, b, 1, Markus Dold a, Marleen Margret Mignon Swoboda a,
Joseph Zohar c, Julien Mendlewicz d, Daniel Souery d, e, Stuart Montgomery f, Chiara Fabbri b, g,
Alessandro Serretti b, Siegfried Kasper a, h, *
a
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria
b
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
c
Psychiatric Division, Chaim Sheba Medical Center, Tel Hashomer, Israel
d
School of Medicine, Free University of Brussels, Brussels, Belgium
e
Psy Pluriel - European Centre of Psychological Medicine, Brussels, Belgium
f
Imperial College School of Medicine, University of London, London, United Kingdom
g
Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, United Kingdom
h
Center for Brain Research, Medical University of Vienna, Vienna, Austria

A R T I C L E I N F O A B S T R A C T

Keywords: Despite plenty of effective antidepressant (AD) treatments, the outcome of major depressive disorder (MDD) is
Major depressive disorder often unsatisfactory, probably due to improvable exploitation of available therapies. This European, cross-
Antidepressant treatment sectional, naturalistic multicenter study investigated the frequency of additional psychotherapy in terms of a
Psychopharmacotherapy
manual-driven psychotherapy (MDP) in 1410 adult in- and outpatients with MDD, who were primarily treated
Psychotherapy
Manual-driven psychotherapy
with AD psychopharmacotherapy. Socio-demographic and clinical patterns were compared between patients
Clinical aspects receiving both treatments and those lacking concomitant MDP. In a total of 1279 MDD patients (90.7%) with
Treatment response known status of additional MDP, those undergoing a psychopharmacotherapy-MDP combination (31.2%) were
younger, higher educated, more often employed and less severely ill with lower odds for suicidality as compared
to patients receiving exclusively psychopharmacotherapy (68.8%). They experienced an earlier mean age of
MDD onset, melancholic features, comorbid asthma and migraine and received lower daily doses of their first-
line ADs. While agomelatine was more often established in these patients, MDD patients without MDP
received selective serotonin reuptake inhibitors more frequently. These two patient groups did not differ in terms
of response, non-response and treatment resistant depression (TRD). Accordingly, the employment of additional
MDP could not be related to better treatment outcomes in MDD. The fact that MDP was applied in a minority of
patients with rather beneficial socio-demographic and clinical characteristics might reflect inferior accessibility
of these psychotherapeutic techniques for socially and economically disadvantaged populations.

1. Introduction effective evidence-based antidepressant (AD) treatment options is

available for MDD, the response- and remission rates remain often un­
The enormous global societal and economic burden of major satisfactory (Bauer et al., 2017; Dold and Kasper 2017). Hence, further
depressive disorder (MDD) (Vos, Allen C et al., 2016) is underlined by refinements as well as off-label treatments are frequently applied in
the fact that the incidence of MDD has doubled within the last three order to achieve adequate improvement of depressive symptoms (Dold
decades (Liu et al., 2020) leading to 322 million individuals suffering et al., 2016; Dold, Bartova et al. 2017, 2018, 2018; Dold et al., 2018;
from this disorder in 2015 (WHO 2007). Even though a plethora of Pjrek et al., 2020). The most obvious approach to counteract outcome

* Corresponding author. Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090, Vienna, Austria.
E-mail address: [email protected] (S. Kasper).
1
Both authors contributed equally.

https://doi.org/10.1016/j.jpsychires.2021.06.028
Received 22 February 2021; Received in revised form 8 May 2021; Accepted 14 June 2021
Available online 16 June 2021
0022-3956/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
L. Bartova et al. Journal of Psychiatric Research 141 (2021) 167–175

deficiencies might be a systematic and individualized exploitation of character of the present investigation the co-occurrence of other psy­
available treatment options, ideally in the course of recommended chiatric and somatic comorbidities was allowed. Similarly, additional
treatment algorithms (Bartova et al., 2019; Kraus et al., 2019). features occurring during the current MDE as the presence of psychotic
Meta-analyses report that psychotherapy (PT) that is performed in and/or melancholic features as well as suicidality for instance did not
the course of the so-called manual-driven psychotherapy (MDP) that is, count as exclusion criterion.
importantly, characterized by the predetermined duration of the indi­
vidual PT sessions and the PT-type per se, as well as its regularity and the 2.3. Clinical assessment
given contentual and setting rationales based on a defined school of
thought (Mansfield and Addis 2001), appears to be efficacious in MDD To evaluate socio-demographic, clinical, and treatment characteris­
with at least moderate effects (Barth et al., 2013). Further evidence tics, exclusively experienced and specifically trained psychiatrists per­
suggests that effect sizes of the various PT-types conducted in terms of formed a thorough clinical examination. Hereby, MDD patients’ medical
MDP, whereby the cognitive behavioral therapy (CBT) currently repre­ records and the Mini International Neuropsychiatric Interview (MINI)
sents the best and the most investigated school of thought, are in the (Sheehan et al., 1998) were considered. Accordingly, the primary psy­
range of AD psychopharmacotherapy (Cuijpers et al., 2014). However, chiatric diagnosis, psychiatric and somatic comorbidities, as well as
the reported selection- and further methodological bias associated with specific features during the current MDE were established. In the course
the heterogeneous manuals of the respective PT-types ranging from the of a rigorous assessment of the administered treatment strategies, PT
rather rigorous CBT-techniques to less strictly predefined psychoana­ was defined by the provision of CBT, psychoanalytic, systemic or not
lytical approaches question this assumption (Munder and Barth 2018). It otherwise specified therapies (e. g. meaning-centered psychotherapy)
is noticeable in this context that current clinical practice guidelines that were employed in addition to the ongoing psychopharmacotherapy
(CPGs) derived from different continents and societies lack consistency during the current MDE and per definitionem followed a rationale or
with respect to recommendations of the multifaceted treatment options manual of the respective school of thought defined by a certain regu­
available for MDD, especially in terms of MDP (Bayes and Parker 2018). larity and a predefined duration of the individual PT-sessions, frames for
While there is considerable evidence about a large number of patients the duration of the PT-type per se as well as the conceptual adherence to
treated with AD psychopharmacotherapy and lacking concomitant MDP various therapeutic rationales/principles (e. g. focus on cognitive dis­
in the United States (US) (Marcus and Olfson 2010; Olfson and Marcus tortions and emotional regulation via reconceptualization, transference
2010), comparable investigations of European patients are scarce. and countertransference or other concepts). Individual PT-interventions
Hence, we firstly sought to determine the proportion of MDD patients lacking these attributes were not considered.
receiving additional MDP to their ongoing psychopharmacotherapy and To assess the severity of depressive symptoms at study entry
secondly, we attempted to identify the related socio-demographic, reflecting a time period after at least four weeks of an adequate AD
clinical and psychopharmacotherapeutic characteristics. Finally, we psychopharmacotherapy, the 21-item Hamilton Rating Scale for
aimed to elucidate associations between the employment of additional Depression (HAM-D) (Hamilton 1960), and the Montgomery and Åsberg
MDP and treatment outcome in a large naturalistic sample of MDD pa­ Depression Rating Scale (MADRS; current MADRS, cMADRS) (Mont­
tients across different European countries. gomery and Asberg 1979) were employed. Concurrently, the evaluation
of the so-called retrospective MADRS (rMADRS) scores, which were
2. Materials and methods calculated based on the MDD patients’ assertions and clinical informa­
tion from their medical records, was mandatory to estimate the severity
2.1. Design of the study of depressive symptoms at the onset of the current MDE. Accordingly,
the rMADRS scores representing the full-blown extent of depressive
This multicenter, cross-sectional, observational, non-interventional symptoms at the beginning of the current MDE, respectively when AD
study with a retrospective assessment of treatment response represents treatment was initiated, refer to a time period that was at least four
a part of the “European Group for the Study of Resistant Depression weeks prior to study entry. Importantly, the ratings were performed by
(GSRD)” (Bartova et al., 2019). The present secondary analyses are experienced psychiatrists who underwent specific trainings to guarantee
based on a project “Clinical and biological correlates of resistant a high level of inter-rater reliability. In line with our previously intro­
depression and related phenotypes” performed between 2011 and 2016 duced staging model for treatment outcome, the MADRS total score
across ten sites in Austria, Italy (two sites), Belgium, Germany, Greece, change (rMADRS – cMADRS) was measured after at least one adequate
France (two sites), Israel, and Switzerland (Dold et al., 2016; Bartova AD trial that was employed ≥ four weeks at sufficient daily dosing
et al., 2019). The study-design and procedures, that were approved by (Bartova et al., 2019). In detail, response was defined by a MADRS total
the local ethics committees, have been thoroughly introduced in our score of <22 and a ≥50% MADRS total score reduction after an adequate
previous reports and a recent overview (Dold et al., 2016; Bartova et al., AD trial. Non-response was characterized by a MADRS total score of ≥22
2019) and are therefore described in a cut-down version. All eligible and a <50% MADRS total score reduction after one adequate AD trial.
patients signed the informed consent before study participation. Treatment resistant depression (TRD) was defined as a non-response to
≥ two consecutive adequate AD trials (Bartova et al., 2019). In accor­
2.2. Patients dance with our previous evidence, suicidality was evaluated according
to the HAM-D item 3 (suicidality) ratings (Dold et al., 2018). Hereby,
Adult in- and outpatients of both sexes were recruited in university as low degree of the current suicidal risk was characterized by the
well as non-academic clinical routine settings in the abovementioned item-score 1, while moderate to high degree of the current suicidal risk
eight European countries. The inclusion criteria comprised the presence was defined by the item-scores 2–4.
of a current major depressive episode (MDE) in the course of MDD ac­
cording to the DSM-IV-TR (Wittchen et al., 1997) as primary psychiatric 2.4. Statistical analyses
diagnosis. Furthermore, an ongoing and adequate psychopharmaco­
therapy encompassing at least one AD drug administered minimally for MDD patients were subdivided into two groups according to whether
four weeks in sufficient daily doses during the current MDE was required they received additional MDP or not. The related socio-demographic,
(Dold et al., 2016; Bartova et al., 2019). The exclusion criteria comprised clinical, and psychopharmacotherapeutic patterns are displayed with
any primary psychiatric diagnosis other than MDD and descriptive statistics (means, standard deviation (SD), and/or percent­
comorbid-substance use disorder present in the previous six months ages; Supplementary Table). Differences between the groups were,
and/or severe personality disorder. According to the naturalistic respectively, analyzed using analyses of variance (ANOVAs) for

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continuous variables and chi-squared tests for categorical variables reuptake inhibitors (SARIs) in 1.8%, vortioxetine in 0.5%, monoamine
(Supplementary Table). The Bonferroni-Holm correction for multiple oxidase inhibitors (MAO-Is) in 0.4%, noradrenaline reuptake inhibitors
comparisons was employed and, in case of statistical significance (set at (NARIs) in 0.2%, and tianeptine in 0.2% of the cases. Regarding add-on
a p ≤ .05), post-hoc analyses of covariance (ANCOVAs, for continuous psychopharmacotherapies, 28.4% of our MDD patients received a
variables) and logistic regression (for categorical variables) including combination treatment with at least one additional AD, whereas 24.9%
age, sex, and research center as covariates were performed (Supple­ were additionally treated with antipsychotics, 10.9% with mood stabi­
mentary Table). Version 27 of IBM SPSS Statistics was applied for all lizers, and 6.6% with pregabalin. Furthermore, benzodiazepines were
analyses. co-administered in 31% and the so-called low-potency antipsychotics
including all antipsychotic agents with potent sedating properties such
3. Results as prothipendyl, levomepromazine, as well as low-dose quetiapine
<100 mg/day (Dold et al., 2016; Bartova et al., 2019) in 6.2% of the
3.1. Sample patients.

In total, 1279 (90.7%) of all 1410 MDD patients (Bartova et al., 3.2. Socio-demographic, clinical and treatment characteristics of MDD
2019) stated whether they received additional MDP or not and were, patients with- and without additional psychotherapy
hence, included in the present analyses. The socio-demographic, clinical
and psychopharmacotherapeutic patterns of the sample of 1279 MDD The below-mentioned differences in terms of socio-demographic,
patients as well as of the two subgroups according to the provision of clinical and psychopharmacotherapeutic patterns were detected be­
MDP (n = 399, 31.2%) versus no additional MDP (n = 880, 68.8%) are tween MDD patients receiving psychopharmacotherapy-MDP combina­
displayed in the Supplementary Table. While 292 MDD patients received tion versus those treated with psychopharmacotherapy without
cognitive behavioral therapy (CBT), 107 patients were treated with additional MDP (Supplementary Table). Contrasts withstanding the
other types of MDP. The proportion of MDD patients lacking- and Bonferroni-Holm correction for multiple comparisons in our initial an­
receiving concomitant MDP itemized according to the different PT-types alyses also remained significant, when age, sex and research center were
is depicted in Fig. 1. considered as covariates in our post-hoc analyses including ANCOVAs
Summarizing the socio-demographic and clinical profile of the final and logistic regression analyses that are displayed in the Supplementary
sample comprising 1279 MDD patients (Supplementary Table), 66.6.% Table in detail.
of them were females, 96.3% were Caucasians, 51% lived in a partner­
ship, 90.8% suffered from a recurrent MDD, 11% experienced psychotic 3.2.1. Socio-demographic patterns
features, 59.3% melancholic features, 45.1% suicidality, and 33.9% MDD patients undergoing concomitant MDP were younger (46.8
received inpatient treatment during their current MDE. 19.9% of our years ±12.9 vs. 51.7 years ±14.4, p < .001), higher educated (64.2% vs.
MDD patients exhibited comorbid anxiety disorders and 1.2% comorbid 48.7%, p < .001) and more often employed (57.5% vs. 43.4%, p < .001)
posttraumatic stress disorders (PTSD), while 45.7% suffered from so­ compared to MDD patients lacking this treatment option.
matic comorbidities. 24.2% of the MDD patients could be categorized as
treatment responders, 34.3% as non-responders and 41.4% developed 3.2.2. Clinical patterns
TRD. 58.7% of the patients were treated with polypharmacy, whereby With respect to the age of MDD onset, patients receiving MDP
the mean number of concurrently administered psychopharmacother­ experienced their first MDE earlier than those without this therapeutic
apeutics amounted to 2.1 ± 1.2 agents. With respect to the first-line AD strategy (31.0 ± 14.2 vs. 40.7 ± 15.1, p < .001). While melancholic
treatment, selective serotonin reuptake inhibitors (SSRIs) were admin­ features occurred more often in patients with MDP (76.2% vs. 51.7%, p
istered in 52.8%, serotonin-norepinephrine reuptake inhibitors (SNRIs) < .001), psychotic features tended to be present in MDD patients
in 22.7%, noradrenergic and specific serotonergic ADs (NaSSAs) in receiving exclusively psychopharmacotherapy at an increased propor­
8.9%, tricyclic ADs (TCAs) in 5.3%, agomelatine in 5.1%, noradrenaline- tion (12.2% vs. 8.5%, puncorrected = .054). MDD patients treated with
dopamine reuptake inhibitors (NDRIs) in 2.2%, serotonin antagonist and MDP exhibited lower odds for a higher degree of the current suicidal risk
(47.9% vs. 62.1%, p = .001). Comorbid migraine (20.6% vs. 6.8%, p <
.001) and asthma (6% vs. 2.3%, p < .001) were more often observed in
this patient group. Furthermore, lower mean severity of depressive
symptoms as measured with the HAM-D (18.8 ± 8.5 vs. 20.6 ± 9.1, p <
.001) and the cMADRS (23.2 ± 10.3 vs. 25.4 ± 11.5, p < .001) at study
entry was detected in MDD patients treated with
psychopharmacotherapy-MDP combination. In addition, the rMADRS at
the onset of the current MDE exhibited a trend in favor of lower scores in
MDD patients receiving MDP (33.4 ± 7.5 vs. 34.4 ± 7.7, puncorrected =
.02) who also showed a trend towards higher mean reductions of the
MADRS total scores during the current MDE (− 10.2 ± 10.9 vs. − 8.9 ±
10.6, puncorrected = .053). With respect to treatment outcome differen­
tiating between response, non-response and TRD, we did not identify
any differences between MDD patients receiving a combination of both
treatments and those offered exclusively psychopharmacotherapy (p =
.369; Table 1; Fig. 2).

Fig. 1. The Proportion of MDD Patients Lacking and Receiving Psychotherapy

3.2.3. Psychopharmacotherapeutic patterns
in Addition to their Ongoing Psychopharmacotherapy.
With respect to the first-line AD treatment, SSRIs were more
Fig. 1 displays the number and the cumulative percentage of MDD patients who
were lacking and receiving psychotherapy in terms of MDP (itemized according frequently employed in MDD patients lacking MDP (55.9% vs. 45.9%, p
to its type) that was employed in addition to their ongoing psychopharmaco­ < .001), while patients undergoing both treatment options more often
therapy during the current MDE. Abbreviations (alphabetical order): CBT = received a first-line AD treatment with agomelatine (11.8% vs. 2%, p <
cognitive behavioral therapy; MDD = major depressive disorder; MDE = major .001) and, trendwise, vortioxetine (1.3% vs. 0.1%, puncorrected = .006).
depressive episode; MDP = manual-driven psychotherapy; n = number. Generally, mean daily doses of the administered first-line ADs calculated

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Table 1 often employed and experienced an earlier mean age of MDD onset as
Treatment Outcome of MDD Patients Lacking and Receiving Psychotherapy in compared to MDD patients offered exclusively psychopharmacotherapy.
Addition to their Ongoing Psychopharmacotherapy. While melancholic features, comorbid asthma and migraine occurred
Treatment MDD patients MDD MDD x2 p- more frequently in patients undergoing both treatments, overall
Outcome with known status patients patients value depression severity and suicidality were less pronounced. Furthermore,
of additional MDP receiving lacking first-line AD treatment with SSRIs was less commonly established,
(n = 1279) MDP MDP
whereas agomelatine was more often prescribed together with MDP.
(n = 399) (n = 880)
Generally, daily doses of the administered first-line ADs were lower than
Response 310 (24.2) 103 (25.8) 207 (23.5) 2.0 .369
in MDD patients lacking concomitant MDP. The combination of psy­
Non- 439 (34.3) 142 (35.6) 297 (33.8)
response chopharmacotherapy and MDP was not associated with a favorable
TRD 530 (41.4) 154 (38.6) 376 (42.7) treatment outcome.
Previous US evidence on therapeutic patterns in MDD indicated that
Table 1 displays the number and the percentages of 1279 MDD patients
achieving treatment response, developing non-response, or fulfilling the criteria
a psychopharmacotherapy-MDP combination is provided in 20% of all
for TRD (Bartova et al., 2019) who are further itemized according to whether or depressed patients with a decreasing trend throughout the last two de­
not they received psychotherapy in terms of MDP that was employed in addition cades (Marcus and Olfson 2010; Olfson et al., 2016). The proportion of
to their ongoing psychopharmacotherapy during the current MDE. Abbrevia­ MDP that was employed in addition to the ongoing psychopharmaco­
tions (alphabetical order): MDD = major depressive disorder; MDE = major therapy was even lower than in our investigation and a clear parallel
depressive episode; MDP = manual-driven psychotherapy; n = number; TRD = could be drawn regarding socio-demographic aspects. Older, less
treatment resistant depression. educated and unemployed patients exhibited significantly lower odds
Bartova, L., M. Dold, A. Kautzky, C. Fabbri, M. Spies, A. Serretti, D. Souery, J. for additional MDP in both, US and European samples, which might
Mendlewicz, J. Zohar, S. Montgomery, A. Schosser and S. Kasper (2019). “Re­ reflect worse access to these psychotherapeutic techniques in MDD pa­
sults of the European Group for the Study of Resistant Depression (GSRD) - basis
tients with potential economic and social disadvantages (Olfson et al.,
for further research and clinical practice.” World J Biol Psychiatry 20(6):
2016). The latter findings are consistent with further reports underlining
427–448.
an obviously low utilization of MDP in depressed outpatients in Ger­
many reflecting a real care situation that is very much in contrast with
recommendations for a broad use of MDP in the national treatment
guidelines (Möller 2014). Hereby, further background factors like a
different availability and extent of psychiatric and psychotherapeutic
care in urban- and rural areas, long waiting times due to an insufficient
number of respective experts, potential arbitrary selection processes
related to specific disease and/or patient characteristics, as well as dif­
ferences in terms of acceptance and implementation resulting from
varying treatment settings that range from general practitioners’ offices
to specialized psychiatric and psychotherapeutic institutions, were
shown to explain the discrepancy in the utilization of MDP (Möller
2014).
An obvious and pursuing question, particularly in times of striving
precision treatments in MDD, is who benefits most from which type of
MDP (Furukawa et al., 2018). In fact, only a limited proportion of
studies conducted in these regards are considered of high quality with
Fig. 2. Treatment Outcome of MDD Patients Lacking and Receiving Psycho­ low risk of bias (Trivedi et al., 2011; Jakobsen 2014). What current
therapy in Addition to their Ongoing Psychopharmacotherapy. evidence reveals so far is that MDP shows comparable efficacy for many
Fig. 2 displays the cumulative percentages of MDD patients achieving treatment groups of MDD patients regardless of age, sex, or somatic comorbidities
response, developing non-response, or fulfilling the criteria for TRD (Bartova
(Cuijpers et al., 2018). A second crucial point is that different forms of
et al., 2019) who are itemized according to whether or not they received psy­
MDP appear to be efficacious in MDD. Hereby, CBT in its original as well
chotherapy in terms of MDP that was employed in addition to their ongoing
as further formats, that were adapted according to the individual pa­
psychopharmacotherapy during the current MDE. Abbreviations (alphabetical
order): MDD = major depressive disorder; MDE = major depressive episode; tients’ needs, represents the currently best investigated form of MDP and
MDP = manual-driven psychotherapy; TRD = treatment resistant depression. is, hence, recommended for the treatment of MDD and TRD in most
Bartova, L., M. Dold, A. Kautzky, C. Fabbri, M. Spies, A. Serretti, D. Souery, J. international guidelines (Trivedi et al., 2011; Jakobsen 2014; Jobst
Mendlewicz, J. Zohar, S. Montgomery, A. Schosser and S. Kasper (2019). “Re­ et al., 2016; Nakagawa et al., 2017; Bockting et al., 2018; Furukawa
sults of the European Group for the Study of Resistant Depression (GSRD) - basis et al., 2018; van Bronswijk et al., 2019). A recent review and
for further research and clinical practice.” World J Biol Psychiatry 20 meta-analysis focusing on augmentation treatments for TRD found
(6): 427–448. modest evidence for MDP that was represented by only three studies
investigating CBT, mindfulness-based CBT and long-term psychoana­
according to fluoxetine dose equivalents (Hayasaka et al., 2015) were lytic PT (Strawbridge et al., 2019). Although the efficacy of augmenta­
higher in MDD patients without additional MDP (41.7 ± 19.0 vs. 36.3 ± tion with MDP and psychopharmacotherapy was shown to be
24.4, p < .001). comparable in this meta-analysis, the authors highlighted the unequal
amount of studies investigating either MDP or psychopharmacother­
4. Discussion apeutics and, hence, emphasized the requirement for a more intensive
investigation of psychological treatments (Husain et al., 2019).
This large, real-world European cross-sectional study with a retro­ Based on recent findings, CBT was reported to be beneficial in older
spective evaluation of treatment response revealed that about one out of populations, as well as in university students and in case of comorbid
three MDD patients was treated by a combination of psychopharmaco­ addiction disorders (Cuijpers et al., 2016). In our sample, MDD patients
therapy and PT in terms of MDP. Precisely, CBT was most commonly treated with psychopharmacotherapy and additional MDP, that was CBT
applied in around three-quarters of the cases. Taken together, MDD in the most cases, were younger and, concurrently, more often suffered
patients receiving additional MDP were younger, higher educated, more from migraine and asthma as comorbid conditions than patients lacking

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this treatment option. In analogy, previous evidence on MDD and co­ treatment sequence was suggested to be initiated by psychopharmaco­
morbid chronic pulmonary disease proved effectivity of MDPs in therapy that directly interferes with the neurobiological underpinnings
reducing both depressive and respiratory symptoms, while focusing on of MDD and, hence, represents the first-line treatment of MDD and its
overcoming barriers of treatment and promoting adherence to medica­ therapeutic basis respectively (Kranz and Kasper 2019). Once the
tion and healthier lifestyle (Alexopoulos et al., 2013). In depressed administered psychopharmacotherapy showed effectivity in terms of
migraineurs, CBT led to reductions of headache and depressive symp­ improvement of depressive symptoms as well as in functionality and
toms simultaneously (Martin et al., 2015), supporting the obvious ben­ quality of life, patients may profit from the employment of additional
efits of MDP, and CBT in particular, for MDD with comorbid somatic MDP, especially when they suffer from residual symptoms (Guidi and
diseases. An auspicious finding in this context is that different formats of Fava 2021). Such sequential integration of MDP following response to
CBT, including group and remote interventions, that are more acute-phase psychopharmacotherapy was shown to reduce the risk of
cost-effective and better accessible than individual therapies, seem to relapse and recurrence and, hence, appears to be particularly indicated
exhibit similar effects (Kamenov et al., 2017), and could therefore be in recurrent and chronic depression (Guidi and Fava 2021).
preferably applied to a broader patient population including individuals Being aware that cross-sectional evaluations are unsuitable to draw
who are potentially disadvantaged in terms of socio-demographic, eco­ causal conclusions, we would like to highlight that our MDD patients
nomic and/or disease factors. receiving additional MDP did not differ from patients offered exclusively
With respect to severity of depressive symptoms, the present study psychopharmacotherapy in terms of treatment outcome. Although MDD
revealed overall lower scores regarding the HAM-D and the MADRS as patients undergoing psychopharmacotherapy-MDP combination
well as a lower degree of suicidal risk in MDD patients treated with a showed a trend towards greater reduction of MADRS total scores during
psychopharmacotherapy-MDP combination as compared to those the current MDE, the rates of response, non-response and TRD were
receiving exclusively psychopharmacotherapy. The latter results might comparable regardless of the provision of concomitant MDP. Accord­
support previous evidence considering psychopharmacotherapy-MDP ingly, the integration of MDP does not seem to suffice to overcome TRD,
combination beneficial in terms of preventing suicides (Zalsman et al., a condition that was repeatedly shown to respond to rather biologically-
2016) with the best available proof of concept existing for CBT, whereby oriented therapies such as psychopharmacotherapeutic augmentation
the treatment success might be attributable to a direct discussion of and combination treatments or electroconvulsive therapy for instance
suicidal ideations and behaviors (Calati et al., 2018). On the other hand, (Kraus et al., 2019).
the less severe disease manifestation in our MDD patients receiving both On the other hand, the fact that treatment outcome was not influ­
treatments might further underline the abovementioned arbitrary se­ enced by additional psychotherapeutic approaches in terms of MDP
lection bias in terms of referring preferably patients with milder symp­ might be associated with the ambiguous and potentially mis­
tom profiles lacking suicidal risk to MDP which is also a common understandable definition of MDP per se, which is mostly characterized
position in international guidelines for the management of MDD (Pilling by sessions at regular intervals that last approximately 50 min in the
et al., 2009; Möller 2014; Bauer et al., 2017). This reflects the unequal most cases regardless of the applied school of thought predefining the
distribution of available treatment strategies in the broad clinical setting, frequency and the procedural alignment of the applied PT-type.
routine. The fact that MDP including rather rigorous CBT-techniques as well as
In terms of specific symptom manifestations, our MDD patients less strictly predefined psychoanalytical approaches can be provided by
suffering from melancholic features more frequently underwent a diverse experts with heterogeneous educational levels and specifications
psychopharmacotherapy-MDP combination, while those with psychotic comprising psychiatrists, psychotherapists, clinical psychologists and
symptoms tended to be less commonly treated with additional MDP. In further specialists may result in a varying quality with potential effects
this context it is noteworthy that generally symptoms inherent to on treatment outcome. In this context, we would like to point out that a
melancholia, anhedonia, psychomotor disturbances, and/or psychotic comprehensive psychotherapeutic education is mandatory for
phenomena were shown to respond well to biological treatments completing psychiatric specialization as medical discipline in some, but
including psychopharmacotherapy, most likely due to repeatedly iden­ not all European countries including Austria, Germany and Switzerland.
tified neurobiological correlates as dysregulation of the hypothalamic- Hereby, the official certification and professional title obtained is called
pituitary-adrenal axis for instance (Bauer et al., 2017; Dold and Kas­ “specialist for psychiatry and psychotherapeutic medicine” in Austria
per 2017; Dold et al., 2019; Kraus et al., 2019). Despite the fact that our and “specialist for psychiatry and psychotherapy” in Germany and
results point towards a more frequent use of additional MDP in MDD Switzerland. The specific title “specialist for psychiatry and psycho­
patients suffering from melancholic features, which may appear counter therapeutic medicine” in Austria has been thoughtfully considered and
intuitive at first glance, it is worth to mention in this regard that in­ explicitly formulated over years and is thought to appropriately describe
dications from the literature about the efficacy of MDP in MDD with the psychiatrists’ daily routine including a simultaneous integration of
melancholic features lack consistency. While results of neurobiological as well as psychotherapeutic approaches. In detail,
randomized-controlled trials (RCTs) comparing CBT and AD psycho­ psychiatrists are physicians undergoing extensive training in all medical
pharmacotherapy in melancholic depression delivered evidence in favor fields to obtain their medical degree who subsequently receive a
of psychopharmacotherapy as first-line AD treatment (Parker et al., comprehensive clinical training in both, psychopharmacotherapeutic
2013; Gilfillan et al., 2014), a recent meta-analysis observed little and and non-pharmacological treatments of the full spectrum of psychiatric
insignificant differences between the efficacy of either CBT or AD psy­ disorders to complete their specialization in psychiatry. Given this
chopharmacotherapy as the first-choice treatment for melancholic and educational process lasting about ten years in the countries mentioned
atypical depression (Cuijpers et al., 2017). Overall, available interna­ above psychiatrists experience a broad scope of understanding of the
tional evidence provide convincing arguments against MDP as treatment nature and course of psychiatric diseases as well as their multifaceted
option of first choice in such MDD patient populations who might have treatment options. Hence, they deem it a privilege to be able to provide
difficulties to engage to interventions of psycho-social nature when they psychotherapeutic interventions in the course of the individual treat­
suffer from severe depressive symptoms such as melancholic and/or ment concepts, in terms of the sometimes depreciatingly called “sup­
psychotic features (Sharpley and Bitsika 2011; McIntyre et al., 2017). In portive PT” that, however, represents an essential aspect of each clinical
this context, the so-called sequential combination of psychopharmaco­ interaction even though the criteria of MDP may not be completely
therapy and psychotherapeutic techniques seems to be justified as this covered. Exemplarily, a short individual psychoeducational or motiva­
approach exhibited advantages over monotherapy in terms of a sus­ tional support towards positive mental health and general well-being,
tained and more stable treatment response (Karyotaki et al., 2016) as that is feasible during the regular rounds at psychiatric hospitals and/
well as the prevention of relapse (Bockting et al., 2018). Hereby, the or consultations at outpatient units, might represent a very effective

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psychotherapeutic intervention, which may significantly contribute to number of MDD patients treated with other MDPs in general. With
the overall beneficial effects together with ongoing psychopharmaco­ respect to the administered psychopharmacotherapy, it is worth to
therapy and/or other modality of the broad armamentarium of available mention that our MDD patients received conventional on-label treat­
treatment strategies. In summary, the comparable treatment outcomes ments, whereby promising novel antidepressant agents like esketamine
between our MDD patients who were receiving- and lacking additional (Kraus et al., 2019; Kasper et al., 2020; Sanders Benjamin 2021) have
MDP might be attributable to the aforementioned supportive psycho­ not yet been considered. Most importantly, it should be highlighted that
therapeutic interventions that were successfully implemented in some of the data analyzed in the present study were derived from a
our patients by psychiatrists in charge and that were, however, not cross-sectional investigation with retrospective evaluation of treatment
officially assessed, since the official definition for MDP was not met. outcome. This may represent a major limitation when the reported
Looking at the administered psychopharmacotherapy, SSRIs were findings are compared with results derived from prospective
less commonly prescribed as first-line AD treatment in MDD patients randomized-controlled longitudinal trials. The concept of retrospective
receiving a psychopharmacotherapy-MDP combination. Agomelatine evaluation of treatment response, that is undoubtedly less accurate than
and, trend-wise, vortioxetine in contrast were more frequently admin­ prospective approaches, however, might enable a very likely exempli­
istered to that patient group. While SSRIs represent the recommended fication of the real care situation without any distortion due to the
first-line AD treatment that is commonly very well accessible in the most related inclusion bias. Furthermore, it is worth to note in this context
countries worldwide, agomelatine and vortioxetine constitute modern that the retrospective assessment in our study was performed according
and effective alternatives in the course of a first-line AD treatment that, to rigorously predetermined conditions exclusively by experienced
however, are far less available and mostly not covered by public health- psychiatrists who underwent specific trainings to guarantee a high level
insurance (HI) systems. Although we did not find any compelling evi­ of inter-rater reliability that was, however, not specifically investigated
dence in comparable international samples of MDD patients, we tend to with respect to the rMADRS. Hereby, the rMADRS reflecting the
interpret this observation in relation to the rather favorable socio- full-blown extent of depressive symptoms at the beginning of their
demographic characteristics identified in our MDD patients undergo­ current MDE, respectively when their AD treatment was initiated,
ing both treatment strategies who might have better access to treatments referred to a time period that was at least four weeks prior to study entry.
beyond those covered by the public HI systems. However, the latter Being aware of the relevant methodological limitation of retrospective
considerations represent subject to certain caveats, as the prescription ratings, available international evidence revealing that MDD patients
rates of agomelatine and vortioxetine were very small. are able to adequately report retrospective symptoms of their MDEs even
The overall lower daily doses of the applied ADs identified in the two years thereafter (Dunlop et al., 2019) supports that the applied
group of MDD patients receiving both therapies might be explained by a approach is not too far-fetched. The latter assumption might be further
less severe disease profile associated with receiving additional MDP, a underlined by the fact that our retrospective evaluations reflect a
lesser focus on psychopharmacotherapy while undergoing MDP, or po­ markedly shorter time period of four and more weeks thereafter as
tential lesser need of dose escalations due to the additional psycho­ compared to a time period of two years thereafter which was previously
therapeutic interventions. It is noteworthy in this context that dose suggested as adequate for retrospective ratings (Dunlop et al., 2019).
escalation failed to show superiority over the continuation of standard- Taken together, we consider our approach justifiable.
dose AD treatment in MDD in the most studies (Dold et al., 2017), and
was repeatedly associated with greater odds for unwanted side-effects 5. Conclusion
(Jakubovski et al., 2016) and potential discontinuation symptoms,
which might occur during tapering and discontinuation of ADs (Fava The abovementioned cross-sectional and retrospective analyses
et al., 2018). revealed that merely about one-third of the present naturalistic sample
Strengths of the present study include the naturalistic design con­ of MDD patients was treated by a psychopharmacotherapy-MDP com­
structing a realistic picture of psychiatric care including the provision of bination, which is in contrast to most available treatment recommen­
MDP in MDD by comprising differently aged adult patients of both sexes dations. The fact that receiving additional MDP was associated with
who were at different stages of treatment and who suffered from a beneficial socio-demographic characteristics as younger age, higher
varying severity of depressive symptoms comprising suicidality, psy­ educational level and ongoing employment points towards a reluctance
chotic features and comorbidities, that are considered as exclusion of exploiting available treatment options to the fullest and evinces sig­
criteria in the majority of available studies. Another major strength is nificant barriers especially in socially and economically disadvantaged
the large sample size derived from different treatment settings including populations. The association of favorable clinical aspects like a lower
in- and outpatient units in university-as well as non-academic centers extent of depression severity and lower odds for suicidality with the
across eight European countries. provision of additional MDP in our study might be explained by a se­
Concerning limitations, it has to be pointed out that this study was lection bias leaving patients with a more severe illness profile fall by the
primarily executed to investigate TRD (Bartova et al., 2019), whereby wayside. Finally, it should be highlighted that the employment of
the present secondary analysis of the impact of additional MDP in MDD additional MDP was not associated with a superior treatment outcome in
patients receiving primarily psychopharmacotherapy represents an our population of adult MDD in- and outpatients, which might empha­
additional aspect. Hereby, the information about which treatment size the fundamental role of the underlying complex biological in­
strategy was commenced or seemed to be pivotal is missing. Further terrelationships in MDD and its treatment.
intrinsic limitations linked to the fact that the present study was not
originally designed to test this hypothesis represent limited knowledge Funding Sources
concerning the reason for initiating MDP as well as its exact duration.
Due to the identified socio-demographic and clinical differences be­ The European Group for the Study of Resistant Depression (GSRD)
tween both patient groups a possible selection bias associated with obtained an unrestricted grant sponsored by Lundbeck A/S. The sponsor
distinct patient- and/or disease factors cannot be fully ruled out. While played no role in designing the study, data collection and analyses,
the majority of our MDD patients was treated with CBT, a comparably interpretation of the data, writing of the manuscript, and in the decision
small proportion of the remaining patients underwent MDPs according to submit the research for publication.
to different schools of thought. Hereby, we did not differentiate between
the distinct psychotherapeutic specifications, which we deem justifiable Statement of Ethics
in light of the fact that superiority of a specific PT school could not be
demonstrated with certainty (Cuijpers 2016) and due to the small The present research complies with internationally-accepted

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standards for research practice and reporting, and has been performed the European Group for the Study of Resistant Depression (GSRD) - basis for further
research and clinical practice. World J. Biol. Psychiatr. 20 (6), 427–448.
with approvals of appropriate ethics committees and with appropriate
Bauer, M., Severus, E., Moller, H.J., Young, A.H., 2017. WFSBP Task Force on Unipolar
participants’ informed consent in compliance with the Helsinki Depressive Disorders. 2017. Pharmacological treatment of unipolar depressive
Declaration. disorders: summary of WFSBP guidelines. Int. J. Psychiatr. Clin. Pract. 21 (3),
166–176. https://doi.org/10.1080/13651501.2017.1306082.
Bayes, A.J., Parker, G.B., 2018. Comparison of guidelines for the treatment of unipolar
Authorship statement depression: a focus on pharmacotherapy and neurostimulation. Acta Psychiatr.
Scand. 137 (6), 459–471.
Bockting, C.L.H., Klein, N.S., Elgersma, H.J., van Rijsbergen, G.D., Slofstra, C., Ormel, J.,
Dr. Bartova and Dr. Fugger contributed to designing the study,
Buskens, E., Dekker, J., de Jong, P.J., Nolen, W.A., Schene, A.H., Hollon, S.D.,
implementation of the research, statistical analyses, and writing the Burger, H., 2018. Effectiveness of preventive cognitive therapy while tapering
report including the first draft of the manuscript. Dr. Kasper contributed antidepressants versus maintenance antidepressant treatment versus their
combination in prevention of depressive relapse or recurrence (DRD study): a three-
to designing the study, implementation of the research, and writing the
group, multicentre, randomised controlled trial. Lancet Psychiatry 5 (5), 401–410.
report. All authors contributed to implementation of the research and Calati, R., Courtet, P., Lopez-Castroman, J., 2018. Refining suicide prevention: a
have critically revised and approved the final manuscript. narrative review on advances in psychotherapeutic tools. Curr. Psychiatr. Rep. 20
(2), 14.
Cuijpers, P., 2016. Are all psychotherapies equally effective in the treatment of adult
Declaration of competing interest depression? The lack of statistical power of comparative outcome studies. Evid. Base
Ment. Health 19 (2), 39–42.
Cuijpers, P., Ebert, D.D., Acarturk, C., Andersson, G., Cristea, I.A., 2016. Personalized
Dr. Bartova has received travel grants and consultant/speaker hon­ psychotherapy for adult depression: a meta-analytic review. Behav. Ther. 47 (6),
oraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, 966–980.
Cuijpers, P., Karyotaki, E., Reijnders, M., Huibers, M.J.H., 2018. Who benefits from
Schwabe Austria, Janssen and Angelini. Dr. Dold has received travel psychotherapies for adult depression? A meta-analytic update of the evidence.
grants and consultant/speaker honoraria from Janssen-Cilag. Dr. Zohar Cognit. Behav. Ther. 47 (2), 91–106.
has received grant/research support from Lundbeck, Servier, and Pfizer; Cuijpers, P., Turner, E.H., Mohr, D.C., Hofmann, S.G., Andersson, G., Berking, M.,
Coyne, J., 2014. Comparison of psychotherapies for adult depression to pill placebo
he has served as a consultant or on the advisory boards for Servier, control groups: a meta-analysis. Psychol. Med. 44 (4), 685–695.
Pfizer, Solvay, and Actelion; and he has served on speakers’ bureaus for Cuijpers, P., Weitz, E., Lamers, F., Penninx, B.W., Twisk, J., DeRubeis, R.J., Dimidjian, S.,
Lundbeck, GlaxoSmithKline, Jazz, and Solvay. Dr. Mendlewicz is a Dunlop, B.W., Jarrett, R.B., Segal, Z.V., Hollon, S.D., 2017. Melancholic and atypical
depression as predictor and moderator of outcome in cognitive behavior therapy and
member of the board of the Lundbeck International Neuroscience
pharmacotherapy for adult depression. Depress. Anxiety 34 (3), 246–256.
Foundation and of the advisory board of Servier. Dr. Souery has received Dold, M., Bartova, L., Fugger, G., Kautzky, A., Souery, D., Mendlewicz, J.,
grant/research support from GlaxoSmithKline and Lundbeck; and he has Papadimitriou, G.N., Dikeos, D.G., Porcelli, S., Serretti, A., Zohar, J.,
served as a consultant or on advisory boards for AstraZeneca, Bristol- Montgomery, S., Kasper, S., 2018a. Major depression and the degree of suicidality:
results of the European group for the study of resistant depression (GSRD). Int. J.
Myers Squibb, Eli Lilly, Janssen, and Lundbeck. Dr. Montgomery has Neuropsychopharmacol. 2 (6), 539–549.
served as a consultant or on advisory boards for AstraZeneca, Bionevia, Dold, M., Bartova, L., Kautzky, A., Porcelli, S., Montgomery, S., Zohar, J., Mendlewicz, J.,
Bristol-Myers Squibb, Forest, GlaxoSmithKline, Grunenthal, Intellect Souery, D., Serretti, A., Kasper, S., 2019. Psychotic features in patients with major
depressive disorder - a report from the European Group for the Study of Resistant
Pharma, Johnson & Johnson, Lilly, Lundbeck, Merck, Merz, M’s Science, Depression. J. Clin. Psychiatr. 80 (1), 17m12090.
Neurim, Otsuka, Pierre Fabre, Pfizer, Pharmaneuroboost, Richter, Dold, M., Bartova, L., Kautzky, A., Serretti, A., Porcelli, S., Souery, D., Mendlewicz, J.,
Roche, Sanofi, Sepracor, Servier, Shire, Synosis, Takeda, Theracos, Montgomery, S., Zohar, J., Kasper, S., 2018b. Clinical factors associated with
augmentation treatment with second-generation antipsychotics and lithium in major
Targacept, Transcept, UBC, Xytis, and Wyeth. Dr. Fabbri has been sup­ depression - results from a European multicenter study. Eur. Neuropsychopharmacol
ported by Fondazione Umberto Veronesi (https://www.fondazionevero 28 (12), 1305–1313.
nesi.it). Dr. Serretti has served as a consultant or speaker for Abbott, Dold, M., Bartova, L., Mendlewicz, J., Souery, D., Serretti, A., Porcelli, S., Zohar, J.,
Montgomery, S., Kasper, S., 2018c. Clinical correlates of augmentation/combination
Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers treatment strategies in major depressive disorder. Acta Psychiatr. Scand. 137,
Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, 401–412.
Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. Within the last Dold, M., Bartova, L., Rupprecht, R., Kasper, S., 2017. Dose escalation of antidepressants
in unipolar depression: a meta-analysis of double-blind, randomized controlled
three years, Dr. Kasper received grants/research support, consulting
trials. Psychother. Psychosom. 86 (5), 283–291.
fees, and/or honoraria from Angelini, Celegne GmbH, Eli Lilly, Janssen- Dold, M., Kasper, S., 2017. Evidence-based pharmacotherapy of treatment-resistant
Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, unipolar depression. Int. J. Psychiatr. Clin. Pract. 21 (1), 13–23.
Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dai­ Dold, M., Kautzky, A., Bartova, L., Rabl, U., Souery, D., Mendlewicz, J., Porcelli, S.,
Serretti, A., Zohar, J., Montgomery, S., Kasper, S., 2016. Pharmacological treatment
nippon Pharma Co. Ltd., sun Pharma and Takeda. All other authors strategies in unipolar depression in European tertiary psychiatric treatment centers –
declare that they have no conflicts of interest. a pharmacoepidemiological cross-sectional multicenter study. Eur.
Neuropsychopharmacol 26 (12), 1960–1971.
Dunlop, B.W., Granros, M., Lechner, A., Mletzko-Crowe, T., Nemeroff, C.B., Mayberg, H.
Acknowledgement S., Craighead, W.E., 2019. Recall accuracy for the symptoms of a major depressive
episode among clinical trial participants. J. Psychiatr. Res. 116, 178–184.
Fava, G.A., Benasi, G., Lucente, M., Offidani, E., Cosci, F., Guidi, J., 2018. Withdrawal
The authors would like to thank all persons involved in the GSRD
symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation:
project and the patients who participated in the present study. systematic review. Psychother. Psychosom. 87 (4), 195–203.
Furukawa, T.A., Efthimiou, O., Weitz, E.S., Cipriani, A., Keller, M.B., Kocsis, J.H.,
Klein, D.N., Michalak, J., Salanti, G., Cuijpers, P., Schramm, E., 2018. Cognitive-
Appendix A. Supplementary data behavioral analysis system of psychotherapy, drug, or their combination for
persistent depressive disorder: personalizing the treatment choice using individual
Supplementary data to this article can be found online at https://doi. participant data network metaregression. Psychother. Psychosom. 87 (3), 140–153.
Gilfillan, D., Parker, G., Sheppard, E., Manicavasagar, V., Paterson, A., Blanch, B.,
org/10.1016/j.jpsychires.2021.06.028.
McCraw, S., 2014. Is cognitive behaviour therapy of benefit for melancholic
depression? Compr. Psychiatr. 55 (4), 856–860.
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