Diabetes Care Volume 38, May 2015 767

Frank Petrak,1,2 Stephan Herpertz,1

Cognitive Behavioral Therapy Christian Albus,3 Norbert Hermanns,4

CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL
Christoph Hiemke,5 Wolfgang Hiller,6
Versus Sertraline in Patients With Kai Kronfeld,7 Johannes Kruse,8
Bernd Kulzer,4 Christian Ruckes,7
Depression and Poorly Controlled Daniela Zahn,9 and Matthias J. Müller10

Diabetes: The Diabetes and

Depression (DAD) Study
A Randomized Controlled Multicenter
Trial
Diabetes Care 2015;38:767–775 | DOI: 10.2337/dc14-1599

1
Department of Psychosomatic Medicine and
Psychotherapy, LWL-University Clinic Bochum,
Ruhr-University Bochum, Bochum, Germany
2
Center for Psychotherapy Wiesbaden, Wiesba-
den, Germany
3
Department of Psychosomatic Medicine and
Psychotherapy, University of Cologne, Köln,
OBJECTIVE Germany
4
Diabetes Center Mergentheim, Bad Mergen-
This study compared the long-term efficacy of a diabetes-specific cognitive be-
theim, Germany
havioral group therapy (CBT) with sertraline in patients with diabetes and de- 5
Department of Psychiatry and Psychotherapy,
pression who initially responded to short-term depression treatment. University Medical Centre, Johannes Gutenberg
University, Mainz, Germany
6
RESEARCH DESIGN AND METHODS Department of Clinical Psychology and Psycho-
therapy, Institute of Psychology, Johannes
A randomized controlled single-blind trial was conducted in 70 secondary care
Gutenberg University Mainz, Mainz, Germany
centers across Germany comparing 12 weeks of CBT with sertraline in 251 patients 7
Interdisciplinary Centre for Clinical Trials Mainz
with type 1 or 2 diabetes (mean HbA1c 9.3%, 78 mmol/mol) and major depression (IZKS Mainz), University Medical Centre,
(Structured Clinical Interview for DSM-IV [SCID]). After 12 weeks, treatment re- Johannes Gutenberg University, Mainz, Germany
8
Clinic for Psychosomatic and Psychotherapy,
sponders (‡50% reduction Hamilton Depression Rating Scale [HAMD-17]) were University Clinic Gießen/Marburg, Philipps Uni-
included in the 1-year study phase where CBT patients were encouraged to use versity Marburg, Marburg, Germany
9
bibliotherapy and sertraline patients received continuous treatment. We ana- Department of Health Psychology, Institute of
lyzed differences for HbA1c (primary outcome) and reduction (HAMD-17) or re- Psychology, Johannes Gutenberg University
Mainz, Mainz, Germany
mission (SCID) of depression from baseline to the 1-year follow-up using ANCOVA 10
Vitos Clinical Centre Gießen-Marburg and
or logistic regression analysis. Justus Liebig University Gießen, Marburg, Germany
Corresponding author: Frank Petrak, mail@
RESULTS dr-frank-petrak.de.
After 12 weeks, 45.8% of patients responded to antidepressant treatment and Received 30 June 2014 and accepted 11 January
were included in the 1-year study phase. Adjusted HbA1c mean score changes from 2015.
baseline to the end of the long-term phase (20.27, 95% CI 20.62 to 0.08) revealed Clinical trial registration: ISRCTN89333241,
no significant difference between interventions. Depression improved in both http://www.isrctn.com.
groups, with a significant advantage for sertraline (HAMD-17 change: 22.59, This article contains Supplementary Data online
95% CI 1.15–4.04, P < 0.05). at http://care.diabetesjournals.org/lookup/
suppl/doi:10.2337/dc14-1599/-/DC1.
CONCLUSIONS A slide set summarizing this article is available
online.
Depression improved under CBT and sertraline in patients with diabetes and de-
© 2015 by the American Diabetes Association.
pression, with a significant advantage for sertraline, but glycemic control
Readers may use this article as long as the work
remained unchanged. CBT and sertraline as single treatment are insufficient to is properly cited, the use is educational and not
treat secondary care diabetes patients with depression and poor glycemic control. for profit, and the work is not altered.
768 CBT vs. Sertraline in Diabetes and Depression
Depression is a common and potentially
life-threatening comorbidity in diabe-
tes. The known adverse effects include
poor treatment adherence (1), hyper-
glycemia (2), increased health care costs
(3), increased complications (4), cogni-
tive decline (5), and increased mortality
(6). Hence, the treatment of comorbid
depression is essential for the clinical
care of patients with diabetes (7). Treat-
ment goals focus not only on remission
or the improvement of depression but
also on the improvement of poor glyce-
mic control (8) to prevent or delay long-
term complications (9).
Interventions were evaluated in ran-
domized controlled trials and summa-
rized in two recent meta-analyses
(10,11). Both meta-analyses concluded
that depression could be treated with
moderate success in patients with diabe-
tes using psychological, pharmacological,
or combined interventions. The overall
result for glycemic control is controver-
sial, mostly due to severe methodological
limitations and the heterogeneity of the
examined populations and interventions
(11). In addition, collaborative care stud-
ies with sound methodology (e.g., studies
by Ell et al. [12] and Katon et al. [13]),
tested the efficacy of this approach as a
whole. However, these studies were not
able to identify single effective compo-
nents of compound treatments or evalu-
ate the superiority of one single treatment
over another because of a design that
allowed a switch between pharmacologi-
cal and psychological interventions. Most
recently, beneficial long-term effects of
CBT to improved treatment adherence
(compared with treatment as usual) in
patients with diabetes with depression
were observed for adherence and glyce-
mic control; however, the hypothesized
superior long-term treatment effects for
depression were not confirmed (14). In
summary, the evidence for a single treat-
ment that could significantly improve
depression outcomes and glycemic con-
trol at the same time remains so far
inconclusive (10,11).
One potential reason for contradic-
tory long term-results regarding depres-
sion outcomes is a lack of distinction
between the initial treatment response
and maintenance of the treatment ef-
fect. Whereas pharmacological and psy-
chological treatments of depression
have similar efficacy for the reduction
of depression (10,11), whether the
same strategies have a similar efficacy
on the maintenance of reduced depres-
sion is unclear. Randomized trials compar-
ing pharmacological and psychological
treatments for maintenance of treatment
response on depression are not yet pub-
lished in people with diabetes. This would
require including only people with diabe-
tes and depression who initially yield a
clinically significant depression reduction
after treatment and to test different treat-
ment strategies for maintenance.
Against this background, we con-
ducted the Diabetes and Depression
(DAD) Study, a randomized controlled
multicenter trial in which the efficacy of
psychotherapy (diabetes-specific cognitive
behavioral therapy [CBT]) was compared
for the first time with a pharmacological
treatment for depression (sertraline) in
patients with poorly controlled diabetes
and major depression who responded
initially to these treatments with a clini-
cally significant reduction of depression.
RESEARCH DESIGN AND METHODS
The study protocol was published in de-
tail previously (15).
Study Participants and Setting
Four coordinating trial centers (located
in Bochum/Dortmund, Mainz, Düsseldorf/
Köln, and Bad Mergentheim) organized the
recruitment and treatment in seventy
trial centers of outpatient secondary
care (specialized diabetes practices and
ambulatory care health services in clin-
ics) located in different parts of Germany
(predominantly in the Rhine-Main area,
Ruhr area, and Düsseldorf/Köln) from
April 2006 through May 2009. Eligibility
criteria included insulin-treated diabetes
(type 1 or 2), 21–69 years of age, major
depression according to DSM-IV criteria,
and HbA1c .7.5% (58 mmol/mol) within
the 9 preceding months and again in the
screening measurement. Key exclusion
criteria were suicidal ideations, psy-
chotic symptoms, bipolar disorder, sub-
stance abuse or dependence in the past
6 months, psychotherapy in the preced-
ing 3 months, current use of mood sta-
bilizers, neuroleptics, antidepressants,
or benzodiazepines, and liver enzyme el-
evations to exclude severe liver dysfunc-
tion (for a detailed list, see [15]).
The following eligibility and exclusion
criteria were revised and amended to
the protocol in August 2006 (when 60
patients were randomized) and April
Diabetes Care Volume 38, May 2015
2007 (when 198 patients were random-
ized): the age range was changed from
21–65 years to 21–69 years to increase
the number of eligible subjects. The in-
clusion criterion of HbA 1c .8% (64
mmol/mol) was changed to .7.5% (58
mmol/mol) because we faced serious
difficulties finding poorly controlled pa-
tients in the secondary care recruitment
centers. To enhance comparability with
international studies and to prevent a
selection bias, our independent scien-
tific advisory board (15) recommended
excluding patients only in case of clini-
cally significant suicide risk or history of
attempted suicide in the past 12
months. Therefore, patients with values
above 1 in the Hamilton Depression Rat-
ing Scale (HAMD-17) “suicide” item
(item 3, range 0–4) were not included
in the trial. The exclusion criterion re-
garding the current use of psychotropic
drugs was modified to allow the inclu-
sion of patients treated with low-
potency neuroleptic drugs in low doses
(,300 mg chlorpromazine dose equiva-
lents per day) because these drugs are
often used to treat sleeping disorders
and restlessness in patients with diabe-
tes. Post hoc analysis revealed that none
of the patients received low-potency
neuroleptic drugs at the beginning or
during the study.
Recruitment Procedures and
Measures
The medical records of the patients
were reviewed to assess age, type of di-
abetes, insulin treatment, and HbA1c
levels. Patients were contacted by tele-
phone to confirm basic eligibility criteria
and to invite them to a baseline screen-
ing. Depression was measured with a
questionnaire-based screening (Center
for Epidemiologic Studies Depression
Scale [CES-D]) (16,17), followed by the
Structured Clinical Interview for DSM-IV
(SCID) (18) for patients with a CES-D
value .22. The severity of depression
was measured with the HAMD-17 (19).
Health-related quality of life was as-
sessed with the Short Form Health Sur-
vey (SF-36) (20), and diabetes-specific
stress was assessed with the Problem
Areas in Diabetes Questionnaire (PAID)
(21). Medical diagnostics included docu-
mentation of current medication, concom-
itant diseases, onset and treatment of
diabetes, liver enzymes, and HbA1c (using
high-performance liquid chromatography).
care.diabetesjournals.org
All blood samples were analyzed in a
central laboratory (Bioscientia Labora-
tory, Mainz, Germany). Moreover, pa-
tient had to participate in a short
diabetes education program to be ran-
domized (see INTERVENTIONS).
Randomization and Blinding
Patients were randomized using block
randomization. For each coordinating
institution, a separate randomization
procedure using permuted blocks strat-
ified by type of diabetes was performed.
Randomization lists were computer gen-
erated and maintained by the Interdis-
ciplinary Centre for Clinical Trials Mainz
(IZKS) and conducted by fax.
The study was a single-blind trial; that
is, the treatment evaluation was con-
ducted by research psychologists un-
aware of the treatment allocation and
not involved in the recruitment or treat-
ment of the patients.
Study Design
Eligible patients were assigned to CBT or
sertraline treatments (Fig. 1). Diabetes
Figure 1—Design of the DAD study. RCT, randomized controlled trial.
treatment was not part of the trial pro-
tocol and was continued “as usual.” Af-
ter 12 weeks, those of both groups who
responded to the short-term therapy
phase ($50% reduction of the HAMD-
17 baseline score or HAMD-17 post-
treatment score #7) were included
in a 12-month, long-term phase. These
patients constituted the intention-to-
treat (ITT) population. Nonresponders
of the short-term phase were excluded
from the treatment protocol. All pa-
tients entering the long-term phase re-
ceived diabetes treatment as usual in
the trial center at 3-month intervals dur-
ing the following 12 months. Sertraline
responders received continuous treat-
ment as relapse prevention. CBT respond-
ers did not receive further treatment
but were encouraged to work with a
patients’ manual in the sense of a biblio-
therapy (22) during the 1-year follow-up
phase. The difference in the active treat-
ment duration between both inter-
ventions corresponds to usual clinical
practices and thus ensures external
Petrak and Associates 769
validity. Generally, group CBT is offered
for a limited time, assuming that “carry-
over” effects will stabilize the results
(23,24), whereas sertraline is given
for a longer period as relapse prevention
in patients responding to the initial
treatment (25). Patients of both groups
underwent the same number of visits
to control for the amount of physician
contact.
At the 12-month follow-up, both
treatment groups were reexamined re-
garding the primary and secondary out-
come variables. The primary outcome
was change of glycemic control, defined
as the difference in the HbA 1c value
from baseline to the end of the long-
term phase. Secondary outcomes were
the reduction of the HAMD-17 score, re-
mission of depression (not fulfilling the
DSM-IV-TR criteria for depression ac-
cording to the SCID and HAMD scores
#7), HbA 1c decrease of $1%, and
changes in SF-36 and PAID scores (all
analyses were compared with the base-
line values to the end of the trial).
770 CBT vs. Sertraline in Diabetes and Depression
Initially, the primary outcome was im-
provement of glycemic control, defined
as a decrease of at least 1% in HbA1c
value (yes/no) from baseline to the
end of the long-term phase. Owing to
advice from the advisory board, the
analysis of the primary outcome param-
eter was changed in November 2008 to
“change of glycemic control,” defined as
the difference in the HbA1c value from
baseline to the end of the long-term
phase. By changing the dichotomous
into a continuous end point, the statis-
tical power of the trial could be en-
hanced and the planned number of
trial subjects had to be reduced. All
changes in eligibility criteria or outcome
were amended to the protocol during
the trial and before breaking of the
blinding after approval by the ethic
committee.
Primary Hypothesis
CBT leads to a better improvement of
glycemic control compared with sertra-
line treatment at the 1-year follow-up in
patients who initially responded to
short-term therapy (CBT or sertraline)
with regards to improvement in depres-
sion. This superiority of the CBT regard-
ing glycemic control was expected
because the CBT focused not only on
depression but also on diabetes-related
aspects (e.g., problems with self-
management and adherence to treat-
ment). In contrast, the sertraline group
received a purely psychopharmacological
treatment, without further focus on their
diabetes-related problems.
Secondary Hypothesis
CBT and sertraline are equally effective
in remission of depression a) after 12
weeks of treatment and b) at the
1-year follow-up.
Interventions
Diabetes Education
Given the poor glycemic control of the
patients and considering that most pa-
tients treated with insulin had likely un-
dergone diabetes education previously
(according to the German guidelines
[26]), a short diabetes education pro-
gram (2 3 3 h) was offered to all pa-
tients as an update by trained diabetes
educators (education manual [15]).
Diabetes-Specific Group CBT
CBT was administered by clinical psy-
chologists who had undergone system-
atic training regarding the manual (CBT
manual [18]). CBT was delivered in
groups of 4 to 10 patients in an outpa-
tient setting within a 12-week period.
This treatment consisted of 10 sessions
(20 h) using a manualized semistruc-
tured CBT for depression, including dif-
ferent diabetes-specific aspects, to
improve adherence to diabetes treat-
ment and coping with diabetes. Psycho-
education included information about
the association of mood, activities, and
the development and maintenance of
depression. Participants learned about
the link between diabetes and mood
and ways to influence impaired mood
with cognitive techniques.
Furthermore, participants were en-
couraged to discuss diabetes-specific
goals, such as HbA1c target values, with
their diabetologists and to specify be-
havioral goals to improve their glycemic
control (15). Individual goal achieve-
ment was assessed, and possible bar-
riers to the goal attainment were
identified and modified, if possible.
Each participant received a patient
workbook that included theoretical
background, worksheets, and exercises
for each session. Patients were encour-
aged to continue working with the book
after the end of the short-term phase to
stabilize and generalize the improve-
ment (patients’ manual [15]).
Sertraline Treatment
Treatment was started at a dose of 50
mg/day and could gradually be raised to
200 mg/day, with changes not exceed-
ing 50 mg/week. Dose changes accord-
ing to response and side effects were
based on the Clinical Global Impression
Rating (27) and the Udvalg for Kliniske
Undersøgelser side effects rating scale
(28).
Statistical Analysis
Sample Size
The power calculation was based on ex-
pected differences in HbA1c levels of the
comparison groups in the ITT sample
that included all randomized patients
who entered the 12-month follow-up
phase. Considering randomized con-
trolled trials evaluating CBT (29) or se-
lective serotonin reuptake inhibitors
(30), a treatment difference of 1.0 6
1.6% HbA1c could be assumed to be rel-
evant. Therefore, with 2 3 46 evaluable
subjects, the trial had an 85% power of
detecting a treatment difference of
1.0% HbA1c by means of a t test on a
Diabetes Care Volume 38, May 2015
two-sided significance level of a =
0.05. Assuming a response rate of 40%
after the short-term treatment, 230
(2 3 115) subjects had to be randomized
(statistical analyses plan) (15).
Outcome Variables
The primary outcome of the trial was
defined as the difference in HbA1c values
from the baseline to the end of the long-
term phase comparing both treatment
groups using an ANCOVA controlling for
baseline HbA 1c value and a baseline
HAMD-17 score. Categorical outcomes
(e.g., remission of depression) were an-
alyzed using logistic regression analysis
controlling for baseline HbA 1c values
and baseline HAMD-17 scores. Improve-
ment in HAMD-17, SF-36, and PAID
scores were evaluated using ANCOVA
controlling for baseline HbA 1c values
and respective baseline scores. Analyses
were repeated controlling for potential
confounders. A correlation analysis was
performed to identify confounders (age,
sex, coordinating institution, diabetes
type, diabetes complications, education
years, income, single/recurrent episode[s],
and comorbidity) with other mental dis-
orders. Baseline variables associated
(P , 0.10) with long-term outcome var-
iables (HbA1c, HAMD-17 score, SF-36,
and PAID score, respectively) were in-
cluded as further control variables. All
analyses were conducted for the ITT
population. Subgroup analyses for the
type of diabetes were also performed.
Owing to the purely exploratory charac-
ter of these analyses, no adjustment for
multiplicity was done.
Quality Assurance and Safety
Clinical monitoring, data management,
pharmacovigilance, regulatory affairs,
and statistical analyses were conducted
by the IZKS Mainz and are described in
detail elsewhere (15).
c Data management: A data manage-
ment plan describing data manage-
ment procedures, data collection,
data flow, and the data validation
was established for the DAD study.
c Monitoring: Clinical on-site monitoring
was performed by personal visits
from a clinical monitor according to
standard operating procedures of the
IZKS. The monitor visited each site at
regular intervals to ensure compliance
with the study protocol, good clinical
practice, and legal aspects.
care.diabetesjournals.org
c Independent scientific advisory
board: An independent scientific ad-
visory board reviewed the outcome
every 12 months.
c Quality assurance of depression se-
verity assessment: To assure the
quality of the HAMD rating, we
established a validated training pro-
cedure (for details [15]).
c Adherence to the CBT manual: CBT
sessions were videotaped to ensure
adherence to the manual and to give
continuous supervision by one of the
authors (F.P.), who is a CBT trainer
and supervisor.
c Adverse events reported by the pa-
tients or detected by the investigator
were monitored and recorded contin-
uously according to good clinical
practice (15).
The trial was approved by the Medical
Ethics Committee Hessen and was con-
ducted according to the Declaration of
Helsinki (31). All patients gave written
informed consent to participate in the
trial.
RESULTS
Study Participants
The recruitment is described in Fig. 2.
The baseline characteristics of the pa-
tients showed no significant differences
between intervention groups as tested
with t tests or x2 tests (Table 1). The
results of the drop-out analyses are re-
ported in Supplementary Appendix 1.
Outcome
The response rate after 12 weeks of
treatment was 45.8% (n = 115 of 251)
for the total sample, with 42.1% (n = 53
of 126) for CBT and 49.6% for sertraline
treatment (n = 62 of 125). This differ-
ence was not statistically significant
(P = 0.231). The 115 treatment responders
of both groups constituted the ITT anal-
ysis group and were included in the long-
term phase of the study.
Primary and Secondary Outcome
Primary and secondary outcomes are re-
ported in Table 2. After 15 months, the
mean HbA 1c remained nearly un-
changed compared with the baseline
measures in both intervention groups,
with no significant difference between
the groups. The estimated treatment
difference from the ANCOVA model
amounted to 20.27% (95% CI 20.62 to
0.08, P = 0.129), indicating no significant
difference between the groups. Hence,
the main hypothesis of the study, which
expected an advantage for CBT treat-
ment, could not be confirmed. The
mean HbA1c values did not change sub-
stantially during the course of the study
in either group. Depressive symptoms
assessed by the HAMD-17 strongly de-
creased in both groups, with a significant
advantage for sertraline (P = 0.020) and a
moderate effect size difference between
groups (d = 0.48, 95% CI 0.11–0.86, P =
0.011). A nonsignificant trend (P = 0.083)
was observed for remission of depres-
sion in favor of sertraline.
In contrast with the physical compo-
nent of the SF-36, which remained
nearly unchanged compared with the
baseline score for both groups, the men-
tal component of the SF-36 improved
considerably in both treatment groups.
This result was similar for diabetes-
related stress, with a strong decrease
in the PAID score in both intervention
groups (SF-36 and PAID differences be-
tween groups were statistically not
significant).
The results of the per-protocol analy-
ses, which included all patients who
completed the treatment, demon-
strated nearly identical results for the
primary outcome and the depression-
related secondary outcome (Supple-
mentary Appendix 2).
Subgroup Analyses
Although patients with type 1 diabe-
tes showed a slight increase in HbA 1c
after 15 months compared with the
baseline, a decrease was observed in
patients with type 2 diabetes (Supple-
mentary Fig. 1). The unadjusted mean
difference between groups was 0.63%
(adjusted P = 0.0036). Patients with
type 2 diabetes showed an improvement
in HbA1c when treated with CBT com-
pared with the sertraline treatment,
which was associated with an increase
in mean HbA 1c values (unadjusted
mean difference between treatments
0.66%, adjusted P = 0.0475; Supplemen-
tary Fig. 1A). Patients with type 1 diabetes
treated with sertraline demonstrated a
stronger improvement in depressive
symptoms after 15 months compared
with patients who received the CBT treat-
ment (P = 0.0044). In contrast, the differ-
ence between the interventions for
patients with type 2 diabetes was not
statistically significant (Supplementary
Petrak and Associates 771
Fig. 1B). Accordingly, remission rates
were better for patients with type 1 di-
abetes in the sertraline group compared
with the CBT group (odds ratio 0.28, 95%
CI 0.095-0.810; P = 0.017; Supplemen-
tary Fig. 1C).
Adverse Events
Throughout the trial, 73 patients had at
least one hospitalization (CBT: n = 44;
sertraline: n = 29), and 2 patients died
(CBT: n = 1; sertraline: n = 1).
CONCLUSIONS
Contrary to our primary hypothesis, CBT
did not lead to a better improvement of
glycemic control compared with sertra-
line treatment after 15 months. In fact,
the very poor glycemic control remained
nearly unchanged during the entire trial
in both intervention groups.
The initial response rate regarding de-
pressive symptoms after 12 weeks of
treatment was 45.8% for all randomized
patients (in agreement with the first
part of our secondary hypothesis), with
similar response rates for the CBT and
sertraline groups.
For the patients who qualified for the
long-term phase of the study by their
initial response to treatment, we ob-
served a significantly better depression
outcome for patients treated with ser-
traline after 15 months, which was
mainly due to better maintenance of re-
duced depression in the sertraline
group. This overall difference in the
HAMD score (0.48 effect size) can be
considered as moderate (32).
For the remission rates of depression,
the observed differences between
groups failed to achieve statistical
significance.
Subgroup analyses showed differen-
tial treatment effects depending on
the type of diabetes. A moderate
HbA1c improvement was shown when
patients with type 2 diabetes were trea-
ted with CBT and a slight deterioration
was shown when treated with sertra-
line, which led to a moderate difference
of 0.66% HbA1c between treatments.
This effect was not seen in patients
with type 1 diabetes.
In contrast, patients with type 1 dia-
betes benefited more from sertraline
treatment than the CBT group with re-
gard to depressive symptoms. This was
also the case for remission of depression
in patients with type 1 diabetes, with
772 CBT vs. Sertraline in Diabetes and Depression Diabetes Care Volume 38, May 2015

Figure 2—Enrollment, treatment, and follow-up of the study participants.

nearly 74% of patients treated with ser- not observed in patients with type 2 sertraline treatment in the current study
traline achieving remission compared diabetes. is in line with randomized controlled trials
with only 44% of the patients treated The short-term treatment response in major depression with and without
with CBT. This differential effect was regarding depression after CBT or comorbid diabetes (33–37). Although
care.diabetesjournals.org Petrak and Associates 773

Table 1—Characteristics of the randomized patients at baseline major depression and the unintended
CBT group Sertraline group Total sample
fact that we included only Caucasians
Characteristics n = 126 n = 125 N = 251 restricts the generalizability of our re-
sults. Adherence to diabetes treatment
Age (years) 49.0 6 10.6 47.9 6 12.8 48.5 6 11.7
was not directly assessed, which is a fur-
Female sex 79 (62.7) 77 (61.6) 156 (62.2)
ther limitation of our study.
Caucasians 126 (100) 125 (100) 251 (100)
A strength of our work is that we con-
Years of formal education
ducted the study with a sound method-
,10 62 (49.2) 56 (44.8) 118 (47.0)
10–14 53 (42.1) 64 (51.2) 117 (46.6)
ology, including multiple quality assurance
.14 10 (7.9) 5 (4.0) 15 (6.0) aspects. These included the measure-
Employment ment of depression with SCID and
Employed or in training 64 (50.8) 62 (49.6) 126 (50.2) HAMD interviews by trained clinical psy-
Retired 21 (16.7) 23 (18.4) 44 (17.5) chologists (instead of questionnaires, as
Unemployed or disabled 22 (17.5) 21 (16.8) 43 (17.1) in some important trials on this topic
Homemaker/other 19 (15.1) 19 (15.2) 38 (15.2) [12,13]), the video-controlled monitor-
Type 1 diabetes 65 (51.6) 64 (51.2) 129 (51.4) ing of adherence of psychologists to
Type 2 diabetes 61 (48.4) 61 (48.8) 122 (48.6) the CBT manual, the establishment of
Diabetes duration (years) 15.7 6 10.4 15.0 6 10.6 15.3 6 10.5 an independent scientific advisory
HbA1c (%) 9.30 6 1.49 9.20 6 1.44 9.25 6 1.46 board, the data management, and data
HbA1c (mmol/mol) 78 6 7.21 77 6 7.76 78 6 7.76 validation with intense validation strate-
Retinopathy, nephropathy, or neuropathy 72 (57.1) 72 (57.6) 144 (57.4) gies. Finally, we limited bias due to cen-
Macrovascular complications 23 (18.3) 23 (18.4) 46 (18.3) ter or investigator effects by including
Coronary heart disease 13 (10.3) 19 (15.2) 32 (12.7) eight clinical psychologists and 70 trial
Major depression (SCID) sites across Germany.
Single episode 62 (49.2) 64 (51.2) 126 (50.2) Several facts might explain the lack of
Recurrent episodes 61 (48.4) 61 (48.8) 122 (50.2) effects regarding control in our study.
Recurrent episodes with seasonal pattern 3 (2.4) 0 (0.0) 3 (1.2)
HAMD-17 scores (range 0–52) 18.3 6 4.8 18.8 6 5.0 18.5 6 4.9 Selection of Patients
Depression severity by HAMD-17 scores Previous trials in the research field of
Mild (8–13) 21 (16.7) 16 (12.8) 37 (14.7) diabetes and depression to a large ex-
Moderate (14–19) 58 (46.0) 63 (50.4) 121 (48.2) tent included primary care patients (e.g.,
Severe (20–25) 38 (30.2) 35 (28.0) 73 (29.1) [12,13]) and the rare positive effects on
Very severe (26–52) 9 (7.1) 11 (8.8) 20 (8.0) glycemic control were mainly seen in
PAID sum score (range 0–100) 47.5 6 18.4 49.1 6 16.5 48.3 6 17.5 studies conducted in primary care pa-
SF-36 HRQoL tients (13,38,39). In contrast, we re-
Mental component (z values) 22.9 6 1.1 22.8 6 1.0 22.9 6 1.1 cruited participants exclusively from
Physical component (z values) 21.1 6 1.2 21.2 6 1.2 21.1 6 1.2 secondary care study sites. In Germany,
Data are shown as means 6 SD or as n (%). Higher HAMD-17 scores indicate more diabetes- it can be expected that most patients
related burden. Higher PAID scores indicate more diabetes-related burden. HRQoL, health- with type 1 diabetes are treated in sec-
related quality of life.
ondary care (40), whereas almost all pa-
tients with type 2 diabetes are treated in
primary care and are referred to second-
negative results regarding glycemic con- depression led to better results for ad-
ary care only when treatment fails. Thus,
trol were observed in most of the studies herence, depression, and glycemic con-
recruiting patients with type 2 diabetes
in the field (10,11), it was still unex- trol. Those differences were no longer
in secondary care is already selecting pa-
pected for us. Our expectation regarding observed after 8 and 12 months for de-
tients in whom usual treatment is failing.
the assumed advantage of CBT was pression but remained stable for adher-
When considering the mean HbA1c base-
based on the specific intervention, ence and glycemic control. Hence, like in
line value of 9.3% (78 mmol/mol) in our
targeting not only depression but also our study, these results demonstrate the
sample, we had to assume that we
adhering to diabetes treatment recom- difficulties identifying a specific treat-
recruited a group of very “difficult-to-
mendations, which was a unique ap- ment with simultaneous effect on
treat patients” even in the secondary
proach in published studies when we depression and glycemic control. How-
care setting and at least with respect to
started our trial in 2006. Meanwhile, re- ever, the observed long-term influence
their glycemic control.
sults of a trial with some similarities to on glycemic control makes it promising
our study became available (14): CBT to include the topic of adherence in Severity of Depression
with a focus on increased treatment for depression treatments for this group of The depression in most of our patients
adherence and depression was com- patients. was moderate to severe. Considering
pared with enhanced treatment as usual that trials with positive results in glyce-
for patients with uncontrolled type 2 di- Study Limitations and Strengths mic control preferentially used ques-
abetes and depression. After 4 months The inclusion of secondary care of pa- tionnaires to assess depression (13,39),
of treatment, CBT for adherence and tients with poor diabetes control with we likely included patients with a more
774 CBT vs. Sertraline in Diabetes and Depression Diabetes Care Volume 38, May 2015

Table 2—Differences between interventions from baseline to the end of the long-term phase in diabetes patients who initially
responded to short-term depression treatment (ITT analysis)
Unadjusted estimated
CBT group Sertraline group
Outcomes n = 53 Change n = 62 Change Adjusted between-group differences (95% CI)
HbA1c , % (mmol/mol)
Baseline 9.37 6 1.63 (79) 9.15 6 1.37 (76)
3 months 9.12 6 1.61 (76) 8.90 6 1.43 (74)
15 months 9.22 6 1.67 (77) 20.15 9.41 6 1.36 (79) +0.26 20.27 (20.62 to 0.08)†
HbA1c decrease of $1% after
15 months vs. baseline 5 (9.4) 4 (6.5) OR 1.43 (0.28–7.65)‡
HAMD-17
Baseline 18.04 6 4.62 18.87 6 5.14
3 months 5.40 6 3.03 5.35 6 3.72
15 months 7.83 6 6.49 210.21 5.46 6 5.75 213.41 2.59 (1.15–4.04)§*
Remission of depression, %
15 months 27 (50.9) 41 (66.1) OR 0.47 (0.20–1.11)|
SF-36 (z values)
Physical component
Baseline 20.88 6 1.06 21.14 6 1.20 d
3 months 21.04 6 1.01 21.29 6 1.13
15 months 21.03 6 1.25 20.15 21.04 6 1.13 +0.10 0.16 (20.60 to 0.28)#
Mental component
Baseline 22.69 6 1.05 22.86 6 1.06
3 months 20.97 6 1.37 20.81 6 1.44
15 months 21.09 6 1.58 +1.6 20.65 6 1.30 +2.21 20.36 (20.94 to 0.22)**
PAID
Baseline 45.93 6 17.89 50.31 6 15.83
3 months 37.12 6 18.86 37.92 6 16.68
15 months 34.96 6 21.01 210.97 31.43 6 20.94 218.88 7.13 (20.87 to 15.12)††
Data are shown as mean 6 SD, as n (%), or as indicated. Change is the baseline mean minus the 15-month mean. OR, odds ratio. *Significant
differences between groups P , 0.05. †Mean adjusted for baseline HbA1c and baseline HAMD-17 in ANCOVA. ‡Mean adjusted for baseline HbA1c,
baseline HAMD-17, and sex in logistic regression analysis. §Mean adjusted for baseline HbA1c, baseline HAMD-17, and years of formal education in
ANCOVA. |Mean adjusted for baseline HbA1c, baseline HAMD-17, and years of formal education in logistic regression analysis. #Mean adjusted for
baseline HbA1c and baseline SF-36 (physical component) in ANCOVA. **Mean adjusted for baseline HbA1c, baseline SF-36 (mental component), age,
and baseline macrovascular complication in ANCOVA. ††Mean adjusted for baseline HbA1c and baseline PAID in ANCOVA.

severe depression and potentially
poorer treatment adherence, which in
turn might have contributed to our
results (41).
Group CBT and Single Intervention
It might be the case that treatment has
to be individualized even more distinctly
to achieve better glycemic control (i.e.,
not only with respect to the type of di-
abetes), as suggested by our subgroup
results, but also regarding the group in-
tervention approach.
Conclusion
Both treatments were effective to im-
prove depression in poorly controlled
patients with diabetes, but sertraline
was slightly more effective to maintain
these effects compared with CBT. Despite
an intense treatment focus on the im-
provement of adherence to diabetes
treatment in the CBT group, glycemic
control did not improve in either inter-
vention. The selection of very difficult-
to-treat patients with poorly controlled
diabetes and depression and currently
unknown aspects of the comorbidity of
diabetes and depression might have con-
tributed to the results of our trial and the
differences that we observed with re-
gards to the results of previous studies.
Our results demonstrate that CBT and
sertraline, two widely used interven-
tions in clinical practice, cannot be con-
sidered as sufficiently effective in the
treatment of secondary care patients
with poor diabetes control and depres-
sion. “Mood repair” alone does not au-
tomatically result in improved diabetes
outcomes. Further research needs to
address potential additional mecha-
nisms that mediate the effect of depres-
sion on glycemic control.
Acknowledgments. The authors thank all of
the patients for their participation in the DAD
trial.
Funding. This work was supported by the
Kompetenznetz Diabetes mellitus (Competence
Network for Diabetes Mellitus) funded by the
German Federal Ministry of Education and
Research (BMBF) (No. 01KG0505). All authors
received financial support from the BMBF for
the submitted work. The BMBF had no role in
the design and conduct of the study; collection,
management, analysis, and interpretation of
the data; and preparation, review, or approval
of the manuscript.
Duality of Interest. C.H. has served as a
consultant for Servier (Paris, France) and Janssen-
Cilag (Beerse, Belgium); has served on the
speakers bureaus of Bristol-Myers Squibb, Eli
Lilly, Janssen-Cilag, Pfizer, and Servier; and is the
managing director of the psiac GmbH, Mainz,
which provides an Internet-based drug interac-
tion program for psychoactive drugs. No other
potential conflicts of interest relevant to this
article were reported.
Author Contributions. All authors designed
the study, were responsible for its conduct, and
contributed to the writing and editing of the
manuscript. F.P., K.K., and C.R. were responsible
for study management and data collection. C.R.
undertook data analysis. F.P. is the guarantor of
this work and, as such, had full access to all
the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
care.diabetesjournals.org
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