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Diabetes and depresi

Study protocol of the Diabetes and


Depression Study (DAD): a multi-center
randomized controlled trial to compare
the efficacy of a diabetes-specific
cognitive behavioral group therapy versus
sertraline in patients with major
depression and poorly controlled diabetes
mellitus
Frank Petrak1*, Stephan Herpertz1, Christian Albus2, Norbert Hermanns3,
Christoph Hiemke4, Wolfgang Hiller5, Kai Kronfeld6, Johannes Kruse7, Bernd
Kulzer3, Christian Ruckes6 and Matthias J Mller8

* Corresponding author: Frank Petrak mail@dr-frank-petrak.de

Author Affiliations
1

Department of Psychosomatic Medicine and Psychotherapy, LWL-University Clinic


Bochum, Ruhr-University Bochum, Bochum, Germany
2

Department of Psychosomatic Medicine and Psychotherapy, University of Cologne,


Kln, Germany
3

Diabetes Center Mergentheim, Bad Mergentheim, Germany

Department of Psychiatry and Psychotherapy, University Medical Centre, Johannes


Gutenberg-University, Mainz, Germany
5

Department of Clinical Psychology and Psychotherapy, Johannes Gutenberg University


Mainz, Mainz, Germany
6

Interdisciplinary Centre for Clinical Trials Mainz (IZKS Mainz), University Medical
Centre, Johannes Gutenberg-University, Mainz, Germany

Clinic for Psychosomatic and Psychotherapy, University Clinic Gieen/Marburg,


Justus-Liebig-University Gieen, Marburg, Germany
8

Vitos Clinical Centre Gieen-Marburg and Justus-Liebig-University Gieen, Marburg,


Germany
For all author emails, please log on.
BMC Psychiatry 2013, 13:206 doi:10.1186/1471-244X-13-206

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-244X/13/206
Received: 15 April 2013
Accepted: 30 July 2013
Published:6 August 2013
2013 Petrak et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
Depression is common in diabetes and associated with hyperglycemia, diabetes related
complications and mortality. No single intervention has been identified that consistently
leads to simultaneous improvement of depression and glycemic control. Our aim is to
analyze the efficacy of a diabetes-specific cognitive behavioral group therapy (CBT)
compared to sertraline (SER) in adults with depression and poorly controlled diabetes.
Methods/Design
This study is a multi-center parallel arm randomized controlled trial currently in its data
analysis phase. We included 251 patients in 70 secondary care centers across Germany.

Key inclusion criteria were: type 1 or 2 diabetes, major depression (diagnosed with the
Structured Clinical Interview for DSM-IV, SCID) and hemoglobin A1C >7.5% despite
current insulin therapy. During the initial phase, patients received either 50200 mg/d
sertraline or 10 CBT sessions aiming at the remission of depression and enhanced
adherence to diabetes treatment and coping with diabetes. Both groups received diabetes
treatment as usual. After 12 weeks of this initial open-label therapy, only the treatmentresponders (50% depression symptoms reduction, Hamilton Depression Rating Scale, 17item version [HAMD]) were included in the subsequent one year study phase and
represented the primary analysis population. CBT-responders received no further
treatment, while SER-responders obtained a continuous, flexible-dose SER regimen as
relapse prevention. Adherence to treatment was analyzed using therapeutic drug
monitoring (measurement of sertraline and N-desmethylsertraline concentrations in blood
serum) and by counting the numbers of CBT sessions received. Outcome assessments
were conducted by trained psychologists blinded to group assignment. Group differences
in HbA1c (primary outcome) and depression (HAMD, secondary outcome) between 1year follow-up and baseline will be analyzed by ANCOVA controlling for baseline
values. As primary hypothesis we expect that CBT leads to significantly greater
improvement of glycemic control in the one year follow-up in treatment responders of the
short term phase.
Discussion
The DAD study is the first randomized controlled trial comparing antidepressants to a
psychological treatment in diabetes patients with depression.
The study is investigator initiated and was supported by the Frderprogramm Klinische
Studien (Clinical Trials) and the Competence Network for Diabetes mellitus funded by
the Federal Ministry of Education and Research (FKZ 01KG0505).
Trial registration
Current controlled trials ISRCTN89333241.

Background
Diabetes and depression
Diabetes mellitus is a highly prevalent chronic disease affecting approximately 9 to 10%
of the global adult population [1]. Based on estimates of the International Diabetes
Federation there were 366 million people with diabetes in 2011, and this rate is expected
to rise to 552 million by 2030 [2]. Diabetes is a major cause of morbidity and mortality
[3] and extremely costly in economic terms [4]. People with diabetes are at twice the risk
of developing depression compared with control groups without diabetes. Accordingly,
9% of patients with diabetes meet the criteria for major depression (controls: 5%) and
approximately 25% of patients with diabetes mellitus are suffering from single or
multiple depression symptoms (controls: 14%), which includes major depression as well
as subclinical depression [5].
There is a strong body of evidence for multiple adverse interactions between diabetes and
depression. Overall, the comorbidity of depression and diabetes is associated with
adverse diabetes outcomes, especially higher hemoglobin A1c (HbA1c) levels [6], microand macrovascular complications [7], mortality [8,9], greater diabetes-related symptom
burden [10], increased functional impairment, and poorer adherence to diet, exercise, and
diabetes self-management [11]. In addition, coexisting depression in people with diabetes
is associated with poorer mental and physical quality of life [12] and markedly increased
health care costs [13,14].
Treatment of depression in diabetes
According to the above mentioned results, the treatment of comorbid depression is
considered as essential for the clinical care of diabetes patients [15]. When treating
depressed diabetes patients, there are two major treatment goals:
(1) remission or improvement of depression, and

(2) improvement of the often poor glycemic control. The second goal is generally
considered as fundamental to the management of diabetes, in order to prevent or delay
long-term complications [16].
Up to now, three different approaches to treat depression in diabetes have been evaluated
in randomized controlled trials (RCT): Antidepressant medication, psychological
treatments (e. g. cognitive behavioral therapy, counseling, problem solving training) and
a flexible combination of both in stepped care approaches. In 2010, treatment effects
were summarized in a meta-analysis of 14 RCTs [17] and in 2012 in a systematic
Cochrane review including 19 RCTs [18].
As a result of both analyses there is growing evidence that depression can be treated with
moderate success in patients with diabetes using either psychological, pharmacological
and stepped care interventions (combined effect sizes [ES] d 0.51; 95% confidence
interval [CI] -0.63 to 0.39). With regard to the goal of improved glycemic control the
results are controversial: while the meta-analysis calculated small combined effect sizes
for all treatments taken together (ES d 0.27; 95% Kl 0.40 to 0.15) [17], the Cochrane
review concluded that glycemic control improved moderately in pharmacological trials,
while the evidence is inconclusive for psychological intervention. Overall, the evidence is
sparse and inconclusive due to several low-quality trials with substantial risk of bias and
the heterogeneity of examined populations and interventions [18].
In sum, despite the relevance of the topic and the increased research activity over the last
two decades, there is still a considerable lack of knowledge when facing the question to
identify the most effective treatment for depression in diabetes. Especially, due to the
combination of interventions in the collaborative care trials with sound methodology, e.g.
[19-21], it is impossible to identify the effective components of compound treatments or
to evaluate the superiority of one treatment (e.g. antidepressants) above another (e.g.
cognitive behavioral therapy, problem solving training). Finally, there exist no published
data to identify the best treatments among effective treatments; and more specifically, to

our knowledge no trial was conducted comparing pharmacological to psychological


interventions in patients with diabetes and comorbid depression.
To address this lack of knowledge we conducted the Diabetes and Depression Study
(DAD study), a randomized, multicenter, controlled trial comparing a diabetes-specific
CBT to SER in poorly controlled diabetes patients with major depression.
Current status of the trial
Data analysis phase.
Research objectives and endpoints
Primary objective
The aim of the planned study is to evaluate the efficacy of a diabetes-specific CBT
combined with diabetes education versus a continuous treatment with SSRI (SER)
combined with diabetes education in high-risk patients with poorly controlled insulintreated type 1 or type 2 diabetes mellitus and depression.
Principal research question
Does a diabetes-specific psychotherapy (CBT) or antidepressant medication (SER)
improve long-term glycemic control in patients with poorly controlled diabetes and
depression?
Primary hypothesis
CBT leads to a better improvement of glycemic control when compared with SER at the
one-year follow-up in patients who initially responded to short-term therapy (CBT or
SER) with regard to improvement in depression.
Primary endpoint: Change of glycemic control (hemoglobin A1C).
Secondary objectives

To provide clear scientific evidence whether the two most widely established treatments
(SSRI and CBT) for patients with depression but without additional somatic diseases can
be applied to high-risk patients with poor metabolic control of insulin-treated diabetes
and comorbid depression.
Secondary hypothesis
CBT and SER are both effective in terms of remission of depression after 12 weeks in an
open label trial as well as at the one-year follow-up.
Secondary endpoints
(a) remission of depression: no longer fulfilling the DSM-IV-TR criteria for depression
according to the Structured Clinical Interview for DSM-IV, SCID [22], and depression
score according to the HAMD Interview [23]<= 7;
(b) improvement of depression (>/= 50% reduction of (HAMD-baseline score);
(c) improved generic HRQoL, per SF-36 [24]; and
(d) decreased problems in daily living with diabetes, per PAID [25].

Methods/Design
Study design, setting, recruitment and procedures
This trial is a prospective, randomized, multicenter, parallel arm controlled clinical trial
that involved the two treatment conditions CBT vs. SER in a parallel group design (see
Figure 1).

Figure 1. Design of the DAD study.


The recruitment of the patients took place between April 2006 and May 2009 in 70 trial
centers of outpatient secondary care (specialized diabetological practices and ambulatory

care health services in clinics) located in different parts of Germany (predominantly in


the Rhine-Main area, Ruhr area and Dsseldorf/Kln). Four coordinating trial centers
(Bochum/Dortmund, Mainz, Dsseldorf/Kln and Bad Mergentheim) organized the
recruitment activities in the diabetological trial centers located in their vicinity. All
insulin-treated outpatients with diagnosed type 1 or type 2 diabetes registered in the
respective diabetological trial centers within the age range of 21 to 69 years and with an
HbA1c value >7.5% received a letter by their diabetologist with a patient information
leaflet about the trial. They were invited to participate and informed that they would
receive a telephone call by a research assistant. During the telephone call, the research
assistant provided further information about the trial and asked consent for the baseline
assessment, which then took place in one of the diabetological trial centers. After having
provided written informed consent, medical eligibility criteria of a patient was checked
by his or her diabetologist.
Psychological eligibility criteria such as depression, excluded history of schizophrenia
etc. were assessed by clinical psychologists who had undergone an intensive standardized
training provided by one of the authors (MJM). Depression was measured in a two stage
screening-procedure starting with a questionnaire-based screening (German version [26]
of the Centre for Epidemiologic Studies Depression Scale (CES-D) [27], followed by the
Structured Clinical Interview for DSM-IV (SCID) [22] for those patients who were
screened positive. Severity of depression was measured with the HAMD. To assure the
quality of the HAMD training we first established an expert standard rating (which
consisted of an agreement of three highly experienced raters). During the training we
computed chance-corrected coefficients (weighted ) of rating agreement with the expert
standards for the single items and the total score of the HAMD. Item ratings within the
accepted range of the standard rating 1 obtained a full credit of 1 and ratings outside the
accepted range a weight of 0 (no credit). Values of w>0.40 denote acceptable chancecorrected agreement, coefficients w>0.80 indicate almost perfect strength of agreement
[28]. High interrater reliability (>0.80) was achieved for most of the HAMD items and
excellent interrater reliability was demonstrated for the total score (w 0.96 0.08), thus

indicating that the raters were well trained before the beginning of their assessment in the
DAD study. Further psychosocial variables were assessed using psychometric
questionnaires (described in the Measures section).
Patients meeting all eligibility criteria (see Eligibility criteria section) were offered a
short structured diabetes education (2 3 hours) by trained diabetes educators as an
update to ensure sufficient diabetes knowledge in all trial participants (see Diabetes
education section). All patients completing the diabetes education program were
allocated randomly to either 10 sessions of group CBT or an algorithm based SERtreatment with 50 to 200 mg/day according to treatment response and side effects (see
Randomization and blinding section and Interventions section). Diabetes treatment
was not part of the trial protocol and was continued as usual.
The trial consisted of a 12-week open label therapy short-term phase. Treatment
responders of both groups ( 50% reduction of the HAMD baseline score or HAMD
post-treatment score7) were included in a 12-month long-term phase. These patients
constituted the intention-to-treat (ITT) population. Non-responders of the short-term
phase were excluded from the treatment protocol and referred to the best available
treatment using standard medical care. The general recommendation to the treating
physicians was to give SER or other medication to CBT-non-responders and to give CBT
or other medication to SER- non-responders.
All patients entering the long-term phase received ongoing diabetological treatment as
usual by their treating physicians in the diabetological trial center at 3-month intervals
during the following 12 months. SER-responders received a continuous SER- treatment
as relapse prevention. CBT responders did not receive further treatment but were
encouraged to work with a patients manual in the sense of a bibliotherapy [29] during the
one year follow-up phase. The difference in the active treatment duration between both
interventions corresponds to usual clinical practice and thus assure external validity.
Generally, group CBT is offered for a limited period of time assuming that carry over

effects will stabilise the results [30,31], while SER in patients responding to the treatment
is given for a longer period of time as relapse prevention (see also German National
Disease Management Guidelines [32]). In order to control for the amount of physician
contact patients of both groups underwent the same number of visits. During the visits,
the CES-D questionnaire was applied and the HbA1c value was assessed. For the patients
treated with SER, additional analyses of SER and its major metabolite (Ndesmethylsertraline) in blood serum were performed as measurement of treatment
adherence (see Assessment of adherence section).
Drug analyses were performed as described previously using a validated high
performance liquid chromatographic method with column switching and
spectrophotometric detection [33]. Intra- and interassay variabilities were below 10%.
At the 12-month follow-up, both treatment groups were re-examined regarding the
primary outcome variable HbA1C. In addition, SCID and HAMD interviews as well as
psychometric questionnaires were administered among others to evaluate the treatment
effects regarding depression, health-related quality of life, and disease-specific burdens.
Eligibility criteria (inclusion and exclusion criteria)
Initially, all insulin-treated diabetes patients within the age range of 21 to 65 years, with
an HbA1c value>8% and major depression according to DSM-IV criteria were to be
included, provided that they also met the other inclusion and exclusion criteria. Two
eligibility criteria and two exclusion criteria were revised and amended to the protocol in
August 2006 and April 2007. The age range was changed from originally 2165 years to
2169 years to increase the number of eligible subjects. The inclusion criterion of HbA1c
>8% was changed into >7.5%, because we faced serious difficulties to find poorly
controlled patients in the secondary care recruitment centers. As an explanation for this
unexpected situation we think that the successful introduction of disease management
programs (DMP) in Germany at that time might have led to a decrease in HbA1c values
in patients with type 2 diabetes [34,35]. Moreover, we assumed that patients with very

poorly controlled type 2 diabetes would have still been treated in primary care settings
not participating in the DMPs.
To enhance comparability with international studies and to prevent a selection bias, our
independent scientific advisory board (see Quality assurance section) recommended
excluding patients only in case of clinically significant suicide risk or history of
attempted suicide in the past 12 months. The exclusion criterion regarding the current use
of psychotropic drugs was modified to allow the inclusion of patients treated with low
potency neuroleptics in low doses (less than 300 mg chlorpromazine dose equivalents per
day), as these drugs are often used to treat sleeping disorders and restlessness in diabetes
patients, particularly in those suffering from diabetic neuropathy. Detailed inclusion and
exclusion criteria are listed in Table 1.
Table 1. Eligibility criteria for the DAD study
Randomization and blinding
Randomization
Patients were randomized using block randomization to ensure equal group sizes. For
each coordinating institution, a separate randomization procedure stratified by type of
diabetes was performed to ensure balanced treatment groups across and within
coordinating institutions. Randomization lists were generated by the Interdisciplinary
Center for Clinical Trials Mainz (IZKS), University Medical Center Mainz by means of a
computer program. These randomization lists included the patient identification number
(SUBJID) used for identifying all data collected from the subject during the study and for
the treatment allocation. The randomization lists were maintained by the IZKS. The
treatment allocation at the coordinating institutions was performed using FAX
randomization. After checking subjects eligibility, the investigator faxed a randomization
request form to the IZKS randomization center. This form included information on the
patients sex, year of birth and type of diabetes. The IZKS randomization center entered

the SUBJID and treatment allocation on the request form and faxed the form back to the
investigators site.
Blinding
In the DAD study, psychotherapy (CBT) was compared to medication and there was no
placebo condition. Thus, a blinding of patients or health care providers was not possible.
However, a blinding of all members of the research team involved in the assessment of
outcomes was carried out.
Interventions
Diabetes education
Given the poor glycemic control of the patients and considering that most patients treated
with insulin had likely undergone diabetes education previously (according to the
German evidence based guidelines that were in force at the time of the patient
recruitment [36]), a short diabetes education program was offered to all patients as an
update. Patients received structured diabetes education (2 3 hours) before
randomization. The program included the following modules: (1) insulin treatment; (2)
self-monitoring with regard to diabetes-relevant behavioral strategies (e.g., nutrition,
physical activity, foot care); (3) the recognition, treatment, and prevention of acute
complications; and (4) risk factors (e.g., hyperlipidemia, arterial hypertension, smoking)
for macroangiopathic diabetes-related illnesses. This diabetes education was offered by
trained diabetes educators using a manual that was established for the DAD study (see
Additional file 1 Structured diabetes education manual for diabetes educators in
German).
Additional file 1. Structured diabetes education manual for diabetes educators (in
German).
Format: PDF Size: 2.8MB Download file or display content in a new window
This file can be viewed with: Adobe Acrobat Reader

Diabetes specific cognitive behavioral group therapy (CBT)


CBT was offered as manualized diabetes-specific treatment delivered by clinical
psychologist who had undergone a systematic training regarding the manual. Each
session was videotaped and a random sample of 13% of the sessions (N=32 sessions)
was used in order to continuously evaluate and ensure the adherence to the manual and to
give continuous supervision by one of the authors, who is a CBT trainer and supervisor
(FP). We additionally developed and evaluated a rating system to assess the expertise of
the therapists with acceptable to good interrater reliability (intraclass correlation
coefficient, ICC 0.73 to 0.96). A second rating system to assess adherence to the CBT
manual was also developed and showed good to excellent interrater reliability (coefficient
0.74 to 1.0) (details of the rating systems will be published separately).
CBT was delivered in groups of 4 to 10 patients per group in an outpatient setting within
a 12week time period. This treatment consisted of 10 sessions (20 hours) using a
manualized semi-structured CBT for depression, including different diabetes-specific
aspects in order to improve adherence to diabetes treatment and coping with diabetes (see
Additional file 2 Diabetes-specific CBT manual for therapists, in German). The
psychoeducation section (sessions 13) included information about the association of
mood and activities and the development and maintenance of depression. In addition,
participants learned about the link between diabetes and mood and ways to influence
impaired mood with cognitive techniques. Furthermore, participants were encouraged to
discuss diabetes-specific goals such as HbA1c target values with their diabetologists and
to specify behavioral goals in order to improve their glycemic control (see Additional file
3 Working sheet for diabetologists and patients: strategies to improve glycemic control,
in German). Individual goal achievement was assessed in sessions six and ten and
possible barriers to the goal attainment were identified and modified if possible. To help
patients identifying and reducing perceived barriers to various aspects of selfmanagement and to enhance coping skills, the problem-solving section (sessions 47)
covered cognitive and behavioral techniques (e.g. cognitive restructuring, stress

management). Fear of diabetes complications and appropriate coping-strategies were


topics of further sessions. In the last session participants learned how to prevent and cope
with depression relapse. Each participant received a patient workbook including
theoretical background, worksheets, and exercises for each session (see Additional file 4
working book for patients of the diabetes-specific CBT group, in German). Patients
were encouraged to continue working with the book after the end of the short-term phase
to stabilize and generalize the improvement in the sense of a bibliotherapy [29].
Additional file 2. Diabetes-specific CBT manual for therapists (in German).
Format: PDF Size: 183KB Download file or display content in a new window
This file can be viewed with: Adobe Acrobat Reader
Additional file 3. Working sheet for diabetologists and patients: strategies to
improve glycemic control (in German).
Format: PDF Size: 32KB Download file or display content in a new window
This file can be viewed with: Adobe Acrobat Reader
Additional file 4. Working book for patients of the diabetes-specific CBT group (in
German).
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This file can be viewed with: Adobe Acrobat Reader
Sertraline treatment
SER treatment was started at a dose of 50 mg/day in the morning following an algorithm
which is described in Table 2. If no clinical response was achieved within 24 weeks, the
dose could be raised to 100 mg/day in the morning. Further dose escalation up to 200 mg
per day was possible with changes not exceeding 50 mg/ week. Recommendation for
dose changes according to response and side effects were based on the Clinical Global
Impression Rating (CGI) [37] and the UKU side effects rating scale [38]. Patients and
clinicians ratings of side effects and treatment response as well as the current course of
treatment (duration of treatment and changes) were taken into account. Optional

supplementary visits and telephone contact were possible at any time. Additionally one of
the authors, a psychiatrist and clinical psychologist (MJM), offered advice to the treating
diabetologists providing a psychiatric hotline if questions regarding the medication
occurred. During the long-term phase of the trial SER responders received a continuous
SER treatment as relapse prevention.
Table 2. Algorithm for the sertraline treatment in the DAD trial
Measures
Outcome measures were assessed at baseline, at the end of the short-term phase
(12 weeks), at months 6, 9, 12 during the long-term phase and at the end of the long-term
phase (15 months). For patients randomized to SER treatment, additional assessments
were scheduled at week 2 and 8 during the short term phase to deliver medication and
monitor the response and side-effects. At week 8 and 12 SER and desmethylsertraline
blood levels were assessed. Figure 2 summarizes all medical and psychosocial variables,
which were assessed in the current trial, by time of data collection. Adverse events were
monitored and recorded continuously during the trial (see Additional file 5 Safety
manual, in German; and Definitions and assessment of adverse events).

Figure 2. Measurements in the DAD study. Note: P = visit to the


coordinating institutions were questionnaire and interviews will be administered by
members of the research team (research assistants, psychologists); D = visit to the
treating physician or research assistants in the diabetologic trial centres. *Visit S2 is
optional by telefone or personally.
Additional file 5. Safety manual (in German); and Definitions and assessment of
adverse events.
Format: PDF Size: 523KB Download file or display content in a new window
This file can be viewed with: Adobe Acrobat Reader
Primary outcome

Initially, the primary outcome was improvement 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. Due to an advice of the advisory board, the analysis of the primary outcome
parameter was changed and amended to the protocol in November 2008 into change of
glycemic control, defined as the difference in HbA1c value from baseline to the end of
the long-term phase. By changing the dichotomous endpoint into a continuous endpoint,
the statistical power of the trial could be enhanced and the planned number of trial
subjects had to be reduced (see Sample size calculation section).
Secondary outcomes
Secondary outcomes were remission of depression; i.e. not fulfilling the DSM-IV-TR
criteria for depression according to the SCID and HAMD scores7, improvement of
depression, i.e. a reduction of the HAMD score from baseline to the end of trial by at
least 50%, improvement of health-related quality of life (HRQoL), i.e. change in
generic HRQoL from baseline to end of trial as assessed per SF-36 mental and physical
component scores [24], and improvement of diabetes related stress, from baseline to
end of trial as measured per PAID [39]. As amended to the protocol, the previous primary
outcome (improvement of glycemic control of at least 1% in HbA1c value from baseline
to the end of the long-term phase) was assessed as a secondary outcome.
Other psychometric measures
A number of other psychometric variables were investigated and measured with validated
German questionnaires or German versions of internationally validated questionnaires at
baseline, after the end of the short-term phase and in the one year follow-up: Diabetes
knowledge was measured with a Diabetes Knowledge Questionnaire for Type 1
(Diabetes-Wissens-Test Typ-I -, DWT-I) [40] and Type 2 Diabetes (Diabetes-WissensTest Typ-II, DWT-II) [41], diabetes self-care by the Summary of diabetes self-care
activities measure (SDSCA) [42], diabetes-specific locus of control by the IPC-DiabetesQuestionnaire (IPC-D1) [43] and psychological barriers to insulin therapy by the Barriers

to Insulin Therapy Questionnaire (BIT) [44]. Coping was assessed using the Freiburger
Coping with Illness Questionnaire (15-item version, FKV-15) [45], self-esteem by the
Rosenberg Self-Esteem Scale (RSE) [46]; hopelessness by the Hopelessness Scale (HScale) [47]; incongruence by Inkongruence Questionnaire (K-INK) [48], childhood
traumata by Childhood Trauma Questionnaire (CTQ) [49,50] psychological problems and
symptoms of psychopathology by the Short-Form of the Symptom Checklist SCL-90-R
[51] (German version, SCL-K-9) [52]; and social support by the Questionnaire of
perceived family support and communication (PFUK) [53].
Assessment of treatment preference
Treatment preference was assessed as follows: If you were depressed and you could
choose between two equally effective treatments that might cure your depression, which
ONE would you choose?
(1) Free medication daily for 15 months (no or only minor side effects to be expected);
(2) 10 sessions (2 hours each, within a 3month time period) of group psychotherapy
with a maximum of 10 group members, with a focus on depression and diabetes-related
problems;
(3) I do not prefere either treatment.
Assessment of the patient- and therapist perspectives of the (CBT) sessions
Each CBT session was rated by patients and therapists assessing the perceived personal
involvement and confidence regarding the group therapy. The group therapists and the
supervisor received the results as continuous feedback before the next session in order to
reflect and if necessary to improve the therapeutic strategy in the respective group. The
questionnaire was validated within the DAD study with good psychometric results [54].
Assessment of adherence to treatment

Adherence to treatment was defined by measuring the received therapy 'dose' (see Table 3
for an overview about the definition of adherence to CBT and SER treatment).
Table 3. Definition of treatment adherence in the CBT and sertraline treatment
groups
Adherence to CBT was assessed by the number of attended CBT-sessions. As there
exists no established measure of adherence for psychotherapy, in the current trial
sufficient adherence to CBT was defined as participation in at least eight out of ten
sessions.
Adherence to SER treatment was assessed by repeated measures of serum SER
concentrations and the ratio of metabolite to parent compound, i.e. ratio of Ndesmethylsertraline (DSER) to SER as recommended by Reis and colleagues [56]. As
patients identified as treatment non-responders after the end of the short-term phase were
excluded from the treatment protocol, SER adherence was evaluated separately for
randomized patients and ITT patients. For randomized patients, adherence was assessed
based on SER concentrations and DSER: SER measured at week 8 and 12. For ITT
patients, adherence was assessed based on SER concentrations and DSER: SER measured
at week 8, 12, 24, 36, 48 and 60. Notwithstanding initial planning and Therapeutic Drug
Monitoring (TDM) guidelines [57], which recommend concentrations between 10
50 ng/ml, target ranges of SER were defined as concentrations between 10100 ng/ml, as
up to 100 ng/ml no severe adverse effects are to be expected. Furthermore, it has to be
taken into account that the trial participants suffer from chronic disease and receive
concomitant medications, which affect drug metabolism potentially resulting in higher
serum concentrations [56]. To avoid biased adherence ratings, patients discontinuing the
trial participation due to severe adverse events or discontinuing SER intake because of
their physicians recommendation, were excluded from the adherence rating. In cases of
missing blood samples or concentrations not detectable due to interferences, all available
blood samples for the patient were discussed with one of the authors with long-standing
expertise in therapeutic drug monitoring (CH). Based on the course of available SER

concentrations, DSER concentrations and ratios DSER:SER, adherence was estimated for
these patients. If only one blood sample was available, the patient was excluded from the
adherence rating. As high SER concentrations (> 100 ng/ml) are often observed in case of
concomitant medication, SER concentrations above the target range were considered
adherent, if the corresponding ratio DSER:SER fell into the target range.
In addition, a binary overall adherence rating was employed distinguishing adherent from
non-adherentpartially non-adherent patients for all randomized patients and all ITT
patients, respectively.
For the SER group, we also aimed at identifying overt and hidden forms of nonadherence. Non-adherence was considered overt, if patients chose to discontinue or
refuse SER treatment or withdrew informed consent during the short-term phase of the
trial for randomized patients and during the whole trial phase for ITT patients,
respectively. All other cases of non-adherence were considered as hidden non-adherence.
Statistical analysis
Sample size calculation
Initially, the power calculation was based on expected differences in the percentage of
patients with 1% improvement in HbA1c levels in both treatment groups. As the primary
outcome variable was changed into a continuous variable due to an amendment to the
protocol in November 2008, the power calculation was changed as follows: The power
calculation was based on expected differences in HbA1c levels of the comparison groups
in the (ITT) sample. This sample consisted of all randomized patients who entered the 12month follow-up phase. Considering RCTs in which CBT [58] or SSRIs [59] were
evaluated, a treatment difference of 1.0% HbA1c could be assumed as relevant. Standard
deviations of HbA1c values of 1.42 and 1.8 were observed in these studies. For the
current trial a standard deviation of slightly more than 1.4 could be expected. However, a
standard deviation of 1.6 as a conservative approach was taken. Therefore, with 246
evaluable subjects, the trial will have 85% power to detect a treatment difference of 1.0%

HbA1c by means of a t-test on a two-sided level of significance =0.05. Assuming a


drop-out rate of 60%, 230 (2115) subjects had to be randomized.
Analyses will be performed using an intent-to-treat principle. However, if in the shortterm phase dropout rates in the two treatment groups differ by more than 10%, the
primary analysis will employ all randomized patients. This would be done because the
comparison of long-term treatment effects on glycemic control in patients who have an
initial short-term improvement of depressive disorder (HAMD reduction 50% or
HAMD score7 after the short-term phase) is valid only if the dropout rates in the shortterm phase are similar.
Analysis of outcome variables
No interim analyses are planned. The primary outcome of the trial change of glycemic
control is defined as the difference in HbA1c value from baseline to the end of the longterm phase compared for the different treatment groups using an analysis of covariance
(ANCOVA) controlling for baseline HbA1c value and baseline HAMD score. The
primary analysis will be focused on observed cases. The analysis will be repeated after
employing the last observation carried forward method for missing HbA1c and HAMD
scores. An appropriate method has to be chosen on an individual basis when the missing
value pattern becomes known. If more than 10% but less than 40% of the values are
missing, multiple imputation methods will be considered.
The main secondary analysis is based on the numbers and proportions of patients who
demonstrate improvement of glycemic control ( 1% improvement in HbA1c values from
baseline to the end of the long-term phase). Differences between treatment groups will be
tested using logistic regression analysis controlling for baseline HbA1c value and baseline
HAMD-score. Further secondary outcomes such as remission of depression and
improvement of depression will be analyzed using logistic regression analysis controlling
for baseline HbA1c value and baseline HAMD score to evaluate treatment effects.
Differences between treatment groups in improvement in HrQoL (SF-36 mental and

physical component scores) and improvement of diabetes related distress (as assessed by
PAID) will be analyzed using analyses of covariance controlling for baseline HbA1c
values and baseline SF-36 scores (mental and accordingly physical component score) or
baseline PAID scores, respectively.
All primary and secondary analyses will be repeated controlling for potential
confounders. To identify confounders such as age, sex, coordinating institution, diabetes
type, diabetes complications, education years, income, single/recurrent episode(s) and
comorbidity with other mental disorders, a correlation analysis will be employed.
Baseline-variables associated (p<.10) with long-term outcome variables (HbA1c, HAMD
score, SF-36 component scores and PAID score, respectively) will then be included as
further control variables.
According to the intent-to-treat principle all analyses will be conducted for the ITT
population. The analyses for safety population, randomized population and per protocol
population will be considered as secondary.
An exploratory subgroup analysis for type of diabetes will be employed for the primary
outcome. Therefore, the primary analysis will be repeated including an interaction term
of diabetes type and treatment group in the ANCOVA. Further covariates will be baseline
HbA1c and baseline HAMD score. For remission of depression from the end of the shortterm phase to the end of follow-up a logistic regression including an interaction term of
diabetes type and treatment group, baseline HbA1c and baseline HAMD score will be
performed, respectively. These analyses have to be considered exploratory.
Adherence to treatment will be displayed descriptively overall and for each treatment
group. Differences in adherence between both treatment groups will be analyzed using
chi-square tests. An exploratory subgroup analysis for adherence groups will be
employed for change in HbA1c from the end of short-term phase to the end of the followup. Therefore, an ANCOVA will be performed including an interaction term of adherence
group and treatment group. Further covariates will be HbA1c and HAMD score at the end

of the short-term phase. For remission of depression from the end of the short-term phase
to the end of follow-up a logistic regression including an interaction term of adherence
group and treatment group, HbA1c and HAMD score at the end of short-term phase will
be performed, respectively. These analyses have to be considered exploratory, as the
statistical power might not be sufficient.
Further exploratory secondary analyses will be performed such as the analysis, whether
improvement in depression shows a stronger association with better HbA1c in the CBT
group than in the on-going medication group; and, if this is the case, to test, if the degree
of diabetes self-care will increase more in the CBT group than in the on-going medication
group (see Additional file 6 Detailed statistical analysis plan).
Additional file 6. Detailed statistical analysis plan.
Format: PDF Size: 252KB Download file or display content in a new window
This file can be viewed with: Adobe Acrobat Reader
Quality assurance
Safety Differences between treatment groups regarding rates of adverse events such
newly emerging tendency will be displayed descriptively. Numbers and percentages of
adverse events and number and percentage of subjects with adverse events will be
presented for each occurring system organ class and for each preferred term within
system organ class by treatment group and with a total column. Additionally, this will be
done for relationship, intensity and seriousness of adverse events. The results will be
displayed for the safety population (see Additional file 5 Safety manual (in German);
and Definitions and assessment of adverse events).
Data management A data management plan (DMP) was established for the DAD study
to specify each data management process for the DAD trial. The purpose of the DMP is
to describe the underlying data management process which governs collection,
management, review and reporting of data from this clinical trial. The content of a DMP

includes, but is not limited to, trial timelines, data management procedures including data
collection and data flow and the Data Validation Plan. The DMP documents the
validation strategy and tools, and references responsibilities for different tasks. All data
management activities were performed according to the current Standard Operating
Procedures (SOPs) of the IZKS (see Additional file 7 Data management plan).
Additional file 7. Data management plan.
Format: PDF Size: 139KB Download file or display content in a new window
This file can be viewed with: Adobe Acrobat Reader
Monitoring Clinical on-site monitoring was performed by personal visits from a clinical
monitor according to SOPs of the IZKS. To initiate the study, the monitor visited each
participating local trial site and coordinating study centers. The monitors ensured that the
investigators and their staff understand all requirements of the protocol and their
regulatory responsibilities. Each site was visited by the monitor at regular intervals to
ensure compliance with the study protocol, GCP and legal aspects. The monitors
reviewed the entries into the Case Report Forms (CRF) on the basis of the source
documents. The presence of correct informed consents was checked for every patient.
Source document verification (SDV) was performed for 100% of core data
(randomization, primary endpoint and SAE) and 20% of other data in this study. Details
were specified in the monitoring manual for the DAD study. The investigators had to
allow the monitor to look at all relevant documents and were requested to provide support
at all times to the monitor. By frequent communications (letters, telephone, fax), the
monitors ensured that the trial was conducted according to the protocol and regulatory
requirements.
Advisory board An independent scientific advisory board was established to supervise
the conduct of the trial and to issue recommendations for early termination, modifications
or continuation of the trial, if necessary.
Members of the Advisory Board are:

Prof. Dr. Ulrich Hegerl, Clinic and Policlinic of Psychiatry and Psychotherapy of the
University of Leipzig, Germany.
Prof. Dr. Walter Lehmacher, (Institute for Medical Statistics, Informatics and
Epidemiology of the University of Cologne, Germany.
Prof. Dr. Martin Hautzinger, Eberhard-Karls-University, Institute of Psychology,
Department of Clinical and Developmental Psychology, Tuebingen, Germany.
Ethical aspects
The procedures set out in the trial protocol regarding the conduct, evaluation, and
documentation of this trial are designed to ensure that all persons involved in the trial
abide by Good Clinical Practice (GCP) and the ethical principles described in the current
revision of the Declaration of Helsinki. Clinical monitoring, data management,
pharmacovigilance, regulatory affairs and biometry according to GCP were conducted by
the IZKS Mainz. The trial was carried out in keeping with local legal and regulatory
requirements. The requirements of the AMG, the GCP regulation, and the Federal Data
Protection Law (BDSG) have been kept. The trial was approved by Medical Ethics
Committee Hessen (Ethikkommission der Landesrztekammer Hessen no. 2/2006) on
14/03/2006. The Federal Institute for Drugs and Medical Devices approved the trial on
17/03/2006. Three substantial amendments have been approved by both institutions in
August 2006, April 2007 and November 2008. All patients were in treatment, regularly
seen by diabetologists and psychologists. Before being admitted to the clinical trial, the
patients agreed to participate after the nature, scope, and possible consequences of the
trial have been explained in a form understandable to them. The patients gave written
informed consent and received a copy of the signed consent document. The documents
were in language that was understandable to the patients and specified who informed
them. During the trial, patients were identified solely by means of year of birth and an
individual identification code (patient number, randomization number).

Discussion
Despite the increasing number of studies evaluating treatment options for depression in
diabetes, the evidence for the identification of a single treatment, which could
significantly improve psychological outcomes and glycemic control at the same time
remains inconclusive [17,18]. Furthermore, as pointed out by Markowietz and colleagues
[60], most interventions were not designed to directly improve diabetes self-care and did
not evaluate effects on further outcome variables such as quality of life or remission of
depression. The current trial attempts to address these limitations by including only
patients with poor glycemic control (HbA1c>7.5%), developing a cognitive behavioral
therapy covering diabetes-specific aspects such as goal-setting to enhance diabetes-selfcare, and by assessment of further outcome variables such as remission of depression,
improvement in quality of life and reduction of diabetes-related distress. As was observed
in the most recent systematic review on this topic the quality of the trials in this field is
very heterogeneous and especially active comparison trials are rare [18]. Therefore, we
conducted this trial comparing for the first time the efficacy of a psychological treatment
to psychopharmacological treatment for depression in patients with depression with a
strong emphasis on sound methodology. Thus, we think that the DAD study will add
important knowledge to the field of depression treatment in diabetes.
Status of the trial
The trial commenced in April 2006, and patient recruitment was completed in May 2009,
resulting in a sample of 251 randomized patients. After reaching the calculated sample
size of 230 patients, all patients already under screening have been randomized
additionally. Currently we are in the analysis phase.

Competing interests
The authors declare that they have no competing interests.

Authors contributions

FP principal investigator (PI), MJM coordinating investigator, KK clinical trialist, CR


biometrician. Significant contribution to the development of the study design and
methods: FP, SH, NH, CH, KK; JK, BK, CR, MJM; Writing of the manuscript. FP. All
co-authors read, edited, and approved the final manuscript. Responsibility for the
coordination, recruitment and treatment in the coordinating regional trial centers: FP, SH,
CA, NH, WH, KK, JK, BK. All authors participated in the work sufficiently to take
public responsibility for their respective parts of the paper. Significant contribution to
biometrics: CR, FP, MJM. Significant contribution to monitoring and quality assurance of
the trial: KK, FP, MJM.

Acknowledgments
The authors would like to thank all patients for their participation in the DAD trial.
Furthermore, we thank the diabetologists and physicians of the diabetological trial
centers: Heinke Adamczewski, Marcus Altmeier, Bernhard Angelkort, Payam
Ardjomand, Holger Arndt, Klaus Badenhoop, Alain Barakat, Bernd Becker, Ulla BehlenWilm, Peter Berndt, Rainer Betzholz, Ralph Bierwirth, Matthias Boehme, Stephan
Bonnermann, Birgit Bttger, Marion Braun, Helga Bcker, Klaus Busch, Frank
Demtroeder, Andreas Derstroff, Iris Donati-Hirsch, Michael Enghofer, Berthold Fohr,
Lutz Fricke, Dirk Gckler, Gudrun Geier, Kai Gtte, Rudolf Groddeck, Martin
Grneberg, Eva Haak, Jrgen Haak, Hubertus Halfas, Wolfgang Hauth, Dorothea Herber,
Karl-Heinz Herber, Eva Hess, Gregor Hess, Gangolf Heussen, Thomas Hipp, Michael
Huptas, Sabine Jkel, Jerzy Jasinski, Cornelia Jaursch-Hancke, Jutta Kalfhaus, Matthias
Kaltheuner, Hans-Thomas Kapp, Hans-Peter Kempe, Hans-Jrgen Kissing, Gerhard
Klausmann, Dieter Klein, Guido Klempt, Werner Kleophas, Beate Korth-Wiemann,
Klaus-Peter Kreisselmeier, Georg Krmer, Klaus Kusterer, Michael Lang, Alice Lange,
Karin Langer, Claudia Leyer, Matthias Leyer, Eckart Lohr, Babette Lorra, Georg Marqua,
Stephan Maxeiner, Frank Merfort, Gesine Meyer, Kathrin Meyer, Angela Minor, Iris
Mitschka, Hansjrg Mhlen, Udo Mller, Dieter Neus, Ulrich Nhlen, Erika-Maria
Oerter, Ursula Ohndorf, Manfred Plum, Uwe Preu, Beate Quadbeck, Wilhelm

Redenbach, Konrad Reimann, Bernadette Reinsch, Alexander Risse, Stefan Rothfritz,


Emilia Ruff, Stephanie Rupprecht, Heinz-J Rmann, Nikolaus Scheper, Michael Schilp,
Manfred Schlotmann, Lothar Schramm, Benno Schulze-Schleppinghoff, Michael
Simonsohn, Wilfried Sobbe, Klemens Sondern, Michael Stammen, Eugen Steffens, Lutz
Stemler, Werner Strmer, Martin Sulliga, Claudia Ulbrich, Simon Vidal, Christian von
Boxberg, Simone von Haag, Ernst-Otto von Reis, Georg Weber, Matthias Weber,
Friedrich Worth, Josef Zimmermann; and the participating psychiatrists and the
physicians specialized in psychosomatic medicine (Christian Albus, Wolf Bresges,
Stephan Herpertz, Johannes Kruse, Matthias J Mller, Alexander Niecke, and Bernd
Sonntag). We also thank the psychologists in the coordinating trial centers, who helped in
the development of the trial design, patient recruitment and trial conduct: Claudia
Baxmann, Isabel Bengesser, Andrea Bennecke, Norbert Hermanns, Sophie Janssen,
Bernhard Kulzer, Mareike Kpper, Beatrix Lehnhoff, Ulrike Lw, Maria Nigro, Esther
Petermann, Frank Petrak, Kristin Plack, Kathrin Post, Monika Renvert, Anna Rodriguez
Rubio, Nadine Rund, Heike Sager, Christopher Scheff, Barbara Schmidt, Sylvia Schmidt,
Katharina Schnitzler, Sabine Wagner, Daniela Zahn, Assad Zahran, and Kathrin Zoubek.
We are indebted to Petra Birkner, Veronika Brill, Anne Ehrlich, Olivia Endress, Peter
Friedrich-Mai, Jana Heuer, Petra Krensel, Kai Kronfeld, Rolf Meinert, Kornelia Pfeiffer,
Christina Reck, Christian Ruckes, Daniel Wachtlin and Sabine Wolf, Interdisciplinary
Centre of Clinical Studies (IZKS) Mainz for clinical monitoring, pharmacovigilance,
regulatory affairs, data management and biometry. We also thank for the contributions of
the DAD trial scientific advisory board (Martin Hautzinger, Ulrich Hegerl and Walter
Lehmacher). We would like to acknowledge the technical staff of the Neurochemical
Laboratory, Department of Psychiatry, Johannes Gutenberg University Mainz, for the
analysis of sertraline concentrations and Monika Winter and her co-workers, Bioscientia
Ingelheim, for the laboratory analysis of endocrinologic parameters.

Funding

This work was supported by the Kompetenznetz Diabetes mellitus (Competence


Network for Diabetes mellitus) funded by the Federal Ministry of Education and
Research (No. 01KG0505).

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PubMed Central Full Text
2

High prevalence of diagnosis of diabetes,


depression, anxiety, hypertension,
asthma and COPD in the total
population of Stockholm, Sweden a
challenge for public health
Axel C Carlsson12*, Per Wndell1, Urban sby34, Ramin Zarrinkoub15, Bjrn
Wettermark56 and Gunnar Ljunggren57

* Corresponding author: Axel C Carlsson axelcefam@hotmail.com

Author Affiliations
1

Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society,
Karolinska Institutet, Alfred Nobels All 12, 141 83 Huddinge, Sweden
2

Department of Public Health and Caring Sciences/ Section of Geriatrics, Uppsala


University, Uppsala, Sweden

Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska


Institutet, Solna, Sweden
4

Department of Psychiatry, Tiohundra AB, Norrtlje, Sweden

Public Healthcare Services Committee Administration, Stockholm County Council, Box


6909, SE- 102 39 Stockholm, Sweden
6

Centre for Pharmacoepidemiology and Department of Laboratory Medicine, Division of


Clinical Pharmacology, Karolinska University Hospital, Huddinge, Sweden
7

Medical Management Centre, Department of Learning, Informatics, Management and


Ethics, Karolinska Institutet, Berzelius vg 3, SE-17177 Stockholm, Sweden
For all author emails, please log on.
BMC Public Health 2013, 13:670 doi:10.1186/1471-2458-13-670

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-2458/13/670
22 October
2012
Accepted: 1 July 2013
Published: 18 July 2013
Received:

2013 Carlsson et al.; licensee BioMed Central Ltd.


This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
There is limited knowledge on the prevalence of disease in total populations. Such studies
have historically been difficult to conduct but the development of health data registers has
facilitated large-scale studies on recorded diagnoses in entire regions. The aim of this

study was to analyze the prevalence of diagnosis of six common diseases in the Swedish
capital region.
Methods
The study population included all living persons who resided in Stockholm County,
Sweden, on December 31st 2011 (N=2 093 717). Information on all consultations
between 2007 and 2011 was obtained from primary health care, specialist outpatient care
and inpatient care. Prevalence was defined as the proportion of individuals with a
recorded diagnosis of diabetes, depression, anxiety disorders, hypertension, asthma and
chronic obstructive pulmonary disease during the five year period, respectively. Analyses
were done by age and gender.
Results
Hypertension had the highest five-year prevalence (12.2%), followed by depression
(6.6%), diabetes mellitus (6.2%), asthma (5.9%), anxiety disorders/phobia (4.8%), and
COPD (1.8%). Diabetes was more common in men (5.3% of women and 7.1% of men)
while depression (8.7% in women and 4.4% in men) and anxiety (6.3% in women and
3.4% in men) were considerably more common in women. Smaller gender differences
were also found for hypertension (13.0% in women and 11.4% in men), asthma (6.4% in
women and 5.4% in men) and COPD (2.1% in women and 1.6% in men). Diabetes,
hypertension and COPD increased markedly with age, whereas anxiety, depression and
asthma were fairly constant in individuals above 18 years. During one year of
observation, more than half of all patients had only been diagnosed in primary health
care, with hypertension being the diagnosis with the largest proportion of patients only
identified in primary health care (70.6%).
Conclusion
The prevalence of common diseases in the population can be estimated by combining
data gathered during consecutive years from primary care, specialist outpatient care and
inpatient care. However, accuracy of disease prevalence is highly dependent on the

quality of the data. The high prevalence of the six diagnoses analysed in this study calls
for preventive action to minimize suffering and costs to society.

Keywords:
Administrative databases; Primary care; Gender differences; Age differences;
Epidemiology

Background
Epidemiological data on the prevalence and incidence of diseases are valuable for making
policy decisions and promoting evidence-based disease prevention and management.
Prevalence can be assessed in several ways [1]. First, by self-reported presence of
diseases, which may contain several uncertainties and result in different validity
depending on the studied diagnosis. Second, by using or combining healthcare source
data based on diagnosis records or on drug prescriptions but where individuals without
prescribed drugs will be lost. Third, by the use of two or more data sources which could
be combined by capturerecapture methods. Fourth, by population-based screenings
which will identify new cases but will have lower validity in studies with low
participation rates.
The establishment of the Swedish Hospital Discharge Register in 1964 has facilitated
studies on the prevalence of diseases that require hospitalization [2,3]. The Swedish
Hospital Discharge Register includes all hospitalizations from 1987 onwards as well as
all outpatient consultations in hospitals from 2001 onwards. A number of studies using
this register have showed that the quality of its data is high and the register has been
widely used in many outcome studies [4,5].
In recent years, the development of electronic medical records and administrative
databases has facilitated studies on the prevalence and incidence of diseases in the total
population of different regions [6,7]. The main advantages of these registers are their full
coverage of healthcare consultations and that they are relatively easy and inexpensive to

use. Disadvantages include possible bias in recording of diagnoses and variability in data
quality [8].
In Stockholm County, with a total population of more than two million people, all
diagnosis codes and reasons for hospitalizations and consultations in primary health care
and specialist care are recorded and stored in a large administrative database. This
comprehensive data collection enables epidemiological research in a large unselected
population cohort. The primary aim of this study was to use these data to estimate the
prevalence of six common diagnoses, namely diabetes mellitus, depression, anxiety
disorders, hypertension, asthma, and chronic obstructive pulmonary disease (COPD) in
the total population of Stockholm County. Furthermore, the distribution of these
diagnoses across the different sectors of the healthcare system, i.e. primary health care
(PC), specialist outpatient care (SOC) and inpatient care (IC), recorded during the last
year of observation, 2011, was also determined.

Methods
Stockholm County has 2.1 million inhabitants, representing more than one-fifth of
Swedens entire population. This area of Sweden includes the capital city of Stockholm
and several other cities and towns, as well as large rural areas and a sparsely-populated
archipelago. The Stockholm County Council is responsible for financing primary and
secondary health care, mainly through taxes. Besides illegal immigrants, the general
health insurance covers all residents. The majority of services are provided by Countyowned facilities. However, during the last decade, more than 50% of primary care and
approximately 8% of acute hospital care services have been outsourced to private
providers, either through tender processes or managed patient choice [9]. Private
providers are in contractual agreements with the County and are legally obliged to record
diagnoses and file reports to the authorities just like public providers [10]. With the
exception of very few private clinics that operate without subsidies in Stockholm, all
consultations and diagnoses are recorded and stored in the so-called VAL, a central
database. Besides consultations and diagnoses, VAL compiles and stores data on

healthcare utilization and socio-demographics. The database has been used for healthcare
planning, practice remuneration and quality assessment since the beginning of the 1980s,
and its content, registration routines, and supporting software have improved over the
years. It has previously been used as a source of information in a number of scientific
studies, e.g. studies of hip fractures and its co-morbidities [11,12], and Parkinsons
disease [13]. As an indication for its accuracy and validity, VAL is used by the Council
for updating the National Patient Register kept by the Swedish National Board of Health
and Welfare (NBHW) as well as the annual benchmarking reports of the NBWH and the
Swedish Association of Local Authorities and Regions [4].
VAL has more than 99% coverage of hospital care. More specifically, for each hospital
stay the VAL database contains a record of the provider unit, an encrypted patient
identification number, age and sex, the type and length of the stay, up to ten diagnoses
given, and ten interventions (primarily surgical procedures, transfusions, anaesthetic
procedures). Since 1997, diagnoses have been coded according to WHOs International
Classification of Diseases, 10th edition (ICD-10) and procedures classified according to
the Nordic Classification of Surgical Procedures (NCSP).
Reporting utilization in specialized ambulatory care, whether in hospital clinics or other
locations, is also mandatory since the late 1990s. This includes reporting diagnoses (up to
eight) for consultations by a physician, date, type of visit, and certain procedures
performed. Also, nurse visits in homecare, visits to occupational or physical therapists as
well as most other healthcare professionals are registered. VAL has more than 90%
coverage of utilization in specialized ambulatory care.
Storing data on primary care diagnoses in VAL has a shorter history. In 2003, a project to
extract information on diagnoses (up to 15) from the electronic medical records, when
available, was launched. It has been estimated that approximately 85% of all diagnoses in
primary care are stored in VAL.
All data extracted from VAL were anonymised in the current study.

Ethics
All data we handled were anonymized and none of the numbers presented could be traced
back to any individual. Management and analysis based on the VAL database is a part of
continuous quality control of healthcare utilization in Stockholm county council.
Research projects deemed as quality control are not subject to ethical research board
decisions in Sweden.
Study population
The present study population included all living persons who resided in Stockholm
County on December 31st 2011 (N=2 093 717). Demography of Stockholm County and
number of doctor visits per person in 2011 are shown in Table 1. Residents who died or
moved from the region during the five-year period of interest (20072011) were
excluded. Data on all healthcare consultations in PC, SOC and IC between 2007 and
2011 were extracted from VAL.
Table 1. The demography and number of doctor visits in Stockholm county as of
December 31, 2011
Major diagnosis groups
The following ICD codes were used to define each major diagnosis group: diabetes
mellitus E10-E14, depression F32-F33, anxiety disorders F40-F41, hypertension I10-I15,
asthma J45-J46, and chronic pulmonary respiratory disease (COPD) J41-J44, J47. The
five-year prevalence of each diagnosis was calculated by dividing the number of persons
with any of the diagnosis groups recorded at least once between January 1st 2007 and
December 31st 2011 with the total population number as for December 31st 2011. In a
similar fashion, one-year prevalence of each diagnosis (2011) was calculated by dividing
the number of persons with any of the diagnosis groups recorded at least once during
2011 with the total population number. The one-year- and five-year prevalence figures
may be viewed as a period prevalence, especially for depression, and anxiety disorders.
Statistical methods

Standard descriptive statistics such as numbers and percentages out of the total
population (N) were used. Prevalence was presented as total/overall and was also
stratified by age and sex. Statistical analysis and data management was performed using
SAS software, version 9.3 (SAS Institute Inc., Cary, NC).

Results
Demography of Stockholm county
The population of Stockholm county was younger than in the rest of the country, with
only 14.2% of the population being 65 years of age and older, and as many as 38.9% in
the age group 1844 years (Table 1).
Prevalence of diagnosed diabetes mellitus
In total, 5.3% of women and 7.1% of men in Stockholm were diagnosed with diabetes
during the five-year period as shown in Table 2A. The highest prevalence was found
among persons aged 7584 years, 23.1% among women and 31.9% among men. In total,
56% of all patients identified with a diabetes diagnosis during a five-year period were
diagnosed during the last year of observation, 2011.
Table 2. The prevalence and the percentage in the population (Dec. 2011) of six
diagnosis groups in 20072011 in men, women and all inhabitants (total) in
Stockholm county by age: A) diabetes mellitus (E10-E14), B) depression (F32-F33),
C) anxiety disorders/phobia (F40-F41) D) hypertension (I10-I15), E) asthma and F)
(J45-J46) chronic obstructive pulmonary disease (COPD) (J41-J44, J47)
Prevalence of diagnosed depression
With the exception of children and adolescents (aged 017 years) where few were
diagnosed (0.18%), a diagnosis of depression was common across all age groups in both
men and women as shown in Table 2B. The highest five-year period prevalence of
diagnosed depression was found among women aged between 4564 years (12.7%) and
men aged 85 years and older (10.8%). In total, 37% of all patients identified with a

depression diagnosis during a five-year period were diagnosed during the last year of
observation, 2011.
Prevalence of diagnosed anxiety disorders / phobia
More women than men were diagnosed with anxiety (6.3% vs. 3.4%) as shown in
Table 2C. The highest prevalence was found among individuals aged between 18
44 years. When stratified by sex, 8.6% of women and 4.6% of men were diagnosed of
anxiety/phobia recorded. In total, 40% of all patients identified with an anxiety/phobia
diagnosis during a five-year period were diagnosed during the last year of observation,
2011.
Prevalence of diagnosed hypertension
As shown in Table 2D, 13.0% of women and 11.4% of men in Stockholm a hypertension
diagnosis was recorded. An increase in diagnosed hypertension with advancing age,
ranging between 0.05% in children and 63.5% in those aged 85 years and older was seen.
Overall, hypertension was more common in women than men. In total, 58% of all
patients identified with a hypertension diagnosis during a five-year period were
diagnosed during the last year of observation, 2011.
Prevalence of diagnosed asthma
As shown in Table 2E, diagnosed asthma was equally common in men and women (6.4%
vs 5.4%) and most prevalent in children (9.6%). In total, 37% of all patients identified
with a asthma diagnosis during a five-year period were diagnosed during the last year of
observation, 2011.
Prevalence of diagnosed COPD
Diagnosed COPD was more prevalent among persons aged 45 years and older with the
highest prevalence in men and women aged between 7584 years (10.1%) as shown in
Table 2F. In total, 50% of all patients identified with a COPD diagnosis during a five-year
period were diagnosed during the last year of observation, 2011.

Distribution of diagnoses recorded across different sectors of the healthcare system


The proportion of patients diagnosed with diabetes, depression, anxiety disorders,
hypertension, asthma and COPD in PC, SOC, and/or IC during 2011 varied depending on
the diagnosis group. A majority of the patients in all six diagnosis groups were only
identified in only PC, with depression (56.5%) and hypertension (70.6%) being the most
commonly recorded diagnoses in PC followed by diabetes mellitus (56.1%), asthma
(55.9%), COPD (53.6%), and anxiety/phobia (51.6%). When comparisons in the
distribution of all six diagnosis groups only in SOC were made, COPD was the most
commonly recorded diagnosis (33.8%). In IC, COPD was the most common diagnosis
recorded of the six (15%). It was uncommon to have a diagnosis recorded in all three
health care sectors. Figures showing the distribution of diagnoses recorded in PC, SOC
and IC can be viewed, Additional file 1: Figure S1.
Additional file 1: Figure S1. Wenn diagrams of reported diagnoses: A) diabetes, C)
depression, D) anxiety/phobia, E) hypertension F) asthma, and G) COPD. Primary care=
PC, Specialist outpatient care=SOC, Inpatient care=IC.
Format: DOC Size: 128KB Download file or display content in a new window
This file can be viewed with: Microsoft Word Viewer

Discussion
The current study estimates prevalence of diagnosed common diseases in the total
population in Stockholm County, a region with more than 2 million inhabitants, using
recorded diagnoses in regional registers. The high prevalence of the six common
diagnosis groups reported in this study calls for preventive action to be taken. Still, there
may be people who are not yet diagnosed and population based health assessments have
yielded individuals with newly diagnosed hypertension and diabetes [1,14]. With more
than 30% of men and 20% of women aged between 7584 years being diagnosed with
diabetes during a five-year period, considerable amounts of health care resources will be
needed. In addition, with 55% of all men and women in this age-group being diagnosed
with hypertension, a considerable burden could be expected as this group would likely

develop cardiovascular complications. The large amounts of younger patients diagnosed


with these conditions, subsequently developing complications, may also pose a challenge
for the future.
The fact that the population is large enables stratification by sex and age. Bearing in mind
that approximately 20% of the inhabitants of Stockholm County are immigrants [15], the
prevalence of common diseases in an urban population of a Western country can be used
as a proxy for the prevalence of these diagnosed diseases in similar populations of other
regions or countries.
The overall prevalence of diagnosed COPD was 1.8%, which was higher than a previous
study of COPD prevalence in a population living in a rural region of Sweden (1.2%) that
had a similar design [7]. The difference in prevalence could be due to more particles in
the air in Stockholm, higher proportion of smokers or a higher awareness of COPD in
recent years. Prevalence of diagnosed COPD increased dramatically among persons aged
between 4584 years whereas it decreased among persons aged 85 years and over which
may be explained by the effect of smoking on longevity [16]. The opposite was observed
for the prevalence of anxiety /phobia which was high in young adults aged between 18
44 years (6.6%). A recent Swedish study, where a population based sample of 75-year-old
persons was interviewed over a period of one month, reported that 3.7% had generalized
anxiety disorder according to ICD-10 [17], which is consistent with the five-year
prevalence of 4.2% among persons aged between 6574 years of the total population of
Stockholm County reported in this study. Another Swedish study reported that as much as
24% of the Swedish population aged 2064 years fulfilled the criteria for anxiety and/or
depression [18].
Diabetes is often regarded as equally common among men and women, although a male
preponderance has been observed in those aged 45 years and over [19]. Wirehn et al.
(2007) found an overall male preponderance in diagnosed diabetes prevalence (4.6% in
men vs 4.1% in women) [7] while in the current study an even larger male predominance

in diagnosed diabetes prevalence was found (7.1% in men vs 5.3% in women). In a


review (2001), Gale and Gillespie concluded that men may be more susceptible to
physical inactivity and obesity than are women [20]. Overall prevalence of diagnosed
diabetes was higher in the current study (6.2%) than in earlier studies in Sweden (4.5%)
[7,21]. One explanation for the discrepancy may be the higher rate of immigrants living
in Stockholm County [22]. A population-based study has shown that two thirds of the 60year old diabetes patients are known [15].
The five-year period prevalence of diagnosed depression was high among adults, ranging
between 9.0% and 12.2% in women and between 4.7 and 7.9% in men. The higher
prevalence of depression among women than among men has been reported previously
[23], and may be due to that women may be more active in seeking health care when they
experience depressive symptoms. Also, the prevalence of diagnosed depression was
lower among individuals younger than 65 years of age than those aged between 65
74 years which may be explained by lack of incentive to be sick-listed in the years
following retirement. Persons with depression have been shown to have a higher risk for
somatic diseases than non-depressed individuals [24], which may have had an effect on
the diagnosed prevalence of all diagnosis groups in women in this study.
Studies of hypertension in the US have shown that the prevalence in the adult population
(18 years of age and over) was nearly 30% [25,26], which was higher than that we
reported in this study (12.2%) implying there may be a large number of undiagnosed
individuals in the total population of Stockholm County. This is in agreement with a
screening study of 60 year-old persons from Stockholm which showed that newly
diagnosed hypertension was more prevalent than already diagnosed hypertension [14].
The prevalence of hypertension is highly dependent on age [27], which was consistent
with our findings. It has been previously shown that prevalence of hypertension is lower
in women than in men until menopause, after which prevalence increases and reach levels
observed in men [28,29]. Large scale population-based investigations are, however, still
sparse and the true prevalence in the population is therefore not fully known, making the

findings of the current valuable. Moreover, hypertension awareness, treatment and


control vary greatly in different studies from around the world [30], and in populations of
different countries studied following the same methodology [31].
In contrast to the other diagnosis groups, asthma appeared to affect children the most.
Furthermore, diagnosed asthma was more common in boys than in girls and in women
than men. The prevalence rates and gender differences are consistent with a recent review
estimating the overall prevalence of asthma at 5-7% in the total population and 8-10% in
children [32]. Previous studies have also shown that women with asthma seek care more
often than do men [33,34]. Asthma in children is often associated with rhinitis and
eczema as well. The BAMSE birth cohort reported that 58% of 12 year-old children had
one, two or all these three conditions at some time [35].
Our study revealed important information on the prevalence of diagnosed common
diseases in the population. It could be useful for the planning of healthcare needs,
resource allocation and disease prevention. Access to electronic longitudinal data from
primary healthcare may also provide unique opportunities for performing post-marketing
comparative effectiveness research [2]. Some benefits include availability of large
populations at a relatively low cost and shortening the time necessary to identify a
sufficient number of patients with a specific diagnosed disease. They may also enable
studies of patient groups that are usually omitted from randomized controlled trials, i.e.
patients with co-morbidities [36]. Recently, prescription data on individuals, using the
same encrypted identification numbers as data from VAL, have been added to the
database. This enables a unique possibility to link drug prescriptions to diagnoses and
patient outcome.
It is important to emphasize that the frequency and diagnosis coverage may vary between
different physicians, primary health care centres and diagnosis group [37]. Additionally,
the reporting of diagnoses may change along with changes in the healthcare
reimbursement system, however, no major changes occurred in the region during the

course of this study. To achieve better prevalence estimates, data from PC, SOC and IC
could be used together and from consecutive years [7]. The applicability of our method
may also vary between different settings. Health care systems vary widely across
different regions and countries. More patients in Stockholm receive their care from
specialists other than GPs, due to an proportionally smaller primary care sector compared
with the UK [38].
Inclusion of only those who were alive at the end of the study period has likely
introduced a survival bias as individuals who died during the five-year period were likely
to have used considerably more healthcare resources than average. Consequently, the
prevalence of diseases that are common among older persons, such as COPD, may have
been underestimated. However, this is not a problem if the data are interpreted as point
prevalences.
Most of the conditions encountered in PC are readily treatable, for example acute
infections and inflammatory conditions, whereas others are chronic or relapsing and often
non-acute such as diabetes mellitus, depression, anxiety disorders, hypertension, asthma,
and chronic obstructive pulmonary disease (COPD). The diagnostic accuracy may also
vary, depending on the disorder and the diagnostic criteria applied. For diabetes, highly
valid diagnostic criteria make the disease easy to identify [39]. In the current study we
did not make a distinction between Type I and Type II diabetes, as one of the most
commonly used diagnosis codes in primary care is diabetes mellitus not otherwise
specified. However, it is well known than Type II diabetes is more prevalent than Type I
diabetes. While data on asthma, hypertension and diabetes diagnoses the diagnostic
accuracy could be expected to be of high validity, data on COPD, anxiety/phobia, and
depression may not be as straightforward.
Stockholm County has seen more people moving in than moving out. Consequently, a
slight underestimation in prevalence of the diagnostic groups may be expected as new
inhabitants may have not yet lived in Stockholm long enough to have diagnoses recorded

during the five-year period of interest. This may hold true for individuals aged between
1844 years. However, this effect may have been balanced out by excluding those who
died during the same period.

Conclusion
In conclusion, the prevalence of known and diagnosed diseases can be estimated using
administrative health data registers. Whether a diagnosis is evaluated and recorded in
primary care, specialist outpatient care or inpatient care, the diagnosed prevalence
estimates are highly dependent on the quality of the diagnosis. It takes further validation
studies to investigate if there are great discrepancies in diagnosis accuracy between
different levels of care, and how that influences our overall knowledge of the existence of
various patient groups. The high prevalence of the six diagnoses analysed in this study
calls for preventive action to be taken to minimize suffering and costs to society.

Competing interests
The authors of this manuscript have no conflict of interest to disclose.

Authors contributions
GL researched data, edited manuscript, contributed to discussion, ACC wrote manuscript,
researched data, contributed to discussion. PW, BW, RZ, and U edited manuscript,
contributed to discussion. All authors read and approved the final manuscript.

Funding
This work was supported by the Stockholm County Council.

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3

Depression, anxiety and stress symptoms


among diabetics in Malaysia: a cross
sectional study in an urban primary
care setting

Gurpreet Kaur1*, Guat Hiong Tee1, Suthahar Ariaratnam2, Ambigga S


Krishnapillai2 and Karuthan China3

* Corresponding author: Gurpreet Kaur dr.gurpreet@iku.moh.gov.my

Author Affiliations
1

Institute for Public Health, Ministry of Health, Jalan Bangsar, Kuala Lumpur, 50590,
Malaysia
2

Faculty of Medicine, Universiti Teknologi MARA, Selayang Campus, Jalan Prima


Selayang 7, Batu Caves, Selangor, 68100, Malaysia
3

Department of Social and Preventive Medicine, University of Malaya, Kuala Lumpur,


50603, Malaysia
For all author emails, please log on.
BMC Family Practice 2013, 14:69 doi:10.1186/1471-2296-14-69

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-2296/14/69
22 February
2013
Accepted: 22 May 2013
Published: 27 May 2013
Received:

2013 Kaur et al.; licensee BioMed Central Ltd.


This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
Diabetes mellitus is a highly prevalent condition in Malaysia, increasing from 11.6% in
2006 to 15.2% in 2011 among individuals 18 years and above. Co-morbid depression in

diabetics is associated with hyperglycemia, diabetic complications and increased health


care costs. The aims of this study are to determine the prevalence and predictors of
depression, anxiety and stress symptoms in Type II diabetics attending government
primary care facilities in the urban area of Klang Valley, Malaysia.
Methods
The study was cross sectional in design and carried out in 12 randomly selected primary
care government clinics in the Klang Valley, Malaysia. A total of 2508 eligible consenting
respondents participated in the study. The Depression, Anxiety and Stress Scale (DASS)
21 questionnaire was used to measure depression, anxiety and stress symptoms. Data was
analyzed using the SPSS version 16 software using both descriptive and inferential
statistics.
Results
The prevalence of depression, anxiety and stress symptoms among Type II diabetics were
11.5%, 30.5% and 12.5% respectively. Using multiple logistic regression, females, Asian
Indians, marital status (never married, divorced/widowed/separated), a family history of
psychiatric illness, less than 2 years duration of diabetes and current alcohol consumption
were found to be significant predictors of depression. For anxiety, unemployment,
housewives, HbA1c level of more than 8.5%, a family history of psychiatric illness, life
events and lack of physical activity were independent risk factors. Stress was
significantly associated with females, HbA1c level of more than 8.5%, presence of comorbidity, a family history of psychiatric illness, life events and current alcohol
consumption. For depression (adjusted OR 2.8, 95% CI 1.1; 7.0), anxiety (adjusted OR
2.4, 95% CI 1.1;5.5) and stress (adjusted OR 4.2, 95% CI 1.8; 9.8), a family history of
psychiatric illness was the strongest predictor.
Conclusion
We found the prevalence of depression, anxiety and stress symptoms to be high among
Type II diabetics, with almost a third being classified as anxious. Screening of high risk

Type II diabetics for depression, anxiety and stress symptoms in the primary care setting
is recommended at regular intervals.

Keywords:
Depression; Anxiety; Stress; Prevalence; Predictors; Diabetes; Outpatients;
Urban; Malaysia

Background
Diabetes and depression are two of the commonest public health problems affecting
people all over the world. About 220 million people are estimated to be suffering from
diabetes, majority of the burden being in low and middle income countries (LMIC) [1].
Diabetes is also responsible for about 1.256 million deaths globally in 2008, with most
deaths occurring in LMIC. Unipolar depressive disorders and diabetes were ranked 3rd
and 19th respectively as leading causes of disability adjusted life years (DALYs) in 2004.
The former also being the leading cause of years lost due to disability (YLD). Unipolar
depressive disorders are in fact projected to be the leading cause of disease burden by
2030.
In Malaysia, a middle income country, the prevalence of diabetes has increased in the last
decade from 5.7% to 9.5% among individuals aged 30 years and above [2] and from
11.6% in 2006 to 15.2% in 2011 among individuals 18 years and older[3]. Of the
estimated 2.6 million diabetics in Malaysia, about 715,550 (27.5%) diabetics are
originating from the most populous regions in Malaysia namely the state of Selangor and
the Federal Territory of Kuala Lumpur [3]. In terms of leading causes of total YLD, the
Malaysian National Burden of Disease and Injury Study 2004 ranked diabetes mellitus as
the third leading cause in both males (6.0%) and females (7.2%) respectively, while
unipolar major depression was ranked as second and top most leading cause in males
(7.2%) and females (12.7%) respectively [4].
It is well recognized that many individuals with chronic illnesses also have co-morbid
unrecognized mental health disorders [5]. The International Federation of Diabetes has

stressed the importance of integrating psychological care in the management of diabetes


[6].
It has been estimated that the risk of getting depression in the general population is 1025% in females and 5 12% in males. For individuals with chronic illnesses, the risk is
higher at 25 33% [7]. Studies have shown that diabetics have a higher prevalence of
depression than non-diabetic populations [8-10]. Globally, an estimated 43 million
diabetics have symptoms of depression [5]. Also, diabetes is associated with anxiety
disorders [11]. Being diagnosed with diabetes is a life stressor by itself. It requires a large
number of physical and mental accommodations. Depression adds to the burden of
managing diabetes. Furthermore, health care utilization and costs [12-14] increase with
the coexistence of diabetes and major depression.
Depression and anxiety are associated with hyperglycemia [15-17]. While depression is
associated with diabetes complications [18,19] and increased functional disability
[20,21]. Co-morbid depression has also been shown to be associated with poor adherence
to diabetes medication and dietary regimens [16,22,23] and reduced quality of life
[24,25]. Several studies have shown the risk of mortality to be increased by depression
[26-29]. The PROSPECT trial has shown that the five year risk of mortality was reduced
with a depression management care program among diabetics compared to similar
patients with usual care practices [30].
In Malaysia, there is paucity of epidemiological estimates on the prevalence,
characterization and risk factors of depression, anxiety and stress among diabetics. An
estimate of the prevalence of these conditions is the first step towards priority setting and
the planning, implementation and evaluation of a depression management intervention
program in diabetes care in the primary care setting. This study was carried out with the
aims of determining the prevalence of depression, anxiety and stress, and its predictors
among Type II diabetic outpatients attending government primary care clinics in the
Klang Valley.

Methods
This was a cross sectional study carried out in 12 selected government primary care
clinics located in the Klang Valley.
Study location
The Klang Valley generally refers to the urban areas of Kuala Lumpur, its suburbs and
adjoining areas in the state of Selangor. To the North and East, it is demarcated by the
Titiwangsa Mountain range, while to the West by the Straits of Malacca. The estimated
population of the Klang Valley is 7.5 million [31]. The two federal territories of Kuala
Lumpur and Putrajaya as well as five districts from the state of Selangor (Sepang, Hulu
Langat, Gombak, Klang and Petaling) were included in the study. In each of these
localities the number of clinics ranged from 1 to 13 with a total of 45 clinics.
Sample size and sampling
Sample size was calculated using both the population survey method for prevalence and
for comparing two proportions using the Sample Size Calculator for Prevalence Studies
[32] and the PS Software [33] respectively. The larger minimum sample size required
based on both these methods was taken as the sample size for the whole study. Based on
80% study power, Type I error of 0.05, design effect of 2, a difference of 8% in two
groups and a non-response of 20%, a sample size of 2261 was required.
For sampling, a two stage stratified sampling technique was employed. About 25% of the
total number of clinics from each locality (with a minimum of one clinic) was randomly
selected, giving a total of 12 clinics from the study area. The sample size was then
proportionately distributed based on the number of clinics selected from each locality.
For three localities where only one single clinic was selected, the minimum sample size
was increased to at least 250 to enable clinic level analyses in future. The final minimum
sample size for the study was 2446.
Study procedure

All patients attending the diabetic clinics during the study period were screened for
eligibility to participate. The inclusion criteria were age 30 years and above, having Type
II diabetes of at least six months (verified with medical records) and being literate in
Malay (which is the official language of the country) or English. Patients with a known
medically diagnosed psychiatric illness in the past (verified with medical records) or with
any form of cognitive impairment such as dementia or mental retardation and females in
the post-partum period were excluded. Eligible patients were then approached for written
consent for the study. Prior to obtaining consent, all potential respondents were explained
about the purpose of the study and the relevant procedures involved. They were assured
that their blood results would be notified eventually to their attending physician.
Subsequently, only consenting patients were recruited in the study.
Ethical issues
Ethical approval for the study was obtained from the Medical Research Ethics
Committee, Ministry of Health Malaysia (NIHSEC 08/0809/P09). Permission to conduct
the study was also obtained from the State Health Directors as well as Medical and
Health Officers in charge of the selected clinics prior to the study.
Data collection tools and measurements
Socio-demographic and other relevant information were collected by five trained
interviewers via face-to-face interview. Depression, anxiety and stress symptoms were
measured using a self-administered short version of the Depression, Anxiety and Stress
Scale (DASS), i.e., DASS 21 (Additional file 1: DAS S 21). The short version has 21
items which are divided into 7 items each assessing the symptoms of depression, anxiety
and stress respectively. The DASS has been shown to have high internal consistency. The
validated Malay or Bahasa Malaysia version of DASS 21 was used in this study [34].
Respondents were asked to rate their experience on each symptom over the past week on
a 4-point severity scale ranging from 0 (does not apply to me), to 3 (applies to me most or

all of the time). Scores for each scale were later summed up and categorized as normal,
mild, moderate, severe and extremely severe according to the DASS Manual [35].
Additional file 1. DAS S 21.
Format: DOC Size: 41KB Download file or display content in a new window
This file can be viewed with: Microsoft Word Viewer
The following anthropometric and blood assay measurements were also taken:
Height and weight for Body Mass Index (BMI) - Both parameters were measured twice
with the patient standing bare footed. Height (to the nearest centimeter) was measured
with fixed stadiometers (Seca, Vogel & Halke, Germany) and weight (to the nearest 0.1
kilogram) was measured using an electronic floor weighing scale (Tanita HD 319
Personal Scale, Australia). BMI was classified according to the World Health
Organisation guidelines [36].
Waist circumference (WC) - Measured twice using a standard tape measure as described
by the National Institutes of Health (NIDDK) [37]. Abdominal obesity was defined by a
waist circumference of 90 cm for men and 80cm for women [38].
Total Serum Cholesterol (TC) - Measured using the Accutrend GCT (Roche Diagnostics,
Germany) from a single finger prick.
HbA1c level - Measured using the DCA Vantage Analyser (Siemens Healthcare
Diagnostics Inc, USA) from the same single finger prick.
For all the measurements except TC and HbA1c an average of two readings was taken for
analyses. Variables were categories based on clinical and statistical reasoning.
Pre-test and pilot study
A pre-test was conducted on 40 Type II diabetic patients selected conveniently from a
government primary care facility which was not included in the study. This was

purposively done to test the study questionnaire. The pilot study was then conducted after
the pre-test in two other government health facilities that were also not selected for the
study. The logistics and feasibility of conducting the study were explored. Weaknesses
that were identified from the pre-test and pilot study were rectified.
Data management and statistical analysis
All questionnaires were checked for completeness of response at the clinic and attempts
were made to improve the response rate for missing items. Data was entered manually
into a database and cleaned before analyses. The Statistical Package for the Social
Science (SPSS) version 16 software was used for both descriptive and inferential
analysis. Items that were not answered by respondents were considered as missing.
Univariate statistics such as mean values, standard deviations, frequencies and proportion
percentages were derived for continuous and categorical variables respectively. Bivariate
and multivariate analyses were used to measure the strength of association between the
variables in the study and identify predictors for the outcomes of interest respectively. All
tests were two-tailed with significance defined as p < 0.05. Odds ratios (OR) along with
95% confidence levels (CI) were derived where appropriate.

Results
Out of 2774 eligible patients approached, 2508 subjects were successfully recruited,
giving a response rate of 90.4%.
Socio-demographic, clinical and other characteristics of sample population
Majority of the respondents were between 50 to 59 years old (35.5%), females (61.1%),
Malays (51.2%) and married (81.7%). Almost 40% had some form of secondary
education and one third earned a monthly household income (MHI) of MYR 1,000 to
1,999. Slightly over one third of respondents were gainfully employed. The mean age and
MHI was about 57 (56.6 SD 10.67) years and MYR 2,000 (1,974.6 SD 1,869.12)
respectively (Table 1).

Table 1. Frequency distribution of respondents by socio-demographic


characteristics and selected variables
Over 41% of the respondents were overweight while almost twice the proportion had
abdominal obesity. Almost 30% and 40% of the respondents had an elevated TC level of
>5.2 mmol and HbA1c of >8.5% respectively. Majority (61%) were diagnosed as having
diabetes for 2 - <10 years (Table 1).
Almost 80% reported having at least one co-morbid condition. Majority reported having
at least one family member with diabetes (73.6%) while only 1% reported having a
history of mental illness in the family. As for life events, about 45% reported
experiencing at least one life event in the past 6 months. Current smokers and current
alcohol drinkers comprised 10% and 4% of the respondents respectively. Almost half of
the respondents were classified as physically inactive (49.1%).
Depression, anxiety and stress
Overall, the prevalence of depression, anxiety and stress symptoms were 11.5%, 30.5%
and 12.5% respectively. On bivariate analysis using binary logistic regression, depression
was found to be significantly associated with sex, ethnicity, educational level, MHI,
marital status, current job status, duration of diabetes and family history of psychiatric
illness (Table 2).
Table 2. Frequency distribution of respondents by depression status and sociodemographic characteristics and other selected variables
For anxiety, all socio-demographic variables; females, Asian Indian, no formal education,
MHI of MYR < 3,000, divorcees/widowers, housewives and unemployment were
significant. In addition, HbA1c >8.5%, 2 years duration of diabetes, presence of
psychiatric illness in the family, life events and physical inactivity were also significantly
associated (Table 3).
Table 3. Frequency distribution of respondents by anxiety status and sociodemographic characteristics and other selected variables

Stress was significantly associated with sex, HbA1c, co-morbidity, diabetes in the family,
psychiatric illness in the family, life events and alcohol consumption (Table 4).
Table 4. Frequency distribution of respondents by stress status and sociodemographic characteristics and other selected variables
Variables with a p value of < 0.25 in the bivariate analyses and thought to be important
risk factors of depression, anxiety and stress were entered into the multivariate model.
The forward likelihood ratio (LR) method was used to predict the associated variables for
depression, anxiety and stress symptoms in three separate models. The presence of
interaction between the explanatory variables was assessed prior to determining the final
model.
In the final model six variables i.e., sex, ethnicity, marital status, duration of diabetes,
psychiatric illness in the family and alcohol consumption were found to be predictors of
depression (Table 5). The strongest predictor was psychiatric illness history with an
adjusted odds ratio (aOR) of 2.8 times followed by marital status (aOR 2.5-2.1) and
current alcohol consumption (aOR 1.8). Individuals with diabetes of less than two years
duration were 1.6 times more likely to have depressive symptoms than individuals with
diabetes of longer duration while females and Asian Indians were 1.4 times more likely to
have depressive symptoms compared to males and Malay diabetic individuals.
Table 5. Multiple logistic regression model predicting depression, anxiety and stress
symptoms among type II diabetic outpatients
In terms of anxiety (Table 5), age group, job status, HbA1c, family history of psychiatric
illness, life events and leisure-time physical activity remained significant in the final
model, while for stress five variables namely sex, HbA1c, co-morbidity, psychiatric
illness in the family, life events and alcohol consumption were found to be significant
contributors. Individuals with a family history of psychiatric illness were 2.4 times more
likely to report anxiety. Anxiety was 1.4 times more likely in respondents experiencing
life events, those physically inactive and with an HbA1c level of >8.5%. All diabetics
who were not gainfully employed were 1.2-1.6 times more likely of experiencing anxiety.

Psychiatric illness in the family was the strongest predictor of stress having aOR of 4.2
followed by current alcohol drinkers with an aOR of 2.2. Having a highly undesirable
level of HbA1c was associated with at least 1.6 times the odds of stress. Female diabetics
and those with co-morbidity were 1.4 times more likely to report stress after controlling
for confounders.
There was also significant correlation (p < 0.01) between depression, anxiety and stress
symptoms (r = 0.360 for depression and anxiety, r =0.547 for depression and stress and r
= 0.504 for anxiety and stress).

Discussion
Depression, anxiety and stress
This study showed that the prevalence of depression, anxiety and stress symptoms were
11.5%, 30.5% and 12.5% respectively among Type II Diabetic outpatients in the Klang
Valley, Malaysia. The prevalence of anxiety in this study was almost three fold more than
that of depression and this is in keeping with current literature in which anxiety rates are
frequently higher than depression [39-42].
Our findings concur with other chronic disease models such as chronic obstructive
pulmonary disease (COPD), whereby a study by Dahlen & Janson found that 12% and
37% of respondents with asthma and COPD had probable depression and anxiety
respectively [43].
The depressive symptom rates we found are also comparable to studies in rural America
(15.8%) [44], the UAE (12.5%) [45] and Germany (10.2%) [11]. Conversely, several
studies among diabetic patients had found higher rates than our study [39,40,46]. A study
in Qatar using the same instrument as ours, i.e., DASS 21 found more than half of the
diabetics have depressive, anxiety and stress symptoms [47]. The sex specific depression
rates in our study were found to be within the estimated range in the general population.
The differences in the rates of depression, anxiety and stress symptoms between our

study and others may be attributed to differences in the screening or diagnostic


instruments used, the socio-cultural differences of different populations and also the
sample size of the subjects. In particular, the study from Qatar had a smaller sample size
of 1788.
Our study revealed that sex, ethnicity, marital status, duration of diabetes, psychiatric
illness in the family and alcohol consumption were predictors of depression. These
findings are consistent with other studies which also found sex [9,39,40,48,49], ethnic
minority groups [50] and duration of diabetes [47] significantly associated with
depression among diabetics. It is not surprising that females have a higher prevalence and
risk of depression compared to males. Many factors have been implicated for this gender
difference including socio-cultural and biological factors [51]. As for ethnicity, minority
ethnic groups have been found to have higher depression rates as quoted in other studies
[52,53]. It could be theorized that Asian Indians being the minority are more likely than
Malays who form the majority to be exposed to a gamut of psychosocial stressors such as
enhanced socioeconomic constraints, poor education and perceived discrimination.
Consequently, these issues might augment distress thereby increasing the levels of
depression among this group of minority. Similar findings and explanations were cited in
a community based cross-sectional study in the United States comparing depression and
anxiety in respondents having insomnia and respondents without among the majority
Caucasians and minority African American. In that study, Taylor et al. [54] established
that African Americans were more likely to have clinically significant depression and
anxiety. This was attributable to the plausible exposure to greater array of stressors in the
form of discrimination, socioeconomic adversities and enhanced caregiver burden for
African Americans as compared to Caucasians.
Generally, it is recognized that being married is associated with less psychiatric morbidity
including depression [55-57]. Our finding of previously married and never married
individuals being associated with depressive symptoms was compatible with a study by

Aqbir et al. [48]. It is very likely that having a partner or spouse in a stable marriage
offers emotional stability as well as shared burden in coping with challenges.
Incidentally a duration of less than 2 years of having diabetes was a predictor of
depressive symptoms in this study. This may be attributed to inadequate or inefficient
coping skills of managing diabetes by the respondents within the relatively short period
since diagnosis. A related study conducted in Bahrain affirmed an association between
duration of diabetes and depressive symptoms [58].
Additionally, this study elucidated the strongest predictor of depressive symptoms was
having a family history or family member with psychiatric illness. It is recognized that
mental illnesses in general tend to run within families [59]. In addition, in an Asian
society such as ours, the responsibility of the family in caring for an ill member whether
physically, emotionally or financially is very much entrenched in the culture. Hence, the
caregivers burden is occasionally translated into physical and mental health adversities
such as depression [60,61].
In terms of alcohol consumption, our study showed that current drinking was an
independent risk factor for depression albeit marginally. Several studies have established
such an association [41,42,62].
For anxiety, our study demonstrated that having a family history of psychiatric illness
was the strongest predictor. The finding is not surprising for the same reasons mentioned
as for depression. That an elevated HBA1c level was an independent risk factor of
anxiety in our study is also echoed by a similar association between blood glucose level
and anxiety in a Mexican population [40].
With reference to current job status, this study noted that housewives and those
unemployed were at risk of reporting anxiety symptoms than those who were gainfully
employed. It is likely that unemployed persons lack feelings of stability and this could

contribute to feelings of anxiety. However, further research is needed to show the reasons
for our finding.
In this present era of modernization, anxiety has considerable influence upon the quality
of life. Balancing work, family and leisure time is a challenge for both working men and
women nowadays. If there was a life event preceding which could upset this delicate
balance, there would definitely be an increased predilection to develop anxiety in the
affected individuals. Our findings concur with several other studies conducted in this area
[63,64].
Physical activity has been shown to promote feelings of well being. Our findings
harmonize with other studies showing association between physical inactivity and anxiety
symptoms [39,65]. Furthermore, regular physical activity has revealed a reduction of
anxiety symptoms in those who already suffer from this disorder [66].
Our data inferred that having a family member with psychiatric illness was the strongest
predictor of stress. Once again caring for a family member who has a chronic illness like
mental disorders is indeed a challenging task that could increase the possibilities of
adversities [60,61].
Pertaining to alcohol consumption, current drinkers were strongly associated with stress
symptoms. Studies have shown that drinking is used as means of coping with lifes
stresses [67]. Childs et al. have suggested a bidirectional relationship between alcohol
use and stress [68].
Experiencing life events is inherently stressful and thus can complicate any stress level
already existing in an individual [69]. Lyod et al. [70] have noted that recent severe
stressors were associated with poorer glycemic control while another study found a
significant correlation between stress and HbA1c [71]. Hence, our findings of life events
and elevated HbA1c levels being independently associated with stress symptoms are
consistent. Females were found to be at risk of stress in this study. The finding is in

accordance with current literature on gender differences and stress symptoms [72-74]. We
did not find any association between other socio-demographic, lifestyle and clinical
factors with stress symptoms.
The strength of our study lies in its large sample size and the sampling method. However,
there are also limitations which need to be considered. Firstly, this being a cross sectional
study does not allow for cause and effect relationships to be studied. Secondly, the DASS
21 questionnaire is only a screening tool and not diagnostic of specific psychiatric
disorders. There is also the possibility of recall biases from respondents, however this
was minimized by limiting the recall period to 1 week prior to the interview using DASS
21. Information such as age, past medical history and types of medication was also
verified with medical records where applicable. A point to note is that the low prevalence
of family history of psychiatric illness elicited from the study could be a result of under
reporting as psychiatric illness is still viewed with suspicion and stigma in our society.
As part of a long term and holistic diabetes care management, we recommend that
screening for depression, anxiety and stress symptoms be conducted at regular intervals
for Type II diabetics with vulnerable characteristics as mentioned above. Policies need to
be in place along with appropriate intervention so that these vulnerable individuals
receive optimal and timely mental health care, thus translating into better overall health
outcomes.

Conclusions
The study showed that while the prevalence of depression and stress symptoms was just
over 10%, almost a third were classified as anxious. As these symptoms are highly
correlated, they should be considered together when managing diabetic patients. Our
findings could help primary care physicians identify high risk diabetics for screening of
mental disorders. A family history of psychiatric illness was found to be a common
predictor for all three symptoms. Females, current alcohol drinkers, experiencing recent

life events and poor glycemic control were the other common predictors of at least two of
these symptoms.

Competing interests
The authors declare that they have no competing interests.

Authors contributions
GK was involved in the conception and design of the project, management of data
collection/entry, cleaning, statistical analyses and manuscript writing/revising. TGH
assisted in the project management, data collection and manuscript writing/revising. SA
was involved in the design of the project, assisted in coordination of data collection and
manuscript writing/revising. ASK assisted in the project design, conducted the data
collection and manuscript writing and revising. KC assisted in the design of the project,
data management and statistical analyses. All authors read and approved the final
manuscript.

Acknowledgements
The authors wish to thank the Director General of the Ministry of Health Malaysia for his
permission in publishing the study findings.

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Cost-effectiveness of a stepped-care
intervention to prevent major
depression in patients with type 2
diabetes mellitus and/or coronary heart
disease and subthreshold depression:
design of a cluster-randomized
controlled trial
Susan EM van Dijk1*, Alide D Pols12, Marcel C Adriaanse1, Judith E Bosmans1,
Petra JM Elders2, Harm WJ van Marwijk2 and Maurits W van Tulder1

* Corresponding author: Susan EM van Dijk s.e.m.van.dijk@vu.nl

Author Affiliations
1

Department of Health Sciences and the EMGO institute for Health and Care research,
Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085,
Amsterdam, HV, 1081, The Netherlands
2

Department of General Practice and the EMGO institute for Health and Care research,
VU University Medical Centre, Amsterdam, The Netherlands
For all author emails, please log on.
BMC Psychiatry 2013, 13:128 doi:10.1186/1471-244X-13-128

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-244X/13/128
10 April
2013
24 April
Accepted:
2013
Published: 7 May 2013
Received:

2013 van Dijk et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
Co-morbid major depression is a significant problem among patients with type 2 diabetes
mellitus and/or coronary heart disease and this negatively impacts quality of life.
Subthreshold depression is the most important risk factor for the development of major
depression. Given the highly significant association between depression and adverse
health outcomes and the limited capacity for depression treatment in primary care, there
is an urgent need for interventions that successfully prevent the transition from
subthreshold depression into a major depressive disorder. Nurse led stepped-care is a
promising way to accomplish this. The aim of this study is to evaluate the costeffectiveness of a nurse-led indicated stepped-care program to prevent major depression
among patients with type 2 diabetes mellitus and/or coronary heart disease in primary
care who also have subthreshold depressive symptoms.
Methods/design
An economic evaluation will be conducted alongside a cluster-randomized controlled
trial in approximately thirty general practices in the Netherlands. Randomization takes
place at the level of participating practice nurses. We aim to include 236 participants who
will either receive a nurse-led indicated stepped-care program for depressive symptoms
or care as usual. The stepped-care program consists of four sequential but flexible
treatment steps: 1) watchful waiting, 2) guided self-help treatment, 3) problem solving
treatment and 4) referral to the general practitioner. The primary clinical outcome
measure is the cumulative incidence of major depressive disorder as measured with the
Mini International Neuropsychiatric Interview. Secondary outcomes include severity of
depressive symptoms, quality of life, anxiety and physical outcomes. Costs will be

measured from a societal perspective and include health care utilization, medication and
lost productivity costs. Measurements will be performed at baseline and 3, 6, 9 and 12
months.
Discussion
The intervention being investigated is expected to prevent new cases of depression
among people with type 2 diabetes mellitus and/or coronary heart disease and
subthreshold depression, with subsequent beneficial effects on quality of life, clinical
outcomes and health care costs. When proven cost-effective, the program provides a
viable treatment option in the Dutch primary care system.
Trial registration
Dutch Trial Register NTR3715

Keywords:
Subthreshold depression; Depression prevention; Cost-effectiveness; Type 2
diabetes mellitus; Coronary heart disease; Stepped-care; Primary care; Nurse
led treatment

Background
Subthreshold depression, the presence of symptoms of depression without fulfilling the
criteria for major depression, is the strongest predictor for the onset of major depression
[1,2]. Currently, major depression is a substantial health problem throughout the
industrialised world [3]. The 12 month prevalence of major depression ranges between 3
and 9% in high-income countries [4,5]. Among patients with type 2 diabetes mellitus
(DM2) and/or coronary heart disease (CHD) estimates of the 12 month prevalence of
major depression usually range from 10% to 20% [6-8]. Even more patients with DM2
and/or CHD experience subthreshold depression, i.e. 25%-40% [9,10]. More than 40% of
diabetic patients with subthreshold depression will develop major depression within two
years [9]. Similar estimates are found for patients diagnosed with CHD [11].

Depression has been shown to adversely affect self-care and medication adherence
related to DM2 and CHD [12,13], to negatively impact quality of life [14,15] and to be
associated with poor health outcomes and an increased risk of mortality [16,17].
Moreover, DM2 and CHD patients with depression use healthcare services more often
than their non-depressed counterparts, which is associated with a substantial increase in
health care related costs. This effect cannot be explained by an increase in mental health
care costs alone and remains present after adjusting for co-morbid medical conditions
[18-21]. In addition, depression is associated with increased work absenteeism, which
raises the total societal costs of depression even more [22].
Unfortunately, even when optimal treatment is given to all patients with major
depression, only about 27 percent of the total disease burden can be averted [23].
Therefore, prevention of the onset of major depression among high risk patients may be a
promising solution to reduce the burden for both patients and society substantially [24].
Meta analyses show that using preventive interventions, a reduction of about 25% in the
incidence of major depression can be obtained [2,25]. Especially promising are
preventive interventions that are offered in a stepped-care format [25]. The aim of
stepped-care interventions is to maximize the effectiveness of an intervention while
making best use of available resources by offering the least intensive treatment necessary
and by tailoring the treatment to the patients preferences. By using such a format, it is
possible to reduce the relative risk of the onset of depression by as much as 50% [25-27].
There is also evidence that stepped-care interventions can be used to treat existing major
depression among patients with DM2 in primary care [28]. This stepped-care depression
treatment was shown to be cost-effective in comparison with usual care as well. The
additional costs associated with the implementation of the stepped-care program did not
result in higher total health care costs over respectively a 2- and 5- year period [29,30].
This effect remained after adjusting for co-morbid medical conditions. A more recent
study showed that a stepped-care program is effective in improving disease control in

chronically ill patients with existing major depression [31]. All these findings combined
suggest that stepped-care is a promising method to not only treat major depression in
patients with DM2 and/or CHD, but also to prevent the onset of this disorder in these
patient groups. However, to the best of our knowledge, there are no studies evaluating the
cost-effectiveness of a stepped-care program to prevent depression among DM2 and
CHD patients.
Therefore, this study aims to evaluate the cost-effectiveness of a nurse-led indicated
stepped-care program to prevent depression among primary care patients with type 2
diabetes mellitus and/or coronary heart disease and subthreshold depression in
comparison with usual care.

Methods/design
Design
An economic evaluation from a societal perspective will be performed alongside a multicenter, cluster randomized controlled trial with a one year follow up.
Ethical approval
The study protocol was approved by the Ethics Committee of the VU University Medical
Centre (NL39261.029.12, registration number 2012/223) and will be conducted
according to the principles of the Declaration of Helsinki (version 2008) and the Dutch
Medical Research Involving Human Subjects Act (WMO).
Setting
The study will be carried out in approximately thirty general practices in the Netherlands.
To select these practices, we will make use of the Academic Network of General
Practitioners (GPs) of the Department of General practice and of the VU medical centre.
Randomization

Randomization will be done at the level of the participating practice nurses to avoid
contamination between the treatment groups and will be performed by a statistician
blinded to characteristics of the general practices using a computer generated list of
random numbers. Before patients are recruited, participating practices will be randomly
allocated to serve as intervention practices where the stepped-care treatment will be
implemented, and control practices where care as usual will be given. Patients will be
allocated to either one of the treatment conditions, based on the general practice where
they are registered. Blinding of patients, GPs and practice nurses is not possible due to
the nature of the intervention.
Participants
Patients are eligible for this study if they are 18 years or older, are treated for DM2 and/or
CHD in primary care, and have subthreshold depressive symptoms (a score of 6 or more
on the Patient Health Questionnaire-9, or PHQ-9 [32]) without fulfilling the criteria for
major depression according to the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV), as measured with the Mini International Neuropsychiatric Interview (MINI)
[33].
Patients are excluded from participation in the study when they have a major depressive
disorder; cognitive impairment or dementia; a psychotic or terminal illness; a history of
(a) suicide attempt(s); or insufficient Dutch language skills, visual impairments or
illiteracy. Also, patients cannot participate when they are pregnant, taking antidepressant
medication, or when they have lost a significant other in the past 6 months.
Recruitment
To recruit eligible patients, in all participating general practices an initial list of adult
patients with DM2 and/or CHD is composed, based on diagnoses classified using the
ICPC (International Classification of Primary Care) in the medical electronic information
system; see Additional file 1 for details. This list is given to the general practitioner, who
checks the preset inclusion criteria and excludes all patients that fulfill our preset

exclusion criteria, based on the medical file and experiences with the patient. All
remaining eligible patients will receive a letter on behalf of the general practitioner, in
which all (at that point) necessary information regarding the study, as well as an
invitation to participate is included. When patients consider to participate, they are asked
to fill out a two question screening form (Patient Health Questonnaire-2, or PHQ-2 [34])
that will be provided with the information letter and send it back using a prestamped
envelope. All patients with a PHQ-2 score of 2 or more [34,35] will receive additional
information from the research team. Based on this information informed consent is
obtained for a telephone interview. During this interview the Dutch version of the PHQ-9
[36] and the MINI [37] will be administered. Patients scoring 6 points or more on the
PHQ-9, but not having a major depression according to the MINI are eligible for the
study and will be asked for written informed consent to participate. From this point on,
patients are either enrolled in the stepped-care program or will receive care as usual,
depending on the general practice at which they are registered. An overview of the study
design and patient flow is provided in Figure 1.
Additional file 1. ICPC codes used for recruitment. This file provides a list of all
registration codes used to identify potentially eligible patients in the medical electronic
information system of participating general practices.
Format: PDF Size: 41KB Download file
This file can be viewed with: Adobe Acrobat Reader

Figure 1. Overview of the study design and patient flow.


Intervention
The intervention is modelled after the flexible stepped-care intervention developed by
van t Veer-Tazelaar et al. [26]. After receiving a specially developed training, practice

nurses in the intervention practices will act as care managers and work together with the
General Practitioner (GP) to provide the stepped-care treatment. The care managers
coordinate the execution of the stepped-care program that consists of four evidence-based
subsequent treatment steps, lasting 3 months each. The flow of participants in the
intervention group through the stepped-care program depends on their depressive
symptom level, measured using the PHQ-9 every 3 months during 1 year. Participants
who still have elevated depressive symptom levels (i.e. a PHQ-9 score of 6 or more) after
concluding a step, are offered participation in the next step. A score below the cut off
point results in a period of watchful waiting until an elevated PHQ-9 score indicates the
need for the subsequent step of the intervention. By only offering more intensive
treatment to patients who continue to have elevated depressive symptom scores, it is
expected that patients will receive treatment tailored to their needs and that available
resources are more efficiently used by providing the more intensive treatments only to
those who need this. Patients who meet the MINI diagnostic criteria for major depression
at baseline or at 3, 6, 9 or 12 months are referred to their GP by the practice nurse for
further assessment. The following treatment steps are offered to participants:
Step 1: Watchful waiting
The first 3 months consist of watchful waiting, because depressive symptoms often
disappear spontaneously over time [26]. After inclusion and obtaining informed consent,
patients are invited by their care manager for an introductory consultation. During this
consultation patients will get acquainted with the care manager and they will receive an
information brochure about mild depression with simple advices on how to cope with
mild depressive symptoms. Patients will be informed about the stepped-care program and
its rationale. In this step, no therapeutic intervention will take place.
Step 2: Guided self-help treatment
During this step, participants are offered a self-help course that is specially designed for
patients with a chronic physical illness and depressive complaints [38]. During a visit to

the general practice, the care manager will give the patient all necessary materials and
explain the self-help course. Participants can work through the course at their
convenience. In doing so, they will be supported by their care manager, who will contact
them every other week by phone to monitor their progress. If it is clear that after two
weeks the patient has not started the course yet, the care manager will use motivational
interviewing techniques by phone to activate the patient. When this does not have the
intended activating effect on the patient after two more weeks, the care manager invites
the patient to come to the practice to discuss the current depressive symptoms (a PHQ-9
will be administered). When depressive symptoms still exist, patients are offered to
progress early to step 3.
Step 3: problem-solving treatment
In this step, participants are offered Problem Solving Treatment (PST) by the care
manager. PST is a brief cognitive behavioural intervention that focuses on practical skill
building. It consists of a maximum of 7 sessions during which the stages of problem
solving are explained and then applied to problems encountered in daily life. The goal of
PST is to help patients regain control of their lives [39,40].
Step 4: Referral to general practitioner
Participants with continuously elevated PHQ-9 scores after 9 months will be referred to
their general practitioner by the care manager for further assessment of their depressive
symptoms. The GP receives a summary of the treatment provided to discuss with their
patient.
Usual care
In the usual care practices, practice nurses and GPs will be blinded to which patients are
participating in the study. They will not receive any training and will provide care as
usual to all their patients according to existing clinical guidelines [41-43]. Participants in
the usual care group will have unrestricted access to care as normally provided by their

general practitioner. Their healthcare uptake (including use of prescribed medication) will
be recorded.
Training of the practice nurses
In the intervention practices, the practice nurses who are going to provide the steppedcare treatment will attend a two day training. This training focuses on how to implement
the stepped-care program, how to provide guidance with the self help course using
motivational interviewing techniques and how to provide the PST. The motivational
interviewing techniques and the PST will be taught by a professional trainer. Before the
trial starts, the trained practice nurses will perform two practice sessions of PST by
telephone. These sessions will be audio taped and evaluated by the training staff to detect
possible competence and/or adherence issues. During the trial, all practice nurses are
regularly supervised by the training staff. Nurses can also contact the training staff to
discuss any questions or problems, should they arise. When practice nurses have
previously received training in motivational interviewing and/or PST, they are offered to
follow a personalized training program.
Outcomes
The primary clinical outcome is the cumulative incidence of DSM-IV major depressive
disorder after 12 months according to the Mini International Neuropsychiatric Interview
(MINI) [33,37]. The MINI will be administered by telephone at baseline and after 6 and
12 months after baseline by qualified research assistants.
Depression severity will be measured using the PHQ-9 [32,44]. The PHQ-9 is a widely
used validated instrument to measure depression symptoms in general practice.
Quality of life will be measured using the EuroQol (EQ-5D) [45]). The obtained EQ-5D
scores will be used to calculate utilities according to the Dutch tariff. QALYs will be
calculated using the area-under-the-curve method with linear interpolation between time
points.

For the economic evaluation, costs will be measured using the TiC-P questionnaire [46].
Costs that will be included are costs for healthcare utilization, informal care, and work
absenteeism and presenteeism. Medication use will be retrieved from the patients
pharmacy. If available, Dutch guideline prices will be used to value resource use.
Medication use will be valued using prices of the Royal Dutch Society for Pharmacy.
Lost productivity costs will be calculated according to the friction cost approach (friction
period 154 days) using the mean age- and sex-specific income of the Dutch population.
According to the friction cost approach a sick employee is replaced after a certain amount
of time (the friction period) after which there are no lost productivity costs anymore. All
costs will be adjusted to the year in which most data is collected using consumer price
indices.
All secondary outcomes mentioned above will be administered at baseline, 3, 6, 9 and 12
months after inclusion through web-based questionnaires. If patients do not have access
to the internet or prefer hard copies, we will provide these. In the intervention group, the
PHQ-9 will also be administered by the nurse in the general practice for clinical
monitoring and adjusting treatment when necessary.
Other secondary clinical outcomes include blood pressure, low-density lipoprotein (LDL)
cholesterol and glycosylated haemoglobin (HbA1C). These outcomes will be measured at
baseline and at 12 months follow-up and are performed as part of the usual care for this
group of patients. Therefore, patients do not undergo any extra physical measurements.
To be able to control for possible confounders, demographics will be measured at
baseline, along with personal and family history of mood disorders, using a subset of the
Diagnostic Interview Schedule (DIS) [47]. The occurrence of co-morbid chronic illnesses
will be assessed with the Dutch questionnaire chronic illnesses [48] at baseline and after
6 and 12 months, as well as locus of control [49]and social support [50]. All these
measurements were previously used for the same purposes in the West Friesland Study

[51]. In addition to this, anxiety symptoms will be measured at baseline, 3, 6, 9 and 12


months by the Hospital Anxiety and Depression Scale- Anxiety (HADS-A) [52].
After 12 months the uptake of the stepped-care program will be evaluated. The number of
contacts with the care manager, the number of PST sessions, antidepressant use, and the
number of referrals to the GP will be assessed by the care manager in the intervention
group. Mental health care utilization outside the general practice will be assessed using
the TiC-P questionnaire [46].
A process evaluation will be performed in which the barriers and facilitators of the
stepped-care program and the experiences with the program will be evaluated. This will
be done by organizing focus groups among volunteering patients, general practitioners
and primary care nurses. In addition, satisfaction with the received care will be measured
in all patients after 12 months by using the CSQ [53,54]. An overview of all
measurements and instruments is provided in Table 1.
Table 1. Overview of all measurements and instruments
Sample size
The trial is powered to detect a difference of 15% in the cumulative incidence rates of
MINI/DSM-IV depressive disorder between the conditions after 1 year. The incidence
rate is expected to be 30% in the usual care group and 15% in the intervention group
based on findings from earlier studies [2,25,26]. Using a standard sample size calculation,
121 patients per group are needed, assuming a power of 0.8 and an alpha of 0.05.
However, we need to correct for the fact that there is a multilevel setting with three
levels: GPs, patients and measurements. Therefore we have first adjusted for the fact that
we do not have one, but multiple measurements per patient. Assuming these
measurements are clustered with an intraclass correlation (ICC) of 0.45, seventy-one
patients per group are needed. Subsequently, we adjusted this figure further for clustering
of patients within GP practices. Assuming an ICC of 0.05 for clustering of patients within
the 30 GP practices, we need a total of 177 patients. Finally, we adjusted for a dropout

rate of 25%, which means that 236 patients (118 patients per group) need to be included
in this trial. This power calculation is based on the method described by Twisk in 2006
[55].
Statistical analyses
Baseline data will be presented comparing the two treatment groups.
All analyses will be on an intention-to-treat basis. Differences between the stepped-care
group and the usual care group will be tested using mixed model analyses. To test the
cumulative incidence of depression over time, logistic mixed model analysis will be used.
The obtained odds ratio describes the reduction in the risk of a MINI/DSM-IV depressive
disorder in the intervention group relative to the control group. Linear and logistic mixed
models (depending on the outcome) will also be used to test differences in symptoms of
depression and anxiety and quality of life between both groups over time. If necessary,
the models will be adjusted for confounders.
Sub group analyses will be performed to check for an interaction effect between
depression severity at baseline and improvement in depressive symptoms at 12 months.
In case of unequal distributions of demographic variables between the two treatment
groups, multivariate analyses techniques will be used to correct for these differences.
Economic evaluation
Both a cost-effectiveness analysis and a cost-utility analysis will be performed. Missing
cost and effect data will be imputed using multiple imputation according to the MICE
algorithm developed by Van Buuren [56]. The results of the imputed datasets will be
pooled using Rubins rules [57]. Costs typically have a highly skewed distribution. Policy
makers want to have information on the difference in mean total costs between the two
treatment groups in order to be able to estimate the total health care budget needed for a
specific condition [58]. Therefore, bias-corrected and accelerated bootstrapping with
5000 replications will be used to estimate 95% confidence intervals around the mean

difference in total costs between the treatment groups. Incremental cost-effectiveness


ratios (ICERs) will be calculated by dividing the difference in mean total costs between
the treatment groups, by the difference in mean effects between the treatment groups.
Bootstrapping will also be used to estimate the uncertainty surrounding the ICERs, which
will be graphically presented on cost-effectiveness planes. Cost- effectiveness
acceptability curves will be estimated as well. Cost-effectiveness acceptability curves
show the probability that the stepped-care program is cost-effective in comparison with
usual care for a range of different ceiling ratios (i.e. the willingness to pay for 1 extra
recovered patient), thereby showing decision uncertainty [59].

Discussion
Based on earlier studies, there is substantial evidence that stepped-care programs for
depression among primary care patients are effective in both improving and preventing
depression. However, evidence concerning the costs and effects of such programs among
patients with DM2 and/or CHD and subthreshold depression in general practices is still
missing.
Given the large number of DM2 and CHD patients with depressive symptoms, and the
limited capacity for depression treatment in primary care, there is an urgent need to
improve care for these patients. Since the presence of subthreshold depressive symptoms
is the largest risk factor for developing major depression, targeting preventive treatments
to patients at risk for developing a major depression is a viable option to reduce the
burden of depression in primary care. Stepped-care interventions are a very promising
method to achieve this goal. The key of stepped-care, delivered by a care manager, is that
treatment is tailored to the needs and preferences of the patient while making the best use
of available recourses. This will help optimizing health related outcomes, as well as
keeping the treatment affordable by saving available resources for patients who really
need them.

By testing a stepped-care program to prevent depression among high risk DM2 and/or
CHD patients in a primary care setting, this study is highly clinically and societally
relevant. Moreover, because a structured evaluation of the feasibility of the stepped-care
program is explicitly taken into account in the study design, the results of this cluster
randomised controlled trial will greatly contribute to the practical evidence about
preventive treatment options for depression in patients with DM2 and/or CHD in general
practice.
A strength of this study is that a pragmatic study design is employed; meaning that
patients, treatments and procedures are similar to daily clinical practice. This greatly
enhances the generalizability of the findings of the study and therefore the possibilities to
implement the Step-Dep treatment in a real-life primary care setting.
The relatively short 12 month follow-up period may turn out to be a limitation of this
trial. It is possible that the potential health benefits of participating in the stepped-care
program will not yet be fully visible after one year. Especially the beneficial effects of
having less depressive symptoms on health care utilisation, work absenteeism, and
clinical outcomes such as Hb1Ac, blood pressure and LDL cholesterol, may take longer
than the follow up period of one year to reach full development. Katon and his
colleagues, for example, found a significant reduction in total health care costs among
DM2 patients that participated in a stepped-care intervention to treat major depression
after two years, but not yet after 12 months [30]. Other studies report similar results [6062]. These findings can be explained by the fact that the extra costs of stepped-care
interventions are made in the first year, while the cumulative effects of the treatment will
become more and more visible after the treatment is finished. Therefore it might be
necessary to perform a follow up study when the results indicate such a delay in
cumulative effects.
Another possible limitation is that it is not possible to blind patients and caregivers to the
randomisation due to the nature of the stepped-care program. However, considering the

pragmatic design of the study, this is a true representation of clinical practice and this also
enables us to measure all possible effects of the intervention. We try to counter possible
contamination between treatments groups by using a cluster randomized controlled
design, in which staff from usual care practices are not trained to perform the steppedcare program until after the follow up period. That way, caregivers cannot unintentionally
apply aspects of the stepped-care program to their usual care for patients.
Overall, this study will provide valuable information about the cost-effectiveness and
feasibility of a stepped-care program in primary care to prevent major depression in
DM2/CHD patients with subthreshold depression, both from a clinical and societal
perspective. When the stepped-care program proves to be cost-effective, the results of
this study will offer a unique venture point for implementation of the stepped-care
program into primary care and further research. The first results of this trial are expected
in 2015.

Abbreviations
CHD: Coronary Heart Disease; CSQ: Client Satisfaction Questionnaire; DIS: Diagnostic
Interview Schedule; DM2: Type 2 Diabetes Mellitus; DSM-IV: Diagnostic and Statistical
Manual of Mental Disorders-IV; EQ-5D: EuroQol- 5 dimensions; GPs: General Practices;
HADS-A: Hospital Anxiety and Depression Scale-A; ICC: Intraclass correlation; ICERs:
Incremental Cost-Effectiveness Ratios; ICPC: International Classification of Primary
Care; LDL cholesterol: Low-Density Lipoprotein cholesterol; PHQ-2: Patient Health
Questionnaire-2; PHQ-9: Patient Health Questionnaire- 9; PST: Problem Solving
Treatment.

Competing interests
The authors declare that they have no competing interests.

Authors contributions

SvD constructed the design of the study and drafted the manuscript. AP constructed the
design of the study and revised the manuscript. MCA, JB, PE and HvM developed the
study, constructed the design and revised the manuscript. MvT participated in the design
of the study and revised the manuscript. The final manuscript was read and approved by
all authors.

Acknowledgements and funding


This study is funded by ZonMw, the Netherlands Organisation for Health Research and
Development (project number 80-82310-97-12110). Publication in this Open Access
journal was funded by NWO, the Netherlands Organisation for Scientific Research.
The Authors would like to thank Hanna Joosten, data manager at the Department of
General Practice, VU University Medical Centre, Amsterdam, for helping us out by
estimating the feasibility of the trial based on a registration sample of the Academic
Network of General Practitioners (GPs) of the Department of General practice of the VU
medical centre.

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Harpole L, Zhou XHA, Langston C, Unutzer J: Cost-effectiveness of improving
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PubMed Central Full Text

Cost-effectiveness of a stepped-care
intervention to prevent major
depression in patients with type 2
diabetes mellitus and/or coronary heart
disease and subthreshold depression:
design of a cluster-randomized
controlled trial
Susan EM van Dijk1*, Alide D Pols12, Marcel C Adriaanse1, Judith E Bosmans1,
Petra JM Elders2, Harm WJ van Marwijk2 and Maurits W van Tulder1

* Corresponding author: Susan EM van Dijk s.e.m.van.dijk@vu.nl

Author Affiliations
1

Department of Health Sciences and the EMGO institute for Health and Care research,
Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085,
Amsterdam, HV, 1081, The Netherlands
2

Department of General Practice and the EMGO institute for Health and Care research,
VU University Medical Centre, Amsterdam, The Netherlands
For all author emails, please log on.
BMC Psychiatry 2013, 13:128 doi:10.1186/1471-244X-13-128

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-244X/13/128
10 April
2013
Accepted: 24 April
Received:

2013
Published: 7 May 2013

2013 van Dijk et al.; licensee BioMed Central Ltd.


This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
Co-morbid major depression is a significant problem among patients with type 2 diabetes
mellitus and/or coronary heart disease and this negatively impacts quality of life.
Subthreshold depression is the most important risk factor for the development of major
depression. Given the highly significant association between depression and adverse
health outcomes and the limited capacity for depression treatment in primary care, there
is an urgent need for interventions that successfully prevent the transition from
subthreshold depression into a major depressive disorder. Nurse led stepped-care is a
promising way to accomplish this. The aim of this study is to evaluate the costeffectiveness of a nurse-led indicated stepped-care program to prevent major depression
among patients with type 2 diabetes mellitus and/or coronary heart disease in primary
care who also have subthreshold depressive symptoms.
Methods/design
An economic evaluation will be conducted alongside a cluster-randomized controlled
trial in approximately thirty general practices in the Netherlands. Randomization takes
place at the level of participating practice nurses. We aim to include 236 participants who
will either receive a nurse-led indicated stepped-care program for depressive symptoms
or care as usual. The stepped-care program consists of four sequential but flexible
treatment steps: 1) watchful waiting, 2) guided self-help treatment, 3) problem solving

treatment and 4) referral to the general practitioner. The primary clinical outcome
measure is the cumulative incidence of major depressive disorder as measured with the
Mini International Neuropsychiatric Interview. Secondary outcomes include severity of
depressive symptoms, quality of life, anxiety and physical outcomes. Costs will be
measured from a societal perspective and include health care utilization, medication and
lost productivity costs. Measurements will be performed at baseline and 3, 6, 9 and 12
months.
Discussion
The intervention being investigated is expected to prevent new cases of depression
among people with type 2 diabetes mellitus and/or coronary heart disease and
subthreshold depression, with subsequent beneficial effects on quality of life, clinical
outcomes and health care costs. When proven cost-effective, the program provides a
viable treatment option in the Dutch primary care system.
Trial registration
Dutch Trial Register NTR3715

Keywords:
Subthreshold depression; Depression prevention; Cost-effectiveness; Type 2
diabetes mellitus; Coronary heart disease; Stepped-care; Primary care; Nurse
led treatment

Background
Subthreshold depression, the presence of symptoms of depression without fulfilling the
criteria for major depression, is the strongest predictor for the onset of major depression
[1,2]. Currently, major depression is a substantial health problem throughout the
industrialised world [3]. The 12 month prevalence of major depression ranges between 3
and 9% in high-income countries [4,5]. Among patients with type 2 diabetes mellitus
(DM2) and/or coronary heart disease (CHD) estimates of the 12 month prevalence of
major depression usually range from 10% to 20% [6-8]. Even more patients with DM2

and/or CHD experience subthreshold depression, i.e. 25%-40% [9,10]. More than 40% of
diabetic patients with subthreshold depression will develop major depression within two
years [9]. Similar estimates are found for patients diagnosed with CHD [11].
Depression has been shown to adversely affect self-care and medication adherence
related to DM2 and CHD [12,13], to negatively impact quality of life [14,15] and to be
associated with poor health outcomes and an increased risk of mortality [16,17].
Moreover, DM2 and CHD patients with depression use healthcare services more often
than their non-depressed counterparts, which is associated with a substantial increase in
health care related costs. This effect cannot be explained by an increase in mental health
care costs alone and remains present after adjusting for co-morbid medical conditions
[18-21]. In addition, depression is associated with increased work absenteeism, which
raises the total societal costs of depression even more [22].
Unfortunately, even when optimal treatment is given to all patients with major
depression, only about 27 percent of the total disease burden can be averted [23].
Therefore, prevention of the onset of major depression among high risk patients may be a
promising solution to reduce the burden for both patients and society substantially [24].
Meta analyses show that using preventive interventions, a reduction of about 25% in the
incidence of major depression can be obtained [2,25]. Especially promising are
preventive interventions that are offered in a stepped-care format [25]. The aim of
stepped-care interventions is to maximize the effectiveness of an intervention while
making best use of available resources by offering the least intensive treatment necessary
and by tailoring the treatment to the patients preferences. By using such a format, it is
possible to reduce the relative risk of the onset of depression by as much as 50% [25-27].
There is also evidence that stepped-care interventions can be used to treat existing major
depression among patients with DM2 in primary care [28]. This stepped-care depression
treatment was shown to be cost-effective in comparison with usual care as well. The
additional costs associated with the implementation of the stepped-care program did not

result in higher total health care costs over respectively a 2- and 5- year period [29,30].
This effect remained after adjusting for co-morbid medical conditions. A more recent
study showed that a stepped-care program is effective in improving disease control in
chronically ill patients with existing major depression [31]. All these findings combined
suggest that stepped-care is a promising method to not only treat major depression in
patients with DM2 and/or CHD, but also to prevent the onset of this disorder in these
patient groups. However, to the best of our knowledge, there are no studies evaluating the
cost-effectiveness of a stepped-care program to prevent depression among DM2 and
CHD patients.
Therefore, this study aims to evaluate the cost-effectiveness of a nurse-led indicated
stepped-care program to prevent depression among primary care patients with type 2
diabetes mellitus and/or coronary heart disease and subthreshold depression in
comparison with usual care.

Methods/design
Design
An economic evaluation from a societal perspective will be performed alongside a multicenter, cluster randomized controlled trial with a one year follow up.
Ethical approval
The study protocol was approved by the Ethics Committee of the VU University Medical
Centre (NL39261.029.12, registration number 2012/223) and will be conducted
according to the principles of the Declaration of Helsinki (version 2008) and the Dutch
Medical Research Involving Human Subjects Act (WMO).
Setting
The study will be carried out in approximately thirty general practices in the Netherlands.
To select these practices, we will make use of the Academic Network of General
Practitioners (GPs) of the Department of General practice and of the VU medical centre.

Randomization
Randomization will be done at the level of the participating practice nurses to avoid
contamination between the treatment groups and will be performed by a statistician
blinded to characteristics of the general practices using a computer generated list of
random numbers. Before patients are recruited, participating practices will be randomly
allocated to serve as intervention practices where the stepped-care treatment will be
implemented, and control practices where care as usual will be given. Patients will be
allocated to either one of the treatment conditions, based on the general practice where
they are registered. Blinding of patients, GPs and practice nurses is not possible due to
the nature of the intervention.
Participants
Patients are eligible for this study if they are 18 years or older, are treated for DM2 and/or
CHD in primary care, and have subthreshold depressive symptoms (a score of 6 or more
on the Patient Health Questionnaire-9, or PHQ-9 [32]) without fulfilling the criteria for
major depression according to the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV), as measured with the Mini International Neuropsychiatric Interview (MINI)
[33].
Patients are excluded from participation in the study when they have a major depressive
disorder; cognitive impairment or dementia; a psychotic or terminal illness; a history of
(a) suicide attempt(s); or insufficient Dutch language skills, visual impairments or
illiteracy. Also, patients cannot participate when they are pregnant, taking antidepressant
medication, or when they have lost a significant other in the past 6 months.
Recruitment
To recruit eligible patients, in all participating general practices an initial list of adult
patients with DM2 and/or CHD is composed, based on diagnoses classified using the
ICPC (International Classification of Primary Care) in the medical electronic information
system; see Additional file 1 for details. This list is given to the general practitioner, who

checks the preset inclusion criteria and excludes all patients that fulfill our preset
exclusion criteria, based on the medical file and experiences with the patient. All
remaining eligible patients will receive a letter on behalf of the general practitioner, in
which all (at that point) necessary information regarding the study, as well as an
invitation to participate is included. When patients consider to participate, they are asked
to fill out a two question screening form (Patient Health Questonnaire-2, or PHQ-2 [34])
that will be provided with the information letter and send it back using a prestamped
envelope. All patients with a PHQ-2 score of 2 or more [34,35] will receive additional
information from the research team. Based on this information informed consent is
obtained for a telephone interview. During this interview the Dutch version of the PHQ-9
[36] and the MINI [37] will be administered. Patients scoring 6 points or more on the
PHQ-9, but not having a major depression according to the MINI are eligible for the
study and will be asked for written informed consent to participate. From this point on,
patients are either enrolled in the stepped-care program or will receive care as usual,
depending on the general practice at which they are registered. An overview of the study
design and patient flow is provided in Figure 1.
Additional file 1. ICPC codes used for recruitment. This file provides a list of all
registration codes used to identify potentially eligible patients in the medical electronic
information system of participating general practices.
Format: PDF Size: 41KB Download file
This file can be viewed with: Adobe Acrobat Reader

Figure 1. Overview of the study design and patient flow.


Intervention

The intervention is modelled after the flexible stepped-care intervention developed by


van t Veer-Tazelaar et al. [26]. After receiving a specially developed training, practice
nurses in the intervention practices will act as care managers and work together with the
General Practitioner (GP) to provide the stepped-care treatment. The care managers
coordinate the execution of the stepped-care program that consists of four evidence-based
subsequent treatment steps, lasting 3 months each. The flow of participants in the
intervention group through the stepped-care program depends on their depressive
symptom level, measured using the PHQ-9 every 3 months during 1 year. Participants
who still have elevated depressive symptom levels (i.e. a PHQ-9 score of 6 or more) after
concluding a step, are offered participation in the next step. A score below the cut off
point results in a period of watchful waiting until an elevated PHQ-9 score indicates the
need for the subsequent step of the intervention. By only offering more intensive
treatment to patients who continue to have elevated depressive symptom scores, it is
expected that patients will receive treatment tailored to their needs and that available
resources are more efficiently used by providing the more intensive treatments only to
those who need this. Patients who meet the MINI diagnostic criteria for major depression
at baseline or at 3, 6, 9 or 12 months are referred to their GP by the practice nurse for
further assessment. The following treatment steps are offered to participants:
Step 1: Watchful waiting
The first 3 months consist of watchful waiting, because depressive symptoms often
disappear spontaneously over time [26]. After inclusion and obtaining informed consent,
patients are invited by their care manager for an introductory consultation. During this
consultation patients will get acquainted with the care manager and they will receive an
information brochure about mild depression with simple advices on how to cope with
mild depressive symptoms. Patients will be informed about the stepped-care program and
its rationale. In this step, no therapeutic intervention will take place.
Step 2: Guided self-help treatment

During this step, participants are offered a self-help course that is specially designed for
patients with a chronic physical illness and depressive complaints [38]. During a visit to
the general practice, the care manager will give the patient all necessary materials and
explain the self-help course. Participants can work through the course at their
convenience. In doing so, they will be supported by their care manager, who will contact
them every other week by phone to monitor their progress. If it is clear that after two
weeks the patient has not started the course yet, the care manager will use motivational
interviewing techniques by phone to activate the patient. When this does not have the
intended activating effect on the patient after two more weeks, the care manager invites
the patient to come to the practice to discuss the current depressive symptoms (a PHQ-9
will be administered). When depressive symptoms still exist, patients are offered to
progress early to step 3.
Step 3: problem-solving treatment
In this step, participants are offered Problem Solving Treatment (PST) by the care
manager. PST is a brief cognitive behavioural intervention that focuses on practical skill
building. It consists of a maximum of 7 sessions during which the stages of problem
solving are explained and then applied to problems encountered in daily life. The goal of
PST is to help patients regain control of their lives [39,40].
Step 4: Referral to general practitioner
Participants with continuously elevated PHQ-9 scores after 9 months will be referred to
their general practitioner by the care manager for further assessment of their depressive
symptoms. The GP receives a summary of the treatment provided to discuss with their
patient.
Usual care
In the usual care practices, practice nurses and GPs will be blinded to which patients are
participating in the study. They will not receive any training and will provide care as
usual to all their patients according to existing clinical guidelines [41-43]. Participants in

the usual care group will have unrestricted access to care as normally provided by their
general practitioner. Their healthcare uptake (including use of prescribed medication) will
be recorded.
Training of the practice nurses
In the intervention practices, the practice nurses who are going to provide the steppedcare treatment will attend a two day training. This training focuses on how to implement
the stepped-care program, how to provide guidance with the self help course using
motivational interviewing techniques and how to provide the PST. The motivational
interviewing techniques and the PST will be taught by a professional trainer. Before the
trial starts, the trained practice nurses will perform two practice sessions of PST by
telephone. These sessions will be audio taped and evaluated by the training staff to detect
possible competence and/or adherence issues. During the trial, all practice nurses are
regularly supervised by the training staff. Nurses can also contact the training staff to
discuss any questions or problems, should they arise. When practice nurses have
previously received training in motivational interviewing and/or PST, they are offered to
follow a personalized training program.
Outcomes
The primary clinical outcome is the cumulative incidence of DSM-IV major depressive
disorder after 12 months according to the Mini International Neuropsychiatric Interview
(MINI) [33,37]. The MINI will be administered by telephone at baseline and after 6 and
12 months after baseline by qualified research assistants.
Depression severity will be measured using the PHQ-9 [32,44]. The PHQ-9 is a widely
used validated instrument to measure depression symptoms in general practice.
Quality of life will be measured using the EuroQol (EQ-5D) [45]). The obtained EQ-5D
scores will be used to calculate utilities according to the Dutch tariff. QALYs will be

calculated using the area-under-the-curve method with linear interpolation between time
points.
For the economic evaluation, costs will be measured using the TiC-P questionnaire [46].
Costs that will be included are costs for healthcare utilization, informal care, and work
absenteeism and presenteeism. Medication use will be retrieved from the patients
pharmacy. If available, Dutch guideline prices will be used to value resource use.
Medication use will be valued using prices of the Royal Dutch Society for Pharmacy.
Lost productivity costs will be calculated according to the friction cost approach (friction
period 154 days) using the mean age- and sex-specific income of the Dutch population.
According to the friction cost approach a sick employee is replaced after a certain amount
of time (the friction period) after which there are no lost productivity costs anymore. All
costs will be adjusted to the year in which most data is collected using consumer price
indices.
All secondary outcomes mentioned above will be administered at baseline, 3, 6, 9 and 12
months after inclusion through web-based questionnaires. If patients do not have access
to the internet or prefer hard copies, we will provide these. In the intervention group, the
PHQ-9 will also be administered by the nurse in the general practice for clinical
monitoring and adjusting treatment when necessary.
Other secondary clinical outcomes include blood pressure, low-density lipoprotein (LDL)
cholesterol and glycosylated haemoglobin (HbA1C). These outcomes will be measured at
baseline and at 12 months follow-up and are performed as part of the usual care for this
group of patients. Therefore, patients do not undergo any extra physical measurements.
To be able to control for possible confounders, demographics will be measured at
baseline, along with personal and family history of mood disorders, using a subset of the
Diagnostic Interview Schedule (DIS) [47]. The occurrence of co-morbid chronic illnesses
will be assessed with the Dutch questionnaire chronic illnesses [48] at baseline and after
6 and 12 months, as well as locus of control [49]and social support [50]. All these

measurements were previously used for the same purposes in the West Friesland Study
[51]. In addition to this, anxiety symptoms will be measured at baseline, 3, 6, 9 and 12
months by the Hospital Anxiety and Depression Scale- Anxiety (HADS-A) [52].
After 12 months the uptake of the stepped-care program will be evaluated. The number of
contacts with the care manager, the number of PST sessions, antidepressant use, and the
number of referrals to the GP will be assessed by the care manager in the intervention
group. Mental health care utilization outside the general practice will be assessed using
the TiC-P questionnaire [46].
A process evaluation will be performed in which the barriers and facilitators of the
stepped-care program and the experiences with the program will be evaluated. This will
be done by organizing focus groups among volunteering patients, general practitioners
and primary care nurses. In addition, satisfaction with the received care will be measured
in all patients after 12 months by using the CSQ [53,54]. An overview of all
measurements and instruments is provided in Table 1.
Table 1. Overview of all measurements and instruments
Sample size
The trial is powered to detect a difference of 15% in the cumulative incidence rates of
MINI/DSM-IV depressive disorder between the conditions after 1 year. The incidence
rate is expected to be 30% in the usual care group and 15% in the intervention group
based on findings from earlier studies [2,25,26]. Using a standard sample size calculation,
121 patients per group are needed, assuming a power of 0.8 and an alpha of 0.05.
However, we need to correct for the fact that there is a multilevel setting with three
levels: GPs, patients and measurements. Therefore we have first adjusted for the fact that
we do not have one, but multiple measurements per patient. Assuming these
measurements are clustered with an intraclass correlation (ICC) of 0.45, seventy-one
patients per group are needed. Subsequently, we adjusted this figure further for clustering
of patients within GP practices. Assuming an ICC of 0.05 for clustering of patients within

the 30 GP practices, we need a total of 177 patients. Finally, we adjusted for a dropout
rate of 25%, which means that 236 patients (118 patients per group) need to be included
in this trial. This power calculation is based on the method described by Twisk in 2006
[55].
Statistical analyses
Baseline data will be presented comparing the two treatment groups.
All analyses will be on an intention-to-treat basis. Differences between the stepped-care
group and the usual care group will be tested using mixed model analyses. To test the
cumulative incidence of depression over time, logistic mixed model analysis will be used.
The obtained odds ratio describes the reduction in the risk of a MINI/DSM-IV depressive
disorder in the intervention group relative to the control group. Linear and logistic mixed
models (depending on the outcome) will also be used to test differences in symptoms of
depression and anxiety and quality of life between both groups over time. If necessary,
the models will be adjusted for confounders.
Sub group analyses will be performed to check for an interaction effect between
depression severity at baseline and improvement in depressive symptoms at 12 months.
In case of unequal distributions of demographic variables between the two treatment
groups, multivariate analyses techniques will be used to correct for these differences.
Economic evaluation
Both a cost-effectiveness analysis and a cost-utility analysis will be performed. Missing
cost and effect data will be imputed using multiple imputation according to the MICE
algorithm developed by Van Buuren [56]. The results of the imputed datasets will be
pooled using Rubins rules [57]. Costs typically have a highly skewed distribution. Policy
makers want to have information on the difference in mean total costs between the two
treatment groups in order to be able to estimate the total health care budget needed for a
specific condition [58]. Therefore, bias-corrected and accelerated bootstrapping with

5000 replications will be used to estimate 95% confidence intervals around the mean
difference in total costs between the treatment groups. Incremental cost-effectiveness
ratios (ICERs) will be calculated by dividing the difference in mean total costs between
the treatment groups, by the difference in mean effects between the treatment groups.
Bootstrapping will also be used to estimate the uncertainty surrounding the ICERs, which
will be graphically presented on cost-effectiveness planes. Cost- effectiveness
acceptability curves will be estimated as well. Cost-effectiveness acceptability curves
show the probability that the stepped-care program is cost-effective in comparison with
usual care for a range of different ceiling ratios (i.e. the willingness to pay for 1 extra
recovered patient), thereby showing decision uncertainty [59].

Discussion
Based on earlier studies, there is substantial evidence that stepped-care programs for
depression among primary care patients are effective in both improving and preventing
depression. However, evidence concerning the costs and effects of such programs among
patients with DM2 and/or CHD and subthreshold depression in general practices is still
missing.
Given the large number of DM2 and CHD patients with depressive symptoms, and the
limited capacity for depression treatment in primary care, there is an urgent need to
improve care for these patients. Since the presence of subthreshold depressive symptoms
is the largest risk factor for developing major depression, targeting preventive treatments
to patients at risk for developing a major depression is a viable option to reduce the
burden of depression in primary care. Stepped-care interventions are a very promising
method to achieve this goal. The key of stepped-care, delivered by a care manager, is that
treatment is tailored to the needs and preferences of the patient while making the best use
of available recourses. This will help optimizing health related outcomes, as well as
keeping the treatment affordable by saving available resources for patients who really
need them.

By testing a stepped-care program to prevent depression among high risk DM2 and/or
CHD patients in a primary care setting, this study is highly clinically and societally
relevant. Moreover, because a structured evaluation of the feasibility of the stepped-care
program is explicitly taken into account in the study design, the results of this cluster
randomised controlled trial will greatly contribute to the practical evidence about
preventive treatment options for depression in patients with DM2 and/or CHD in general
practice.
A strength of this study is that a pragmatic study design is employed; meaning that
patients, treatments and procedures are similar to daily clinical practice. This greatly
enhances the generalizability of the findings of the study and therefore the possibilities to
implement the Step-Dep treatment in a real-life primary care setting.
The relatively short 12 month follow-up period may turn out to be a limitation of this
trial. It is possible that the potential health benefits of participating in the stepped-care
program will not yet be fully visible after one year. Especially the beneficial effects of
having less depressive symptoms on health care utilisation, work absenteeism, and
clinical outcomes such as Hb1Ac, blood pressure and LDL cholesterol, may take longer
than the follow up period of one year to reach full development. Katon and his
colleagues, for example, found a significant reduction in total health care costs among
DM2 patients that participated in a stepped-care intervention to treat major depression
after two years, but not yet after 12 months [30]. Other studies report similar results [6062]. These findings can be explained by the fact that the extra costs of stepped-care
interventions are made in the first year, while the cumulative effects of the treatment will
become more and more visible after the treatment is finished. Therefore it might be
necessary to perform a follow up study when the results indicate such a delay in
cumulative effects.
Another possible limitation is that it is not possible to blind patients and caregivers to the
randomisation due to the nature of the stepped-care program. However, considering the

pragmatic design of the study, this is a true representation of clinical practice and this also
enables us to measure all possible effects of the intervention. We try to counter possible
contamination between treatments groups by using a cluster randomized controlled
design, in which staff from usual care practices are not trained to perform the steppedcare program until after the follow up period. That way, caregivers cannot unintentionally
apply aspects of the stepped-care program to their usual care for patients.
Overall, this study will provide valuable information about the cost-effectiveness and
feasibility of a stepped-care program in primary care to prevent major depression in
DM2/CHD patients with subthreshold depression, both from a clinical and societal
perspective. When the stepped-care program proves to be cost-effective, the results of
this study will offer a unique venture point for implementation of the stepped-care
program into primary care and further research. The first results of this trial are expected
in 2015.

Abbreviations
CHD: Coronary Heart Disease; CSQ: Client Satisfaction Questionnaire; DIS: Diagnostic
Interview Schedule; DM2: Type 2 Diabetes Mellitus; DSM-IV: Diagnostic and Statistical
Manual of Mental Disorders-IV; EQ-5D: EuroQol- 5 dimensions; GPs: General Practices;
HADS-A: Hospital Anxiety and Depression Scale-A; ICC: Intraclass correlation; ICERs:
Incremental Cost-Effectiveness Ratios; ICPC: International Classification of Primary
Care; LDL cholesterol: Low-Density Lipoprotein cholesterol; PHQ-2: Patient Health
Questionnaire-2; PHQ-9: Patient Health Questionnaire- 9; PST: Problem Solving
Treatment.

Competing interests
The authors declare that they have no competing interests.

Authors contributions

SvD constructed the design of the study and drafted the manuscript. AP constructed the
design of the study and revised the manuscript. MCA, JB, PE and HvM developed the
study, constructed the design and revised the manuscript. MvT participated in the design
of the study and revised the manuscript. The final manuscript was read and approved by
all authors.

Acknowledgements and funding


This study is funded by ZonMw, the Netherlands Organisation for Health Research and
Development (project number 80-82310-97-12110). Publication in this Open Access
journal was funded by NWO, the Netherlands Organisation for Scientific Research.
The Authors would like to thank Hanna Joosten, data manager at the Department of
General Practice, VU University Medical Centre, Amsterdam, for helping us out by
estimating the feasibility of the trial based on a registration sample of the Academic
Network of General Practitioners (GPs) of the Department of General practice of the VU
medical centre.

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6
Study protocol

Health coaching to promote healthier


lifestyle among older people at
moderate risk for cardiovascular
diseases, diabetes and depression: a
study protocol for a randomized
controlled trial in Sweden
Klas-Gran Sahlen12*, Helene Johansson1, Lennarth Nystrm1 and Lars
Lindholm1

* Corresponding author: Klas-Gran Sahlen klasse.sahlen@nurs.umu.se


Equal contributors

Author Affiliations
1

Department of Public Health and Clinical Medicine, Division of Epidemiology and


Global Health, Ume University, SE-901 85 Ume, Sweden
2

2Department of Nursing, Ume University, SE-901 85 Ume, Sweden

For all author emails, please log on.


BMC Public Health 2013, 13:199 doi:10.1186/1471-2458-13-199

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-2458/13/199
28 January
2013
28 February
Accepted:
2013
Published: 6 March 2013
Received:

2013 Sahlen et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
The challenge of an aging population in the society makes it important to find strategies
to promote health for all. The aim of this study is to evaluate if repeated health coaching
in terms of motivational interviewing, and an offer of wide range of activities, will
contribute to positive lifestyle modifications and health among persons aged 6075 years,
with moderately elevated risk for cardiovascular disease (CVD), diabetes, or mild
depression.
Methods/Design
Men and women between 60 and 75 are recruited in four regions in Sweden if they fulfill
one or more of the four inclusion criteria.
Current reading of blood pressure (140-159/90-99) without medication.
Current reading of blood sugar (Hba1c 4252 mmol/mol) without medication.
A current waist-circumference of 94 cm for men and 80 for women.
A minor/mild depression (1220 points) according to Montgomery-sberg Depression
Rating Scale without medication.
Individuals with a worse result than inclusion criteria are treated according to regular
guidelines at the PHCs and therefore not included. Exclusion criteria for the study are
dementia, mental illness or other condition deemed unsuitable for participation.

All participants fill out a questionnaire at baseline, and at the 6-, 12- and 18-month
follow-ups containing questions on demographic characteristics, social life, HRQoL,
lifestyle habits, general health/medication, self-rated mental health, and sense of
coherence. At the 12-month follow-up, the health coach will give each participant a
second questionnaire to capture attitudes and perceptions related to health coaching and
venues/activities offered.
Qualitative data will be collected twice to obtain a deeper understanding of perceptions
and attitudes related to health and lifestyle/lifestyle modifications. A health economic
assessment will be performed. Individual costs for health care utilisation will be collected
and QALY-scores will be estimated.
Discussion
Several drawbacks can be identified when conducting research in real life. However,
many of the identified problems can diminish the positive results of the intervention and
if the intervention shows positive effects they might be underestimated.
Trial registration
Current Controlled Trials ISRCTN01396033.

Keywords:
Life style changes; Prevention; Motivational interviewing; Older people; RCT;
Health coaching; Health economics

Background
In 2025, one third of the Swedish population will be 60 years or older; in 2050, the
average life expectancy is predicted to rise to 86.2 years for women and 83.6 years for
men [1]. A higher proportion of the elderly may increase the demand for health care and
elderly care [2].
In Sweden, the county councils/regions (n=21) are responsible for health care while the
municipalities (n=290) are responsible for elderly care. There is no hierarchical relation

between counties/regions and municipalities since they each have their own selfgoverning local authority with responsibilities for different activities.
Elderly care and health care are fundamental to the Swedish welfare model. They are
publically financed, available to all according to needs. Elderly care is provided through a
wide range of services, including home services, sheltered houses, housing adaption,
transportation services, etc.[3], while health care is provided mainly by hospitals and
primary health care. Half of the county councils/regions budget is allocated to hospital
care and 16% to primary health care. In 2010, Sweden spent 3.2% of the gross domestic
product (GDP) [4] for elderly care and 9.7% for health care [5] of which the majority is
utilized by older people, similarly to other contexts [6].
The possible resource savings in health care and elderly care through health promotion
and preventive activities are great, and in the short term likely to be even greater for older
than for younger persons due to the fact that the older use more resources [2,7]. The
demographic transition is a challenge regarding the need of health care and elderly care,
and that challenge implies a great potential for improvement.
A key objective of Swedish national public health policy is to give the elderly the chance
to live a good life with high quality. Public health policy also emphasizes that effective
public health work is based on a shared responsibility between the public and non-profit
sectors. Collaboration increases the possibilities to develop more and better ways to
understand and influence health [8]. Accordingly, it is crucial for counties, municipalities
and the non-profit sector to invest in health promotion activities. Improving the
conditions for the development of better health promotion can lead to increased wellbeing and less disability in older people, and the need for care can be postponed.
The challenge of an aging population in the society led to the government commissioning
the Swedish National Institute of Public Health (SNIPH) to develop and manage a
partnership model for healthy aging. Collaboration amongst county councils,
municipalities and non-profit organizations is the foundation for the partnership model.

The goal is to facilitate collaboration on different activities that will help older people
with mild illness to change their lifestyle. A specific part of the mission is to launch an
intervention directed to the target group aged 6075 years with moderately elevated risk
for cardiovascular disease (CVD), diabetes, or mild depression. Through repeated health
coaching sessions and opportunities to visit venues and participate in various physical,
social and cultural activities, participants will be supported to better health through
lifestyle modifications. An independent research-based process and outcome assessment
will be made of this intervention.
This study protocol describes the design of the intervention, with a focus on the outcome
assessment.
Aim
The aim of this study is to evaluate if repeated health coaching in terms of motivational
Interviewing (MI) [9] will contribute to positive lifestyle modifications and health among
persons aged 6075 years, with moderately elevated risk for cardiovascular disease
(CVD), diabetes, or mild depression. The specific aims are to estimate the impact of the
intervention on the health-related quality of life (HRQoL), clinical parameters and
measurements (especially blood pressure, HbA1c and waist circumference), self-reported
lifestyle habits and whether the intervention is cost-effective.

Design/Methods
Institutional responsibilities and intervention
Four county councils/regions with a total of 17 associated municipalities are included in
the intervention. The intervention may be described as a partnership for healthy aging.
The partnership refers to the local primary health care center (PHC) and the municipality
as each of them is responsible for one part of the project: the PHC for the health coaching
and the municipality for the organization and responsibility for local venues.

In addition, SNIPH and the non-profit sector each have their roles but share the same
goal, to promote health and facilitate lifestyle modification from a holistic perspective.
The Swedish National Institute of Public Health (SNIPH)
SNIPH is responsible for management, education, and financial issues of the intervention.
To increase the willingness of the county councils/regions to participate, the SNIPH
allocated 15,000 SEK (1750 Euro) per participant in the intervention group and 3000
SEK (350 Euro) per participant in the control group, to cover all costs including
intervention management costs.
Communication with the government and recruiting stakeholders started in 2010. The
recruitment of four county councils/regions interested in preventive activities was
finalized during spring 2011: they are Skne, Jnkping, Srmland and Vrmland
(Figure1). These county councils/regions were selected from different parts of Sweden to
include different socio-cultural living conditions.

Figure 1. Selected county councils/regions and included health care


centers.
In order to prepare for the intervention, SNIPH carried out educational activities in each
county council/region, inviting personnel from both the PHCs and the venues. The goal
was to gain a mutual understanding on concepts and methods used in the intervention,
and on how active and healthy aging can be promoted. Main topics at the educational
activities were inclusion criteria, measurements, the roles of different actors, learning
more about MI and stimulating the development of venues and related activities.
The county councils/regions

In collaboration with the municipalities, the county councils/regions selected a total of 21


PHCs (Figure1). In each county council/region, one project manager is responsible for
the activities operated by the PHCs, and for carrying the collaborative work forward
together with the municipalities. The selection of PHCs was made to represent both urban
and rural areas as well as different socio-economic structures.
The PHC is responsible for recruiting health coaches with suitable educational
qualifications and experiences, e.g. physiotherapists or community health nurses.
Furthermore, the PHC is in charge of recruiting participants to the intervention. Methods
for recruiting are advertising, information given at the PHCs, active outreach in public
places, such as information to senior organizations, and letters of invitation to participate
generated from patient records. The PHC is also responsible for initial screening,
randomization to the control group or the intervention group, follow-up measurements
and recording and storing data.
All participants have access to regular primary care. Participants in the intervention group
are offered repeated health coaching sessions based on MI, including recommendation
and motivation to participate in different physical, social and cultural activities. Persons
developing high blood pressure or diabetes during the intervention period will be treated
following available practices at each PHC. Test results are communicated to the
participants in the intervention group during the MI session and to participants in the
control group by the ordinary staff at the PHC.
The role of the health coaches is by MI, to motivate and support participants to modify
their lifestyle. The completed questionnaires and the results from the measurements
should be used as points of departure for the MI sessions.
The health coach and the participant meet at baseline and after 3, 6 and 12 months. In
between these planned meetings, opportunities will be given for additional supporting
conversations though extra meetings or telephone calls to increase the likelihood of
lifestyle modifications.

In addition to MI, the participants will be offered and, depending on the individual
motivation, encouraged to participate in activities available at venues operated by
municipalities and non-profit organizations. Health coaches have enough knowledge
about venues in the surrounding area to help participants find a suitable type of activity.
MI is an evidence-based approach built on cooperation between the interviewer and the
individual. Individual motivation or resistance to events such as lifestyle changes plays a
significant role in health and can be influenced by the interviewer's conversation
strategies. The use of MI is growing rapidly, and there is strong evidence that MI is an
effective treatment, especially with alcohol, tobacco and drug abuse but also in other
behavioural changes. MI is more effective than traditional counselling, and MI effects are
more prolonged and stable than other interventions ([10]). Furthermore, MI is regarded as
cost-effective ([11]).
To ensure the quality of the interview technique, all health coaches were offered five MI
conversations spread over 18 months and coded according to Motivational Interviewing
Treatment Integrity Code 3.1. (MITI) [12]. The coaches sent in a tape of 20 minutes of
MI conversation to Miclab [13], which conducted the coding. The MITI is a behavioural
coding system which includes coding of twelve variables and estimates how well the MI
is applied by the health coach. This method is used both as a treatment integrity measure
of MI and to provide structured, formal feedback to the practitioner.
The municipalities
The municipalities are responsible for organizing venues. The venues should offer health
promoting activities that meet the participants interests and need. A venue can either be
operated by the municipalities or by non-profit organizations. Four factors are important
to promote healthy aging (known as the four cornerstones); physical activity, healthy
eating habits, social interaction/support and participation/meaningfulness/feeling. These
four factors can affect health, especially for those who are still independent [14]. Hence,
the requirements for venues are opportunities for physical activities, activities related to

food and cooking, as well as cultural and social activities. The social activities should
promote the creation of new relationships and fellowship among the participants and can
vary depending on local conditions. One municipality has identified 43 venues, among
which are found the city library, the art museum, yoga sessions, gyms, hydro-gymnastics,
health lecturers and cooking courses. Another municipality, though, offers only three
specific activities for participants.
Each municipality has a local coordinator who has the overall knowledge about the
venues/activities offered by the municipalities as well as by non-profit organizations. The
local coordinators are responsible for the development of venues and interaction with the
stakeholders.
The non-profit sector
Non-profit organizations have no particular area of responsibility, but since they already
run a range of physical and social activities, their involvement is considered necessary to
meet the needs of the target population. Through collaboration with the municipalities,
the non-profit sectors expertise may be used to add resources in health promotion among
the elderly.
Study population
The financial framework provided by the government allowed recruitment of 2000
participants, of which 1500 were assigned to the intervention group and 500 to the
control group.
The target group comprises persons aged 6075 years with early signs of hypertension,
diabetes, obesity or mild depression. The following four inclusion criteria were applied:
1. Current reading of blood pressure (140-159/90-99) without medication.
2. Current reading of blood sugar (Hba1c 4252 mmol/mol) without medication.

3. A current waist-circumference of 94 cm for men and 80 for women.


4. A minor/mild depression (1220 points) according to Montgomery-sberg Depression
Rating Scale (MADRS) [15,16] without medication.
Individuals with a worse result than inclusion criteria are treated according to regular
guidelines at the PHCs and therefore not included. Exclusion criteria for the study are
dementia, mental illness or other condition deemed unsuitable for participation.
Randomization
The randomization procedure was done in two steps. First, each PHC centre received a
list with code (ID) numbers where each number was assigned to either intervention or
control group by using Excel software. By random assignment each included participant
was given an ID number and allocated to the corresponding group. The total number of
codes for each PHC differed, depending on the number of participants planned to recruit,
but the distribution between intervention and control group were the same.
Data collection
Measurements
At baseline and at 6, 12 and 18 months (Figure2), the following measurements will be
made of all participants according to the standardized procedures shown in Table1: blood
pressure, waistline, weight, blood sugar level, cholesterol levels, resting heart rate and 6Minute Walk Test [17]. Height will only be measured at baseline.

Figure 2. Timing of data collection and measurement instruments


used.

Table 1. Standardized procedures of measurements


Questionnaires
All participants fill out a questionnaire (Q1) at baseline, and at the 6-, 12- and 18-month
follow-ups containing questions on demographic characteristics (only assessed at
baseline), social life, HRQoL (EQ5D) [19,20], lifestyle habits, general health/medication,
self-rated mental health (MADRS) [16,21], and sense of coherence (SOC-13) [22-24]
(Table2).
Table 2. Questionnaire areas with associated variables and references
At the 12-month follow-up, the health coach will give each participant a questionnaire
(Q2) and a pre-paid return envelope addressed to the research group. The aim of Q2 is to
capture attitudes and perceptions related to health coaching and venues/activities offered.
The participants are instructed to fill out the questionnaire at home and send it by surface
mail.
Focus group discussions (FGDs)/in-depth interviews
Qualitative data will be collected twice: at the beginning of the intervention and after the
last MI at the 18-month follow-up. This is mainly to obtain a deeper understanding of
perceptions and attitudes related to health and lifestyle/lifestyle modifications, as well as
experiences of health coaching and venues. Focus group discussions will be held only in
the intervention group.
One PHC in each county will be selected, guided by the pursuit of variation (urban/rural,
high/low percentage of immigrants, women/men, etc.). Focus group discussions will be
supplemented by a number of in-depth interviews. The study adheres to the RATS
guidelines.
Health economy

A health economic assessment will be performed. Costs for the intervention will be
gathered from counties/regions and municipalities. Individual costs for health care
utilisation will be collected from medical records and registers. QALY-scores are
estimated for each individual based on their answers in the questionnaire and the cost per
QALY gained will be estimated.
Data management
A prepared Excel document is delivered to every PHC. For each individual, a personal ID
is created from the county ID, the PHC ID and a random individual ID. All ID numbers
belong to either the control group or the intervention group. All data transferred from the
PHC to the research group are anonymous.
The Excel document is organized to store one sheet for each period of data collection.
Every cell in the document is prepared to minimize errors. Data collected at baseline are
more comprehensive than the following as they contain background characteristics of the
participants.
Outcome measures
The possible effect of lifestyle changes will be estimated for participants fulfilling each of
the four inclusion criteria. Thus, primary outcome variables are blood pressure, HbA1c,
waist circumference and the MADRS scale [16,21]. Effects on participants fulfillingq
more than one criterion will also be analysed. Independently of inclusion criteria, the
health-related quality of life will be followed over time using the instrument EQ-5D [19]
as well as the clinical parameters triglycerides, HDL and LDL.
In addition, we will analyse some participant performance indicators related to the four
cornerstones for healthy life [14]. These indicators are the validated SOC questionnaire
[24], self-assessed frequency of physical activity, 6-minute walk test, and self-assessed
frequency of eating habits.
Data analysis

The difference between measurements at baseline and at the 6-, 12- and 18-month followups will be calculated, and the estimates in the intervention groups will be compared with
the controls. Time trend analysis will be applied to test for a possible trend pattern.
EQ5D score is assumed to be 0,8 in the intervention group and 0,75 in the control group,
and the standard deviation is assumed to be 0,3 in both groups. The intervention groups
should be three times larger than the control group, power equal to 0,8 and alpha equal to
0,05. A two-side test requires thus 1132+377 = 1509.
Interviews and FGDs will be analysed using qualitative content analysis [27].
Ethics and trial registration
All participants are informed about the purpose of the study. Written informed consent is
obtained and participants are ensured confidentiality. They are all informed about the
possibility to end their participation whenever they want. All data are collected at each
PHC and handled with secrecy. All participants are given a unique ID number which is
sent together with data to the research group. The Regional Ethical Review Board in
Ume, Sweden, approved the study in August 2011, ref: Dnr 2011-230-31. The
intervention is registered at the Current Controlled Trials web page (ISRCTN01396033).

Discussion
To do research in real life settings is challenging. There are a number of problems and
drawbacks that are important to be aware of that might introduce problems in drawing
definite conclusions.
It is time-consuming and difficult to educate and instruct health coaches in more than 20
PCC units. In total, at least 100 staff persons are involved in the intervention. We have
tried to write a concrete and comprehensive manual to cover all questions regarding how
to recruit participants, how to get informed consent, how to randomize participants, how
to register the questionnaires, how to make the medical and functional tests, how to

register the test results and how to send the data to the research group. However, during
the process, new questions have arisen, and even topics that are covered in the manual
have not always been understood properly. These factors may introduce error in the
results.
MI is a relatively well-known and widespread method that is used as a tool in
intervention as well as part ofusual primary care. This may reduce differences between
the control group and the intervention group. However, in the present study, the health
coaches dispose radically more resources in the intervention group than a usual PHC does
for participants in the control group.
County councils/regions that initially were invited to participate in this intervention were
characterized as being in the forefront among Swedish counties with regard to preventive
actions. This selection may diminish the potential of the method since other county
councils/regions might have more to gain by implementing a successful strategy.
The staffs at the PHC are continuously informed on the importance of lifestyle changes
that might affect ordinary work and thus also affect the control group. This may reduce
the differences between the intervention group and the control group and thus diminish a
possible positive result.
Controls were selected at the same PHC unit, implying that they are living in the same
context as those who get the MI intervention, but this can also introduce a couple of
problems. Firstly, some of the controls might be affected by neighbours and relatives who
get the intervention. Secondly, when a person in the control group makes progress (as a
result of the intervention tests) and receives care according to current procedures and care
programs at the PCC unit, this may be regarded as an intervention in itself. The
comparison between groups is supposed to be between regular care and intervention, but
it could be a comparison between two interventions as even the control group receives
intervention in the form of testing and questionnaires. Both problems will reduce the
differences between the two groups and hence positive effects may be underestimated.

The intervention comprises MI and the described tests and questionnaires. In addition,
municipalities offer social meeting points. They can be organized and carried through
differently in different settings. If one health coach can refer to a successful meeting
point, it can be interpreted as a positive way of working with the MI. However, this will
not affect the differences between the two groups, since both groups will gain or suffer
from the same local differences.

Abbreviations
BP: Blood pressure; CVD: Cardiovascular disease; EQ5D: EuroQol 5 dimensions; GDP:
Gross domestic product; HRQoL: Health-related quality of life; MI: Motivational
Interviewing; MADRS: Montgomery-sberg Depression Rating Scale; SNIPH: Swedish
National Institute of Public Health; SOC: Sense of coherence; VAS: Visual analogue
scale.

Competing interests
All authors declare that they have no competing interests.

Authors contributions
All authors have made substantial contributions to this manuscript and the final version is
a result of several discussions and team work among the authors. KGS, LL, LN, and HJ
worked together with the study design. KGS made the first draft of the paper and HJ
made substantial contribution to the draft. LN and LL contributed to the final version by
writing and structuring the article. LL developed the health economic part. LL, LN, HJ,
and KGS all approved the final version.

Acknowledgements
We would like to acknowledge Swedish National Institute of Public Health for financing
the project. In addition we would like to acknowledge Anna Jansson, coordinator for the
project at Swedish National Institute of Public Health.

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7
Research Article

Depression and Risk of Mortality in


People with Diabetes Mellitus: A
Systematic Review and Meta-Analysis

Fleur E. P. van Dooren,


Giesje Nefs,
Miranda T. Schram,
Frans R. J. Verhey,
Johan Denollet,
Franois Pouwer mail

Article
About the Authors
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Abstract

Introduction
Methods
Results
Discussion
Supporting Information
Acknowledgments
Author Contributions
References

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Abstract
Objective
To examine the association between depression and all-cause and cardiovascular
mortality in people with diabetes by systematically reviewing the literature and carrying
out a meta-analysis of relevant longitudinal studies.

Research Design and Methods


PUBMED and PSYCINFO were searched for articles assessing mortality risk associated
with depression in diabetes up until August 16, 2012. The pooled hazard ratios were
calculated using random-effects models.

Results
Sixteen studies met the inclusion criteria, which were pooled in an overall all-cause
mortality estimate, and five in a cardiovascular mortality estimate. After adjustment for
demographic variables and micro- and macrovascular complications, depression was
associated with an increased risk of all-cause mortality (HR = 1.46, 95% CI = 1.291.66),
and cardiovascular mortality (HR = 1.39, 95% CI = 1.111.73). Heterogeneity across
studies was high for all-cause mortality and relatively low for cardiovascular mortality,
with an I-squared of respectively 78.6% and 39.6%. Subgroup analyses showed that the
association between depression and mortality not significantly change when excluding
three articles presenting odds ratios, yet this decreased heterogeneity substantially (HR =
1.49, 95% CI = 1.391.61, I-squared = 15.1%). A comparison between type 1 and type 2
diabetes could not be undertaken, as only one study reported on type 1 diabetes
specifically.

Conclusions
Depression is associated with an almost 1.5-fold increased risk of mortality in people
with diabetes. Research should focus on both cardiovascular and non-cardiovascular

causes of death associated with depression, and determine the underlying behavioral and
physiological mechanisms that may explain this association.
Citation: van Dooren FEP, Nefs G, Schram MT, Verhey FRJ, Denollet J, et al. (2013)
Depression and Risk of Mortality in People with Diabetes Mellitus: A Systematic Review
and Meta-Analysis. PLoS ONE 8(3): e57058. doi:10.1371/journal.pone.0057058
Editor: Heiner K. Berthold, Charit University Medicine Berlin, Germany
Received: August 31, 2012; Accepted: January 17, 2013; Published: March 5, 2013
Copyright: 2013 van Dooren et al. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are
credited.
Funding: Funded by Tilburg University and Maastricht University. The funders had no
role in study design, data collection and analysis, decision to publish, or preparation of
the manuscript.
Competing interests: The authors have declared that no competing interests exist.

Introduction
Depression is common in people with diabetes, affecting approximately 20% of the
patients [1], [2]. Two meta-analyses revealed that people with type 2 diabetes mellitus are
1524% more likely to develop depression compared to people without diabetes [3], [4].
Furthermore, individuals with previously diagnosed diabetes have an increased risk of
depression relative to those with impaired glucose metabolism or undiagnosed diabetes
[5]. Depressed individuals with diabetes report lower quality of life [6] have higher
HbA1c levels, indicating suboptimal glycemic control [7] and are characterized by poor
self-care behavior that may contribute to suboptimal glycemic control [8]. They
demonstrate lower levels of physical activity [9], have more negative appraisals of insulin
therapy [10], are likely to be less adherent to the prescribed treatment regimen and have
less healthy eating behaviors [8].
Several longitudinal epidemiological studies concluded that the combination of diabetes
mellitus and depression is associated with higher mortality rates [11], [12], [13]. For
example, Black et al. [11] demonstrated that people with comorbid depression and
diabetes have a higher risk of developing diabetes-related complications and also
mortality, than those with depression or diabetes alone or without either condition.
Lin and colleagues [14] showed that people with type 2 diabetes and comorbid
depression had a 36% increased risk of developing microvascular complications such as
end-stage renal disease, low vision or blindness, retinopathy, foot ulcers or amputations,
compared to individuals with diabetes without depression. Furthermore, a 25% higher

risk of developing macrovascular complications, such as myocardial infarction or stroke,


was established.
However, the research question whether depression in diabetes is associated with an
increased mortality risk has not been the subject of a systematic review and metaanalysis. Therefore, the objective of the present paper was to examine whether depression
increases the risk for all-cause and cardiovascular mortality in people with diabetes, both
by (a) reviewing the literature in a systematic way and (b) carrying out a meta-analysis of
longitudinal studies on this subject.

Methods
Search Strategy
Literature searches were conducted through August 16, 2012 using the electronic
databases PUBMED and PSYCINFO. The following search terms were applied:
diabetes (title/abstract) or the medical subject headings (MeSH) Diabetes Mellitus, in
combination with depression (title/abstract) or depressive disorder (title/abstract) or
depressive (title/abstract) or the MeSH terms Depression or Depressive disorder,
combined with mortality (title/abstract) or death (title/abstract) or the MeSH terms
Mortality or Death or Diabetes Complications/mortality, combined with cohort
study (title/abstract) or longitudinal (title/abstract) or prospective (title/abstract) or
cohort (title/abstract) or the MeSH term Cohort Studies. No restrictions were used.
Additionally, reference lists of included articles were screened by the first author (FvD)
to detect complementary articles which met the selection criteria.
Study Selection
Two authors (FvD, GN) independently evaluated the articles for eligibility. Studies that
met the following criteria were included: 1) the study design was longitudinal, including
both retrospective as prospective studies, 2) the study population included people
diagnosed with diabetes (clinical or self-report) either as total sample or subgroup, 3) the
outcome variable was mortality, 4) the association between baseline depression (yes/no,
clinical diagnosis or self-report) and mortality during follow up was analysed. Studies
presenting clinical trials meeting these inclusion criteria were not included in the metaanalysis, considering these studies describe the effect of a treatment in people with
diabetes and depression on mortality and not the effect of depression on mortality in
people with diabetes.
All discrepancies were resolved after rechecking the source papers and further discussion
among both authors, and consultation of a third co-author (FP) where needed, with full
consensus before inclusion. Regarding multiple reports on the same dataset, only one
report was included in the meta-analysis, based upon population size (largest sample
size), aim of the article (with mortality as the main end point) and primary analysis (as
compared to secondary analysis). Three corresponding authors were contacted for
additional information, but we did not receive further information. No restriction on type

of language was placed. Figure 1 depicts the process of article selection by means of a
flow diagram.

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Figure 1. Flow diagram for selection of studies.


doi:10.1371/journal.pone.0057058.g001

Endpoint
The endpoint was all-cause mortality and, where available, cardiovascular mortality.
Data Extraction and Statistical Analysis
The results of the data extraction were summarized in a systematic manner including the
following information: first author name, publication year, country of study, length of
follow-up, study design and sample size (mean age, % female, type of diabetes), number
of depression cases, assessment method of diabetes/depression/mortality (Table 1),
hazard ratios (HRs) with corresponding 95% CI and multivariable adjustment (Table 2).

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Table 1. Overview of all included studies, sorted on publication date in descending


order.
doi:10.1371/journal.pone.0057058.t001

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Table 2. All-cause and cardiovascular mortality risk in people with diabetes and
depression, compared to people with diabetes without depression.
doi:10.1371/journal.pone.0057058.t002

Data from all studies were pooled using the program Comprehensive Meta-Analysis
version 2 (Biostat, Englewood NJ, 2005). If multiple hazard ratios were presented in a
given article, the estimate that most closely adjusted for demographic variables and
micro- and/or macrovascular complications (e.g. retinopathy, neuropathy) was selected,
to expose the independent effect of depression.

When appropriate, the meta-analysis will be performed using the fixed effects or the
random effects model: in case of homogeneity (or low heterogeneity) the fixed effects
model will be used. If heterogeneity is substantial (above 50%) the random effects model
will be used. In two studies [11], [15] more than one measure of depression was used.
Black and colleagues [11] measured depressive symptoms at baseline with the CES-D,
and also used a modified version of the CIDI at two years follow up to determine whether
patients suffered from a depressive disorder. Depressive symptom-scores were included,
as they were measured at baseline. Sullivan et al. [15] reported minor and major
depression based on the PHQ-9, the dichotomisation of PHQ-910 and the continuous
PHQ-9 score. As combining major and minor depression into one estimate would require
an additional step, the readily available dichotomised PHQ-9 score was used.
For three studies [11], [14], [16] hazard ratios needed to be combined in order to obtain
the estimate of interest (example of procedure explained in Figure S1 in Supporting
Information S1). In one paper [16] the hazard ratios for men and women were separately
reported. In the case of Lin et al. [17] we assembled the hazard ratio for minor and major
depression into one depression hazard ratio. For Black et al. [11], we combined the group
with minimal depression (CES-D = 115) and without any depressive symptoms (CES-D
= 0) into one group (CES-D <16).
Five studies [11], [18], [19], [20], [21] used the no diabetes, non-depressed group as the
reference category, while we were interested in the comparison of the two diabetes
groups only (depressed versus non-depressed). Two of these studies [18], [21] performed
post hoc analyses in people with diabetes only, producing the desired estimate.
For the other three studies, we used the information from the four group scenario to
calculate the HR for the comparison of the depressed and non-depressed diabetes groups
(example of procedure explained in Figure S2 in Supporting Information S1).
In two papers [13], [22] no hazard ratios or odds ratios were presented, so the odds ratios
and confidence intervals for these studies were calculated based on the number of
patients who died in each group.
Statistical heterogeneity was assessed using the I-squared statistic, which quantifies the
percentage of total variation across studies due to heterogeneity rather than chance, with
values of 50% or more indicating a substantial level of heterogeneity [23]. When study
outcomes were heterogeneous based on this statistic, the potential influence of follow-up
length, age, method of depression assessment, method of diabetes assessment, number of
participants and the percentage of females included were examined. Differences in effect
estimates between the subgroups were assessed by comparing the pooled effect estimates
using chi-squared analysis, comparing logarithms of these estimates. Additionally, a
sensitivity analysis where each study is removed one by one was done.
Potential publication bias was assessed with Eggers test of the intercept [24]. A funnel
plot was constructed by plotting the effect measure against the inverse of its standard
error (see Figure S3 in Supporting Information S1. An asymmetric plot indicates a likely

publication bias, and p<0.05 is considered representative of statistically significant


publication bias.

Results
A total of 400 potentially relevant articles were retrieved by the database searches (Figure
1). From this set, 34 full-text articles were assessed for eligibility. Of these, 15 articles
met our inclusion criteria and were included in the systematic review. Three of these
articles [13], [22], [25] used a different measure of effect size (odds ratio) which cannot
be pooled in a meta-analysis with hazard ratios [26]. However, odds ratios can be
converted to risk ratios, which then can be combined with hazard ratios in a metaanalysis as forms of relative risks [27].
One additional relevant article that was not indexed for MEDLINE yet, was included in
both the review and meta-analysis [15]. The characteristics and extracted data of the 16
articles are presented in Table 1, and the hazard ratios with corresponding 95%
confidence intervals and covariates used for analysis in Table 2.
All-cause Mortality
Sixteen studies were included in the meta-analysis, comprising 109046 individuals with
diabetes and including 21443 (19.7%) with comorbid depression. The follow-up periods
of included studies ranged from 210 years, with a mean follow-up of 6 years. The mean
age at baseline ranged from 62 to 76 years, with exception of the only article focusing on
type 1 diabetes, with a mean age of 39 years at baseline [16]. Twelve analyses (75%)
showed a statistically significant association between depression and mortality in
individuals with diabetes.
The pooled hazard ratio for mortality was significantly increased in patients with diabetes
and depression compared with those without depression (HR 1.46, 95% CI 1.291.66,
p<0.0001) (Figure 2). The I2 value was 78.6%, demonstrating high heterogeneity in the
study results. After conducting subgroup analyses, there were no significant differences
for follow-up length, age, method of depression assessment, method of diabetes
assessment, number of participants and the percentage of females included. Only a
significant difference was found after excluding the three articles presenting odds ratios
(converted to risk ratios). The pooled hazard ratio of 13 studies presenting hazard ratios
was 1.49, 95% CI 1.391.61 (p<0.0001) (in both random as fixed effects model) and an Isquared statistic of 15.1%.A funnel plot of the 16 studies (Figure S3 in Supporting
Information S1) suggests evidence of publication bias and Eggers test confirmed this
finding showing significant asymmetry (p [one-tailed] <0.05).

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Figure 2. Meta-analysis of the association between depression and all-cause and


cardiovascular mortality.
doi:10.1371/journal.pone.0057058.g002

Cardiovascular Mortality
Five of the 16 studies, comprising 11375 individuals with diabetes and including 2619
(23%) with comorbid depression, also specifically reported on cardiovascular mortality
as separate endpoint. Two examined cardiac mortality, two cardiovascular disease
mortality and one coronary disease mortality. The follow-up periods ranged from 58
years, with a mean follow-up of 6.6 years. The mean age at baseline ranged from 63 to 68
years. Two out of 5 studies found a significant association between depression and
cardiovascular mortality in people with diabetes [19], [21], and there was a trend in a
third study [17]. After pooling the HRs for cardiovascular mortality, the HR was
significant (HR = 1.39, 95% CI 1.111.73, p<0.0001) (Figure 2).

Discussion
This meta-analysis of 16 longitudinal studies shows a positive association between
depression and subsequent mortality rates in people with diabetes. Compared to those
without depression, depressed individuals had a 46% increased risk for all-cause
mortality. Although based on only 5 studies, our results also show a 39% increased risk
for cardiovascular mortality associated with the presence of depression in diabetes.

Previous meta-analyses have also found positive associations between depression and
mortality rates in the general population (RR = 1.81, 95% CI 1.582.07) [28] and in
patients with established heart disease (OR = 2.38, 1.763.22 and OR = 2.59, 1.773.77
for all-cause and cardiac mortality, respectively) [29]. The triad of depression, diabetes
and cardiovascular disease is closely interrelated. Premature cardiovascular disease is the
most common cause of morbidity and mortality in people with diabetes [30] and comorbid depression appears to increase the risk of developing vascular conditions in this
group [11], [15], [17]. However, depression is also common in people with established
cardiovascular disease [31]. Rather than being a (in)direct causal factor, depression in
diabetes may be secondary to having cardiovascular complications. It may owe its
association with mortality to the increased risk of new cardiovascular events in people
with established cardiovascular conditions [32]. We took this issue into account by
including the risk estimates that were adjusted for existing vascular disease, and still
found an almost 1.5-fold increased risk of mortality in depressed people with diabetes.
Further prospective studies are needed to examine whether depression exerts a negative
influence on mortality through the development of new vascular complications. These
studies may also explore whether people with comorbid diabetes and depression face
increased mortality risks beyond cardiovascular deaths, as suggested by recent results
from the Pathways Epidemiologic Follow-up Study [17].
There are several potential behavioral or physiological mechanisms that could explain the
increase of mortality for people with diabetes and depression. Depression is correlated
with a decline in health-maintenance behaviors (e.g. physical activity, smoking, diet) in
general [33], which is also true for people with diabetes [34]. In addition, depression is
associated with several biological alterations; activation of the hypothalamic-pituitaryadrenal axis and proinflammatory cytokines, sympathic nervous system dysregulation,
decrease in heart rate variability and cardiac fibrillation threshold, which can contribute
to an increased risk of cardiovascular mortality, but also mortality of other causes [35].
In line with previous studies examining post-myocardial infarction depression [29] or
depression in community samples [28], we did not observe a difference in mortality risk
between studies assessing depression using a self-report questionnaire versus a clinical
psychiatric interview. Only a minority of 3040% of people with diabetes with an
increased level of depressive symptoms suffers from clinically relevant depressive
disorder [36], [37]. However, both major depression and self-reported depressive
symptoms appear to be chronic/recurrent conditions in people with diabetes [38], [39],
and both are associated with the development of diabetes complications [11].
Furthermore, depressive symptoms have been shown to predict the development of major
depression [40].
The results need to be considered in relation to the study limitations. One important
limitation in carrying out a meta-analysis is the inevitability to combine data from studies
that are not equally designed. This meta-analysis included studies with differing study
design and characteristics, and the results demonstrated significant heterogeneity. After
conducting subgroup-analyses on follow-up length, age, method of depression
assessment, method of diabetes assessment, number of participants and the percentage of

females included, heterogeneity remained. However, after excluding the three articles
presenting odds ratios (converted to risk ratios) the heterogeneity decreased substantially.
This may be due to the fact that odds ratios and hazard ratios are different risk estimates,
even after converting odds to risk ratios and combining them with relative risks [41].
In addition, the included studies often reported multiple hazard ratios, each adjusted for
different covariates. To reveal the independent effect of depression on mortality we
selected the hazard ratio that was most closely adjusted for both demographic and microand macrovascular complications. Unfortunately, these estimates sometimes also include
adjustment variables through which depression may influence mortality rates, e.g.
smoking, physical activity, HbA1c. By correcting for these potential mediators the hazard
ratio can be an underestimation of the real effect of depression on mortality in people
with diabetes. With respect to type of diabetes of study participants, five articles did not
specify this information. Moreover, only one article reported on individuals with type 1
diabetes, and two articles reported on a combined study population of people with both
type 1 and type 2 diabetes. Because type 2 diabetes is the most prevalent form of
diabetes, cohort studies with patients with type 1 diabetes are scarce. Finally, we found an
indication for publication bias: negative or insignificant result are often not submitted for
publication by authors, or rejected by reviewers and editors. This form of bias generally
results in an overestimation of the effect.
Despite these limitations several strengths should also be acknowledged. First, our metaanalysis comprises both all-cause and cardiovascular mortality. In addition, the
independent effect of depression on mortality was assessed by adjusting for both
demographic variables and micro- and macrovascular complications where possible.
It is still unclear whether adequate depression recognition and subsequent depression
treatment can help to decrease mortality rates. Bogner et al. [42] have conducted the
Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study
that examined a care-management intervention for older primary care patients with
depression. The study had a median follow-up of more than 4 year. The authors reported
that depressed patients with diabetes in the intervention category were less likely to have
died during the 5-year follow-up interval than depressed diabetic patients in usual care
after accounting for baseline differences among patients (adjusted hazard ratio 0.49 [95%
CI 0.240.98]). However, the statistical methods used by Bogner et al. [42] were
criticized, as they may have resulted in model overfitting [43], [44]. Screening for
depression in clinical practice may be a helpful first step, and should be embedded in
collaborative care approaches [45]. Effective intervention strategies include cognitive
behavioral therapy and treatment with antidepressant medication [46]. Given the close
association of depression with suboptimal self-care behaviors [34], interventions that
target behavioral mechanisms directly (e.g. coping skills training) may be of value as
well.
In conclusion, the results of this meta-analysis suggest that depression is associated with
a 1.5-fold increased risk of all-cause mortality in people with diabetes. Although based on
only five studies, similar results were found for cardiovascular mortality. In consideration

of the study limitations and strengths, we believe that a 1.5-fold increased risk of allcause (and cardiovascular) mortality in people with diabetes is not an over- or
underestimation, but could be an accurate risk estimation.
Future studies are encouraged to explore whether the association between depression and
mortality is similar for people with type 1 and type 2 diabetes, and to address the
behavioral or physiological pathways that may explain this association.

Supporting Information
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doi:10.1371/journal.pone.0057058.s001
(DOCX)
Supporting Information S1.
Online Appendix. Figure S1, Example of calculation combining two hazard ratios.
Figure S2, Example of calculation recalculating hazard ratios with corresponding 95%
CI. Figure S3, Funnel plot meta-analysis all-cause mortality.
doi:10.1371/journal.pone.0057058.s002
(DOCX)

Acknowledgments
The authors thank Wobbe Zijlstra of the Department of Medical and Clinical Psychology
and Neuropsychology, Tilburg University, The Netherlands and Wolfgang Viechtbauer of
the Department of Psychiatry and Psychology, School of Mental Health and
Neuroscience, Maastricht University, The Netherlands, for help with the calculations.

Author Contributions
Contributed to the discussion: GN JD FP. Reviewed and edited the manuscript: FvD GN
MS FV JD FP. Conceived and designed the experiments: FvD GN FP. Performed the
experiments: FvD. Analyzed the data: FvD. Contributed reagents/materials/analysis tools:
FvD. Wrote the paper: FvD.

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8
Research Article

Risk for High Depressive Symptoms in


Diagnosed and Previously Undetected
Diabetes: 5-Year Follow-Up Results of
the Heinz Nixdorf Recall Study

Andrea Icks mail,

Bernd Albers,
Burkhard Haastert,
Sonali Pechlivanis,
Noreen Pundt,
Uta Slomiany,
Raimund Erbel,
Karl-Heinz Jckel,
Johannes Kruse,
Bernd Kulzer,
Bettina Nowotny,
Christian Herder,
Guido Giani,
Susanne Moebus

Article
About the Authors
Metrics
Comments
Related Content

Hide Figures
Abstract
Introduction
Methods
Results
Discussion
Acknowledgments
Author Contributions
References

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Figures

Abstract
Objective
The objective of this study was to determine the risk for the development of high
depressive symptoms in study participants with diagnosed and previously undetected
diabetes mellitus compared to those without diabetes in a prospective population-based
cohort study in Germany.

Methods
We estimated the 5-year cumulative incidence of high depressive symptoms in
participants without high depressive symptoms at baseline (n = 3,633, 51.4% men, mean
age (SD) 59.1 (7.6) years, 7.0% diagnosed diabetes, 5.3% previously undetected

diabetes) from the population-based Heinz Nixdorf Recall study. Diabetes was assessed
by self-report, medication, and blood glucose. High depressive symptoms were assessed
using CES-D. We calculated odds ratios and their corresponding 95% confidence
interval, using multiple logistic regression analyses.

Result
Cumulative 5-year incidences (95% CI) of high depressive symptoms in participants with
diagnosed, undetected, and without diabetes were 7.1 (4.210.9), 4.1 (1.88.0), and 6.5
(5.67.4), respectively. The age-sex-adjusted OR for developing high depressive
symptoms was 1.22 (0.742.03) in participants with diagnosed compared to those without
diabetes, and 1.00 (0.591.68) after adjustment for BMI, physical activity, education,
stroke, and myocardial infarction. The age-sex adjusted OR for developing high
depressive symptoms in participants with previously undetected diabetes compared to
those without diabetes was 0.72; 0.351.48; and fully adjusted 0.62; 0.301.30.

Conclusion
We found no significant associations, maybe due to low power. However, our results are
in line with a recent meta-analysis suggesting that risk of developing high depressive
symptoms in patients with diagnosed diabetes may be moderately higher than in those
without diabetes, and that comorbidity may explain in part this association. In
participants with previously undetected diabetes, this first longitudinal study indicates
that the risk is not increased or may even be decreased. These results support the
hypothesis that high depressive symptoms develop due to diabetes-related burden and
comorbidity and not due to hyperglycemia or hyperinsulinaemia.
Citation: Icks A, Albers B, Haastert B, Pechlivanis S, Pundt N, et al. (2013) Risk for
High Depressive Symptoms in Diagnosed and Previously Undetected Diabetes: 5-Year
Follow-Up Results of the Heinz Nixdorf Recall Study. PLoS ONE 8(2): e56300.
doi:10.1371/journal.pone.0056300
Editor: Hamid Reza Baradaran, Tehran University of Medical Sciences, Islamic
Republic of Iran
Received: August 20, 2012; Accepted: January 8, 2013; Published: February 18, 2013
Copyright: 2013 Icks et al. This is an open-access article distributed under the terms
of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are
credited.
Funding: This study was supported in the context of the Competence Network for
Diabetes Mellitus by the German Federal Ministry of Education and Research (BMBF,
www.bmbf.de). The German Diabetes Center is funded by the German Ministry of Health
(http://www.bmg.bund.de) and the North Rhine-Westphalia Ministry of Innovation,

Science and Research (http://www.wissenschaft.nrw.de/). This study was supported in


part by a grant from the German Federal Ministry of Education and Research (BMBF) to
the German Center for Diabetes research (DZD e.V.). The Heinz Nixdorf Recall Study
(HNR) is supported by the Heinz Nixdorf Foundation, Germany (http://www.heinznixdorf-stiftung.de/). An additional research grant was obtained from the German
Ministry of Education and Science and the German Research Council (DFG; Project SI
236/8-1, SI236/9-1, ER155-6-2). The authors acknowledge the support of the Sarstedt
AG & Co. concerning laboratory equipment, and thank the investigative group and the
study staff of the Heinz Nixdorf Recall Study. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have the following interests: Co-author Burkhard
Haastert is self employed working in his company mediStatistica. Co-author Christian
Herder is Academic Editor with PlOS ONE. There are no patents, products in
development or marketed products to declare. This does not alter the authors adherence
to all the PLOS ONE policies on sharing data and materials.

Introduction
There is sufficient evidence for an association between prevalent depressive disorders and
diabetes, with up to twofold higher prevalence of depressive disorders in persons with
diabetes [1]. The combination of diabetes and depressive disorders is of high clinical
relevance, due to an increased risk of mortality [2][4], micro- and macro-vascular comorbidities [5], and physical and psychological disabilities [3], [6], [7] in people with a
combination of these two health problems.
It remains controversial whether diabetes predicts depressive disorders or vice versa or
whether there is a bidirectional association. Prospective studies examining the association
between diabetes and high depressive symptoms are scarce and reveal conflicting results.
A meta-analysis including seven studies reported a weakly increased risk for the
development of high depressive symptoms in individuals with diabetes compared with
those without diabetes (RR = 1.15, 95% CI 1.021.30) [8]. A more recent meta-analysis
found the relative risk to be slightly higher (RR 1.24; 95% CI 1.091.40) [9].
Possible reasons for a higher risk of high depressive symptoms in diabetes are still a
matter of debate [8], [9], [10]. Depression may develop in association with somatic
disorders as (diabetes-related) comorbidity. However, also hyperglycemia or
hyperinsulinemia per se is being discussed as a possible underlying factor for an
increased risk of high depressive symptoms as follows: Biochemical changes associated
with diabetes increase the activity of the hypothalamicpituitaryadrenal axis, which may
in turn induce depression [8]. If this explanation were true, one would expect not only
increased high depressive symptoms in diagnosed diabetes but also in previously
undetected diabetes. However, only a few cross-sectional studies have investigated high
depressive symptoms in participants with previously undetected diabetes. A recent
systematic review and meta-analysis of Nouwen et al. including 10 cross-sectional
studies has found no difference between the prevalence of high depressive symptoms in

individuals with undetected diabetes and without diabetes (OR 0.94; 95% CI 0.711.25)
[11]. The analysis of the cross-sectional baseline data of the population-based Heinz
Nixdorf Recall study yielded an even lower prevalence of high depressive symptoms in
men with previously undetected diabetes than in those without diabetes [12]. To the best
of our knowledge, no study to date has investigated the association between previously
undetected diabetes and the onset of high depressive symptoms in a longitudinal setting.
In light of these findings, we sought to estimate the 5-year cumulative incidence of high
depressive symptoms in participants with diagnosed and previously undetected diabetes
and to compare it with that in participants without diabetes in a population-based sample.
By calculating the odds ratios, we estimated the effects of diabetes and undetected
diabetes on the development of high depressive symptoms.

Methods
Population
We analysed baseline and follow-up data from the ongoing population-based prospective
Heinz Nixdorf Recall study, performed in large adjacent cities (Essen, Mlheim,
Bochum) of the Ruhr Area in Germany. The design of the study has been described
elsewhere in detail [13]. Briefly, the cohort comprises 4,814 randomly selected men and
women aged 4575 years at baseline. The baseline visits were performed at the
Epidemiological Study Centre, Essen, between 2000 and 2003, the 5-year follow-up
visits between 2005 and 2008, with a median follow-up of 5.1 years. The baseline
recruitment efficacy was 55.8% [14] and the 5-years follow up response 90.2% [15]. Data
assessment at baseline and 5-year follow-up included self-administered questionnaires,
face-to-face interviews for personal risk factor assessment and various medical
conditions, conducted by trained study personnel. Comprehensive laboratory tests,
anthropometric and blood pressure measurements were performed according to standard
study protocols. The study was approved by the relevant institutional ethics committees
and followed strict internal and external quality assurance protocols. All participants gave
their written informed consents.
The effective sample size in the study was 4,157 participants. For the present analysis, we
excluded 373 participants with high depressive symptoms at baseline (for definition see
below), 119 with unknown depressive symptoms at baseline and 32 participants with
unknown status of depressive symptoms at follow-up, yielding the final study sample of n
= 3,633 participants.
Variables

Outcome: high depressive symptoms.


We assessed high depressive symptoms using the 15-item short form of the Center for
Epidemiologic Studies Depression scale (CES-D), a commonly used instrument [16],
[17] and assumed a cut-off point of 17, as defined in validation studies [18]. The short

form of the CES-D has been validated in detail [19], [20]. It identifies patients with
clinical depression when compared to ICD 10 diagnoses with a sensitivity of 91.8 and a
specifity of 83.9 [21].

Exposure assessment: diagnosed and previously


undetected diabetes.
Diagnosed diabetes mellitus was defined if clinician-documented diagnosis of diabetes
was reported in the medical history interview or if glucose-lowering drugs were taken
[12]. Previously undetected diabetes was considered when (i) fasting glucose was 7.0
mmol/l (60% and 79% of study participants were in a fasting state at baseline and followup, respectively, with fasting state defined as fasting for 8 hours) or random blood
glucose 11.1 mmol/l [22], [23] (the remaining participants were in a non-fasting state)
and (ii) participants had not reported diabetes diagnosis and were not taking any glucoselowering agents. In both baseline and follow-up examinations, the participants were
informed when previously undetected diabetes was identified, and suggested to contact
their general practitioners.

Covariates.
Covariates known to modify depressive symptoms (outcome), that were also associated
with diabetes (exposure of interest), were identified from clinical experience and the
literature and discussed prior to the analyses. At baseline, physical exercise was assessed
by asking our participants about the kind and duration of exercise performed in the
preceding month, whereby physically inactive meant having performed no physical
exercise at all [24]. Education was used as a proxy for the socio-economic status,
classified in years of formal education according to the International Standard
Classification of Education [25] combining school and vocational training: 10 years
(lowest education), 1113 years, 1417 years and 18 years (highest education).
Information on previous medical events including stroke and myocardial infarction were
assessed during a standardized medical computer-assisted personal interview. Height and
weight were measured by clinical examination according to standard protocols.
Statistical Analysis
The baseline characteristics, stratified by diabetes status, were summarized by using
descriptive statistics. Five-year cumulative incidences of high depressive symptoms were
estimated as proportions of participants developing high depressive symptoms during
follow-up. We estimated the cumulative incidences with 95% confidence intervals (95%CI) in the population of participants with diagnosed, with previously undetected, and
without diabetes at baseline.
The association between diabetes (diagnosed or previously undetected) at baseline and
the risk of developing high depressive symptoms during follow-up was analysed by using
multiple logistic regression models, with high depressive symptoms at follow-up as the
dependent variable, and baseline diabetes (diagnosed and undetected diabetes separately

on both corresponding subpopulations of non-diabetic participants and diagnosed resp.


undetected diabetic cases) and additional covariates as independent variables. Model 1
was adjusted only for age and sex. In Model 2, we included the further covariates
(education, physical activity, BMI, stroke, and myocardial infarction).
Sensitivity Analysis
The aforementioned meta-analysis [11] reported higher relative risks for developing
depressive symptoms in individuals with compared to those without diabetes when
diagnostic-based instead of questionnaire-based criteria were used. Furthermore,
excluding individuals with depression history at baseline revealed lower relative risks [9].
Thus, we performed corresponding sensitivity analyses: (1) We defined high depression
symptoms using the questionnaire-based CES-D and additionally a physiciandocumented life-time depression diagnosis in the medical history. (2) We excluded
participants with a physician-documented life-time depression diagnosis in the medical
history from the analysis. Furthermore, considering that the prevalence of subclinical
depression as a strong predictor of depression may differ between participants with
diagnosed or undetected diabetes and those with normal glucose tolerance, we adjusted
for this condition by adding an indicator as indendent variable in the logistic regression
models. Since no corresponding cut-off for the CES-D is defined, we assumed subclinical
depression when CES-D-values were between mean+standard deviation ( = 7.9+6.1 on
the whole population, n = 4,038, 119 missings) and the cut-off for clinical depression,
that is between 14 and 17. Additionally, in an explorative analysis we estimated the
association between comorbidity (stroke, myocardial infarction, diabetic retinopathy,
chronic kidney disease, or diabetic foot syndrome) and development of depression in
participants with diagnosed diabetes.

Results
Baseline Characteristics of the Study Cohort
The baseline characteristics of our study cohort stratified by diabetes status are presented
in Table 1. A total of 51.4% of the study population were men and the mean age (SD) was
59.1 years (7.6). As expected, participants with diagnosed and previously undetected
diabetes were older, more frequently male, were less educated, had a higher BMI, and
were less often physically active than participants without diabetes. Furthermore, they
reported more often a history of myocardial infarction or stroke.

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Table 1. Baseline participant characteristics, stratified by diabetes status.


doi:10.1371/journal.pone.0056300.t001

Cumulative Incidences and Odds Ratios from Multiple Analysis


During follow-up (mean 5.10.3 years), we observed a total of 232 incident cases of high
depressive symptoms in n = 18, 8, and 206 participants with diagnosed, with previously
undetected, and without diabetes, respectively. The 5-year cumulative incidences were
7.1% (95%CI 4.210.9) in those with diagnosed diabetes, 4.1% (1.88.0) in those with
undetected diabetes, and 6.5% (5.67.4) in participants without diabetes.
In the multiple regression analysis, the age- and sex-adjusted risk for developing high
depressive symptoms in participants with diagnosed diabetes was 1.22 (95%CI, 0.74
2.03) compared to those with no diabetes (Table 2). After adjustment for further
covariates the OR was 1.00 (0.591.68). On the other hand, the age- and sex-adjusted OR
for developing high depressive in participants with previously undetected diabetes
compared to those without diabetes was 0.72 (0.351.48), and 0.62 (0.301.30) after full
adjustment (Table 2).

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Table 2. Multiple logistic regression models analyzing the relationship between


diagnosed and undetected diabetes and the development of high depressive
symptoms.
doi:10.1371/journal.pone.0056300.t002

Sensitivity Analyses
The exclusion of participants with a depression in the medical history at baseline (n =
242) did not change the results substantially (diagnosed diabetes versus no diabetes: agesex adjusted OR 1.34 (0.792.26; n = 3,206); previously undetected diabetes versus no
diabetes: age-sex-adjusted OR 0.84 (0.411.75; n = 3,145).
When we defined high depressive symptoms using CES-D and additionally a physiciandocumented depression in the medical history, the age- and sex-adjusted OR for the
development of high depressive symptoms in participants with diabetes was 1.57 (0.96
2.57; n = 2,571) compared with participants with no diabetes, and 1.33 (0.802.22, n =
2,557) after controlling for further covariates. In participants with previously undetected
diabetes, we achieved almost unchanged results as in the base case analysis (age-sexadjusted OR 0.74 (0.361.54; n = 2,538; fully adjusted model 0.65 (0.311.37, n =
2,524).
Subclinical depression was significantly and strongly associated with the risk for
developing high depressive symptoms (OR about 6). However, the base case ORs
remained almost unchanged in all models (data not shown).

With regard to comorbidity in participants with diagnosed diabetes, the age-sex-adjusted


OR for developing high depressive symptoms in participants with comorbidity (n = 255)
compared to those without comorbidity (n = 217) was 1.55 (95% CI 0.534.53), and 1.48
(0.494.45) after full adjustment.

Discussion
Study Findings and Implications
Our 5-year observational study is, to the best of our knowledge, the first study that
analysed the incidence of high depressive symptoms in individuals with diagnosed as
well as with previously undiagnosed diabetes mellitus versus participants without
diabetes in a prospective study design.
We did not find a significant association between diagnosed diabetes and the risk to
develop high depressive symptoms. However, an age-sex-adjusted risk increase of about
20% as in our study would be well in line with a recently published meta-analysis
including 11 studies with 48,800 study participants which found an OR of 1.24 (95% CI
1.091.40) [9]. Consistent with the findings from de Jonge [26] the OR tended to
diminish after controlling for covariates like comorbidities. This finding supports the
hypothesis that not the metabolic situation per se, but diabetes-associated comorbidities
increase the risk of developing high depressive symptoms. In our regression model we
observed that particularly stroke is associated with an increased risk for high depressive
symptoms, which is in line with earlier findings [27]. Also physical inactivity was
associated with an increased risk for high depressive symptoms. Furthermore, the risk for
high depressive tended to be increased with obesity. This is in line with a recent review
showing that obesity can induce low self-esteem and body dissatisfaction and increases
the risk for developing a depression [28]. An association between diabetes-associated
comorbidities and the risk of developing high depressive symptoms has been observed in
previous studies [29], and is also supported by our explorative analysis of participants
with diagnosed diabetes: those with comorbidities tended to have a higher risk of
developing high depression symptoms compared to those without comorbidities.
However, the results are yet uncertain due to wide confidence intervals.
No significant association between undetected diabetes and the risk of developing high
depressive symptoms was found. Our study results may indicate that the risk of high
depressive symptoms in participants with previously undetected diabetes at baseline
could be even lower compared to participants without diabetes. The observation that there
is no association between undetected diabetes and high depressive symptoms has been
described: In a review of cross-sectional studies, the prevalence odds ratio of high
depressive symptoms in participants with undetected diabetes and those without diabetes
was 0.94 (0.711.25) [11]. Note that in our study, participants without previously
detected diabetes have been informed about their elevated blood glucose measures and
recommended to consult their doctors. Hence, they have not longer been undetected
during the follow-up period. The question arises why these participants have still a lower
risk for developing high depressive symptoms than those with previously diagnosed

diabetes. This may be explained by the hypothesis that depressive symptoms are
associated with burden of treatment and the presence of diabetes-related complications,
as discussed by Nouwen in its review about the prevalence of depressive symptoms in
people with undetected diabetes, and confirmed e.g. by the finding that untreated diabetes
has not been associated with an increased risk of developing high depressive symptoms
[29]: Our follow-up investigation revealed, that only about one third of participants with
undetected diabetes at baseline received antihyperglycemic medication (64 of 194),
compared to 81% (206/255) of the participants with previously diagnosed diabetes. At
baseline, HbA1c was 6.31.5% and 6.91.3% in participants with previously undetected
diabetes and those with previously diagnosed diabetes, respectively. In the follow-up
investigation, 8% (16/194) of participants with undetected diabetes at baseline had
diabetes-related complications, compared to 25% (63/255) of those with previously
diagnosed diabetes. Thus, indeed, the intensity of treatment and the severity of diabetes
can be considered to be lower in participants with previously undetected diabetes
compared to those with previously diagnosed participants. U However, further studies
including a higher number of participants and additional covariates, e.g. stress, are
warranted to analyse the underlying reasons.
Several sensitivity analyses did not substantially change our findings. We (i) excluded
participants who reported a physician-documented lifetime history of depression, and (ii)
performed all analyses defining high depressive symptoms as a CES-D score 17 or a
lifetime history of physician-documented depression. In both sensitivity analyses, the risk
of developing high depression symptoms in participants with diagnosed diabetes
compared to those without diabetes tended to be about 30% and 40% increased, however,
with confidence intervals including the 1. A somewhat higher risk would be well in line
with the meta-analysis of Nouwen, who found higher risk ratios when depression was
assessed by clinical interviews compared to questionnaire-based definition of high
depressive symptoms [9]. In participants with undetected diabetes compared to those
without diabetes, the decrease of risk of developing high depressive symptoms tended to
be somewhat larger than in the base case analysis, however, confidence intervals were
still wide.
Study Strengths and Limitations
The strength of the study is that it is a well-performed investigation including carefully
assessed variables. The number of participants lost to follow-up is very low. Since about
two thirds of the participants were in a fasting state at baseline, we could identify
undetected diabetes. High depressive symptoms could be assessed by a widely used and
well established instrument.
However, the study has several limitations: (1) Not all participants were examined in a
fasting state and no oral glucose tolerance test was performed, causing potential
misclassifications. However, our study results remained unchanged when excluding nonfasting participants without diabetes from our analyses. (2) The number of participants
with high depressive symptoms in the groups with diagnosed and undetected diabetes
was low, resulting in wide confidence intervals and missing statistical significance. (3)

The gold standard to for assessment of depression is a structured interview. However, this
is difficult to realize in an epidemiological studies involving a large number of
participants. Thus, we used the CES-D to assess depressive symptoms. This wellestablished instrument has been used in a number of studies which analysed the
association between diabetes and depression [9], [30]. (4) Emotional stress as a predictor
of depression was not assessed [31]. (5) We had to exclude some participants due to
missing information about their diabetes status. However, the number was small, and we
have no indication that this could have led to any selection bias.
Conclusion
Although we found no significant associations, our results suggest that the risk of
developing high depressive symptoms in participants with diagnosed diabetes may be
moderately higher than in those without diabetes, and that co-morbidity and lifestyle may
explain in part this association. For the first time we estimated the risk of developing high
depressive symptoms in participants with previously undetected diabetes and found no
significant association, maybe an even lower risk than in participants without diabetes.
However, our results have to be replicated and corroborated in studies with a larger
number of cases and higher statistical power. Corresponding results would support the
hypothesis that high depressive symptoms develop mainly due to diabetes-related
treatment and comorbidity.

Acknowledgments
We like to thank the Heinz Nixdorf Recall Study Group and the BMBF German Network
Diabetes mellitus.

Author Contributions
Project leader: AI. Developed the conception and design of the study: AI. Project
management: BA. Contributed biometric/statistical expertise: GG K-HJ. Contributed to
the study design and methodology: RE K-HJ SM. Guarantors of the Heinz Nixdorf
Research Study: RE K-HJ SM. Contributed clinical expertise: BN CH JK. Reviewed the
manuscript and made substantial contributions to subsequent drafts: BA BH SP NP US
RE K-HJ JK BK BN CH GG SM AI. Approved the final manuscript: BA BH SP NP US
RE K-HJ JK BK BN CH GG SM AI. Conceived and designed the experiments: BA BH
SP NP US RE K-HJ JK BK BN CH GG SM AI. Analyzed the data: BH. Contributed
reagents/materials/analysis tools: BN SP US. Wrote the paper: AI BA.

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Endocrine and inflammatory profiles in


type 2 diabetic patients with and
without major depressive disorder
Adriana Alvarez15*, Jose Faccioli1, Mnica Guinzbourg1, Mara M Castex1, Claudia
Bayn1, Walter Masson2, Ignacio Bluro2, Andrea Kozak1, Patricia Sorroche1, Lina
Capurro1, Luis Grosembacher1, Adrin Proietti1, Carlos Finkelsztein1, Lucas Costa3,
Patricia Fainstein Day1, Arturo Cagide2, Len E Litwak1 and Sherita H Golden4

* Corresponding author: Adriana Alvarez adriana.alvarez@hospitalitaliano.org.ar

Author Affiliations
1

Diabetes Division, Endocrinology and Nuclear Medicine Department, Hospital Italiano


de Buenos Aires, Buenos Aires, Argentina
2

Cardiology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

LBAL (Laboratory for Biological & Artificial Learning) of Hospital Italiano de Buenos
Aires, Buenos Aires, Argentina
4

Department of Medicine, Johns Hopkins University School of Medicine and


Department of Epidemiology, Johns Hopkins University Bloomberg School of Public
Health, Baltimore, USA
5

Asamblea 1458, 7th floor, Buenos Aires, Argentina

For all author emails, please log on.


BMC Research Notes 2013, 6:61 doi:10.1186/1756-0500-6-61

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1756-0500/6/61
Received: 24 July 2012
22 January
Accepted:
2013
14 February
Published:
2013

2013 alvarez et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
There is a high prevalence of depression in individuals with type 2 diabetes mellitus.
Depressive disorders are associated with increased medical morbidity and mortality in
individuals with diabetes. It has been demonstrated that there is a higher prevalence of
diabetic complications among individuals with diabetes and depression compared to
those without depression. Several biological alterations have been reported in individuals
with depressive disorders, particularly abnormal levels of endocrine-inflammatory
markers.
This study aims to determine the prevalence of major depressive disorder (MDD) in type
2 diabetes patients, the prevalence of cardiovascular events in individuals with and
without MDD and to compare the endocrine-inflammatory profile between groups.
Methods
The study was approved by the Comit de Etica de Protocolos de Investigacin del
Departamento de Docencia e Investigacin del Hospital Italiano de Buenos Aires with
the number 1262 and included only patients who provided written informed consent.
The study was conducted in accordance with the Declaration of Helsinki and the Habeas
Data law on protection of personal data (Law N 25326, Argentina).
Type 2 diabetes patients (n=61) were included and they were classified as having MDD
or not according to DSM-IV. Macrovascular disease was obtained from the medical
history. Additionally, the intima-media thickness of the common carotid, carotid
bifurcations and internal carotid arteries was measured non-invasively by two-

dimensional ultrasound imaging. Fasting glucose, fasting lipid profile, inflammatory


(CRP, TNF-) and endocrine (urine free cortisol and saliva cortisol) markers. Student t
tests were used to compare means for normally distributed variables and Mann-Whitney
test for variables without normal distribution. Relative frequencies were calculated and a
chi-square analysis was conducted. Data were expressed as meanstandard deviation
(SD) or median and interquartile range. Multivariable logistic regression was used to
determine the relative odds of clinical cardiovascular disease in individuals with
compared to those without depression. Differences were considered significant using a
two-sided p<0.05.
Results
21 patients (34%) had MDD and 40 patients (66%) didnt have MDD. Diabetic patients
with MDD had significantly higher CRP levels (4.1(1.9-7.6) vs 1.5(0.5-4.4) mg/l; p=
0.02) and 24-hour urine free cortisol (71.421.3 vs 59.829.3 ug/24 h; p=0.03). The
other metabolic and inflammatory parameters were not statistically different between
groups. There was a significantly higher prevalence of cardiovascular events in
individuals with MDD: 38% for the depressive group vs 15% for non-depressive group,
p=0.04). Patients with MDD had a 3.5-fold greater odd of having cardiovascular disease.
Conclusions
Diabetic patients with depression are more likely to have cardiovascular events, and
different factors can determine this high association.

Keywords:
Depression; Type 2 diabetes mellitus; Cardiovascular disease

Background
Type 2 diabetes is a chronic illness with established cross-sectional and longitudinal
relationships with depression. There is a high prevalence of depression in individuals
with type 2 diabetes mellitus. A meta-analysis and two systematic reviews [1-3] reported

that individuals with diabetes had a 2.9-fold significantly increased odds of having
depression compared to non-diabetic individuals. Depressive disorders are associated
with increased medical morbidity and mortality in individuals with diabetes [4]. It was
demonstrated that there is a higher prevalence of diabetes complications, including
retinopathy, nephropathy, neuropathy, macrovascular complications and sexual
dysfunction, among individuals with diabetes and depression compared to those without
depression [5].
Depression has been associated with poor adherence to diet and exercise regimens and
poor glycemic control, including hyperglycemia and high hemoglobin A1c (HbA1c)
levels [6-8]. Several studies, recently summarized in a meta-analysis by Mezuk et al [9],
have shown that depression is associated with an approximately 60% increased risk of
type 2 diabetes. Thus, depression is a modifiable risk factor whose treatment could
prevent the development of type 2 diabetes and improve glycemic control and health
outcomes in patients with depression and pre-existing diabetes.
Several biological alterations have been reported in individuals with depressive disorders
that might increase the risk for type 2 diabetes, including activity of the hypothalamicpituitary-adrenal (HPA) axis leading to hypercortisolism, sympathetic nervous system
(SNS) activation, increases in C-reactive protein (CRP) and inflammatory cytokines as
tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and alterations in
norepinephrine and serotonin metabolism [4-8].
The aims of this study were (1) to determine the prevalence of major depression in a
sample of individuals with type 2 diabetes using a diagnostic psychiatric interview, (2) to
determine the prevalence of cardiovascular risk factors and clinical cardiovascular events
in individuals with and without depression and, (3) to characterize the endocrineinflammatory profile in this population.

Methods

Study population
Sixty one patients (30 men and 31 women), aged 18 to 65 years, with physiciandiagnosed type 2 diabetes mellitus were included in this observational study. Patients
were recruited from the Diabetes Division, Endocrinology and Nuclear Medicine Service
of Buenos Aires Italian Hospital, Argentina from 12/05/2008 to 10/12/2009. To be
included in the study, patients had to have been followed up in the hospital for at least
one year and been able to understand and cooperate with study procedures. Patients were
excluded if they were being treated with corticosteroids or rimonabant (because they
could produce mood disorders) or had any clinically organic disorder that could interfere
with the results. The study was approved by CEPI (Comit de Etica para Protocolos de
Investigacin del Hospital Italiano de Buenos AIres) a local ethics committee and
included only patients who provided written informed consent. The study was conducted
in accordance with the Declaration of Helsinki and the Habeas Data law on protection of
personal data (Law N 25326, Argentina). Each participant was assigned a number by
which he/she was identified to keep his or her privacy.
Psychiatric evaluation
After the evaluation by a psychiatrist and a psychologist from the Mental Health Division
of the hospital the patients were classified as having MDD or not according to Diagnostic
and Statistical Manual of Mental Disorder criteria (DSM-IV) [10]. The evaluation
included an interview with the 17-items Hamilton Rating Scale for Depression (HAMD17) [11], Mini International Neuropsychiatric Interview (M.I.N.I.) [12] and Beck
Depression Inventory (BDI) [13] for depression severity assessment. HAM-D17 scale
consists of 17 items, which are rated on a scale from 0 to 2 points or 0 to 4 points
depending on severity levels. The total score range is from 0 to 52 points with a remission
cut point of 18. The M.I.N.I. is a structured diagnostic interview that explores the
psychiatric disorders. The BDI is a multiple-choice self-report questionnaire inventory
used for evaluation of subjective consciousness of depressive symptoms and also allows
analysis of cognitive versus somatic symptoms of depression. The cut-off value for

depression was 24 for the Hamilton scale. Additionally, family history of depression was
documented.
Clinical evaluation
A complete medical history was taken and anthropometric data were collected. Weight
and height were measured to calculate body mass index (BMI=weight/ height2 [Kg/
m2]). Waist circumference (cm) was obtained by measuring the waist in the mean point
between the iliac crests and ribs, with the patient standing after expiration. The systolic
and diastolic blood pressures (mmHg) were measured with the patient in sitting position
after 5 minutes of rest.
Cardiovascular disease
Macrovascular disease was obtained from the medical clinical history. A history of
cardiovascular events was defined as a history of acute myocardial infarction, coronary
bypass surgery, angioplasty, angina pectoris, peripheral vascular disease or stroke.
Additionally, the intima-media thickness of the common carotid, carotid bifurcations and
internal carotid arteries was measured non-invasively by two-dimensional ultrasound
imaging mode, using a Logiq Book XP ultrasound (General Electric) with a linear
transducer of 7.5 MHz in 37 patients (12/21 with depression and 25/40 without
depression). Presence of atherosclerotic plaque was defined as: (1) abnormal wall
thickness (defined as an intima-media thickness >1.5 mm), (2) abnormal structure
(protrusion into the lumen, loss of alignment with the adjacent wall) and (3) abnormal
echogenicity of the wall [14]. Increased intima-media thickness was defined as greater
than 0.8 mm. An ankle-brachial index was measured according to a standard protocol by
trained technicians. Briefly, the participant was asked to lie flat on an examination table,
and after 5 minutes of rest, standard arm blood pressure cuffs were applied to the right
arm and to each ankle (with the lower end of the bladder within 3 cm of the malleoli). A
Doppler vascular probe (7.5 MHz, General Electric) and a standard mercury manometer
were used to assess systolic blood pressure in the right brachial artery and in each

posterior and anterior tibial artery in rapid succession. The ankle-brachial index in the
right and left leg was calculated by dividing the right and the left ankle pressure by the
brachial pressure. Of the ankle-brachial index values obtained in each leg, the lower was
used in all analysis. A value between 0.9 and 1.3 was considered normal [15].
Measures
Fasting glucose was measured with the UV-hexokinase method on a Synchron LX20
(Beckman-Coulter) and HbA1C by HPLC on a Variant II instrument (Bio-Rad
Laboratories). A fasting lipid profile was also obtained. Cholesterol in serum was
measured by an enzymatic method on a Synchron LX 20 (Beckman Coulter).
Triglycerides were measured by an enzymatic/GPO-Trinder method on a Synchron LX
20 (Beckman-Coulter). HDL cholesterol was measured by a homogeneous method on the
same instrument. The LDL cholesterol concentration was calculated with the Friedewald
formula when the serum triglyceride concentration was <400 mg/dL. Apo B was
measured by nephelometry on an Immage (Beckman-Coulter). High Sensitivity CRP was
measured by a latex turbidimetric method on a Synchron LX20 (Beckman-Coulter). The
human TNF- was measured by an immunoenzymetric assay (Biosource Europe S.A.).
Twenty four hour urine free cortisol levels and 23.00 pm saliva cortisol were collected in
the outpatient setting and were measured by radioimmunoassay. All the parameters were
measured in a centralized laboratory.
Statistical analysis
The statistical evaluation of data was performed using commercially available SPSS
Statistics 17.0 software. Student t tests were applied to compare means for normally
distributed variables and Mann-Whitney test for variables without normal distribution.
Relative frequencies were calculated and a chi-square analysis was conducted. Data were
expressed as meanstandard deviation (SD) or median and interquartile range.
Multivariable logistic regression was used to determine the relative odds of clinical
cardiovascular disease in individuals with depression compared to those without

depression. Because of the small sample size, only two covariates at a time, determined
to be different by depressive status in univariate analyses, were adjusted for. Differences
were considered significant using a two-sided p<0.05.

Results
Participant characteristics
Following psychiatric evaluation, 61 participants (mean age 62 7 years) were classified
into two groups: 21 patients (34%) with MDD and 40 patients (66%) without depression.
The characteristics of individuals with and without depression are summarized in Table 1.
There was not significant difference in ratio of male/female patients, age, diabetes
duration, insulin therapy, weight, BMI, waist circumference or systolic or diastolic blood
pressure between the groups. There was also no difference in family history of
depression: depressive group=5/21 (24%); non-depressive group=7/40 (18%).
Table 1. Participant characteristics by depressive status
The prevalence rates of depression in type 2 diabetes in uncontrolled studies are between
17.8 and 39%, with higher much lower rates in controlled studies (between 3.2 and
6.5%). [10] Our study reflects similar rates of the comorbidity than previously published
data.
Metabolic parameters
Several metabolic parameters were assessed and no significant differences were found
between groups in glycemic control, lipid profile, ApoB, or TNF (Table 2). However,
compared to those without depression, individuals with depression had significantly
higher CRP levels (4.1(1.9-7.6) vs 1.5(0.5-4.4) mg/l; p=0.02; Mann Whitney test) and
24-hour urine free cortisol (71.421.3 vs 59.829.3 ug/24 h; p=0.03; Mann Whitney
test).
Table 2. Metabolic parameters by depressive status

Cardiovascular disease
There was a significantly higher prevalence of total cardiovascular events in individuals
with depression compared to those without depression: 38% (n=8) for the depressive
group vs 15% (n=6) for non-depressive group (Chi-square test, p=0.04) with a stronger
association in males compared to females (Chi-square test, p=0.01). Compared to the
non-depressive group, those in the depressive group had a 3.5-fold greater odd of having
clinical cardiovascular disease (Table 3). This association persisted following adjustment
for UFC and become stronger following adjustment for CRP.
Table 3. Relative odds (95% confidence intervals) of clinical cardiovascular disease
by depressive status
There was a trend toward a higher prevalence of atherosclerotic plaque among depressed
compared to non-depressed individuals (75% for the depressive group vs 44% for nondepressive group; p=0.07); however, the difference was not statistically significant,
likely due to the smaller number of patients (n=37) who underwent carotid ultrasound
measurements. There was no significant difference in carotid intimal-medial thickness or
ankle-brachial indices between the two groups (data not shown).

Discussion
Multiple biological links that potentially mediate the adverse effect of comorbid
depression on diabetes-related and cardiovascular mortality have been described. These
include increased pro-inflammatory cytokines, abnormalities of the hypothalamic
pituitary axis (HPA), changes in homeostasis between the sympathetic and
parasympathetic nervous systems and changes in metabolism [16-19].
Our study found that individuals with diabetes and depression had significantly higher
24-h urine free cortisol levels and CRP than individuals without depression. While there
was a trend toward higher late-evening salivary cortisol in individuals with depression
compared to those without depression, this difference was not statistically significant.

There were no differences in glycemic and metabolic control or subclinical


atheroscleorsis between the two groups. This association persisted following adjustment
for UFC and became stronger after adjusting for CRP.
Our depressed patients tended to be older in age, to have a longer duration of diabetes
and a higher percentage were receiving insulin treatment. However, none of these trends
were statistically significant.
Our study confirms prior findings that MDD is associated with subclinical
hypercortisolism and HPA axis activation and increased levels of some inflammatory
markers [20-23] and that these associations are present among depressed individuals with
type 2 diabetes.
We hypothesized that these physiological abnormalities associated with MDD might
explain the higher prevalence of clinical cardiovascular events that we found in the
depressed individuals. Hypercortisolism produces increased visceral adiposity by
stimulating increased adipocyte size and number [24] and visceral adiposity is a risk
factor for cardiovascular disease [25]. Activation of the HPA axis results in simultaneous
activation of the sympathetic nervous system, which in turn stimulates release of IL-6,
inducing an inflammatory cascade [16]. Elevated CRP and IL-6 has been shown to
predict development of cardiovascular disease [26]. UFC and inflammatory markers
could explain in part our observed association; however, our results should be interpreted
with caution given the small sample size.
Our study has several strengths. First, our participants had physician-confirmed diagnosis
for both depression and diabetes status using standardized assessment methods as
opposed to questionnaires or self-report. We were also able to characterize several
biological determinants in the association between depression and cardiovascular disease
in individuals with diabetes, including measures of HPA axis activity (i.e. 24-hour urine
free cortisol and salivary cortisol) and inflammatory markers.

However, our study has some weaknesses that should be kept in mind when interpreting
our data. First, our sample size was small, which may have limited our power to examine
other associations. Second, our study was cross-sectional, which does not allow us to
determine the temporality of association between depression, biological factors, and
clinical cardiovascular events among those with diabetes. Finally, our participants were
recruited from one race/ethnicity, which may limit the generalizability of findings to
other populations.

Conclusions
Our study showed that people with diabetes and depression are more likely to have
cardiovascular events than non-depressed patients. The higher levels of CRP and urinary
cortisol did not appear to explain the higher number of cardiovascular events, suggesting
that other biological factors, such as alterations in the serotonin system, may also be
implicated. Larger studies are needed to elucidate the biological mechanisms linking
depression to cardiovascular disease in diabetes to identify targets for future preventive
interventions.

Competing interests
The authors declared that they have no competing interests.

Authors contributions
AA conceived the study, participated in its design and coordination and helped to draft
the manuscript. JF and MG conceived the study, and participated in its design and
coordination. PFD, PS and AK carried out the immunoassays. IB, WM and AC
performed cardiovascular measurements. LC, and CB participated in the design of the
study and performed the statistical analysis. MMC, LG, LC, CB, CK and LEL
participated in the recruitment of patients. All authors read and approved the final
manuscript. SHG helped to draft the manuscript.

Acknowledgements

None of the authors reported conflicts of interest. Research Foundation for Diabetes,
Endocrinology and Nuclear Medicine (DIEM). Lucas Brun and Ramiro Pena Requejo
collaborated in the manuscript.

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10

Higher levels of psychological distress are


associated with a higher risk of incident
diabetes during 18 year follow-up:
results from the British household
panel survey
Paula MC Mommersteeg1*, Raphael Herr2, Wobbe P Zijlstra13, Sven Schneider2 and
Franois Pouwer1

* Corresponding author: Paula MC Mommersteeg


P.M.C.Mommersteeg@tilburguniversity.edu

Author Affiliations
1

CoRPS, Center of Research on Psychology in Somatic diseases, Department of Medical


and Clinical Psychology, Tilburg University, Tilburg, The Netherlands
2

MIPH, Mannheim Institute of Public Health, Social and Preventive Medicine, Medical
Faculty Mannheim, Mannheim, Germany
3

Department of Methodology and Statistics, Tilburg University, Tilburg, The Netherlands

For all author emails, please log on.

BMC Public Health 2012, 12:1109 doi:10.1186/1471-2458-12-1109

The electronic version of this article is the complete one and can be found online at:
http://www.biomedcentral.com/1471-2458/12/1109
Received: 30 May 2012
10 December
Accepted:
2012
23 December
Published:
2012

2012 Mommersteeg et al.; licensee BioMed Central Ltd.


This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Abstract
Background
Reviews have shown that depression is a risk factor for the development of type 2
diabetes. However, there is limited evidence for general psychological distress to be
associated with incident diabetes. The aim of the present study was to test whether
persons who report higher levels of psychological distress are at increased risk to develop
type 2 diabetes during 18 years follow up, adjusted for confounders.
Methods
A prospective analysis using data from 9,514 participants (41 years, SD=14; 44% men) of
the British Household Panel Survey. The General Health Questionnaire 12 item version
was used to assess general psychological distress, diabetes was measured by means of
self-report. Cox proportional hazards regression models were used to calculate the
multivariate-adjusted hazard ratio (HR) of incident diabetes during 18 years follow up,
comparing participants with low versus high psychological distress at baseline (1991).

Results
A total of 472 participants developed diabetes 18 year follow up. Those with a high level
of psychological distress had a 33% higher hazard of developing diabetes (HR=1.33, 95%
CI 1.101.61), relative to those with a low level of psychological distress, adjusted for
age, sex, education level and household income. After further adjustment for differences
in level of energy, health status, health problems and activity level, higher psychological
distress was no longer associated with incident diabetes (HR=1.10, 95% CI 0.91-1.34).
Conclusions
Higher levels of psychological distress are a risk factor for the development of diabetes
during an 18 year follow up period. This association may be potentially mediated by low
energy level and impaired health status.

Keywords:
Type 2 diabetes; Psychological distress; Prospective; Risk factor; British
household panel survey

Background
Psychological distress has long been suspected as having important effects on the
development of diabetes. The famous English physician Thomas Willis (16211675) for
example, already noted that diabetes often appeared among persons who had experienced
significant life events, sadness, or long sorrow [1]. In this context, psychological distress
can be defined as the unique discomforting, emotional state experienced by an
individual in response to a specific stressor or demand that results in harm, either
temporary or permanent, to the person [2]. Psychological distress measures are sensitive
screening instruments to detect mental disorders, affective disorders and anxiety
disorders, in epidemiological studies and clinical populations [3,4]. In addition
measurements of psychological distress reflect a general tendency toward expressing
psychological distress rather than detecting psychological caseness. Thus screening for
psychological distress goes beyond screening for either depression or anxiety and can
have added value in examining general populations at risk.

In recent decades, most studies have focused on depression as a risk factor for type 2
diabetes. For example, meta-analyses by Knol et al. and Mezuk et al., showed that the
risk for incident diabetes was 37-60% higher in depressed participants, compared to nondepressed controls [5,6]. Studies that have investigated different forms of distress
associated with type 2 diabetes incidence point toward an increased risk for increased
distress [7]. Concepts associated with psychological distress as stress [8], stress in daily
life [9], Type A behavior [10], and anger temperament [11] show that mostly distressed
men [9], but not women [8,10], or both men and women [11] were more likely to develop
diabetes. In addition, whereas both psychological distress, as measured with the general
health questionnaire (GHQ), and diabetes have been associated with increased mortality
[12], the coexistence of both psychological distress and diabetes were associated with an
increased mortality risk above and beyond of either factor alone [12].
Due to the various concepts of psychological distress used in previous studies, we sought
to examine the association between psychological distress in general, using the GHQ12
and diabetes incidence. The aim of the present study was to examine the risk of
psychological distress to develop type 2 diabetes, adjusted for potential confounders,
using data from a large prospective and representative cohort study: the British
Household Panel Survey [13]. We hypothesize that reporting increased psychological
distress at baseline, is associated with an increased diabetes incidence, over the course of
18 years follow-up, independent of potential confounding variables.

Methods
Design and participants
Data are part of the British Household Panel Survey (BHPS), a nationally representative
cohort of British households, recruited in 1991 and being re-interviewed each successive
year (or wave) [13]. The main aim of the BHPS is to further understanding of social and
economic change at the individual and household level in Britain [], to identify, model
and forecast such changes, their causes and consequences in relation to a range of socio-

economic variables. The British Household Panel Survey is conducted by the ESRC UK
Longitudinal Studies Centre (ULSC), together with the the Institute for Social and
Economic Research (ISER) at the University of Essex. In the present study, data collected
between 1991 and 2009 were used (18 year follow-up cohort)[14]. The households were
randomly selected from postcode districts in order to be nationally representative. In total
10,264 persons were annually interviewed starting in 1991, from age 16 and up. In each
wave data were collected on several topics e.g. income and wealth, housing, and
health by a trained interviewer during a home visit. Data collection was done in
accordance to the declaration of Helsinki, and the study was ethically approved by the
University of Essex, Institute for Social and Economic Research [13]. For the present
study, data on general psychological distress, diabetes presence, demographic
characteristics, life style, and general health were extracted from the online database.
Of the 10,264 individuals who participated in 1991, respondents with missing data on the
psychological distress questionnaire (n = 589/10,264; 5.7%) or who reported diabetes in
1991 (n = 179/10,264; 1.7%) were excluded. After exclusion of these two groups, the
maximum number of participants available for analysis at baseline was 9,514 (Table 1).
In total 45% of the non-diabetes group had information until the end of the study (Wave
18), and mean loss to follow-up time was 7.3 years. The percentage of dropouts was
largest between wave 1 and 2 (10%), and between wave 2 and 3 (6%), and gradually
decreased in consecutive waves, ranging between 5% and 2%. When comparing the
characteristics of the dropout group between wave 117 to the group with information
available in wave 18 (completers) at baseline, the dropout group showed no difference in
psychological distress at baseline and was not different in BMI. Both groups comprised
people with and without diabetes. However, the dropout group was significantly more
likely to be older, male, not married, lower educated, have a lower average household
income, nonwhite, less energetic (compared to age), have an impaired health status, were
more likely to report health problems, more often reported an inactive/sedentary lifestyle,
and were more likely to smoke. At the same time, the dropout group had a lower diabetes
incidence of 4% (219/5225), compared to 6% (253/4289) in the completers group (2 =

14.6, p<.001). It must be noted that information on wave of diabetes presence and wave
until last measurement was used in the analysis, thus optimizing the information available
of people who dropped out during the 18 waves.
Table 1. Baseline characteristics of participants without diabetes, stratified by
psychological distress
Baseline data were used for age, sex, marital status (married = 1,
separated/divorced/widowed/never married = 0), smoking (yes=1), educational level
(lower education, medium education (up to O-level) and higher education (A+ level),
annual household income (<15,000 , 15,000 -<35,000 , and 35,000 ), health status,
and health problems. Race/ethnicity was defined as: white and non-white.
Diabetes
In each consecutive wave, diabetes presence was assessed using a list of self-reported
health problems (Do you have any of the health problems or disabilities listed on this
card). In another study, self-reported diabetes was shown to reliably correlate with
physician diagnosed diabetes [15]. There was no distinction between type 1 diabetes and
type 2 diabetes, but as type 1 diabetes is generally diagnosed before the age of 25, most
cases with type 1 diabetes are most likely excluded in the first wave.
Psychological distress
General psychological distress was measured with the 12 item version of the General
Health Questionnaire, the GHQ12 [4]. This questionnaire was self-completed by the
participants during the home visit of the BHPS interviewer. The GHQ12 is used as a short
screening instrument initially used to detect probable caseness of psychological disorders
in epidemiological studies [4]. However, the GHQ reflects a general tendency toward
expressing psychological distress rather than detecting psychological caseness, and it was
used as an indicator of psychological distress in the present study. The reliability of the
scale in the present sample was = 0.85 (N = 9,675). The items are scored on a 14 item
response scale, adapted to a dimensional scale, which coded 0-0-1-1 for the positive

items, and 0-1-1-1 for the negative items (cGHQ12) [16]. In the present study a cut-off of
4 for the low-psychological distress group, and >4 for the high psychological distress
group was used for the cGHQ12, based on previous large scale validation studies [4]. In
the additional analysis, the continuous range of scores (012) were used.
Measurement of potential confounders
Energy level, health status, health problems, and leisure-time activity were studied as
potential confounders, as lower energy, poor health, and reduced physical activity can
contribute to both higher levels of distress and a higher risk to develop diabetes [17].
Energy
How energetic do you feel as compared to most people of your age? With three
response categories: more energetic, about the same, less energetic.
Health status
Does your health in any way limit your daily activities compared to most people of your
age? (No=0/Yes=1).
Health problems
Diabetes is often preceded by prodromal complaints, which may not be identified as
being related to diabetes. Therefore different categories of self-reported health problems
were recoded into none=0 versus one/some=1, based on the following categories:
heart/blood pressure, chest/breathing problems, asthma, bronchitis, skin
conditions/allergies, stomach/liver/kidneys, problems with arms/legs etc, difficulty
in seeing, difficulty in hearing, and migraine or frequent headaches.
Leisure-time activity
People reported in a Leisure-time activities item how frequently they did leisure
activities. A score of 2 (=Active) was assigned if someone reported at least once a week
to play sport or go walking or swimming, a score of 1 (=Moderately active) was

assigned if a person reported at least once a week to either work in the garden, attend
activity groups such as evening classes, keep fit, yoga etc., or Do Do-It-Yourself, home
maintenance or car repairs. Finally a score of 0 (=Inactive/sedentary) was assigned for
the remaining answer categories.
BMI and leisure-time activity from other waves
Data on body mass index (BMI) and leisure-time activity were not available in the first
wave. Data on leisure-time activity was available from 1996 (wave 6), and BMI was
available from 2004 (wave 13). Still, as both variables have been found to be related to
diabetes development, these variables were used to predict diabetes incidence. There was
a considerable number of missing cases in the waves of leisure-time activity (73%
available, n = 6,906/9,514), and BMI (52% available, n = 4,933/9,514), and we choose to
analyze BMI in a separate model in the additional analysis.
Statistical analysis
Cox proportional hazards regression models were used to calculate the multivariateadjusted hazard ratios (HR) of diabetes for the high-distress compared to the low-distress
group using new diabetes cases in each consecutive wave [18]. Information on diabetes
(present or absent), and time (coded as either first wave of diabetes presence, or last wave
of diabetes absence) were used for the analysis. In total 12 cases were left-censored as
there was missing information on diabetes in 13 waves preceding the the first wave of
diabetes presence. As this time frame and number of cases were limited, these leftcensored cases were not excluded.
We used two analysis strategies: first the effect of each covariate was examined
separately, and second, the multivariate effect of a complete model was tested. In the first
analyses, the individual HR of each covariate on diabetes incidence in the (age adjusted)
model of high distress was investigated (Table 2, first columns, with 95% CI and pvalue). The covariate adjusted HR of (age adjusted) high distress on diabetes incidence
was reported (Table 2; column HRcovariate adjusted). This was done by adding each covariate

separately to the crude model. The change and the percent change in the log hazard ratio
(B = Log HR) of high psychological distress (Bcrude model Bnew model) was calculated before
and after adjustment for each individual potential confounder for the complete model
available and reported in Table 2 as well (Table 2: Change (Bcrude model Bnew model) and %
Change). To deal with loss to follow-up, a separate, additional, complete model was
assessed for absolute or categorized BMI. A negative value depicts a decrease in LogHR
for the high distress group after adjustment, whereas a positive score indicates an
increase in the LogHR for the high-distress group after adjustment. We considered an
absolute change in LogHR >1% to have a substantial effect as a confounder or mediator
on the diabetes-associated risk of psychological distress, based on the present sample
size, the number of covariates and adapted in line with the method used by Whooley and
colleagues [19]. Second, a complete multivariate adjusted model was built. The
covariates with a substantial effect (>1% absolute change in LogHR) were included
hierarchically in three blocks of factors (sociodemographic, health, and lifestyle) (Table
3).
Table 2. Covariate adjusted hazard ratio table
Table 3. Covariate adjusted hazard ratios for high distress (top panel) and hazard
ratio of the covariates for the complete model (lower panel) for 18-year follow-up
diabetes incidence
The proportional hazards assumptions of these models were verified using log-minus-log
survival plots, Pearson correlations of the partial residuals, and the inclusion of
interaction effects with process time. If the proportionality assumption was violated,
nonproportional Cox models were used, by including interaction effects of the
corresponding variable with process time, which corrects the violation of the
proportionality assumption. This correction was used for health status and health
problems. Additional analyses examined models with psychological distress as a
continuous score, and models with interactions of sex or age with psychological distress.
Statistical analyses were conducted using SPSS Statistics version 19.0 (IBM SPSS Inc.,
Chicago, IL, USA).

Results
Descriptives
Among the 9,514 included individuals, there were 472 incident cases of diabetes during
the 18 year follow-up period. The incidence rate of new diabetes was 4.3 per 1000
person-years for this period of 18 years for the total sample. The incidence rate was 3.8
per 1000 person-years for low psychological distress and 4.9 per 1000 person-years for
high psychological distress. In total 42% of the participants reported a high level of
psychological distress at baseline (4,021/9,514). There was no difference in diabetes
prevalence in 1991 between the high and low distress group (high psychological distress
= 1.8%, low psychological distress = 1.5%, 2 = 1.01, p = 0.313). The high psychological
distress group reported to be less energetic compared to people of their age, have an
overall poor health status and more health problems, including more psychiatric problems
(Table 1). Moreover, the high distress group reported an inactive/sedentary lifestyle more
often, had a higher prevalence of smoking, but showed no overall difference in average
BMI, or BMI categories (Table 1).
Diabetes incidence by psychological distress and covariate adjusted risk
There was a significantly increased incidence of diabetes in the high distress group (HR =
1.33, 95% CI = 1.10-1.61, p=0.003), adjusted for age (Figure 1). In Table 2, the hazard
ratios of the covariates, adjusted for psychological distress and age (columns 13), and
the covariate adjusted change in logHR for the high distress group are reported (column
46). After controlling for sex, marital status, and BMI, the adjusted LogHR for the highdistress group increased, whereas controlling for educational level, race/ethnicity,
income, energy level, health status, health problems, leisure-time activity, and smoking
lowered the LogHR for incident diabetes. Thus each of these factors explained some of
the variance ascribed to the high distress group. The percentage change in LogHR is
given for the effect of each covariate on the logHR of high psychological distress (Tables
1, 2), and a 1% absolute change was observed for sociodemographic factors: sex, marital

status, education level and household income; health factors: energy, health status, and
health problems, and lifestyle factors: leisure-time activity, smoking, and BMI.

Figure 1. Cumulative hazard of diabetes stratified by general


psychological distress.
High distress and diabetes incidence
In Table 3 the adjusted model the hazard of the high psychological distress group on
incidence diabetes, consecutively adjusted for each block of covariates is given. In the
first step, the effect of high psychological distress was adjusted for four
sociodemographic factors (age, sex, marital status, education level, and household
income) which did not affect the risk (HR = 1.33, 95% CI = 1.10-1.61, p=0.003). In the
second and third step, three health factors (energy level, health status, and health
problems) and two lifestyle factor (leisure-time activity and smoking) were added to the
model. The association between high distress and diabetes incidence in the final model
became nonsignificant (HR = 1.10, 95% CI = 0.91-1.34, p =0.332). In the complete
model younger age, female sex, having more energy or impaired health status were
significant predictors of diabetes incidence (Table 3). Of the two time-dependent
covariates impaired health status was significantly associated with a gradual decreased
risk over time (HR = 0.95, 95% CI = 0.90-1.00, p=0.034), whereas no significant change
over time for health problems was observed (HR = 1.00, 95%CI = 0.95-1.05, p=0.901)
(data not shown in Table 3).
Additional analyses
The continuous psychological distress score was entered in the additional analysis. Age
adjusted HR showed an increased hazard for diabetes with each unit of increase in
psychological distress (HR = 1.07, 95% CI = 1.03-1.10, p<0.001), which remained
significant after controlling for sociodemographic factors sex, marital status, education

level and income (HR = 1.07, 95% CI = 1.03-1.10, p<0.001), and became nonsignificant
after controlling for health (energy, impaired health status, and health problems), and
lifestyle (leisure-time activity, and smoking) (HR = 1.02, 95% CI = 0.98-1.05, p=0.309).
Since BMI was not introduced until wave 13, we decided not to include this variable in
the main analysis. We performed an additional analysis, introducing the continuous BMI
score to the complete adjusted model (not shown). Age adjusted high psychological
distress was significantly associated with an increased diabetes incidence (HR=1.28, 95%
CI = 1.04-1.58, p = 0.022), which was nonsignificant in the complete model (HR = 1.16,
95% CI = 0.93-1.44, p = 0.190). BMI was significantly associated with an increased
hazard for diabetes (HR= 1.11, 95% CI = 1.10-1.13, p<0.001).
In two separate models potential interaction of age or sex with psychological distress was
examined. There were no significant interaction effects of age and distress (HRage*distress=
0.99, 95% CI = 0.98-1.00, p = 0.193), and sex and distress (HRsex*distress= 1.32, 95% CI =
0.90-1.94, p = 0.152).

Discussion
In this large prospective cohort study among men and women without known diabetes at
baseline, a higher level of baseline symptoms of psychological distress, based on the
GHQ 12 item version, were directly associated with a 33% increased hazard to develop
diabetes during 18 year follow up. This association appeared to be confounded by energy
level and health status after complete adjustment.
Earlier studies have examined the association between general psychological distress
measures and incident diabetes, with varying results [7]. For example, both in the
Copenhagen City Heart Study and two Japanese studies [8-10], particularly men with
high levels of general distress but not distressed women were more likely to develop
diabetes during follow up. In contrast, in the Whitehall II cohort, a high baseline GHQ
score was not predictive of incident diabetes during a 10 year follow up period [20]. In

the Whitehall II cohort study, a similar diabetes incidence rate was reported; 3.8 and 4.3
per 1000 person years in men and women respectively, compared to 4.3/1000 person
years in the present study. The Whitehall II cohort was between 3555 years at the start,
whereas the BHPS included everyone > 16 years, with an average of 41 years. The
Whitehall II cohort used odds ratios to predict the incidence of diabetes after an average
of 10.5 years, whereas time dependent hazard ratios of 18 years were examined in the
present study. Examining HRs of 18 waves is a more sensitive method of analysis, more
likely to detect small differences.
The association between general psychological distress and incident diabetes in the
present study was confounded by level of energy and impaired health status. There was
an decreased hazard for an active lifestyle based on leisure-time activities with diabetes
risk, compared to a moderate leasure-time activities, but no longer in the complete
adjusted model. This is in contrast to other studies which consistently show an
association between activity level, depression and diabetes [17,21]. In the present study,
activity level was operationalized by leisure-time activity instead of a metabolic
equivalent of physical activity and leisure-time activity was not measured until wave 6,
which could have affected the strength of association with the variables measured at
baseline. At the same time a persons energy level compared to age and whether or not a
persons health status was impaired could be proxy measures of a persons health status
and ability to be active, therefore more variables were present to determine health and
potential activity at baseline. The overlap between health status, energy, leisure-time
activity and psychological distress with diabetes is consistent with previous findings. For
example, the study of Shirom and colleagues showed that vigor, a mood state comprising
emotional energy, was related to a reduced diabetes risk 20 years follow-up, independent
of depressive symptoms or anxiety [22]. Leisure-time physical activity has been found to
mediate the association between emotional wellbeing and diabetes presence [23]. Rod
and colleagues showed that respondents who reported high levels of psychological
distress had less adequate health behaviors, such as being physically inactive [8].
Integrating increased activity into daily practice has been shown to be beneficial for

mood as well as improve disease indicators [24]. Still, other factors such as a general
healthier lifestyle, including a healthier diet with less saturated fat, reduced salt intake
and increased fiber, and interventions aimed to reduce bodyweight have been effective in
preventing diabetes [25], and could have played a role in the present study, though were
not further investigated. Since adjustment for confounders does not provide information
on whether a covariate is a mediator or a moderator in the association between
psychological distress and diabetes incidence, we cannot draw firm conclusions on
mediators or moderators. Rather, we can hypothesize that energy level, and health status
may act as mediating factors in explaining the association between general psychological
distress and incident diabetes, which remains to be investigated.
The observed association could also be confounded by the general psychopathology of
affected participants, as psychological traits have been previously linked to incident type
2 diabetes [5-7]. In our study self-reported psychiatric morbidity was investigated, which
was more prevalent in the high psychological distress group, however small sample sizes
prevented inclusion in the main analysis.
Given that psychological distress is associated with an increased diabetes incidence,
explanatory pathways may be via increased chronic stress. Chronic stress can increase the
risk of type 2 diabetes directly, for example by long term activation of
psychoneuroendocrine pathways with the release of catecholamines, such as adrenaline
and norepinephrine and glucocorticoids as cortisol. This generally results in an increased
hepatic glucose output, decreased insulin secretion and sensitivity, central accumulation
of body fat, hypertension, and an adverse lipid profile [26,27]. Indirect pathways can
operate through lack of adherence to healthy lifestyle behaviors, such as a low level of
physical activity, unhealthy eating behaviors (e.g. higher saturated fat and carbohydrate
intake), and smoking. The health associated factors energy level compared to age, and
impaired health status appeared to be of influence in the present study.

We suggest that future studies include clinical assessment of diabetes using an oral
glucose tolerance test in association with measures of psychological distress, energy, and
health status, and to observe potential biological mechanisms to further explore the
association between general distress and diabetes incidence. At the same time
interventions specifically aimed to increase activity level could potentially lead to
reduced depressive symptoms and improve diabetes outcomes are currently being
investigated [28,29]. Whereas screening for depression in diabetes appears to be of
limited effect in improving diabetes distress or HbA(1c) levels [30], improving regimen
adherence by a structured self-monitoring of blood glucose lead to significantly greater
reductions in distress, compared to an active control group [31]. Clinical implications of
the present study could be that a broader range of psychological distress symptoms needs
to be taken into account in general practice, not just depressive symptoms. Primary
prevention and anamnesis should also cover social history and biopsychosocial aspects of
the patient. Caregivers and treatment providers (e.g. general practitioners and
diabetologists) should therefore also take the case history, the persons general health
status, and perceived level of energy into account. Interventions aimed to improve
lifestyle behavior (e.g. applying a diabetes prevention protocol to real-world settings)
were effective in attaining weight loss, which is associated to a reduced diabetes risk
[32]. This type of intervention could easily be expanded by adding techniques specifically
addressing psychological distress, yet whether addressing psychological distress has
additional value in diabetes prevention programmes needs to be determined with a
randomised controlled trial.
Despite the longitudinal character of the present study and the use of 18 waves, we
cannot infer conclusions regarding causality from these results, which is a limitation of
the present study. At the same time, there was no information available on the exact date
of diabetes diagnosis which might be a limitation, but since information about diabetes
was available in 18 consecutive waves we used the wave of first positive assessment of
diabetes instead of the date. The variables related to drop out were also related to diabetes
incidence, however in the dropout group the incidence rate of diabetes was lower.

Therefore, it is difficult speculate about the effect of dropouts on the results. As our study
was non-randomized there might be residual confounding, despite our attempted to adjust
for the most important confounders in the multivariate analyses. Moreover, diabetes was
measured by means of self-report in our study. Though studies have reported a strong
association between physicians report of diabetes and the patients self-report [15], there
is still a considerable number of patients with type 2 diabetes who are generally not
aware of the fact that they have type 2 diabetes. This is because type 2 diabetes has a long
asymptomatic pre-clinical phase, often with prodromal symptoms, which frequently goes
undetected. Of people with Type 2 diabetes, the proportion who are undiagnosed ranges
from 30% to 90% [33]. We did take into account self-reported health problems that might
be associated with prodromal complaints, e.g. problems related to blood pressure, skin
conditions, kidney, difficulty seeing, though this was not further specified towards
diabetes specific complaints. The present dataset may be subject to bias, as the diabetes
prevalence at the onset of the study was low (1.7% in 1991), compared to the National
diabetes prevalence (2.8% in 1996) [34]. Still, the selection of participants took place
based on a random draw of postal code areas. At the same time, the diabetes incidence
rate of 4.3/1000 person years was representative of national findings of 4.4/1000 person
years in 2005 [34]. Finally, we need to acknowledge that the assessment of physical
activity was merely focused on leisure-time activities, and may not have represented
people with a high active lifestyle or who were frequent sporters. As a result, activities
such as (heavy) labor activities or household work were not covered.
Strengths of our study include not only the population based approach and the relatively
large sample size, but also the long follow-up period, the use of Cox-proportional hazards
model, which is more adequate and more sensitive in comparison to a logistic regression
analysis. The availability of data from wave to wave was optimized by examining either
the first wave of diabetes presence or the last wave of absence of diabetes. The study
addresses an innovative question with potential clinical implications.

Conclusion

Results of the present study show that persons with elevated levels of psychological
distress are at increased risk to develop type 2 diabetes, potentially affected by low
energy level and health status. These findings warrant a detection of psychological
complaints beyond depression, and further investigation of life-style related interventions
which include a module on psychological distress.

Competing interests
SvS was supported by a small grant from Roche Diagnostics Deutschland GmbH,
Mannheim, Germany, for a study on gestational diabetes. All other authors: Nothing to
declare.

Authors' contributions
PM contributed to the statistical analyses, wrote the results section, reviewed/edited the
manuscript, contributed to the discussion, revised the manuscript. RH retrieved the data,
conducted the statistical analyses, drafted the manuscript, reviewed/edited the
manuscript, contributed to the discussion. WZ contributed to the statistical analyses,
reviewed/edited the manuscript. SvS reviewed/edited the manuscript, contributed to the
data analyses, and discussion. FP wrote the introduction and first draft of the discussion,
reviewed/edited the manuscript. All authors read and approved the final manuscript.

Acknowledgments
The data (and tabulations) used in this publication were made available through the UK
Data Archive. The data were originally collected by the ESRC Research Centre on
Micro-social Change at the University of Essex (now incorporated within the Institute for
Social and Economic Research). Neither the original collectors of the data nor the
Archive bear any responsibility for the analyses or interpretations presented here. All
authors declare no conflict of interest.

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