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

BMC Psychiatry (Impact Factor: 2.21). 05/2013; 13(1):128. DOI: 10.1186/1471-244X-13-128
Source: PubMed

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 cost-effectiveness 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

Full-text

Available from: Judith E Bosmans
ST UD Y P R O T O C O L Open Access
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 Dijk
1*
, Alide D Pols
1,2
, Marcel C Adriaanse
1
, Judith E Bosmans
1
, Petra JM Elders
2
,
Harm WJ van Marwijk
2
and Maurits W van Tulder
1
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 signif icant 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 cost-effectiveness 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 Neuropsyc hiatric 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.
(Continued on next page)
* Correspondence: s.e.m.van.dijk@vu.nl
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, 1081, HV, Amsterdam, The Netherlands
Full list of author information is available at the end of the article
© 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.
van Dijk et al. BMC Psychiatry 2013, 13:128
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Page 1
(Continued from previous page)
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 de-
pression, is the strongest predictor for the onset of major
depression [1,2]. Currently, major depression is a sub-
stantial 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 pa-
tients diagnosed with CHD [11].
Depression has bee n 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 counte rparts,
which is associated with a substantial increase in health
care related cost s. 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 in-
creased 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 per-
cent 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 substan-
tially [24].
Meta analyses show that using preventive interven-
tions , 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 inter-
ventions is to maximize the effectiveness of an interven-
tion while making best use of available resources by
offering the least intensive treatme nt 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 im-
proving disease control in chronically ill patients with
existing major depression [31]. All these findings com-
bined suggest that stepped-care is a promising meth od
to not only treat major depression in patients with DM2
and/or CHD, but also to prevent the onset of this dis-
order 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 de-
pression among DM2 and CHD patients.
Therefore, this study aims to evaluate the cost-
effectiveness of a nurse-led indicated stepped-care pro-
gram to prevent depression among primary care patients
with type 2 diabetes mellitus and/or coronary heart dis-
ease and subthreshold depression in comparison with
usual care.
Methods/design
Design
An economic evaluation from a societal perspective will
be performed alongside a multi-center, cluster random-
ized controlled trial with a one year follow up.
Ethical approval
The study protocol was approved by the Ethics Commit-
tee 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 Involv-
ing Human Subjects Act (WMO).
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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 practic e and of the VU medical centre.
Randomization
Randomization will be done at the level of the participat-
ing 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 pa-
tients are re cruited, participating practices will be ran-
domly alloc ated to serve as intervention practices where
the stepped-care treatment will be implemented, and
control practices where care as usual will be given. Pa-
tients 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 de-
pression 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, pa-
tients cannot participate when they are pregnant, taking
antidepressant medication, or when they have lost a sig-
nificant 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 gen-
eral 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 in-
formed 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 con-
sent to participate. From this point on, patients are
either enrolled in the stepped-care program or will re-
ceive 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.
Intervention
The intervention is modelled after the flexible stepped-
care intervention developed by van t Veer-Tazelaar et al.
[26]. After receiving a specially de veloped training, prac-
tice nurses in the intervention practices will act as care
managers and work together with the General Practi-
tioner (GP) to provide the stepped-care treatment. The
care managers coordinate the execution of the stepped-
care program that consists of four evidence-based subse-
quent treatment steps, lasting 3 months each. The flow
of participants in the intervention group through the
stepped-care program depends on their depressive symp-
tom level, measured using the PHQ-9 every 3 months dur-
ing 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 effi-
ciently 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
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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 inform ation brochure about mild de-
pression 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, part icipants are offered a self-help
course that is specially designed for patients with a
chronic physical illness and depressive complaint s [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 adminis-
tered). 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
Figure 1 Overview of the study design and patient flow.
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cognitive behavioural intervention that focuses on prac-
tical skill building. It consists of a maximum of 7 ses-
sions 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 con-
trol 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 practi-
tioner 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 (includ-
ing 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 stepped-care treatment will at-
tend 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 tau ght by a professional trainer. Before the trial
starts, the trained practice nurses will perform two prac-
tice 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 cumu lative inci-
dence of DSM-IV major depressive disorder after 12
months according to the Mini International Neuro-
psychiatric 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 in-
cluded are costs for healthcare utilization, informal care,
and work absenteeism and presenteeism. Medication use
will be retrieved from the patients pharmacy. If avail-
able, Dutch guideline prices will be used to value re-
source 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 ap-
proach (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 ad-
ministered at baseline, 3, 6, 9 and 12 months after inclu-
sion 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 pres-
sure, low-density lipoprotein (LDL) cholesterol and
glycosylated haemoglobin (HbA1C). These outcomes
will be measured at baseline and at 12 month s 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, demo-
graphics will be measured at baseline, along with per-
sonal 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 pur-
poses 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 Depres-
sion Scale- Anxiety (HADS-A) [52].
After 12 months the uptake of the stepped-care pro-
gram will be evaluated. The number of contacts with the
care manager, the number of PST sessions, antidepres-
sant use, and the number of referrals to the GP will be
assessed by the care manager in the intervention group.
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Mental health care utilization outside the general prac-
tice 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 volun-
teering 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.
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 inci-
dence 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, a s-
suming 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 measure-
ments. Therefore we have first adjusted for the fact that
we do not have one, but multiple measurements per pa-
tient. Assuming these measurements are clustered with
an intraclass correlation (ICC) of 0.45, seventy-one pa-
tients 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 pa-
tients 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 treat-
ment groups.
All analyses will be on an intention-to-treat basis. Differ-
ences 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 de-
pressive 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 differ-
ences 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 ana-
lysis 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 treat-
ment groups in order to be able to estimate the total
health care budget needed for a specific condition [58].
Therefore, bias-corrected and accelerated boot strapping
with 5000 replications will be used to estimate 95% con-
fidence intervals around the mean difference in total
Table 1 Overview of all measurements and instruments
screening baseline 3 months 6 months 9 months 12 months
Depression symptoms (PHQ-2) x
Demographics x
Depression symptoms (PHQ-9) xxxx x
Clinical depression (MINI) xx x
Health care costs (Tic-P) xxxx x
Quality of life (EQ-5D) xxxx x
Anxiety (HADS-A) xxxx x
Personal and family history (DIS) x
Social support xx x
Existing chronic illnesses xx x
Locus of control xxxx x
Satisfaction with provided care (CSQ) x
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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 esti-
mate 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 ceil-
ing 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 pri-
mary 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 practic es 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 pres-
ence of subthreshold depressive symptoms is the largest
risk factor for developing major depression, targeting
preventive treatments to patien ts 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 treat-
ment is tailored to the needs and preferences of the pa-
tient 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 re-
sources for patients who really need them.
By testing a stepped-care program to prevent depres-
sion 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 pre-
ventive 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 proce-
dures are similar to daily clinical practice. This greatly en-
hances 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 ab-
senteeism, 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 signifi-
cant reduction in total health care costs among DM2 pa-
tients 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
[60-62]. 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 treat-
ment will become more and more visible after the treat-
ment 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 en-
ables us to measure all possible effects of the interven-
tion. We try to counter possible contamination between
treatments groups by using a cluster randomized con -
trolled design, in which staff from usual care practices
are not trained to perform the stepped-care 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 re-
sults 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.
Additional file
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.
Abbreviations
CHD: Coronary Heart Disease; CSQ: Client Satisfaction Questionnaire;
DIS: Diagnostic Interview Schedule; DM2: Type 2 Diabetes Mellitus;
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http://www.biomedcentral.com/1471-244X/13/128
Page 7
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.
Author details
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, 1081, HV, Amsterdam, The Netherlands.
2
Department of
General Practice and the EMGO institute for Health and Care research, VU
University Medical Centre, Amsterdam, The Netherlands.
Received: 10 April 2013 Accepted: 24 April 2013
Published: 7 May 2013
References
1. Smits F, Smits N, Schoevers R, Deeg D, Beekman A, Cuijpers P: An
epidemiological approach to depression prevention in old age.
Am J Geriatr Psychiatr 2008, 16:444453.
2. Cuijpers P, Van Straten A, Smit F, Mihalopoulos C, Beekman A: Preventing
the onset of depressive disorders: a meta-analytic review of
psychological interventions. Am J Psychiatr 2008, 165:12721280.
3. Mathers CD, Loncar D: Projections of global mortality and burden of
disease from 2002 to 2030. PLoS Med 2006, 3:e442.
4. de Graaf R, ten Have M, van Gool C, van Dorsselaer S: Prevalence of mental
disorders and trends from 1996 to 2009. Results from the Netherlands
Mental Health Survey and Incidence Study-2. Soc Psychiatr Psychiatr
Epidemiol 2012, 47:203213.
5. Kessler RC, Ustun T (Eds): The WHO World Mental Health Surveys. Cambridge:
Cambridge University Press; 2008.
6. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ: The prevalence of
comorbid depression in adults with diabetes. Diabetes Care 2001,
24:10691078.
7. Härter M, Baumeister H, Reuter K, Jacobi F, Höfler M, Bengel J, Wittchen HU:
Increased 12-month prevalence rates of mental disorders in patients
with chronic somatic diseases. Psychother Psychosom 2007, 76:354360.
8. Rudisch B, Nemeroff CB: Epidemiology of comorbid coronary artery
disease and depression. Biol Psychiatr 2003, 54:227240.
9. Bot M, Pouwer F, Ormel J, Slaets JPJ, De Jonge P: Predictors of incident
major depression in diabetic outpatients with subthreshold depression.
Diabet Med 2010, 27:12951301.
10. Thombs BD, Bass EB, Ford DE, Stewart KJ, Tsilidis KK, Patel U, Fauerbach JA,
Bush DE, Ziegelstein RC: Prevalence of depression in survivors of acute
myocardial infarction. J Gen Intern Med 2006, 21:30 38.
11. Hance M, Carney RM, Freedland KE, Skala J: Depression in patients with
coronary heart disease: A 12-month follow-up. Gen Hosp Psychiatr 1996,
18:6165.
12. Gehi A, Haas D, Pipkin S, Whooley MA: Depression and medication
adherence in outpatients with coronary heart disease: findings from the
Heart and Soul Study. Arch Int Med 2005, 165:2508
2513.
13. Lin EHB, Katon W, Von Korff M, Rutter C, Simon GE, Oliver M, Ciechanowski
P, Ludman EJ, Bush T, Young B: Relationship of depression and diabetes
self-care, medication adherence, and preventive care. Diabetes Care 2004,
27:21542160.
14. Ruo B, Rumsfeld JS, Hlatky MA, Liu H, Browner WS, Whooley MA:
Depressive symptoms and health-related quality of life: the heart and
soul study. JAMA 2003, 290:215221.
15. Ali S, Stone M, Skinner TC, Robertson N, Davies M, Khunti K: The association
between depression and health-related quality of life in people with
type 2 diabetes: a systematic literature review. Diabetes Metab Res Rev
2010, 26:7589.
16. Lin EHB, Heckbert SR, Rutter CM, Katon WJ, Ciechanowski P, Ludman EJ,
Oliver M, Young BA, McCulloch DK, Von Korff M: Depression and increased
mortality in diabetes: unexpected causes of death. Ann Fam Med 2009,
7:414421.
17. Katon W, Lin EHB, Von Korff M, Ciechanowski P, Ludman E, Young B, Rutter
C, Oliver M, McGregor M: Integrating depression and chronic disease care
among patients with diabetes and/or coronary heart disease: the design
of the TEAMcare study. Contemp Clin Trials 2010, 31:312322.
18. Simon GE, Katon WJ, Lin EHB, Ludman E, VonKorff M, Ciechanowski P,
Young BA: Diabetes complications and depression as predictors of
health service costs. Gen Hosp Psychiatr 2005, 27:344351.
19. Rutledge T, Vaccarino V, Johnson BD, Bittner V, Olson MB, Linke SE, Cornell
CE, Eteiba W, Sheps DS, Francis J, et al: Depression and cardiovascular
health care costs among women with suspected myocardial ischemia:
prospective results from the WISE (Women's Ischemia Syndrome
Evaluation) Study. J Am Coll Cardiol 2009, 53:176183.
20. Bosmans JE, Adriaanse MC: Outpatient costs in pharmaceutically treated
diabetes patients with and without a diagnosis of depression in a Dutch
primary care setting. BMC Health Serv Res 2012, 12:46.
21. Egede LE, Zheng D, Simpson K: Comorbid depression is associated with
increased health care use and expenditures in individuals with diabetes.
Diabetes Care 2002, 25:464470.
22. Smit F, Willemse G, Koopmanschap M, Onrust S, Cuijpers P, Beekman A:
Cost-effectiveness of preventing depression in primary care patients.
Br J Psychiatr 2006, 188:330336.
23. Andrews G, Issakidis C, Sanderson K, Corry J, Lapsley H: Utilising survey
data to inform public policy: comparison of the cost-effectiveness of
treatment of ten mental disorders. Br J Psychiatr 2004, 184:
526533.
24. Cuijpers P, Beekman ATF, Reynolds CF: Preventing depression: a global
priority. JAMA 2012, 307:10331034.
25. Muñoz RF, Cuijpers P, Smit F, Barrera AZ, Leykin Y: Prevention of major
depression. Annu Rev Clin Psychol 2010, 6:181212.
26. van't Veer-Tazelaar PJ, van Marwijk HWJ, van Oppen P, van Hout HPJ, van
der Horst HE, Cuijpers P, Smit F, Beekman ATF: Stepped-care prevention of
anxiety and depression in late life: a randomized controlled trial.
Arch Gen Psychiatr 2009, 66:297304.
27. van't Veer-Tazelaar PJ, van Marwijk HW, van Oppen P, van der Horst HE,
Smit F, Cuijpers P, Beekman AT: Prevention of late-life anxiety and
depression has sustained effects over 24 months: a pragmatic
randomized trial. Am J Geriatr Psychiatr 2011, 19:230239.
28. Katon WJ, Von Korff M, Lin EHB, Simon G, Ludman E, Russo J, Ciechanowski
P, Walker E, Bush T: The Pathways Study: a randomized trial of
collaborative care in patients with diabetes and depression. Arch Gen
Psychiatr 2004, 61:10421049.
29. Katon WJ, Russo JE, Von Korff M, Lin EHB, Ludman E, Ciechanowski PS:
Long-term effects on medical costs of improving depression outcomes in
patients with depression and diabetes. Diabetes Care 2008, 31:11551159.
30. Katon W, Unützer J, Fan MY, Williams JW Jr, Schoenbaum M, Lin EHB,
Hunkeler EM: Cost-effectiveness and net benefit of enhanced treatment
of depression for older adults with diabetes and depression. Diabetes
Care 2006, 29:265270.
31. Katon WJ, Lin EHB, Von Korff M, Ciechanowski P, Ludman EJ, Young B,
Peterson D, Rutter CM, McGregor M, McCulloch D: Collaborative care for
patients with depression and chronic illnesses. N Engl J Med 2010,
363:26112620.
32. Kroenke K, Spitzer RL: The PHQ-9: a new depression diagnostic and
severity measure. Psychiatr Ann 2002, 32:509515.
van Dijk et al. BMC Psychiatry 2013, 13:128 Page 8 of 9
http://www.biomedcentral.com/1471-244X/13/128
Page 8
33. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E,
Hergueta T, Baker R, Dunbar GC: The Mini-International Neuropsychiatric
Interview (MINI): the development and validation of a structured
diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatr
1998, 59:2233.
34. Kroenke K, Spitzer RL, Williams JBW: The Patient Health Questionnaire-2:
validity of a two-item depression screener. Med Care 2003, 41:12841292.
35. Arroll B, Goodyear-Smith F, Crengle S, Gunn J, Kerse N, Fishman T, Falloon K,
Hatcher S: Validation of PHQ-2 and PHQ-9 to screen for major depression
in the primary care population. Ann Fam Med 2010, 8:348353.
36. Zuithoff NPA, Vergouwe Y, King M, Nazareth I, van Wezep MJ, Moons KGM,
Geerlings MI: The Patient Health Questionnaire-9 for detection of major
depressive disorder in primary care: consequences of current thresholds
in a crosssectional study. BMC Fam Pract 2010, 11:98.
37. Van Vliet I, De Beurs E: Het Mini Internationaal Neuropsychiatrisch
Interview (MINI) Een kort gestructureerd diagnostisch psychiatrisch
interview voor DSM-IV- en ICD-10-stoornissen. Tijdschr Psychiatr 2007,
49:393397.
38. Voordouw I, van Osch B, Terweij M: De cursus Leven met een chronische
ziekte. Utrecht: Trimbos-instituut; 2005.
39. Bosmans JE, Brook OH, van Hout HPJ, de Bruijne MC, Nieuwenhuyse H,
Bouter LM, Stalman WAB, van Tulder MW: Cost effectiveness of a
pharmacy-based coaching programme to improve adherence to
antidepressants. Pharmacoeconomics 2007, 25:2537.
40. Mynors-Wallis L, Davies I, Gray A, Barbour F, Gath D: A randomised
controlled trial and cost analysis of problem-solving treatment for
emotional disorders given by community nurses in primary care.
Br J Psychiatr 1997, 170:113119.
41. Platform Vitale Vaten: Zorgstandaard Vasculair Risicomanagement deel I
(voor zorgverleners). Den Haag: Platform Vitale Vaten; 2009.
42. Trimbos-instituut: Naar een zorgstandaard voor depressie: Checklists
depressiezorg voor zorgaanbieders en zorgverzekeraars. Utrecht: Trimbos-
instituut; 2007.
43. Nederlandse Diabetes Federatie: NDF Care Standard: Transparency and
quality of diabetes care for people with type 2 diabetes. Amersfoort:
Nederlandse Diabetes Federatie; 2007.
44. Wittkampf K, van Ravesteijn H, Baas K, van de Hoogen H, Schene A, Bindels
P, Lucassen P, van de Lisdonk E, van Weert H: The accuracy of Patient
Health Questionnaire-9 in detecting depression and measuring
depression severity in high-risk groups in primary care. Gen Hosp
Psychiatr 2009, 31:451459.
45. Brooks R: EuroQol: the current state of play. Health Policy
1996, 37:5372.
46. Roijen L, Straten A, Tiemens B, Donker M: Handleiding Trimbos/iMTA
questionnaire for Costs associated with Psychiatric illness (TiC-P). Rotterdam:
Institute of Medical Technology Assessment (iMTA); 2002.
47. Robins LN, Helzer JE, Croughan J, Ratcliff KS: National Institute of Mental
Health diagnostic interview schedule: its history, characteristics, and
validity. Arch General Psychiatr 1981, 38:381389.
48. Kriegsman DMW, Penninx BWJH, Van Eijk JTM, Boeke AJP, Deeg DJH: Self-
reports and general practitioner information on the presence of chronic
diseases in community dwelling elderly: A study on the accuracy of
patients' self-reports and on determinants of inaccuracy. J Clin Epidemiol
1996, 49:1407 1417.
49. Pearlin LI, Schooler C: The Structure of Coping. JHealthSocBehav1978, 19:221.
50. Penninx BWJH, Van Tilburg T, Kriegsman DMW, Deeg DJH, Boeke AJP, van
Eijk JTM: Effects of social support and personal coping resources on
mortality in older age: the Longitudinal Aging Study Amsterdam.
Am J Epidemiol 1997, 146:510519.
51. Bijl D, Van Marwijk H, Beekman A, De Haan M, Van Tilburg W: A
randomized controlled trial to improve the recognition, diagnosis and
treatment of major depression in elderly people in general practice:
design, first results and feasibility of the West Friesland Study.
Int J Psychiatr Clin Pract 2003, 8:135140.
52. Spinhoven PH, Ormel J, Sloekers PPA, Kempen GIJM, Speckens AEM, Hemert
AM: A validation study of the Hospital Anxiety and Depression Scale (HADS)
in different groups of Dutch subjects. Psychol Med 1997, 27:363370.
53. De Brey H: A cross-national validation of the client satisfaction
questionnaire: the Dutch experience. Eval Program Plann 1983, 6:395400.
54. De Wilde EF, Hendriks VM: The Client Satisfaction Questionnaire:
psychometric properties in a Dutch addict population. Eur Addict Res
2005, 11:157162.
55. Twisk JW: Applied multilevel analysis: a practical guide. Cambridge:
Cambridge University Press; 2006.
56. Van Buuren S, Groothuis-Oudshoorn K: MICE: Multivariate imputation by
chained equations in R. J Stat Softw 2011, 45:168.
57. Rubin DB: Multiple imputation for nonresponse in surveys. New York: John
Wiley & Sons; 1987.
58. Thompson SG, Barber JA: How should cost data in pragmatic randomised
trials be analysed? BMJ 2000, 320:11971200.
59. Fenwick E, O'Brien BJ, Briggs A: Cost-effectiveness acceptability curvesfacts,
fallacies and frequently asked questions. Health Econ 2004, 13:405415.
60. Simon GE, Katon WJ, Lin EHB, Rutter C, Manning WG, Von Korff M,
Ciechanowski P, Ludman EJ, Young BA: Cost-effectiveness of systematic
depression treatment among people with diabetes mellitus. Arch Gen
Psychiatr 2007, 64:6572.
61. Katon WJ, Schoenbaum M, Fan MY, Callahan CM, Williams J Jr, Hunkeler E,
Harpole L, Zhou XHA, Langston C, Unutzer J: Cost-effectiveness of
improving primary care treatment of late-life depression. Arch Gen
Psychiatr 2005, 62:13131320.
62. Katon W, Russo J, Von Korff M, Lin E, Simon G, Bush T, Ludman E, Walker E:
Long-term Effects of a Collaborative Care Intervention in Persistently
Depressed Primary Care Patients. J Gen Intern Med 2002, 17:741748.
doi:10.1186/1471-244X-13-128
Cite this article as: van Dijk et al.: Cost-effectiveness of a stepped-care
intervention to prevent major depression in patients with type 2
diabetes mellitus and/or coronary heart disease and subth reshold
depression: design of a cluster-randomized controlled trial. BMC
Psychiatry 2013 13:128.
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van Dijk et al. BMC Psychiatry 2013, 13:128 Page 9 of 9
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  • Source
    • "Concealed depression among type-2 diabetes patients needs to be assessed in every diabetes care setting. Stepped and collaborative care models for treatment [66,67] of diabetes and depression should be explored for treatment options in Nepal and other low-income countries [23]. Moreover, education about the connection between physical health and mental health, which has been used in high-income settings [68], should be considered for psycho-education programs within this population. "
    [Show abstract] [Hide abstract] ABSTRACT: Diabetes is a growing health problem in South Asia. Despite an increasing number of studies exploring causal pathways between diabetes and depression in high-income countries (HIC), the pathway between the two disorders has received limited attention in low and middle-income countries (LMIC). The aim of this study is to investigate the potential pathway of diabetes contributing to depression, to assess the prevalence of depression, and to evaluate the association of depression severity with diabetes severity. This study uses a clinical sample of persons living with diabetes sequelae without a prior psychiatric history in urban Nepal. A cross-sectional study was conducted among 385 persons living with type-2 diabetes attending tertiary centers in Kathmandu, Nepal. Patients with at least three months of diagnosed diabetes and no prior depression diagnosis or family history of depression were recruited randomly using serial selection from outpatient medicine and endocrine departments. Blood pressure, anthropometrics (height, weight, waist and hip circumference) and glycated hemoglobin (HbA1c) were measured at the time of interview. Depression was measured using the validated Nepali version of the Beck Depression Inventory (BDI-Ia). The proportion of respondents with depression was 40.3%. Using multivariable analyses, a 1-unit (%) increase in HbA1c was associated with a 2-point increase in BDI score. Erectile dysfunction was associated with a 5-point increase in BDI-Ia. A 10mmHg increase in blood pressure (both systolic and diastolic) was associated with a 1.4-point increase in BDI-Ia. Other associated variables included waist-hip-ratio (9-point BDI-Ia increase), at least one diabetic complication (1-point BDI-Ia increase), treatment non-adherence (1-point BDI-Ia increase), insulin use (2-point BDI-Ia increase), living in a nuclear family (2-point BDI-Ia increase), and lack of family history of diabetes (1-point BDI-Ia increase). Higher monthly income was associated with increased depression severity (3-point BDI-Ia increase per 100,000 rupees, equivalent US$1000). Depression is associated with indicators of more severe diabetes disease status in Nepal. The association of depression with diabetes severity and sequelae provide initial support for a causal pathway from diabetes to depression. Integration of mental health services in primary care will be important to combat development of depression among persons living with diabetes.
    Full-text · Article · Nov 2013 · BMC Psychiatry
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    [Show abstract] [Hide abstract] ABSTRACT: Background Depression is associated with a variety of diabetes complications, including diabetic retinopathy, nephropathy, neuropathy, and macrovascular complications. The prevalence of the symptoms of anxiety (32%) and depression (22.4%) in patients with diabetes is considerably higher than in general population samples (10%). The aim of this study was to evaluate the prevalence and determinants of anxiety and depression symptoms in patients with type 2 diabetes (T2DM). Material/Methods This survey was conducted during 2007–2010. In total, 1500 patients were invited to participate in the study. The Hospital Anxiety and Depression Scale (HADS) was used to measure depression and anxiety for the evaluation of the depressive state and anxiety. Statistical analysis was carried out using SPSS 17.0. Results More than 70% of all respondents who participated in the study had diabetes mellitus complications (72.2%). The prevalence of mild to severe depression score was 28.5% (95% CI 25.7–31.4). The prevalence of anxiety was 42.4% (95% CI 39.3–45.5). Anxiety was more frequent among females (46.8%) than among males (34.7%) (p<0.001). A significant negative trend was observed between prevalence of anxiety and depression, and age and education (p for trend <0.001). Conclusions A significant association between depression and diabetic complications was identified (p<0.05). Duration of diabetes was a risk factor significantly associated with higher scores of anxiety among the patients with T2DM.
    Full-text · Article · Feb 2014 · Medical science monitor: international medical journal of experimental and clinical research
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    [Show abstract] [Hide abstract] ABSTRACT: Background: In stepped care models patients typically start with a low-intensity evidence-based treatment. Progress is monitored systematically and those patients who do not respond adequately step up to a subsequent treatment of higher intensity. Despite the fact that many guidelines have endorsed this stepped care principle it is not clear if stepped care really delivers similar or better patient outcomes against lower costs compared with other systems. We performed a systematic review and meta-analysis of all randomized trials on stepped care for depression. Method: We carried out a comprehensive literature search. Selection of studies, evaluation of study quality and extraction of data were performed independently by two authors. Results: A total of 14 studies were included and 10 were used in the meta-analyses (4580 patients). All studies used screening to identify possible patients and care as usual as a comparator. Study quality was relatively high. Stepped care had a moderate effect on depression (pooled 6-month between-group effect size Cohen's d was 0.34; 95% confidence interval 0.20-0.48). The stepped care interventions varied greatly in number and duration of treatment steps, treatments offered, professionals involved, and criteria to step up. Conclusions: There is currently only limited evidence to suggest that stepped care should be the dominant model of treatment organization. Evidence on (cost-) effectiveness compared with high-intensity psychological therapy alone, as well as with matched care, is required.
    Full-text · Article · Mar 2014 · Psychological Medicine
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