Project
Project title: (max. 3 lines)
Addiction in anxiety and depression: a ten year prospective study of co-morbidity, communality of risk
factors, public health consequences and barriers to effective care
Research Program ZonMw:
Addiction – Mental Health /Addiction
Project type: Research
Summary: (max. 50 lines)
Background. In the 2001 WHO health report depression, anxiety and addiction disorders
constitute three of the top-10 disorders causing years lost due to disability world wide. Due to their
high prevalence, enormous public health impact and tendency to co-occur they constitute the larger
part of what is known as the common mental disorders. Passing through the successive filters in the
health service, the prevalence of more severe, more longstanding, less treatment-responsive and
more complex (in terms of co-morbidity) disorders rises. Several hypotheses have been offered to
explain the relationship between addictive disorders and depression or anxiety: (1) the addictive agent
is used as a form of self- medication against anxiety or depression- or in the case of benzodiazepines
as a iatrogenic addiction; (2) depression or anxiety are part of a withdrawal syndrome from an
addictive agent; (3) co-morbidity is a consequence of behavioural factors common to addiction and
depression and anxiety; and (4) co-morbidity follows from genetic factors common to addiction and
depression or anxiety. The clinical course and treatment methods of co-morbid conditions could be
improved if it can be clarified which of the above models offers the best explanation of co-morbidity.
For this, research is needed in which demographic, psychosocial, clinical, and biological (including
genetic) factors are studied in combination and prospectively over a long time span. A problem for comorbid patients in the Netherlands is that psychiatric and addiction services are organised separately.
This leads to poor co-ordination and unproductive referrals between services. Although it is well known
that a large proportion of patients referred to mental health care facilities have co-morbid addiction
disorders, the majority remain undetected. This has serious consequences for all aspects of the
delivery of adequate care, including compliance, patient- satisfaction and the effectiveness of
interventions.
Research Questions. (i) What is the incidence and long term course of co-morbidity of ABN-addictive
disorders with depression or anxiety?. (ii) Which demographic, psychosocial, clinical, and biological
factors determine the incidence and prognosis of co-morbidity of ABN-addictive disorders with
depression or anxiety? (iii) What is the impact of co-morbid ABN addiction on a) disease course of
anxiety or depression; b) wellbeing, levels of disability and handicap, and ability to work, c) treatment
history, including barriers to health care; d) the patients' perspective; e) the development of further
psychiatric and physical co-morbidity? (iv) Are genetic polymorphisms in known and newly found
candidate genes associated with symptomatology, treatment outcome, and biological endophenotype?
(v) Which is the most efficient way to screen for alcohol addiction in patients with anxiety and
depression.
Methods. Prospective cohort study involving over 2800 adults with anxiety and/or depressive
disorders participating in the NESDA programme. Participants are recruited in the community, primary
care and specialised mental health using established methods and instruments. Data on addiction
disorders, anxiety and depression, demographics, physical illness, life-events and support, personality;
the public health consequences of ABN-addiction and both care trajectories and the patients'
perspective will be collected at three year intervals in all participants. Genetic and biochemical data
will also be collected in all participants. Power analyses carried out for the most sensitive research
questions have shown that the study will have sufficient power.
Feasibility/embedding. The embedding of this study within the NESDA programme ensures
feasibility and access to a large cohort of patients with anxiety and depression in relevant health care
settings.
Deliverables will include (i) the formation of the infrastructure, study cohort and the data of the first
two measurements (1 year follow-up data), (iii) scientific reports on(a) the co-morbidity and (b)
communality of risk-factors of ABN addiction and anxiety and depression in different echelons of the
health service, (c) the prognostic impact of co-morbidity among ABN-addiction and depression/anxiety
over 1 year of follow-up, (d) the incidence of ABN-addiction in patients with depression/anxiety, (e) the
comparative quality and efficiency of both psychometric and biological screeners for alcohol-related
disorders in patients with anxiety and depression. Given the established infrastructure, the opportunity
will exist to extend the study of ABN addiction over the full follow-up period.
Keywords: (max. 8)
alcohol, benzodiazepines, nicotine, addiction, co-morbidity, anxiety, depression, longitudinal
Applicant
Titles
Initials
Prefix
Surname
Suffix
Gender
Phone number
Fax number
E-mail address
Organisation
Sub-organisation
Department
Postal address
Postal code / City
State / Country
Internet address
MD PhD
R
prof dr
van Dyck
male
020-5736620
0205736687
[email protected]
Vumc/ GGZ Buitenamstel
Psychiatry
Valeriusplein 9
City : 1075 BG Amsterdam
Country : NL
http://
Principal investigator/Project leader
Applicant and project leader is same person.
Titles
Initials
Prefix
Surname
Suffix
Gender
Phone number
Fax number
E-mail address
Organisation
Sub-organisation
Department
Postal address
Postal code / City
State / Country
Internet address
MD PhD
ATF
prof dr
Beekman
male
020-576600
020-5736687
[email protected]
Vumc/GGZ Buitenamstel
Psychiatry
Valeriusplein 9
City : 1975BG Amsterdam
Country : NL
http://
Other members of project group
Initials
Prefix
BWJ
dr
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Initials
Prefix
Surname
Suffix
Penninx
female
principal investigator NESDA consortium
see applicant
see applicant
see applicant
W
prof dr
van den Brink
Male
Professor of Psychiatry and Addiction
AMC
AIAR
Psychiatry
Amsterdam
WJG
prof dr
Hoogendijk
Male
Prof Biological Psychiatry
Same as applicant
Same as applicant
Amsterdam
J
prof dr
Ormel
Male
prof Social Psychiatry and Psychiatric Epidemiology
RUG
Psychiatry
Groningen
FG
Prof dr
Zitman
Male
prof Psychiatry
LUMC
Psychiatry
Leiden
P
dr
Verhaak
Gender
Function
Organisation
Sub-organisation
Department
City
male
Researcher
NIVEL
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
R
dr
de Graaf
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Initials
Prefix
Surname
Suffix
Gender
Function
Organisation
Sub-organisation
Department
City
Utrecht
male
Researcher
Netherlands Institute for Mental Health and Addiction (Trimbos)
Utrecht
R
prof dr
Grol
male
Prof primary care medicine
WOK
Nijmegen
J
dr
Smit
male
Logistic manager NESDA
Vumc
Psychiatry
Amsterdam
Participating organisation(s)
Organisation
Sub-organisation
Department
City
Nature of the co-operation
NETSA, prof dr D Boomsma
Biological Psychology
Amsterdam
Genetic basis co-morbidity; data analysis
Organisation
Sub-organisation
Department
City
Nature of the co-operation
Vumc, prof dr T Schoffelmeer
Organisation
Sub-organisation
Vumc, prof dr G Smit
Pharmacology
Amsterdam
Pharmacology; data analysis
Department
Molecular and cellular neurobiology
City
Amsterdam
Nature of the co-operation Neurobiology, data analysis
Organisation
Sub-organisation
Department
City
Nature of the co-operation
Organisation
Sub-organisation
Department
City
Nature of the co-operation
Project
Duration of the project:
48
months
ZonMw-Estimate
Project year
Cost item
Personnel
Material
1
23.727
2
24.334
3
24.929
4
25.501
55.640
5
6
Implementation
Equipment
Remaining
Total
7
8
Total
98.492
55.640
154.132
Estimate
requested ZonMw contribution
Amount : E 154.132
Personal contribution
From co-financing:
1. name co-financer
GEESTKRACHT
2. name co-financer
3. name co-financer
4. name co-financer
5. name co-financer
6. name co-financer
7. name co-financer
8. name co-financer
Amount : E 4.200.000
Amount : E 4.200.000
status: granted
Amount :
Amount :
Amount :
Amount :
Amount :
Amount :
Amount :
status: granted
status: granted
status: granted
status: granted
status: granted
status: granted
status: granted
9. name co-financer
10. name co-financer
Amount :
Amount :
Project Total
Amount : E 4.354.132
status: granted
status: granted
Justification of budget (max 25 lines)
Screening and diagnostic procedures for ABN-addiction, which were not planned or costed in the
original NESDA plan will be incorporated in the NESDA interview procedures. For example, the AUDIT
and CAGE, use of Benzodiazepine use and smoking habits. The CIDI diagnostics interview will be
extended with specific addiction-related parts. Moreover, the LIFE-CHART interviews, both at baseline
and at follow-up, will be extended to include detailed longitudinal assessments of ABN-addiction
In the first measurement and one year follow up approximately 5000 interviews (ca 2900 on baseline
and 2100 on follow up) will be administered. Extra interview time and data processing for this part is
estimated on ca 45 minutes (25 minutes of assessment(s) and 20 for additional data processing: A
total of 3750 hours of extra data collection and -processing time in 4 years.) For this additional data
collection and processing 0,6 fte research nurse is needed. (0,2 Amsterdam; 0,2 Groningen and 0,2
Leiden) for 4 years.
We expect to collect about 2600 blood samples in the first measurement wave. Additional biochemical
markers are requested in order to answer specific research questions (see below).
A specification of the budget can be found in appendix A.
Problem definition: (max. 50 lines)
In the 2001 WHO health report depression, anxiety and addiction disorders constitute three of
the top-10 disorders causing years lost due to disability world wide. In the industrialised world, the
impact of these disorders is even higher and it is expected that their impact will rise during the coming
decades. The co-occurrence of depression, anxiety and addiction disorders is well known. Due to their
high prevalence, enormous public health impact and tendency to occur they constitute the larger part
of what is known as the common mental disorders. These disorders are common in the community, in
primary care and in specialised (mental) health settings. Passing through the successive filters in the
health service, the prevalence of more severe, more longstanding, less treatment-responsive and
more complex (in terms of co-morbidity) disorders rises.
Co-morbid alcohol abuse or addiction is
associated with a poorer prognosis of anxiety and depression. Conversely, anxiety and depression in
alcohol addicted patients predicts a higher rate of relapse after treatment of the addiction disorder.
Anxiety and depression frequently arise after withdrawal from alcohol. Benzodiazepine dependence
is only recently recognised as type of substance abuse. Diagnostic instruments and criteria for the
diagnosis have become available. As benzodiazepines are usually obtained through medical
prescription, this form of dependence is often of iatrogenic origin. As many as 40% of patients
receiving normal doses of benzodiazepines may develop dependence (Kan et al 1997). In spite of
caution urged in Guidelines and professional standards, physicians continue to prescribe
benzodiazepines as a long term treatment for anxiety or depression, although evidence is lacking that
there is a lasting positive effect (Zandstra et al 2002). On the contrary, long term benzodiazepine use
is associated with poorer outcome in the treatment of panic disorder (van Balkom et al, 1996).
Nicotine is the most common addiction world wide. Both population studies and clinical studies have
shown that prevalence of smoking is higher in people with the diagnosis of major depression,
especially among low -income women. A history of depression has been associated with increased
smoking severity and higher relapse after smoking cessation (Glassman et al, 1990). Several studies
have shown that smoking cessation is frequently followed by depressive symptoms. (Covey et al,
1990). Antidepressants, such as bupropion and nortryptiline show effectiveness in supporting smoking
cessation. Much less is known about the association of anxiety to smoking.
Several hypotheses have been offered to explain the relationship between addictive disorders and
depression or anxiety: (1) the addictive agent is used as a form of self- medication against anxiety or
depression- or in the case of benzodiazepines as a iatrogenic addiction; (2) depression or anxiety are
part of a withdrawal syndrome from an addictive agent; (3) co-morbidity is a consequence of
behavioral factors common to addiction and depression and anxiety; and (4) co-morbidity follows from
genetic factors common to addiction and depression or anxiety.
The clinical course and treatment methods of co-morbid conditions could be improved if it can be
clarified which of the above models offers the best explanation of co-morbidity. For this, research is
needed in which demographic, psychosocial, clinical, and biological factors are studied in combination
and prospectively over a long time span. It is believed that among the biological factors associated
with these co-morbidities, genetic polymorphisms are of particular importance (Flint at al., 1995;
Holsboer et al., 1995). It is expected that in the coming years a large number of polymorphisms will be
discovered in candidate genes involved in the pathogenesis of depression (Merikangas, 2002) and
ABN-dependence (Evans et al 2000, Tyndale, 2003; Dick and Foroud, 2003).
A problem for co-morbid patients in the Netherlands is that psychiatric and addiction services are
organised separately. This frequently leads to poor co-ordination and unproductive referrals between
services. Although it is well known that a large proportion of patients referred to mental health care
facilities have co-morbid addiction disorders, the majority remain undetected. This has serious
consequences for all aspects of the delivery of adequate care, including compliance, patientsatisfaction and the effectiveness of interventions. In order to improve health care, detection of
addiction disorders should improve and data must be collected on both the patient’s and caregivers
perspectives about care utilisation in relation to clinical course.
Relevance: (max. 50 lines)
The public health relevance of co-morbidity among addiction, anxiety and depression is
undisputed. At an individual level, co-morbidity adds disproportionate disability and impairment of wellbeing to already compromised health status. The focus on co-morbidity with anxiety and depression is
highly relevant for the ZON-MW programme 'Psychische Problematiek en Verslaving'.
The primary aim of treatment is to change the natural history of a disorder. Sound knowledge about
the prognosis of patients in different phases of their illness, contacted in different health care settings
is a prerequisite for adequate communication with the patient, planning of treatment and for the
allocation of scarce recourses to those at risk for an unfavourable course. Sound knowledge on factors
predicting the outcome or consequences are similarly necessary to be able to tailor treatment, for the
implementation of stepped-care type treatment strategies and to reach sustained co-operation of the
patient with treatment. Given the high levels of co-occurrence and the impact co-morbidity of
depression, anxiety and addiction disorders may have on the prognosis, it is surprising how little is
known about the long term development of co-morbidity in different health care settings.
The NESDA programme offers a unique opportunity to follow-up large cohorts with relevant
disorders, representative for those in different health-care settings over long periods (10 years). The
aim of the NESDA program is to study the long- term prognosis of anxiety, depression and their comorbidity, in order to contribute to improved quality of care and prevention of chronicity. A sequence
of four groups of research questions are distinguished ; (1) the long term course and public
health/economic consequences; including the development of co-morbidity; (2) Determinants of
chronicity and adverse consequences; (3) The role of stress-regulating brain-systems; and (4) the
functioning of the health care system and the patients' perspective in relation to barriers to effective
care. For each of these questions the study of co-morbidity with addictive disorders is highly relevant
and feasible. The research questions of NESDA are highly congruent with the themes of the ZON-MW
programme concerning addiction disorders.
There exists a large gap between available data from research and implementation in daily
care. Clinical guidelines and quality standards have been developed in response and have helped to
improve the quality of care. However, allocating treatment to those who would have recovered without
treatment is both wasteful and leads to unnecessary exposure to the side effects of treatment. Those
at risk for a chronic or chronic intermittent prognosis should be offered vigorous treatment early on in
the development of the disorder. Given the variation in outcomes, current clinical guidelines, which are
not tailored to specific prognostic subgroups, may well prove inadequate to manage the majority of
cases. At present existing clinical guidelines do not account for co-morbid addiction. This may be an
important reason for the lack of adherence to clinical guidelines. One of the most common
unfavourable outcomes is the development of co-morbidity: either in terms of co-morbidity among
anxiety and depression, or in terms of co-morbidity with addiction or dependence. The project aims to
further the understanding of pathways to co-morbidity, again furnishing data necessary to identify
those in which preventative action is warranted.
The programme is further innovating as it integrates biological, psychosocial and public health
research paradigms within an epidemiological framework. The data will be used to design promising
interventions to prevent chronicity or other unfavourable outcomes. The data from the present project
can also be used in public education programmes about anxiety and depression, in communication
with patients’ organisations and in the training of health personnel involved in day to day clinical
practice.
Adequate representation of the diversity of the population with regard to addiction disorders,
anxiety and depression has received high priority in the design. In all stages of case-finding large
investments are made to ensure adequate representation of the population in the relevant health-care
settings. Specific analyses with regard to sex-differences, age-differences and with regard to further
demographic diversity in the population will be possible.
Knowledge transfer/implementation/feasibility: (max. 50 lines)
The present proposal will be embedded in the NESDA-project, a collaboration between
universities, research centres, mental health care institutions and patients’ organisations. If the present
grant is awarded, NESDA not only yields data on the long-term outcome of depression and anxiety but
also on co-morbid addictive disorders (alcohol, benzodiazepines and nicotine; ABN). Since NESDA
provides the infrastructure for ongoing design and testing of new interventions aimed to improve
outcome and to prevent co-morbidity and chronicity, the present study gives the opportunity to focus
also on the co-morbidity of depression and anxiety with ABN addiction. Moreover, barriers in the
delivery of care to patients with co-morbid depression/anxiety and addiction can be identified, and
studies on problems with the implementation of guidelines aimed at this target population can be
performed, in order to improve the quality of care. The NESDA collaboration offers a unique chance to
combine the production of scientific knowledge on depression, anxiety and co-morbid ABN addiction,
and the translation of this knowledge into information for professionals working in mental health care.
Communication of the aims and results of the programme will include publications in scientific
and professional journals, publications in journals and other media reaching the general public, using
the results in the training of relevant professionals and communication with patients' organisations.
Moreover, the results will be used to adapt existing interdisciplinary guidelines for depression and
anxiety to the target population of patients with co-morbid ABN addiction. Finally, the results will be
used to level barriers of implementation and to develop improvements and they will enable providers
to adjust treatments to the needs and demands as perceived by patients with co-morbid
depression/anxiety and ABN addiction. The WOK, Nivel and Trimbos Institutes co-ordinate the
research on the implementation process.
In this improvement process, the patients’ and care providers perspective will receive
systematic attention throughout. The NESDA infrastructure is built up sequentially to systematically
provide an evidence base to design and test interventions to improve the quality of care under day-today conditions. This will continue throughout the programme.
Although most investigators recognise the importance of implementation of their results, the
complexity of the process of changing clinical practice remains underestimated. In order to be effective
it is crucial to involve the patients’ and care providers perspective in all stages of implementation.
Therefore, key figures and organisations will be contacted in the first years in order to develop
measurements (e.g. QUOTE for patients, list of indicators, attitude questionnaire for providers). As
successful implementation requires motivated providers, patients and managers, they will be involved
as early as possible. The national associations of professionals will be stimulated to help performing
these tasks, and thereby create a platform for the implementation of research findings later on (the
members of the consortium hold leading posts in the relevant national associations of professionals
and participate in the manufacture of interdisciplinary guidelines for depression and anxiety disorders).
Since the present project becomes part of the NESDA consortium, the NESDA infrastructure
ensures optimal transfer of knowledge from its research into mental health care. Meetings will be
organised between researchers of WOK, Trimbos and Nivel and experts in the field on the translation
of the present findings in daily practice. This will lead to concrete implementation strategies which will
be first tested on a small scale for their feasibility and acceptance. In this process, the results of the
research into barriers for implementation and the implementation process will be taken into account.
Objective/hypothesis/task allocation: (max. 25 lines)
The primary aim of the present project is to identify predictors, course and consequences of comorbidity between ABN-addiction (alcohol, benzodiazepines and nicotine) and depression and
anxiety. Additional aims are to identify relevant genetic polymorphisms and to compare screening
methods for alcoholism.
The research questions therefore are:
1. What is the incidence and long term course of co-morbidity of ABN-addictive disorders with
depression or anxiety?
2. Which demographic, psychosocial, clinical, and biological factors determine the incidence and
prognosis of co-morbidity of ABN-addictive disorders with depression or anxiety?
3. What is the impact of co-morbid ABN addiction on a) disease course of anxiety or depression;
b) wellbeing, levels of disability and handicap, and ability to work, c) treatment history,
including barriers to health care; d) the patients' perspective; e) the development of further
psychiatric and physical co-morbidity?
4. Are genetic polymorphisms in known and newly found candidate genes associated with
symptomatology, treatment outcome, and biological endophenotype?
5. Which is the most efficient way to screen for alcohol addiction in patients with anxiety and
depression in the community, primary care and specialised mental health: a) which screening
questionnaire should be used (CAGE vs AUDIT), b) what is the added value of standard
(ALAT, ASAT, γ-GT, MCV) and specific biological markers (CDT) and c) is the efficiency of
screening dependent on setting, duration, type or severity of the co-morbid anxiety/affective
disorder .
Plan of action: (max. 600 lines)
The study will be fully integrated within the NESDA program (Netherlands Study on Depression and
Anxiety).
1) Design Prospective cohort study, within which case-control studies will be nested.
2) Time schedule (see table 1) The NESDA program is costed for 10 years. Inclusion will be
completed within 3 years (table 1). This means that the average duration of follow-up per subject will
be 8,5 years. Follow-up data will be collected after 1 year, 4 years, and 8 years. The present study is
costed for 4 years. This will allow inclusion and a 1-year follow-up of all subjects. The study is
designed to allow an extended (long term) prospective study of co-morbidity of ABN addiction and
anxiety/depression, for which additional funding will be sought elsewhere. For NESDA, the course of
depression and anxiety will be monitored in detail between measurements using the LIFE-CHART
method (see measurements). Relevant questions will be added to monitor the incidence and course of
ABN addiction. All procedures are currently undergoing testing in pilot-studies.
3) Criteria for the inclusion and exclusion of subjects The NESDA program aims to follow cohorts of
adults with anxiety and/or depression, representative for different health care settings and phases of
illness. Included will be subjects with current DSMIV diagnoses of Major Depression (MDD),
Dysthymia (DD), Minor Depression (MinD), General Anxiety Disorder (GAD), Panic Disorder (PAN),
and Phobic Disorders excluding simple phobias (PHOB). OCD, PTSD and bipolar disorder patients will
not be included as primary diagnosis, as it was deemed impossible to be able to recruit large enough
samples. Inclusion is limited to adults (18-65 years). Besides patients fulfilling DSMIV criteria for
disorders, two cohorts of those at risk will be included: adolescents with a parent with anxiety or
depression and a cohort with subthreshold disorders (SUB). A control cohort of subjects with none of
the above disorders (normals) will also be recruited. As the samples should be representative of
patients seen in different settings, there are very few a priori exclusion criteria. Excluded will be
patients with a primary diagnosis of an organic psychiatric or psychotic disorder. The reason is that
both the course and the care-trajectories of these patients will be determined largely by the primary
disorder, which is not subject to the current program.
4) Sampling frame and setting Subjects will be recruited from the general population (NEMESIS and
ARIADNE), from primary care (LIN-H) and from specialised mental health (AMSTERDAM,
GRONINGEN, LEIDEN). The sampling frame is stratified by setting (community, primary care,
specialised care), phase of illness (normals, familial risk, SUB, first episode, recurrent episode) and
type of disorder (MDD, DD/MinD, Anxiety disorder, Subthreshold disorder, normals)(table 2).
Subthreshold disorders and normals will only be recruited from primary care and in these groups
differentiation in first and recurrent episodes will not be made.
The specialised mental health patients are recruited from outpatient regional facilities for mental health
care in Amsterdam, Leiden and Groningen. In Amsterdam patients will be recruited consulting
GGZBuitenAmstel, which is a large mental health service, serving a catchement area of 275.000
people. The department of Psychiatry in Leiden collaborates with the Rijngeestgroep and the Robert
Fleury Stichting. Together with the outpatient clinic of Leiden University Medical Centre these clinics
serve a catchement area of over 300.000 people. In Groningen the outpatient clinic of the University of
Groningen and regional mental health services in Drenthe and Friesland will be included. All facilities
serve regional catchement areas, enhancing the representativeness of the data.
For the primary care patients, the LINH (Landelijk Informatie Netwerk Huisartsen = National Data
Network General Practice) will be used as the sampling frame. LINH is a network of GP practices,
managed by Nivel and WOK and under jurisdiction of Nivel, WOK (Workinggroup research in quality
of care), LHV and NHG (associations of Dutch GPs). LINH conducts continuous computerised
registration of contacts between patients and general practices (n = 114) and of the resulting actions.
LINH GPs (n = 228) are representative of the Dutch GP population. The practices are computerised
and have electronic patient files and an electronic prescribing system. They are not different from noncomputerised practices in terms of prescribing and referral patterns. The LINH doctors have a total of
424,170 patients, who are representative of the general population in terms of age, sex and insurance
type. LINH has been in existence since 1991 and the number of participating practices has doubled
since 1996. Although improving rapidly, considerable inter-GP variation remains in the detection and
diagnosis of depression and anxiety. Overall, those with more severe and more persistent symptoms
are more likely to be diagnosed. Although clinically desirable, this would bias the outcome of the study.
Therefore, the sampling frame is defined as those patients contacting their GP whom are picked up
through a two-phase screening approach (see procedures and instruments).
The community samples build on cohorts that are already available. From the NEMESIS study, those
with the disorders listed in table 2 will be followed up in NESDA. NEMESIS is a prospective
community-based study of mental health, in which three measurement cycles are available
(1996,1997 and 1999). Table 3 summarises the numbers of those participating in three waves of data
collection with relevant disorders. In total there are 408 (266+142) with MDD, 87 (54+33) with DD and
371 (303+68) with GAD, PHOB or PAN. At the third interview 93,3% of participants have provided
consent to further data collection. Assuming a 25% attrition rate for the planned follow-up of this
cohort, the resulting numbers are listed in table 2. Adolescents at RIsk of Anxiety and Depression
(ARIADNE) is a prospective study of the incidence of anxiety and depression in adolescent children
(16-25 at inclusion) of parents treated for depression or anxiety disorders in mental health centres in
Groningen and Drenthe. In these adolescents both psychosocial and biological risk factors for
depression and anxiety were measured at baseline - that is, before the development of disorders. The
cohort (n=500) is recruited between 2000-2002 and funding is available for two, yearly follow-ups
(2002-2004). After that, the cohort will be followed-up for a further 10 years within NESDA. All
participants to ARIADNE will be asked informed consent for NESDA. When NESDA starts, it is
assumed that 20%-40% has developed subthreshold or case-level psychopathology. Given an
expected 20% drop-out, 400 participants are expected in this cohort (table 2).
5) Numbers of patients, attrition, power and methods of data analysis. Power analyses determining the
numbers needed have been described in the NESDA proposal. Table 2 lists the numbers needed with
different disorders at baseline in the different strata. Co-morbidity and attrition influence the actual
numbers of participants needed. Using the NEMESIS data the numbers with co-morbid disorders can
be predicted. Table 3 summarises the numbers of subjects with first ever versus recurrent cases,
identified during the three year follow-up of NEMESIS, who had co-morbid disorders during the same
period. Table 3 confirms the high level of co-morbidity over only three years of follow-up. Of the
projected 600 new subjects with MDD who will be recruited (300 in primary care and 300 in
specialised care), approximately 40% (n=240) are expected to have a co-morbid anxiety disorder.
Conversely, of those with anxiety disorders, approximately 60% are expected to have co-morbid
depression. Again using the NEMESIS data as a reference for projected numbers, 653 subjects
suffered the total of 866 disorders in table 3. These figures can be used to predict the number of
patients with anxiety or depressive disorders which need to be newly recruited in the primary care and
specialised care cohorts, to reach the number of disorders listed in table 2. Combining the total
numbers with DSMIV disorders in primary and specialised care in table 2 amounts to 1800 disorders.
Assuming a similar rate of co-morbidity as found in NEMESIS (which is conservative), the total number
of patients with disorders needed is 1357 (approximately 675 in each setting - see table 4 appendix).
The total number of patients followed-up further includes 300 with SUB, 300 normals, 530 participants
from NEMESIS and 400 from ARIADNE (total n = 2887).
Attrition after baseline is expected to be highest in the community, lower among the primary care
patients, and lowest in those treated in specialised mental health. In previous studies in which subjects
with depression were recruited from general practices using a similar two-stage case-finding
procedure, over 60% of those eligible for inclusion gave their consent. To be safe, an initial loss of
66,6% is projected here. This is extremely conservative but was used to demonstrate that there can be
no doubt with regard to the feasibility of the program. After inclusion, a loss of 25% over the first three
years is expected, which drops to 20% and 15% over the next three-year intervals. These are again
conservative estimates, based on experience with the LASA and NEMESIS projects. In the specialised
health service, initial consent to participate is projected to be higher (50%). Here a similar drop out rate
per three years of follow-up is projected. In the NEMESIS and ARIADNE cohorts similar drop-out rates
per three year follow-up are projected. As in both studies consent to follow-up was given by more than
90% of participants, this is also a conservative estimate.
Table 4 summarises the projected numbers of participants at different stages of the study, integrating
the data from tables 2 and 3. It is assumed that (i) attrition rates are similar across disorders, but differ
across settings, (ii) all those referred to specialised mental health services are screen positive and (iii)
the positive predictive value of the screener (see measurement section) is 25% (in NEMESIS it was
27%). The numbers needed to screen are based on the 900 cases with different disorders listed in
table 2. In the course of case-finding much larger than necessary numbers of those with SUB and
normals are identified. Random samples will be taken to achieve the necessary 300 per cohort.
Projected numbers of participants for the present study were calculated for research questions most
sensitive to the power of analyses. They were carried out for alcohol dependence, as the numbers
with alcohol abuse and both benzodiazepine and nicotine dependence are higher. Data from the
NEMESIS study were used to predict the numbers with co-morbid mood disorders and alcohol
dependence in the community (de Graaf et al 2003, see table 3). The figures for anxiety disorders are
very similar. As these are figures from the community, they underestimate the co-morbidity that will be
found among the patients recruited from general practice and specialised mental health. It is
(conservatively) estimated that the level of co-morbidity will be 10% higher in primary care and 25%
higher in specialised mental health settings. Among men with MDD or dysthymia, 16,9% respectively
18,8% reported concurrent alcohol dependence. Among women these figures were much lower at
4,6% and 4,9%. Given a 2:1 prevalence ratio of anxiety and depression among women versus men, it
is estimated that the NESDA cohort will include twice as many women. There will be 700 subjects
recruited from the community, 1200 from primary care and 900 from specialised mental health care
(total = 2800). Using the above estimates for prevalence of co-morbid alcohol dependence and the
projected male:female ratios, the numbers with co-morbid alcohol dependence are 62 (community) +
114 (primary care) + 98 (specialised mental health) = a total of 264 participants with alcohol
dependence at baseline. This is the group in which (i) cross-sectional analyses concerning the
(psychosocial, biological and genetic) characteristics of those with co-morbidity, and research
questions concerning (ii) the course (iii) health care utilisation, (iv) the patients’ perspective, (v) the
public health consequences and (vi) the development of further co-morbidity can be studied. The
numbers (264 cases versus 2536 controls), are clearly sufficient to conduct both univariate and
multivariate analyses. There will be 2800 – 264 = 2536 subjects at risk to develop incident alcohol
dependence. A conservative estimate, based on the NEMESIS data is that 3% (n=75) will develop
incident alcohol dependence during the course of first year of follow-up (de Graaf et al submitted). In
order to be able to detect clinically meaningful impact of potential risk factors for co-morbid alcohol
dependence (d=0,5), using conventional alpha = 0,05, power = 0,80 and two-sides tests, 63 cases
would be necessary. Although sufficient for univariate analyses, the extra power gained from the
detailed measurement of alcohol use in the LIFE-CHARTS will be necessary to be able to conduct
more complex analyses. Analysis of the cross-sectional data will include both univariate (tests
depending on the measurement level of the variables) and multivariate (linear and logistic regression)
procedures. The longitudinal analyses will exploit the available LIFE-CHART data, using both survivaland Cox regression analyses and multilevel analysis. This will ensure sufficient power for multivariate
analyses regarding the factors predicting incidence of ABN addiction.
6) Procedures and informed consent All subjects will be asked written informed consent prior to
inclusion. Measurement cycles will consist of two face-to-face interviews, each with an average
duration of 90 minutes. After the first interview a written questionnaire will be given to the respondent,
with the appropriate instructions for completion. This form will be collected and checked at the second
interview. This procedure (and the length of the interview) has been tested extensively. In addition,
data will be derived from medical records and blood samples. All interviews will be administered by
specially trained personnel, blind to prior diagnoses or treatment arrangements. Interviews will take
place at home visits or at participating health centres. All procedures and measurement instruments
are currently being tested in pilot studies. The pilot studies have been approved by the medical ethical
committee of the Vrije Universiteit Amsterdam. The program, including all projects will be submitted to
the medical ethical committee. In primary care, subjects with disorders are identified using a two-stage
screening. This was chosen as (i) there is considerable GP variation in detection and diagnosis of
anxiety and depression, (ii) this reduces the burden for participating GPs and (iii) it reduces the
number of diagnostic interviews. The procedure has been tested extensively in previous studies
carried out by the group.
7) Measurements Internationally accepted measures will be used throughout the NESDA program. In
the ARIADNE and NEMESIS cohorts, which started before NESDA, the key measures are the same
as those to be used in NESDA. The measurement instruments are listed in table 5. All variables will be
measured at baseline. Follow-ups at 1,3,6 and 9 years will include all variables open to change.
Constant variables will only measured at baseline. The course of anxiety and depression will be
monitored in detail between interviews using the LIFE-CHART method. This has been previously used
in NEMESIS (Spijker et al 2002). For the present study, relevant questions regarding ABN addiction
will be added to the LIFE-CHARTS.
Table 1: Time schedule NESDA
Year
Project
I
Now
1
2
A, b
b, d, e, f
f, g, h,
II
A, b
b, d, e, f
f, g, h,
III
A, b
b, d, e, f
f, g, h
IV
B, c
f, g, h, i, j
V
A, b
a, b, c, d,
e, f, g, h
b, d, e, f
f, g, h
3
f, g, h, i,
k, l
f, g, h, i,
k, l
f, g, h, i,
k, l
f, g, h, i, j,
k, l
f, g, h, i, j,
k, l
4
5
6
7
8
9
10
g, h, i, l
g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i , k, g, h, i, k, l g, h, i, k, l
l
g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l
g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l
g, h, i, j,
k, l
g, h, i, j,
k, l
g, h, i, j,
k, l
g, h, i, j,
k, l
g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l g, h, i, k, l
g, h, i, j,
k, l
a = pilot studies: selection and testing of instruments and procedures
b = reviews of the relevant literature
c = preparing interventions
d = preparing field work
e = recruitment of personnel
f = inclusion of subjects and baseline measurements
g = data cleaning
h = follow-up measurements
i = description and dissemination results
j = implementation: barriers and goals
k = preparing new cycle of (intervention) studies
l = dissemination and implementation results
g, h, i, j,
k, l
g, h, i, j,
k, l
g, h, i, j,
k, l
g, h, i, j,
k, l
Table 2: Stratified sampling frame and projected numbers with disorders in NESDA
First episode
Specialised mental health
MDD
DD, MinD
GAD, PHOB, PAN
Primary care
MDD
DD, MinD
GAD, PHOB, PAN
SUBa, SUBd
Normals
Community (NEMESIS)
MDD
DD, MinD
GAD, PHOB, PAN
Community at risk
(ARIADNE)
Total
Recurrent episode
Total
100
100
100
200
200
200
300
300
300
200
200
200
100
100
100
300
300
300
300
300
200
75
225
100
50
50
300
125
275
1400
1100
400
3500
Table 3: Co-morbidity among depression and anxiety in the community: NEMESIS data
N
First ever cases
MDD
DD
GAD, PHOB, PAN
Recurrent cases
MDD
DD
GAD, PHOB, PAN
266
54
303
142
33
68
% co-morbidity
MDD/DD
% co-morbidity
GAD,PHOB,PAN
% co-morbidity
alcoholabuse/dependence1
37,2%
70,4%
11,3%
16,7%
15,8%
45,1%
60,6%
11,8%
17,6%
11,8%
60,1%
55,9%
1. Figures much higher for men than for women - see plan of action, paragraph 5.
Table 4: Numbers of participants necessary in different stages of the study in primary care and
specialised care.
Screened
Negative
Positive
Primary care
Specialised care
Totals
40500
32400 (normals)1
8100
5400
none
5400
45.900
5400
4050
1350
13.500
Diagnosed
Negative
Positive
8100
6075 (SUB)2
2025
Attrition inclusion phase
66%
50%
Patients with disorders
Disorders
675
900
675
900
1.350
1.800
Attrition 4 years
Number left
25%
675
25%
675
1.350
1. A random sample of 300 normals will be included and followed-up
2. A random sample of 300 with SUB will be included and followed-up
New application for research grant
PROJECTNR: 60-60600-98-017
Table 5 Measurement instruments
Topic
Demographic
Age
Sex
Marital/partner status
Religious/ethnic
Socio-economic
Anxiety and depression
Screen
Diagnosis
Severity
Symptom dimensions
Course between measures
Psychopathology: other
Somatisation & hypochondriasis
Alcohol abuse/dependence
- Screen
-Diagnosis
Benzodiazepine dependence
- Screen
- Diagnosis
Nicotine dependence
- Screen
- Diagnosis
Suicide attempts and ideation
Suicide attempts
Suicidal ideation
Physical illness
Symptoms
Chronic physical illness
History with physical illness
Neurobiological determinants
HPA-axis
Immune factors
Serotonine functioning
Genetic polymorphisms
Biological markers alcohol use
disorders
Name instrument
First autho
General Health Questionnaire (short)1
Composite International Diagnostic Interview 2
Montgomery Asberg Depression Rating Scale
Hamilton Anxiety scale
Mood and Anxiety Symptom Questionnaire
LIFE-CHART
Goldberg,
Robins, L.
Montgome
Hamilton,
Watson, D
Spijker, J.
Whitely Index
Pilowsky, I
CAGE (Mayfield et al., 1974),
AUDIT (Babor et al., 1989; Saunders et al., 1993)
CIDI
Bendep-SRQ (Kan et al 1993)
CIDI
Fägerstrom Questionnaire (Fägerstrom, 1978; Pomerlau et al.,
1994)
CIDI
WHO/EURO
WHO/EURO
Scale for Suicide Ideation (short form)
Kerkhof, A
Kerkhof, A
Beck A.T.
Physical illness and symptoms
CBS health interview
Checklist
van Heme
Bloodsample / saliva
Bloodsample
Bloodsample
Bloodsample
Stamboom
Bloodsample (ALAT, ASAT, γ-GT, MCV, CDT)
pag. 15
New application for research grant
PROJECTNR: 60-60600-98-017
Life events and social support
Recent events & childhood trauma
Social support / network
Loneliness and affiliation
Personality
Five factor model
Self esteem
Locus of Control
Public health consequences
Quality of life
Disability
Loss of productivity
Mortality / causes of death
Care trajectories
Medical consumption
Informal care
Use of medication
Patients' perspective
Perceived need of care
Patient's beliefs about symptoms
Causes and possible help
Patient evaluation of care
NEMESIS
Social Support Inventory
Loneliness scale
Brown/ de
Timmerma
de Jong G
Five Factor Personality Inventory
Rosenberg scale
Pearlin Mastery Scale (short form)
Goldberg L
Banos R.M
Pearlin, L.
EUROQoL
SF-36
Disability days, beddays
TIC-P ziekte en werk /Diary days lost from work
CBS data
The EuroQ
Ware J.E
TIC-P Zorggebruik + GP data
List NESDA
Inspection and GP data
Perceived Need of Care Questionnaire
Oorzakenvragenlijst/ behandelverwachtingen
Nivel Consumers Panel Questionnaire on Trust in Mental Health
Care
QUOTE-depression/anxiety
EUROPEP
1. General Health Questionnaire: used as screener in primary care; is also available in all
participants in NEMESIS.
2. Composite International Diagnostic Interview. Was also used in NEMESIS and in ARIADNE
Time schedule: (max. 20 lines)
See plan of action and table 1. The current project is restricted to the inclusion (3 years) and first
follow-up (1 year) of the NESDA program (total study duration = 4 years). Deliverables will include (i)
the infrastructure for a long term study of the co-morbidity of ABN addiction with anxiety and
depression, (ii) the formation of the study cohort and the data of the first two measurements (1 year
follow-up data), (iii) scientific reports on(a) the co-morbidity and (b) communality of risk-factors of ABN
addiction and anxiety and depression in different echelons of the health service, (c) the prognostic
impact of co-morbidity among ABN-addiction and depression/anxiety over 1 year of follow-up, (d) the
incidence of ABN-addiction in patients with depression/anxiety, (e) the comparative quality and
efficiency of both psychometric and biological screeners for alcohol-related disorders in patients with
anxiety and depression. Given the established infrastructure, the opportunity will exist to extend the
study of ABN addiction over the full follow-up period.
Expertise, preceding activities and end products: (max. 75 lines)
The NESDA consortium consists of academic (Amsterdam, Groningen, Leiden) and non-academic
(Trimbos, Nivel ,WOK) research groups with previous collaborations in the fields of epidemiological,
biological, treatment-effect and implementation studies concerning anxiety, depression and addiction.
In the past years, a large number of project and program proposals have been granted by ZONMW,
NWO and others. All research groups participate in Research Schools (CARE, Psychology and
Health, ECS, ION, MASH.) Results have been published in top ranked international journals (see
below). More specifically, AIAR, Jellinek and the VU Medical Center have initiated a successful
scientific collaboration on the treatment of phobic alcoholics, which resulted in some important
publications and a closer collaboration in the treatment of patients with comorbid anxiety and alcohol
pag. 16
Meadows
Faller, H.
Friele
to be deve
Wensing
New application for research grant
PROJECTNR: 60-60600-98-017
use disorders. In Leiden expertise has been developed in close collaboration with general practice
medicine on benzodiazepine dependence, which has resulted in several dissertations and
international publications. Trimbos Institute is the Dutch national institute for mental health and
addiction. A principal aim is to produce and disseminate scientific knowledge. There is close
collaboration with AIAR and several psychiatric and primary care groups, e.g. in the analysis of data
obtained in the NEMESIS study. WOK, Nivel and Trimbos have a common expertise in health services
research and implementation in primary care and mental health care.
Key publications by the research group:
Publications (max. 75 lines)
The mean impact factor (IF) within the field of Psychiatry in general is about 1.5.
IF = 6.5 Beekman ATF, de Beurs E, van Balkom AJLM, Deeg DJH, van Dyck R, van Tilburg W. Anxiety and depression in later life:
co-occurrence and communality of risk factors. Am J Psychiatry, 2000; 157: 89-95.
IF = 10.8 Beekman. A.T.F., Geerlings, S.W., Deeg, D.J.H., Smit, J.H., Schoevers, R.S., de Beurs, E., van Tilburg, W. The natural
history of late-life depression: a 6-year prospective study in the community. Arch of Gen Psychiatry 2002; 59: 605-11.
IF 6.6 Brink, W. van den, Hendriks, V.M., Blanken, P., Koeter, M.W.J., Zwieten, B.J. van, Ree, J.M. van Medical prescription of
heroin to chronic, treatment-resistant heroin dependent patients: two randomized controlled trials. BMJ 2003, 327: 310-312.
IF = 3.2 Couvee JE, Bakker A, Zitman FG. The relevance of psychiatric and somatic comorbidity in depressed chronic
benzodiazepine users. Psychother Psychosom 2002; 71: 263-8.
IF = 6.5 De Graaf R, Bijl RV, Smit F, Vollebergh WAM, Spijker J. Risk factors for 12-month comorbidity of mood, anxiety, and
substance use disorders: findings from the Netherlands Mental Health survey and Incidence study. Am J Psychiatry 2002; 159:
620-9.
IF 6.5 Ormel J, Oldehinkel AJ, Brilman EI. The Interplay And Etiological Continuity Of Neuroticism, Difficulties And Life Events
In The Etiology Of Major And Subsyndromal, First And Recurrent Depressive Episodes In Later Life. Am J of Psychiatry 2001;
158: 885-91.
IF = 10.8 Ormel J, VonKorff M. Synchrony of change in depression and disability: what next? Arch of Gen Psychiatry 2000; 57:
381-2.
IF = 10.8 Penninx BWJH, Geerlings S, Deeg DJH, van Tilburg W, Beekman ATF. Minor and major depression and the risk of death
in older persons. Arch Gen Psychiatry, 1999; 56: 889-96.
IF = 10.8 Penninx BWJH, Beekman ATF, Honig A, Deeg DJH, van Eijk, JThM van Tilburg W. The effect of depression on cardiac
mortality: a study among cardiac patients and non-patients. Arch Gen Psychiatry 2001; 58: 221-7.
IF 6.9 Rinne, T., Brink, W. van den, Wouters, L., Dyck, R. van (2002) SSRI treatment of borderline personality disorder: a
randomized, placebo-controlled clinical trial for female patients with borderline personality disorder. American Journal of
Psychiatry, 159, 2048-2054.
Slaap BR, den Boer JA. The prediction of nonresponse to pharmacotherapy in panic disorder: a review. Depress Anxiety 2001;
14: 112-22.
IF = 10.8 Vollebergh WAM, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J: The Structure and Stability of Common Mental
Disorders; The NEMESIS Study. Arch of Gen Psychiatry 2001; 58: 597-603.
IF = 6.5 De Graaf R, Bijl RV, Smit F, Vollebergh WAM, Spijker J. Risk factors for 12-month comorbidity of mood, anxiety, and
substance use disorders: findings from the Netherlands Mental Health survey and Incidence study. Am J Psychiatry 2002; 159:
620-9.
IF 6.5 Ormel J, Oldehinkel AJ, Brilman EI. The Interplay And Etiological Continuity Of Neuroticism, Difficulties And Life Events
In The Etiology Of Major And Subsyndromal, First And Recurrent Depressive Episodes In Later Life. Am J of Psychiatry 2001;
158: 885-91.
IF = 10.8 Ormel J, VonKorff M. Synchrony of change in depression and disability: what next? Arch of Gen Psychiatry 2000; 57:
381-2.
IF = 10.8 Penninx BWJH, Geerlings S, Deeg DJH, van Tilburg W, Beekman ATF. Minor and major depression and the risk of death
in older persons. Arch Gen Psychiatry, 1999; 56: 889-96.
IF = 10.8 Penninx BWJH, Beekman ATF, Honig A, Deeg DJH, van Eijk, JThM van Tilburg W. The effect of depression on cardiac
mortality: a study among cardiac patients and non-patients. Arch Gen Psychiatry 2001; 58: 221-7.
IF 6.9 Rinne, T., Brink, W. van den, Wouters, L., Dyck, R. van (2002) SSRI treatment of borderline personality disorder: a
randomized, placebo-controlled clinical trial for female patients with borderline personality disorder. American Journal of
Psychiatry, 159, 2048-2054.
Slaap BR, den Boer JA. The prediction of nonresponse to pharmacotherapy in panic disorder: a review. Depress Anxiety 2001;
14: 112-22.
IF = 10.8 Vollebergh WAM, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J: The Structure and Stability of Common Mental
Disorders; The NEMESIS Study. Arch of Gen Psychiatry 2001; 58: 597-603.
IF = 4.3 Verwey B, Eling P, Wientjes H, Zitman FG . Memory impairment in those who attempted suicide by benzodiazepine
overdose. J Clin Psychiatry 2000; 61(6):456-459
IF = 4.4 Zitman FG, Couvee JE. Chronic benzodiazepine use in general practice patients with depression: an evaluation of
controlled treatment and taper-off: report on behalf of the Dutch Chronic Benzodiazepine Working Group. Br J Psychiatry 2001;
178:317-324
IF = 2.2 Couvée JE, Timmermans EAY, Zitman FG Longitudinal evaluation of prescription of psycho-active medication unto 3.5
years after taking part in a benzodiazepine discontinuation program in depressed chronic users (in Dutch general practice) J Aff
Disorders 2002;70:133-141
IF = 2.2 Couvee JE, Timmermans MA, Zitman FG. The long-term outcome of a benzodiazepine discontinuation programme in
depressed outpatients. J Affect Disord 2002; 70(2):133-141.
pag. 17
New application for research grant
PROJECTNR: 60-60600-98-017
IF = 1.6 Oude Voshaar RC, Mol AJ, Gorgels WJ, Breteler MH, van Balkom AJ, van de Lisdonk EH, Zitman FG. Cross-validation,
predictive validity, and time course of the Benzodiazepine Dependence Self-Report Questionnaire in a benzodiazepine
discontinuation trial. Compr Psychiatry 2003; 44(3):247-255.
IF = 4.4 Oude Voshaar RC, Gorgels WJ, Mol AJ, van Balkom AJ, van de Lisdonk EH, Breteler MH, Zitman FG. Tapering off
long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial.
Br J Psychiatry 2003; 182:498-504.
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Dick DM, Foroud T. Candidate genes for alcohol dependence: a review of genetic evidence from
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Evans SM, Levin FR, Fischman MW. Increased sensitivity to alprazolam in females with a paternal
history of alcoholism. Psychopharmacology (Berl). 2000; 150:150-62
Fagerstrom KO. Measuring degree of physical dependence to tobacco smoking with reference to
individualization of treatment. Addict Behav 1978; 3: 235-251.
Kan CC, Breteler MH, Timmermans EA, van d, V, Zitman FG. Scalability, reliability, and validity of the
benzodiazepine dependence self-report questionnaire in outpatient benzodiazepine users. Compr
Psychiatry 1999; 40(4):283-291
Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening
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Pomerleau C, Carton SM, Lutzke ML, Flessland KA, Pomerleau OF. Reliability of the Fagerstrom
Tolerance Questionnaire and the Fagerstrom Test for nicotine dependence. Add Behav 1994; 19: 3339.
Saunders JB, Aasland OG, Babor TF, de la Fuente JR, grant M. Development of the Alcohol Use
Disorder Identification Test (AUDIT): WHO collaborative project on early detection of persons with
harmful alcohol consumption. Addiction 1993; 88: 791-804.
Tyndale RF. Genetics of alcohol and tobacco use in humans. Ann Med 2003; 35: 94-121.
Zandstra SM, Furer JW, van de Lisdonk EH, Bor JH, Zitman FG, van Weel C. Differences in health
status between long-term and short-term benzodiazepine users. Br J Gen Pract 2002; 52(483):805808.
Additional information
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New application for research grant
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If so, do you have the approval?
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New application for research grant
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Have you ever submitted this proposal before within this ZonMw-research program or within any other
research programme?
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If your answer to the former question was yes:
ƒ Within witch ZonMw-programme?
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pag. 20