DEPRESSION AND ANXIETY 23:312–324 (2006)

Theoretical Review
A BIOPSYCHOSOCIAL MODEL AS A GUIDE FOR
PSYCHOEDUCATION AND TREATMENT OF DEPRESSION
Chris K.W. Schotte, Ph.D.,1,2 Bart Van Den Bossche, M.D.,3 Dirk De Doncker, M.A.,1
Stephan Claes, M.D.,4 and Paul Cosyns, M.D.1

Effective treatment of severe or chronic unipolar depression requires the

combination of pharmacological and psychotherapeutic interventions, and
demands a theoretical paradigm integrating biological and psychosocial aspects
of depression. Supported by recent research, we propose in our article a
biopsychosocial diathesis–stress model of depression. Its basic aim is psychoeduca-
tional: to provide therapists, patients, and their environment a constructive
conceptual framework to understand depressive complaints, vulnerability, and
stress. The core of the model consists of the concept of psychobiological
vulnerability, which is determined by risk factors—of a biogenetic, psychological,
somatic, and societal nature—and by protective factors. Life events with an
idiosyncratic, stress-inducing value interact with this vulnerability, triggering
severe or chronic distress that affects the individual’s resilience and leads to
symptoms of depression. The pathogenesis of depression is symbolized by a
negative downward loop, in which interactions among symptoms, vulnerability,
and stressors drive the patient toward a depressive condition. Moreover,
experiencing recurrent depression influences psychobiological vulnerability, the
occurrence of stressors, and tremendously increases the risk of further relapse.
The model stresses the self-evident integration of biological and psychological
therapeutic interventions that need to focus on symptom reduction and on
relapse prevention. Moreover, it offers the patient and therapist a psychoeduca-
tional context in which the individual’s vulnerability and depressive symptoms
can be treated. Finally, applications of the depression model as a therapeutic
approach to severe depression in the phases of remoralization, symptom
reduction, and relapse prevention are presented. Depression and Anxiety
23:312–324, 2006. & 2006 Wiley-Liss, Inc.

Key words: major depression; cognitive-behavioral therapy; biopsychosocial

approach; stress; treatment; psychoeducation

1
UZA, University Hospital Antwerp, Department of Psychiatry,
Edegem, Belgium, and CAPRI, Collaborative Antwerp Psy-
chiatric Research Institute, Faculty of Medicine, University of
Antwerp, Campus Drie Eiken, Wilrijk, Belgium
2
VUB, Free University Brussels, Faculty of Psychology,
Brussels, Belgium
3
GGZ WNB, Mental Health Care West North Brabant, Halste-
ren, The Netherlands
4
University Hospital Leuven, Department of Psychiatry,
Leuven, Belgium
Correspondence to: C. Schotte, Department of Psychiatry,
University Hospital Antwerp (UZA), Wilrijkstraat 10, B-2650
Edegem, Belgium. E-mail: chris.schotte@uza.be
INTRODUCTION
Numerous epidemiological findings suggest that the
era we live in can be described as the ‘‘age of
melancholy.’’ Indeed, roughly 1 in 5 women and 1 in
10 men will experience a clinically significant depres-
sive episode during their lifetime. The large-scale
Received for publication 24 June 2005; Revised 5 October 2005;
Accepted 9 December 2005
DOI 10.1002/da.20177
Published online 10 May 2006 in Wiley InterScience (www.
interscience.wiley.com).

r 2006 Wiley-Liss, Inc.

 Theoretical Review: Depression Model
epidemiological Depression Research in European
Society (DEPRES) study [Tylee, 2000] in which over
78,000 adults from six different European countries
were interviewed, revealed a 17% 6-month prevalence
of depression. Moreover, the incidence of depression is
steadily increasing, and episodes start at an ever-earlier
age [Fombonne, 1994]. Depressive disorders have a
severe social and economic impact [Sartorius, 2001;
Simon, 2003]. Üstün et al. [2004] found depression
to be the fourth leading cause of disease burden: It
provokes the largest amount of nonfatal burden,
accounting for almost 12% of all total years living
with disability worldwide. The tendency toward under-
diagnosis and undertreatment, the strong association
with somatic problems, the high rate of relapse [e.g.,
Duggan, 1997], and the high prevalence of suicide,
which is estimated at 15% [American Psychiatric
Association, 1994; Lönnqvist, 2000], further stress the
fact that the depressive disorders are some of the most
severe mental health problems.
With respect to the treatment of depression, the
options are multiplying, increasing not only in quantity
but also in sophistication. Generally speaking, and most
certainly with respect to the severe and chronic forms of
depression, increasing numbers of psychiatrists and
psychologists are in favor of combined treatments, in
which concurrent, sequential, or crossover combina-
tions of pharmacological and psychotherapeutic ap-
proaches are used [e.g., Arean and Cook, 2002;
Kornbluh et al., 2001; Lenze et al., 2002; Nierenberg,
2001; Segal et al., 2002; Thase et al., 1997].
However, combined treatments demand a biopsy-
chosocial [Engel, 1977, 1980] depression model that
integrates biological and psychosocial aspects. The
integration of theories of depression, such as the
cognitive and biological, is an important direction for
theory and research [Abramson et al., 2002]. Moreover,
treatments are most effective when therapists, patients,
and families have a shared, constructive view of the
pathology and a rationale for the treatment [Margison
et al., 2000]. Starting from this psychoeducational
viewpoint, we propose in this article an integrative
model of unipolar depression.
THEORETICAL MODELS
OF UNIPOLAR DEPRESSION
To avoid misunderstanding, it is useful to define the
term ‘‘depression.’’ As a normal expression of mood,
depression refers to a combination of ‘‘misery and
lethargy’’ [Wilner, 1985]: It is an emotion with
functional and adaptive aspects [Nesse, 2000]. Depres-
sion can also be considered as a syndrome, referring to
a constellation of depressive symptoms, and as a
nosological category, such as that described in DSM-
IV classification of the affective disorders [American
Psychiatric Association, 1994]. In this article, the term
‘‘depression’’ refers to the severe, often chronic, and
313
highly dysfunctional unipolar major depressive disor-
ders: Because we concentrate on these severe forms
of depression, the ‘‘sickness’’ aspect is emphasized in
our model.
First, we briefly review the various theoretical
schools that influenced our view on depression.
Descriptive diagnostic models concern themselves with
recording, describing, measuring, and classifying de-
pressive phenomena. In the Department of Psychiatry
of the University of Antwerp, dimensional depression
assessment tools such as the Beck Depression Inven-
tory and Hamilton Depression Rating Scale [Schotte
et al., 1997b] and the Zung Self-Rating Depression
Scale [Schotte et al., 1996] were examined for their
psychometric qualities. Research on the categorical
DSM-IV classification of affective disorders supported
the validity of the melancholic/vital depression and
proposed the ‘‘integrated threshold model,’’ which
integrates the quantitative and qualitative views of the
taxonomy of depressive disorders (Schotte et al., 1997b;
Schotte and Maes, 2001). An adequate description and
classification of depression is a necessary precondition
for diagnosis, treatment, and research: It is crucial to
determine the form and the severity of the depressive
disorder and to assess suicidal behavior. However, this
is only a point of departure: A second, essential step
involves the consideration of theoretical models that
take etiological and pathogenic mechanisms into
account and that are therapy-oriented. Modern models
are based on the biological, cognitive, interpersonal,
and life-events research [e.g., Gotlib and Hammen,
2002]. All these models belong to the class of
diathesis–stress models [Akiskal, 1995], which are
based on the hypothesis that certain genetic disposi-
tions or other characteristics, such as a particular
cognitive style, a biological dysfunction, or a social
skills problem, make people vulnerable to depression
when they are confronted with specific life events or
forms of stress. Biological models view depression as a
consequence of genetic vulnerability or of biological
disturbances of the biochemical, neuroendocrine, im-
mune, or chronobiological systems. One of the most
influential models starts from the phenomenological
similarities between depressive symptomatology and a
hyperarousal of the stress response, and assumes that
depressive disorders imply dysregulations of the stress
system such as hypothalamic–pituitary–adrenal (HPA)
axis hyperactivity and alterations in the autonomous
nervous system [for reviews, see Gold and Chrousos,
2002; Holsboer, 2000]. In melancholic depression, for
example, one observes a hyperactive stress response,
anxiety, fear of the future, reduction in responsiveness
to the environment, insomnia, loss of appetite, and
diurnal mood variation. These symptoms are asso-
ciated with an activated corticotropin-releasing hor-
mone (CRH) system and a reduced level of activity of
the growth hormone and reproductive systems [Gold
and Chrousos, 2002]. Another burgeoning line of
research, the affective neurosciences, try to gain
Depression and Anxiety DOI 10.1002/da
314 Schotte et al.
understanding of the structures in the brain, the
mechanisms and cognitive functions involved in the
regulation and dysregulation of mood and emotion, by
using functional brain imaging techniques and experi-
mental psychological procedures. Recent findings
indicate that depression is associated with abnormal-
ities in the structure and functions of the prefrontal
cortex, the hippocampus, the anterior cingulate, and
the amygdala [e.g., Davidson et al., 2002; Pine, 2002;
Pizzagalli et al., 2002]. Cognitive-behavioral models [Beck
et al., 1979] emphasize the relationship between
depression and automatic, negative thinking processes
and dysfunctional patterns of information processing,
and state that dysfunctional schemas, which are
memory representations regarding the self and its
relationships with others, increase one’s vulnerability to
depression. Interpersonal models [Coyne, 1976; Joiner,
2002; Klerman et al., 1984; Markowitz, 1999] relate
several levels of social functioning to depression:
(1) vulnerability as a result of interpersonal factors,
(2) social skills and behavior of patients with depres-
sion, and (3) the effect of depression on social
interactions and relations. Research into the associa-
tion between depression and stressful or adverse life events
corroborates the idea that serious losses, threatening
occurrences, or difficulties in life play a major
etiological role, particularly in initial depressive epi-
sodes [e.g., Brown, 1993; Brown and Harris, 1978;
Brown et al., 1994; Jenaway and Paykel, 1997]. The
individual, idiosyncratic attribution of meaning regard-
ing the degree of stress or emotional disturbance elicited
by an event does matter greatly: The perceived effect on
self-esteem and self-effectiveness is an important inter-
mediary factor for determining the stressfulness of the
event. Apart from the influence of acute life events, other
research reveals relations between chronic stress and
depression [e.g., Ingram et al., 1998; Turner and Lloyd,
1995]. Another particularly relevant line of life events
research looks at the effect of trauma early in life on
biological [e.g., Ladd et al., 2000; Van Voorhees and
Scarpa, 2004] and psychological [e.g., Young et al., 2003]
vulnerability. Finally, epidemiological studies of depres-
sion indicate the rising incidence of depression in ever-
younger cohorts: This finding may be indicative of the
importance of stress factors, situated in a societal context.
Despite their essential contributions, each of these
depression theories as such is too fragmentary and
reductionistic. Seen in etiological terms, depressive
disorders are an extremely heterogeneous group and
form the final stage of a wide variety of causal
pathways. The models sketched here often give too
simple explanations for the complex pathogenetic
processes in the heterogeneous diagnostic depression
groups and take too little account of developmental
aspects and the reciprocal effects of biological pro-
cesses and interactions between persons, environments,
and symptoms. Clinicians, who combine biological and
psychological therapeutic interventions, need a more
eclectic vision that integrates biological and individual
Depression and Anxiety DOI 10.1002/da
psychological factors, as well as social, environmental,
and stress factors into a biopsychosocial [Engel, 1977,
1980] depression paradigm.
VULNERABILITY
THE PSYCHOBIOLOGICAL SUBSTRATE
The notion of vulnerability is considered from the
psychological (mind) and the biological (brain and
body) view: Both systems are essentially and irrever-
sibly linked. The psychological aspect is the substrate
of the biological aspect and vice versa. Just a few of the
numerous research findings that support this view are
mentioned below [for a review, see Gabbard, 2000].
The research group headed by Kendler in Virginia
has provided striking examples of how genes, biology,
psychology, and stressors need to work in ‘‘harmony’’
to provoke a depressive episode. This research group
monitored a sample of more than 2,000 female twins
for a period of 17 months on average [Kendler et al.,
1995]. Recent severely stressful life events appeared to
be the most powerful risk factor for an episode of major
depression; genetic factors played a substantial, albeit
not dominant, role. The twins with the lowest genetic
risk factors had 0.5% probability of depression onset if
they were not exposed to a serious life event. If a severe
stressor occurred, this probability rose to 6.2%. The
group of twins with the highest genetic risk had a 1.1%
chance of developing a depressive episode in the
absence of a stressor, but this risk soared to 14.6%
with the occurrence of a serious life event. Thus,
genetic factors affect the sensitivity or vulnerability of
persons to the depression-inducing effects of stressful
life events. In a further study of this survey of twins
[Kendler et al., 2002] 18 risk factors associated with five
phases in life—childhood, early and late adolescence,
adulthood, and the previous year—were used to
develop a model for predicting depressive episodes.
For example, risk factors associated with childhood
include genetic risks, a disturbed family environment,
sexual abuse, and loss of a parent. The Kendler model
states that the risk for a depressive disorder in women
is the result of three broad, interacting pathways that
reflect internalizing symptoms (neuroticism and early-
onset anxiety disorders), externalizing systems (conduct
disorders and substance misuse), and psychosocial
misfortune in the various phases of life. Genetic risk
factors for major depression appear to contribute to the
three paths. These findings illustrate the complex
interweaving and interactions of psychosocial and
genetic vulnerability factors.
Psychotherapists have for a long time been aware
that severe traumatic experiences (e.g., abuse, neglect,
and maltreatment) in (early) childhood can have
disastrous effects on most aspects of adult functioning
and increase vulnerability to depression [e.g., Browne
and Finkelhor, 1986; Toth et al., 1992]. An important
recent line of research shows that such psychologically
 Theoretical Review: Depression Model
traumatic experiences also lead to significant and often
permanent dysregulations of many aspects of biological
functioning: HPA axis, stress parameters, heart rate,
neurotransmitters, and hormonal and immunological
parameters [e.g., Heim et al., 2001; Ladd et al., 2000;
Van Voorhees and Scarpa, 2004]. Severe early traumas
are likewise associated with neurotoxicity and may,
for example, lead to atrophy in the hippocampus
[Andersen and Teicher, 2004; Teicher et al., 2002;
Vythilingam et al., 2002].
Moreover, brain imaging studies have consistently
described hippocampal atrophy in mood disorders
[e.g., Sheline et al., 1999]. The discovery of neurogen-
esis—the adult mammalian brain creating new neurons
from pools of stemlike cells—meant a breakthrough
in neuroscience. Although a role for neurogenesis in
mood disorders is speculative, it has been suggested
that a fall in neurogenesis in the dentate gyrus of the
hippocampal formation contributes, together with
atrophy and death of hippocampal neurons, to hippo-
campal attrition. This neurotoxicity can be the target of
novel ‘‘plasticity enhancing’’ strategies [Abrous et al.,
2005; Glitz et al., 2002; Gold and Chrousos, 2002;
Manji et al., 2003]. In severe, treatment-resistant
depression, the application of chronic deep brain
stimulation might reverse symptoms in otherwise
untreatable conditions [Mayberg et al., 2005]. Anti-
depressants and mood stabilizers such as lithium and
valproate [Gray et al., 2003], and electroconvulsive
therapy (ECT) may exert some of their therapeutic
effects on mood disorders by stimulating neurogenesis
[Abrous et al., 2005].
Finally, a further striking illustration of how closely
psychology and biology are linked is the finding that
effective cognitive-behavioral, interpersonal, and psy-
chodynamic psychotherapeutic interventions influence
various aspects and parameters of biological function-
ing [e.g., Brody et al., 2001; Gabbard, 2000; Thase,
2001].
In summary, it may therefore be said that numerous
research paradigms emphasize the interrelatedness of
the psychological and the biological: These aspects are
like the two sides of a coin. The psychological is the
substrate of the biological and vice versa: One’s
emotional life, one’s self-image, and one’s being are all
governed by biological processes, but biological func-
tioning is equally influenced by what one experiences or
has experienced, by how one feels, and by what one
believes he or she is. Consequently, we consider the
concept of vulnerability as a psychobiological substrate
that determines the vulnerability to depression.
RISK FACTORS AND PROTECTIVE FACTORS
Figure 1 gives an overview of the risk factors of a
biogenetic, psychological, somatic, and social/societal
nature, and of the protective factors that influence the
vulnerability for depression.
315
Figure 1. The psychobiological vulnerability for depression: risk
and protective factors.
Biogenetic risk factors. When researchers con-
sider biological vulnerability, they often refer to genetic
factors. Traditional methods for the assessment of
genetic factors, such as twin, adoption, and family
studies, have demonstrated the influence of genetic
vulnerability factors in the etiology of depressive
disorders [Hamet and Tremblay, 2005; Souery et al.,
1997; Tsuang and Faraone, 1990]. Although, as of this
date, molecular biological research has not turned up
any genetic factor that can be linked with certainty to
a predisposition to mood disorders, it may nonetheless
be assumed that biological dysregulations associated
with depression are influenced by genetic variations.
Researchers who consider dysfunctions in neurohor-
monal stress regulation have observed that first-degree
family members—even though they have never been
depressed—of persons with depression display a defect
in this regulation that is stable in time [Modell et al.,
1998]. Caspi et al. [2003] found that a functional
polymorphism in the promoter region of the serotonin
transporter gene moderates the influence of stressful
life events on depression. In the same vein, it is
supposed that temperament characteristics such as
‘‘harm avoidance’’ and ‘‘reward dependence’’ are
associated with specific biological functions and
increase vulnerability to depression [Cloninger et al.,
1993]: There is evidence that these temperamental
dispositions are influenced by genetic factors [Heath
et al., 1994].
Psychological risk factors. Psychological risk
factors for depression are considered in the cognitive-
behavioral approach to therapy [Beck et al., 1979;
Gloaguen et al., 1998; Young et al., 2003], which
postulates that cognitive phenomena such as schemas
and automatic thoughts mediate depressive emotions
and behaviors. Schemas reflect the individual’s funda-
mental views and are organized representations of
earlier experiences in life that govern information
Depression and Anxiety DOI 10.1002/da
316 Schotte et al.
processing at the present time. Dysfunctional schemas
are immature, absolutistic, and display major themes
such as helplessness and being unloved [Beck, 1995].
Stressful life events can activate these dysfunctional
schemas, facilitate cognitive distortions, and result in
automatic thoughts (i.e., the virtually reflexive patterns
of thought and internal discourse that mediate between
situation and emotions, behavior, and physiological
reactions). The content of depressive automatic
thoughts reflects the negative cognitive triad about
the self, the world, and the future [Beck et al., 1979].
Basic elements of the therapy are the identification and
modification of the automatic thoughts and schemas.
This Beckian cognitive-behavioral therapy is especially
effective in mild and moderately severe forms
of depression [Gloaguen et al., 1998]. In the case of
comorbidity with personality disorders, one can con-
sider schema therapy as an entry [Young et al., 2003].
Young’s model particularly emphasizes psychological
vulnerability; in the current integrative model, chronic
or severely stressful experiences in early life are just as
likely to cause hypersensitivity or damage to numerous
biological systems, thus increasing overall psychobio-
logical vulnerability to psychopathology [e.g., Ladd
et al., 2000; Van Voorhees and Scarpa, 2004]. More-
over, it should be emphasized that dysfunctional
schemas and coping styles are self-perpetuating and
elaborated throughout one’s lifetime, and consequently
generate chronic stress and problems that are a
constant burden on the psychobiological substrate.
It is a well-known fact that the occurrence of
depression in the family likewise increases psychobio-
logical vulnerability to depression. Apart from the
genetic aspects, there are risk factors that can be
described as ‘‘intergenerational.’’ For example, a
number of authors [e.g., Newport et al., 2002] found
that depression in pregnant women has a biochemical
effect on the developing fetus. Moreover, witnessing
the depression of one of the parents can constitute a
learning experience or life example that increases one’s
psychobiological vulnerability to depression in later life
[e.g., Essex et al., 2002].
Research on the psychological risk factors for
depression from an interpersonal context distinguishes
three nonexclusive domains of vulnerability. Impaired
social skills, excessive interpersonal dependency, and
excessive interpersonal inhibition may render people
vulnerable to future onset of depression [Joiner, 2002].
Somatic risk factors. Depression is especially
common in the medically ill: Research reveals comor-
bidity with numerous somatic disorders, such as—
among many others—pain, thyroid disease, immunity
problems, cancer, viral infections, cardiovascular dis-
orders, and skin diseases [for a review, see Robertson
and Katona, 1997]. These physical illnesses give rise to
a heightened psychobiological vulnerability to depres-
sion; particularly in elderly people, the likelihood of
depression increases in persons who have physical
disease. The reverse phenomenon is also true: Regard-
Depression and Anxiety DOI 10.1002/da
less of age, and when suicide is discounted, depression
leads to greater morbidity and mortality in a number of
somatic clinical disorders. For example, the presence of
depressive characteristics promotes susceptibility to
heart disease [Gold and Chrousos, 2002], heightens
mortality in cardiovascular diseases [Denollet et al.,
2000], and increases the risk of breast cancer in women
[Gallo et al., 2000]. Vulnerability to depression is also
associated with the abuse of, intoxication with, or
withdrawal from substances such as alcohol, ampheta-
mines, and sedatives [e.g., American Psychiatric Asso-
ciation, 1994].
Sociocultural risk factors. The last group of risk
factors lies in the realm of the societal and the
sociocultural. Our basic proposition is that the changes
and instability of many societal aspects of economically
advanced countries have an impact on the vulnerability
of the individual [e.g., Fullilove, 2002; Millon and
Davis, 2000; Paris, 1996]. Some relevant observations
include the following: Myers [2000] describes the
‘‘American paradox,’’ which can be extended to all
economically advanced countries: On the one hand,
one observes an ‘‘economic expansion,’’ a prodigious
increase in the wealth produced; on the other hand,
there is an increase in numerous indicators of ‘‘social
recession,’’ such as a strong erosion of the social link
and increasing divorce, suicide, violence, and depres-
sion rates. Americans are less happy today than they
were 40 years ago, despite the fact that they make
2.5 times as much money. Millon and Davis [2000]
describe how traditional social structures, the nuclear
familial and extrafamilial structures are being broken
down, and how there is less intergenerational con-
tinuity, with less importance attached to family values.
In fact, these observations recapture the ideas of Émile
Durkheim on the growing social disintegration and
anomie in modern society at the beginning of the
previous century. Social networks are important and
protect the individual: Social disintegration and weak
social networks result in all kinds of problems, such as
substance abuse, violence, neglect, suicide, and psy-
chopathology. For many people in Western societies,
global social structures are becoming uncertain and
unclear, even though it is important for people to be
aware of their roots, to have a place in social networks.
A good example of this longing is the immense success
of new social networks, such as the mobile phone, short
message service (SMS), Internet chatting, and similar
information technology novelties. By participating in
an electronic network, one has a feeling of belonging to
and being part of a larger but in many aspects artificial
social network. More generally, there seems to be a
significant ideological vacuum in the Western World
now that communism has collapsed and society is
becoming increasingly secular. Since the victory of the
free market economy and ‘‘globalization,’’ ethical and
social values are subordinate to profit and profit taking.
Considering this, Hunout et al. [2003] argue that the
mainstream individualistic, hedonistic, and consumer-
 Theoretical Review: Depression Model
ist system of values erodes contemporary society in
economically advanced countries. In short, our social
and ideological world is changing immensely and
quickly. People experience their living environment
as unstable, unpredictable, unclear, and unsafe. The
(post)modern man or woman has trouble finding his
or her own place, identity, and role: This uncertainty
is stressful and undermines the quality of life.
Also worth mentioning is the link between poverty
and a heightened vulnerability to depression [e.g.,
Brown, 1997; Yen and Kaplan, 1999]. Finally, we may
wonder whether the high prevalence of depressive
complaints and fatigue should be linked to environ-
mental factors such as exposure to contamination or
harmful agents in water, air, soil, crops or foods, or
changes in our daily diet [e.g., Sparks et al., 1991;
Vozoris and Tarasuk, 2003].
Gender as a risk factor for psychobiological
vulnerability. It is a fairly consistent epidemiological
finding that the prevalence of depressive disorders in
women is roughly twice as high as that in men [Kessler,
2000; Piccinelli and Wilkinson, 2000; Smith and
Weissman, 1991]. This observation can be explained
in terms of greater psychobiological vulnerability, with
female gender as a factor in all four risk groups (see
Fig. 1) and in terms of women’s higher frequency and
severity of stressful life events.
Sociocultural ideas about female and male identity
have such an impact on the development of self-image
that women display more internalizing disorders, such
as depression and anxiety, and men display more
externalizing problems, such as antisocial behavior
and substance abuse [e.g., Rosenfield, 2000]. Women
identify more closely with the feelings of others, are
more interpersonally dependent, and have a greater
need for emotional support. Compared to men, women
experience the well-being of their family members as a
major source of concern; stressful life events experi-
enced by significant others are associated with more
distress in women than in men [Rosenfield, 2000]. The
latter observations may explain to a certain extent the
interesting finding [Thase et al., 2000] that women
with severe depression respond better to interpersonal
therapy than to cognitive-behavioral therapy. At any
rate, one assumes that women in general do have a role
that entails more stress, with more limited personal
autonomy and access to resources, and greater un-
certainty [e.g., Cotton, 1990; Fullilove, 2002]. For
example, working mothers are exposed to overload and
often conflicting demands between work and family
roles. Thus, the idea here is that the responsibilities
and obligations associated with the female role make
women more vulnerable and at higher risk for
depression when confronted with events that foil the
fulfillment of their duties. In more somatic terms, there
are numerous psychological and somatic problems
related to the female reproductive cycle [e.g., Parry,
2000], and sex hormones most certainly play a role
in creating vulnerability for depression [Kessler, 2000].
317
In short, not only do women have a greater psycho-
biological vulnerability to depression but they are also
exposed to more stressful, traumatizing life events and
circumstances that heightens the risk of depressive
disorders.
Protective factors. Protective qualities, such as
material prosperity, adopting a less hectic or stressful
life, being in good health, being raised in a warm and
loving home, and having loved ones, a functioning and
supportive social network, social solidarity, well-devel-
oped social skills, and meaningful activities, can buffer
or diminish the vulnerability to depression. A short list
of the relatively sparse research findings about potential
protective factors includes physical activity and sports
[Fox, 1999; Gore et al., 2001]; a long-term intimate or
marriage-like relationship [Heath et al., 1998]; religi-
osity [Miller et al., 1999]; well-developed problem-
solving skills for adolescents and young adults, and
social connectedness among young men [Donald and
Dower, 2002]; being married [for men; Kessler, 2000];
a healthy and regular diet, with regular breakfasts
and slow weight reduction [for overweight women;
Lombard, 2000] or dietary supplements when being
treated for depression [Peet and Horrobin, 2002].
Worth mentioning here is the research conducted by
the group associated with Brown [Harris et al., 1999]
on factors that promote recovery from chronic depres-
sion. Befriending a female volunteer and ‘‘fresh start’’
experiences—occurrences that bring hope and change
to a situation of deprivation—combined with the
absence of new, severe stressors and markedly poor
coping strategies appear to have a positive effect on
chronic depression in women with a standard attach-
ment style. In particular, the ‘‘fresh start’’ experience
appears to be a basic predictor for recovery from
depression.
DISTRESS AS A CONSEQUENCE
OF INTERACTIONS
BETWEEN STRESSORS
AND VULNERABILITY
The pathogenesis of depression stems from dynamic
interactions between psychobiological vulnerability
and stressors or life events. Between 66% and 90% of
depressive episodes in adults are preceded by one or
more life events that have a long-term, threatening
impact, if they are to provoke a depression [Brown and
Harris, 1978]. As already mentioned, the depressogenic
quality of the life events is highly dependent on the
individual’s idiosyncratic interpretation of the events
[Brown, 1997]. The distress caused by a life event is
largely determined by personal and contextual factors;
the degree of intrinsic stressfulness is perhaps less
important. It is therefore an oversimplification to speak
of positive and negative life events: The clinician needs
to assess the life events within the heuristic framework
Depression and Anxiety DOI 10.1002/da
318 Schotte et al.
of the patient’s individual context and cognitive
schemas [Young et al., 2003], and to interpret them in
terms of congruence with psychobiological vulnerabil-
ity [or verstehen; Brown, 1997]. A life event such as a
divorce, a loss, or a promotion may affect one person
very deeply, causing serious distress or even a break-
down, whereas another person may be hardly affected
at all and may be even buoyed up by the event.
Attribution models [e.g., Abramson et al., 2002] have
shown that the likelihood of a depressive reaction
increases when the individual feels unable to control
the situation or when his or her objectives and goals
seem unattainable [Nesse, 2000]. Characteristic is a
developing sense of hopelessness, of being trapped in
a desperate situation that the individual nonetheless
continues to resist and refuses to accept, resulting in a
subversion of the individual’s strength, causing a low
mood state. This state of being imprisoned, this
‘‘entrapment’’ [Brown et al., 1995; Gilbert and Allan,
1998] and hopeless struggle are essential to the
pathogenesis of many depressive episodes and states
of exhaustion: Entrapment and humiliation appear
to be crucial elements for determining to what extent
a life event will have a depressive impact [Brown, 1998;
Brown et al., 1995]. Apart from acute life events,
persons suffering from depression are often found to be
exposed to chronic stress factors [Ingram et al., 1998;
Turner and Lloyd, 1995], in which the pressure of the
stressors slowly undermines the subject’s psychobiol-
ogical resistance and abilities to recover.
DEPRESSION: DEVELOPMENT
OF A NEGATIVE SPIRAL
Severe, threatening life events initiate a stress
reaction or a low-mood emotional state. This can be
regarded as an adaptive process [e.g., Nesse, 2000]:
In much the same way that the sensation of pain is
unpleasant and makes clear that action is needed to
stop it, the depressive mood is a signal that action is
necessary. However, if the state of distress persists too
long, it leads to a dysregulation of the stress feedback
system, which results in the individual getting psycho-
biologically ‘‘stuck’’ in a permanent condition of
hyperarousal. This hyperarousal entails major changes
to the functioning of the central nervous system and
the remainder of the body as well [e.g., Holsboer,
2000]. Neuroimaging studies reveal that prolonged or
chronic conditions of stress and hyperarousal can result
in neurotoxicity: Changes in the central nervous
system, for example, entail the suppression of the
flexible cognitive reaction patterns of the prefrontal
cortex by the fixed reaction patterns of the amygdala
governing behavior [Gold and Chrousos, 2002]. It is
characteristic of this maladaptive condition that the
‘‘normal,’’ flexible coping mechanisms for reducing
stress are no longer effective.
Depression and Anxiety DOI 10.1002/da
In clinical practice, reconstructions of the depresso-
genic process reveal that the emotional distress sets off
a ‘‘negative spiral,’’ a process in which interactions
among cognitive factors, biological processes, depres-
sive symptoms, and interpersonal factors reinforce one
another and push the individual further into depres-
sion. At the behavioral level, one observes highly
inadequate stress management: Even though the
patient feels bad, severely stressed, and exhausted, he
or she will persist in trying to fight the depression
and keep control over the situation. Patients often
neglect themselves, deny themselves the rest and rela-
xation they absolutely need, and get stuck in a
depressive state characterized by the peculiar combina-
tion of cognitive hyperactivity—endless, anxious
ruminations—and physical exhaustion.
Several factors influence the derailment of distress or
low mood into depression: the degree of psychobiolo-
gical vulnerability, the severity of the life events, the
coping skills of the individual, the number of previous
depressive episodes [Duggan, 1997], the extent to
which the subject feels that he or she is entrapped in
a hopeless situation [Brown et al., 1995], and the
degree of potential support from the social network.
From a life-span viewpoint, one can identify moments
of difficult transition between phases in life, such as
adolescence and young, midlife, and late-life adult-
hood. Each of these life stages has its specific
developmental tasks and social, psychological, and
biological issues. For instance, by midlife, individuals
are expected to have established a family, to have found
a clear career direction in which they will peak, and to
have have taken on responsibility with respect to their
children, their own aging parents, and sometimes their
community. Researchers have explored issues such
as ‘‘midlife crisis,’’ menopause, ‘‘empty nest,’’ caring
for both parents and children, and the transition
to retirement and leisure [e.g., Staudinger and
Bluck, 2001].
Quite often there is an unfortunate convergence of
circumstances: too much stress in several areas of life at
the wrong moment. Personality factors such as
dependency, perfectionism, and the flexibility to adjust
aims and values also constitute well-known key
mediating factors [e.g., Enns et al., 2002]. Finally, the
duration of the depression episode is quite important
[e.g., Keller et al., 1992]: The longer a person is
afflicted with severe distress, the greater will be the
burden on the psychobiological substrate and the
greater the likelihood of a psychological and physical
attrition resulting in a depressive picture that will be
more difficult to treat. Figure 2 summarizes the broad
lines of the depression model.
RECURRENT DEPRESSION
The diathesis–stress model works satisfactorily and
stands up well as a frame of reference for patients with
first episodes of depression. Indeed, etiologically
 Theoretical Review: Depression Model
Figure 2. The diathesis–stress model for depression. The dotted
line highlights feedback effects in recurrent depression.
relevant, stressful life events are almost always observed
when first episodes of severe depression arise [Brown,
1993; Brown et al., 1994; Jenaway and Paykel, 1997].
However, in chronic and recurring depression, epi-
sodes often seem to arise even though no significant life
events are manifest. The explanation for this ‘‘endo-
genous’’ quality lies in the fact that the greater the
number of depressive episodes already experienced, the
likelier it is that new episodes will arise independently
of external stress factors [e.g., Kendler et al., 2000] and
the higher the risk for new depressive episodes [e.g.,
Rakel, 1999; Solomon et al., 2000]. Additionally, partial
remission and residual symptoms after a depressive
episode seem to be strongly associated with relapses
[e.g., Pintor et al., 2003]. Using the model, we propose
various complementary etiological mechanisms, indi-
cated by the feedback effects (dotted lines) in Figure 2.
Repeated depressive episodes are a burden for the
psychobiological substrate and increase the vulnerabil-
ity to depression. It might be that the substrate
becomes so excessively sensitive or vulnerable [e.g.,
Post, 1992] that stressors that originally would have
had a rather low depression-inducing power can
generate a depressive episode. Supporting this assump-
tion is the previously mentioned evidence from
neuroimaging and postmortem studies that severe
mood disorders are associated with neuronal atrophy
and with impairments of structural plasticity and
cellular resilience that enhance biological vulnerability
[e.g., Shelines et al., 1999].
The experience of repeated depressive episodes
is itself a very significant psychosocial stress factor:
It goes without saying that chronic psychiatric pro-
blems are intrinsically severely stressful in individual,
relational, social, professional, and financial terms. In
319
fact, one can assume a relationship between the number
of depressive episodes, an increased vulnerability and
a rise in chronic, disease-related psychosocial stressors,
causing episodes to arise quickly and apparently
independently of life events.
SOME PRACTICAL
IMPLICATIONS OF THE
DEPRESSION MODEL
The model is a biopsychosocial–theoretical frame of
reference offering an explanatory rationale for depres-
sion acquisition and maintenance, and providing a
theory-driven basis for diagnostic assessment and
treatment planning. Concerning psychodiagnostic as-
sessment, we advocate a two-tier strategy [e.g., Van
Praag, 1990; Schotte, 2002]: The first tier comprises
a dimensional or categorical descriptive diagnosis of
the depressive phenomena, whereas the second tier is
linked to a biopsychosocial theory and is therapy-
oriented. The model can be used as a guide, as a
blueprint for the second-tier diagnostic assessment, in
which the vulnerability, risk, and protective factors and
interactions with life events are the elements of an
individual case formulation.
To conclude we mention some of our reflections on
the impact of the model on the therapeutic approach to
severe depressive disorders. The implementation of the
model has an impact on how we shaped the inpatient
treatment context at the University Hospital Antwerp
for patients with severe depression [Schacht, 2004;
Schotte et al., 2003]. An individually oriented approach
with combined biological and psychological interven-
tions is sought. Essentially, the treatment process is
organized in three consecutive phases: remoralization,
remediation or symptom reduction, and rehabiliation
and relapse prevention [Howard and Marinovitch,
1996]. Special attention is given to the consideration
of suicidal ideation in all phases of treatment: Suicidal
tendencies are assessed regularly, need to be discus-
sable, and for each patient, specific agreements and
actions are negotiated in the event of the patient being
overwhelmed by the suicidal thoughts.
In the remoralization phase the aims are to generate
hope and to educate the patient and his or her family
using the reference frame of the model. Specific
therapeutic communication techniques have been
developed to break through the demoralization of
depression [Schacht, 2004]: Therapists emphasize the
possibilities for remission and recognize that depres-
sion is a severe but curable disease with very high levels
of suffering and burden caused by the psychobiological
consequences of stress and hyperarousal. The essence
of the model is nondiscriminatory and constructive
toward patients: One of the central assumptions is well
reflected by the adage ‘‘all men (women) are equal.’’
Every human being is vulnerable to depression because
of the interplay between psychological and biological
Depression and Anxiety DOI 10.1002/da
320 Schotte et al.
characteristics, genes, and life experiences. Psychoedu-
cation, using an explanatory rationale and having a
formulation is about the core beliefs with regard to
etiology and treatment helps to maintain the therapeu-
tic alliance and consolidates adherence of compliance
[Jorm, 2000; Pampallona et al., 2002]. Feedback
according to the model suggests a treatability, a
malleability of psychological and biological factors that
can lead to an improved resistance, coping, and stress
management, and to the modification of life objectives
and values. The model gives information on depression
and its symptoms and helps to formulate hypotheses on
the ‘‘negative spiral’’: the etiological factors and
pathogenesis of the patient’s depression. In this
idiosyncratic model, this case formulation is generally
more constructive, beneficial, and hopeful compared to
the fatalistic and self-denigrating illness and treatment
models of the depressed patients and their family.
Furthermore, several aids are used for the psychoedu-
cation on depression and its treatment: Worth men-
tioning is the video program Depressionythe Answers
[Schotte et al., 1993]. The tape consists of three parts:
In the first part, ‘‘The Psychiatric Ward’’ (6 min),
patients are welcomed and sympathy is expressed for
the painful experience of being admitted to the ward.
However, the hospitalization can help to alleviate the
symptoms of depression. The second part, ‘‘Symptoms,
Causes, and Therapy’’ (11 min) provides information
from a medical, psychiatric/biological viewpoint on
symptomatology, etiology, and antidepressive medica-
tion and its possible side effects. The third part,
‘‘Thinking, Acting, and Feeling’’ (18 min), provides
concrete, role-played, and lifelike examples of the
cognitive, behavioral, and affective characteristics of
depression. The tape is shown to each inpatient by
a trained nurse, and if they so desire, to the family
members. Research [Schotte et al., 1993] and experi-
ence with the video program indicate that patients and
their families respond well to the videotape and believe
in its utility as an introduction to the psychotherapeutic
and medical treatments.
In the remediation or symptom reduction phase, it is
stressed that initially recovery is possible without the
patient explicitly being responsible for it: The idea
behind this ‘‘deresponsibilization’’ strategy is to bring
an end to the ‘‘entrapment’’ situation. The patient and
persons in his or her environment learn how to stop the
senseless and exhausting ‘‘battle against depression’’
and come to realize that—apart from compliance with
the medication schedules and the endeavor to strive for
tranquillity, recuperation, and rest—no direct active
effort is expected of him or her at the beginning of the
treatment. The core characteristics of the treatment
approach harmonize well with the assumptions and
principles from new developments in behavioral
therapy such as the mindfulness-based stress reduction
program and the acceptance and commitment therapy
approach [ACT; Hayes et al., 1999]. In the first days
after admission, the importance of medication and
Depression and Anxiety DOI 10.1002/da
rest is therefore stressed. Simply stated, the message
here is: ‘‘As a person with depression, a severe
but treatable illness, take good care of yourself.’’
Rumination, agitation or retardation, and disability
are regarded as depressive symptoms, and are ‘‘normal-
ized’’ and treated in the context of severe depression.
Gaining peace of mind, rest, and medication play
the most important role in the initial objective of
reducing symptoms. In fact, the ward creates an
initial treatment context in which patients learn to
develop an attitude of ‘‘mindfulness’’ with respect to
their severe depressive symptomatology, rather than
working directly to change dysfunctional cognitions or
decrease levels of negative emotions. This mindfulness
attitude does not imply a passive coping style: On the
contrary, all ‘‘pleasant’’ activities that enhance physical
recuperation, that distract the patient from depressive
ruminations, are encouraged and proposed by thera-
pists and by the nursing staff. Patient-mindedness and
patient/family–friendliness are of primary importance
in this phase. Therapists and nursing staff present
themselves as competent experts in their knowledge of
depression and its treatment, but patients and staff
stand on an equal footing. The ward is open and
applies its rules flexibly; therapeutic activities are
offered, and participation is reinforced but is not
obligatory.
On the other hand, when the acute symptomatology
is diminished, the responsibility of and the possibilities
for patients are gradually emphasized. During the
phases of rehabilitation and relapse prevention, patients
are stimulated and encouraged to participate in
activities within and outside the ward; weekends can
be used to try out leisure and task activities at home.
The improvements during treatment are considered a
symbol of the first steps of the ‘‘fresh start.’’ This
element is further enhanced by a reconsideration of the
idiosyncratic model at the end of the admission.
Patients, their families, and therapists discuss realistic
expectations for further recovery and formulate short-
and long-term strategies to cope with remaining
depression symptoms to decrease patients’ psychobio-
logical vulnerability—increase protective factors and
diminish risk factors—and to reduce (the harm of)
stressful life events. The likelihood of relapse can be
drastically limited by improving loyalty to outpatient
antidepressant psychiatric treatment and, with the
eventual aid of outpatient psychotherapeutic follow-
up, working toward improved stress resistance and
optimizing the quality of life. Ultimately, the aim of
a treatment strategy for severe depression, rooted in
the present biopsychosocial model, is not only the
reduction of symptoms and the prevention of
subsequent episodes but also the optimization of the
quality of life, social (re)integration, and engagement in
the community.
The deduction that effective treatment of de-
pression should be more than a mere alleviation of
the symptoms and equally should bring about a
 Theoretical Review: Depression Model
reduction in psychological vulnerability and improved
resistance to depression is fairly self-evident: The
therapeutic plan should stress both symptom reduction
and prophylactic measures. Prophylaxis implies
influencing patients’ psychobiological vulnerability;
moreover, one should aim at preventing or minimizing
the effects of stressful, traumatic life circumstances
[Lam et al., 1996]. Psychotherapeutic interventions
that appear to be most effective in the treatment
of depression are cognitive-behavioral and interperso-
nal therapy [e.g., Arean and Cook, 2002; Jarrett et al.,
2001; Kornbluh et al., 2001; Lenze et al., 2002;
Michalak and Lam, 2002; Nierenberg, 2001;
Segal et al., 2002; Thase et al., 1997]. In view of the
high risk of relapse [Duggan, 1997], the importance
of a long-term treatment of depressive disorders is
being increasingly stressed [e.g., Geddes et al., 2003].
There are indications that combinations of psycho-
therapeutic and pharmacological interventions offer
better outcomes in severe depression over extended
periods of time than do monotherapies; this applies
to improved recovery and to the reduction of the risk of
relapse [e.g., Arean and Cook, 2002; Arnow and
Constantino, 2003; Lenze et al., 2002; Michalak
and Lam, 2002; Segal et al., 2002; Thase et al.,
1997]. This superior effect can be achieved, for
example, by cognitive-behavioral techniques that con-
centrate specifically on the residual symptomatology
following a response or partial remission resulting from
pharmacotherapy [Segal et al., 2002]. Such sequential
combination therapies highlight the possibilities of
integrated cooperation between the psychiatric and
psychological disciplines. Combined therapies reduce
the likelihood of dropout or therapy disloyalty, and
patients experience them as being more ‘‘customer-
friendly’’ [e.g., De Jonghe et al., 2001]. ECT is a
significant option for treating severe forms of depres-
sion [UK ECT Review Group, 2003]; however, there
has been little or no work investigating the sequential,
combined integration of ECT and psychotherapeutic
interventions.
The application of meditation techniques to the
treatment of chronic depression and particularly the
mindfulness-based stress reduction program appears to
be a promising development in treating chronic
depression [Bishop, 2002; Kabat-Zinn, 1990; Kabat-
Zinn et al., 1992]. ‘‘Awareness’’ or ‘‘mindfulness’’
meditation techniques are used to teach people how
to distance themselves from their feelings and thoughts
by regarding them as events rather than as products of
the self. Unlike the conventional cognitive therapeutic
interventions in the tradition of Beck, it is not the
content of the thoughts that comes under scrutiny;
rather, the therapy tries to influence the attitude of the
patient toward the depressive thoughts and feelings.
Applications of these techniques in a cognitive-
behavioral program appear to be effective in preventing
relapse into depression [Teasdale et al., 2000, 2002;
Mason and Hargreaves, 2001].
321
CONCLUSION
Because of the high burden of depression worldwide,
there is a need for effective strategies to shorten
episode duration and to prevent recurrence. For severe
forms of depression, treatments combining pharmaco-
logical and psychotherapeutic approaches are pre-
ferred. This requires interdisciplinary teamwork and
an integration of biological and psychological theories
of depression. Unfortunately, these two lines of
research and theory proceed in relative isolation from
each other. In this article, we have proposed an
integrative biopsychosocial model, describing onset
and treatment of depression, and introducing the
concept of psychobiological vulnerability. Our inten-
tion is that the framework inform clinical practice by
providing a context for psychoeducation and dialogue
between clinician and patient that aims to enhance
treatment compliance and improve outcome. Despite
the fact that contemporary research lines are accumu-
lating important knowledge that contributes to the
understanding of depression, future research needs
to emphasize the development of integrative theories
of depression.
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