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http://intl.elsevierhealth.com/journals/mehy
a
IUNICS, Psychiatric Department, Hospital Son Llatzer, C/Ctra de Manacor km 4,
07198 Palma de Mallorca, Spain
b
IUNICS, Psychiatric Department, Hospital Son Dureta, Palma de Mallorca, Spain
Summary There are two fundamental etiological perspectives about mental disorders; biomedical and psychosocial.
The biopsychosocial model has claimed to integrate these two perspectives in a scientific way, signalling their
interconnection and interdependence. To that end, it used a systemic conceptual framework, taking advantage of the
possibilities which it offers to establish general principles for diverse systems, independently of their physical,
biological or sociological nature. In recent years, drawing on the theory of systems, theories have been developing of
the dynamic non-linear systems, applicable to networks of a large quantity of densely interconnected elements (also
called complex systems), like the mind or the brain. We believe that this revised systemic conceptual framework can
bring integrative ideas to apply to Depression, such as the ‘‘binding dysfunction’’ concept we use in this article.
According to this, vulnerability or predisposition to Depression would be associated with the imbalance between
activating and inhibiting interactions (between some cognitions and emotions at a mental level, and between certain
neuronal groups at a cerebral level). Precipitating factors would imply the increase of the activation level over this
pattern of cognitions and emotions, or over those neuronal systems. When stress goes beyond the vulnerability
threshold an excessive positive feedback between cognitions and emotions would appear (and between groups of
neurons) with insufficient inhibitory control to mitigate it, which would imply a mental/cerebral dissociation in
dominions of different level of activation. As a consequence, the generation and dissolution of patterns of cerebral and
mental activation will no longer have the dynamism and flexibility that permits an optimal interaction with the
environment (‘‘binding dysfunction’’). Therefore, our hypothesis is that the person with Depression will suffer at a
cerebral level a functional dissociation in neural dominions (some rigidly hyperactive and others rigidly hypoactive) in
determined locations, which would be a different combination from those found in other mental disorders. At a mental
level, this would correlate with a functional dissociation in several cognitive–emotive dominions; some corresponds to
over activated patterns of ‘‘depressive’’ cognitions and emotions that for that reason invade the consciousness
frequently, intrusively and repetitively; meanwhile there are other alternative hypoactive emotions and cognitions
that do not manage to become powerful enough to avoid the consequent distortion in the communication with the
environment.
c 2006 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +34 871 202154; fax: +34 871 202174.
E-mail address: mgarciat@hsll.es (M. Garcia-Toro).
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2006.02.049
684 Garcia-Toro and Aguirre
A systemic and unified framework for the under- connected. The brain and the mind have been con-
standing of biological and social phenomena will sidered paradigmatic examples of complex
only be able to emerge when the concepts of the systems. The first section of this study enumerates
non-linear dynamic are combined with the ideas 10 findings from empiric research which we con-
of these fields of study. sider of great importance in the ‘‘jigsaw of Depres-
Fritjof Capra [1]. sion’’. What follows is the proposition of an idea
that aims to assemble coherently these very di-
verse findings.
Depression is probably the illness that brings most Without doubt, the first thing one must do to try to
suffering and incapacity, as its prevalence is very solve a jigsaw is ‘‘to put the pieces on top of the
high and on the increase [2,3]. It is concerning table’’. And it is here where we find the first prob-
that we, the mental health professionals, are still lem, as the choice of the number of pieces is arbi-
not clear about its origin. As a consequence, there trary and suspect of being biased in the interest of
is not always unanimity about the best way to defending preconceived ideas. Keeping this limita-
treat and prevent Depression [4]. To advance tion in mind, but trying to move things forward, we
understanding of the mechanisms which generate have selected 10 of the numerous verified empiric
Depression and to understand how they explain findings around Depression.
such a wide range of etiological and therapeutic
factors is one of the great challenges of 1. Genetic predisposition. The available genetic
psychiatry. studies are irrefutable for the evidence they
The two main perspectives currently used to ex- provide of the existence of a hereditary fac-
plain Depression which are in conflict are the bio- tor in the origin of many Depressions [15].
medical perspective and the psychosocial 2. Predisposition due to early cerebral damage.
perspective. The biomedical perspective asserts Certain perinatal events, such as viral infec-
that the psychopathological syndromes are essen- tions during pregnancy, obstetrical complica-
tially caused by disturbances in the functioning of tions, low birth weight and so on are
the brain, while for the psychosocial perspective epidemiologically associated to Depression
life experiences are the main cause of mental dis- [16].
turbance. Often, this double perspective influences 3. Multiplicity of predisposing or precipitating
implicitly the different affirmations that are made biological factors. A great variety of somatic
about mental disorders [5], although explicitly it is illnesses, pharmaceuticals, toxic substances
increasingly recognized that biological and psycho- and drugs have been proven capable of
social aspects are always involved, interacting in a increasing the incidence of Depression above
complex way [4]. Without a doubt, this is the rea- expected levels by virtue of the psychosocial
son why the term ‘‘biopsychosocial model’’ has changes that they involve [15].
prospered [6]. Nonetheless, it has been criticized 4. Findings around neuroimaging as possible
for having remained a mere declaration of inten- markers of cause and state. Depression has
tions and until now, for its inability to provide a been associated in structural neuroimaging
transdisciplinary idea able to articulate minimally with certain findings, mainly reduction in cor-
the enormous volume of biological and psychoso- tical volume [17]. In functional neuroimaging
cial data that is available [7]. It has also been noted the hyper and hypometabolic areas have been
that the biopsychosocial model has been incapable found to be very variable in different
of inspiring empiric research into the etiology, patients, but with a preference for certain
diagnosis and treatment of Depression [8–10]. locations [18].
Therefore, there is still an acute need for new con- 5. Effective biological treatments. The pharma-
ceptual bridges between the biomedical and psy- cological change in the activity of some neu-
chosocial models, as Engel already pointed out 25 rotransmission systems clearly improves the
years ago [11–14]. symptoms of Depression in a large proportion
Systems theory has inspired in recent years the of cases. Also, it has been proven that the dis-
development of the theories of non-linear dynam- turbance of certain parts of the brain electri-
ics and complexity, applicable to open systems, cally or magnetically can relieve Depression
with a big quantity of elements, intensively inter- in certain patients [19,20].
Biopsychosocial model in Depression revisited 685
6. Predisposing early psychological stress. dition of studying them separately, interact and
Childhood adversities predispose to Depres- modulate in a constant and reciprocal manner.
sion in adulthood, although positive parenting Assuming that circumstance, associative and con-
style may protect [21,22]. nectionist models about mental function have been
7. Predisposing personality. Neuroticism is a proposed [34,35]. We have tried to coordinate both
predisposing factor for Depression and other ‘‘complex’’ perspectives of the mind and the brain
mental disorders, such as the tendency to emphasizing a mechanism of common functioning,
anxiety in interpersonal relationships [23,24]. from which we can start to explain also its dysfunc-
8. Predisposition due to social maladjustment. tion. The following is the development of this idea.
A precarious network of social support and a A complex system (cerebral/mental) can be con-
low socioeconomic level increase the risk of sidered as a dynamic and self-organized network of
suffering Depression [25]. elements (neurons/cognitions–emotions) in con-
9. Precipitating psychological stress. It is well stant interaction [35]. This network is in part inter-
established that stressing life events are asso- nally self-regulated, but also it is hetero-regulated
ciated temporarily with the appearance of by multiple networks (systems) with which it inter-
Depressive disorders, especially their first connects (biological/psychosocial environment)
episodes [26]. [1,29,36]. The excitability of the system (capacity
10. Effective psychosocial treatments. Psycho- of activation by stimuli) must be sufficiently
therapeutic work with cognitions, emotions homogenous to maximize the possibilities of com-
and behaviours improves Depression. The psy- munication with the environment, and it is based
chological schools that have most concerned on the balance between stimulating interactions
themselves to demonstrate experimentally and inhibitory interactions in each of its parts.
the efficacy of its methods to relieve Depres- Thus, the elements of the system (neurons/cogni-
sion have been the interpersonal and the cog- tions–emotions) are densely interconnected by po-
nitive behaviourist schools [27]. sitive and negative feedback curves that should be
adequately proportioned. In this way, constant
All these factors have demonstrated empirically interaction is achieved, the elements (associating
their relevance in the appearance and remission of and disassociating functionally) forming flexible
Depression, but we do not know how they interact. patterns of activation in answer to all the multiple,
Putting forward a hypothesis which assembles them varied and changeable stimuli that are received
is at least as important as continuing to investigate from the environment. This implies that ideally
them separately [28]. Taking up this challenge im- the network would never be uniformly activated,
plies accepting justified criticisms of incomplete- as it should be changing according to the constant
ness and imperfection and this might be the variations of the environment. Therefore, at each
reason why the attempts are so relatively few. instance we will find hyper and hypoactive areas
However, in our opinion, it is worth any effort in in the system, but they will not always be the same
this direction, in spite of the limitations. ones. In summary, generating and dissolving
dynamically very different patterns of activation,
the system (brain, mind) manages to communicate
Binding dysfunction in the mind and the with the environment in a flexible and adaptable
brain manner.
So far, this is the associative normal functioning
The brain contains thousands of millions of neurons in a complex system, but . . . when would ‘‘binding
united by hundred of connections between them. dysfunction’’ appear and in what would it consist?
We still have a quite basic knowledge about the A particular level of stimulation in a cerebral/men-
electrochemical activity that maintains its func- tal area can upset the balance between stimulating
tioning. It seems naı̈ve to try to understand the and inhibiting functional reserves in that area. This
complexity of the brain from a very reduced field upset can occur to anyone if the level of stimula-
of study, at least in reference to the possibility of tion is sufficient (we all have a ‘‘breaking point’’
finding global and integrative explanations [29]. or ‘‘bifurcation point’’ to use another term of com-
That is why it is often suggested that it is pertinent plexity theory). At that moment positive feedback
to consider the brain as a complex system and to curves start to work that cannot be slowed due to
try to explore the usefulness of explanatory pro- insufficient inhibitory control. It is then that rever-
posals inspired in it [14,30–33]. The mind is insep- berating cerebral circuits and cognitive–emotive
arable from the brain in function. At a mental patterns appear which expand and strengthen,
level, cognitions and emotions, in spite of the tra- being able to resist the efforts of the rest of the
686 Garcia-Toro and Aguirre
system to dissolve them, managing to self-perpetu- emotive dominions; one corresponds to over acti-
ate. For this reason, they suppose a seizure of vated patterns of ‘‘depressive’’ cognitions and
activity (cerebral/mental) that reduces the capac- emotions that for that reason invade the conscious-
ity for activation in other parts of the system, ness frequently, intrusively and repetitively; mean-
especially the ones most interconnected with it. while there are alternative hypoactive emotions
This functional fragmentation into dominions and cognitions that do not manage to become pow-
(cerebral/mental) of a different level of activation erful enough to avoid the consequent distortion in
implies a certain functional independence of those the communication with the environment.
areas ‘‘in revolt’’ that ignore the regulatory signals
of the rest of the system. In addition, the genera-
tion and dissolution of patterns of cerebral and Assembling the 10 empiric findings with
mental activation will no longer have the dynamism
and flexibility that permits an optimal interaction
the help of the model
with the environment (‘‘binding dysfunction’’). As
From the 10 key findings that we have selected,
a consequence, there will be areas (circuits, cogni-
which we mention below some are clearly related
tive–emotive patterns) with a tendency to be hy-
to an associative dysfunction at a cerebral level
per or hypoactivated independently of the signals
and others at a mental level, although there are
that are received from the environment and conse-
many that can be approached in both ways.
quently, these areas will reinforce themselves
autonomous and reciprocally more and more
[37,38]. There are concepts of complexity theo- Genetic predisposition
ries, such as ‘‘attractor’’ or ‘‘dissipative struc-
tures’’ that we can relate to this mechanism We have related the predisposition to suffer from
[39,40]. In this study, we have opted for the con- Depression to the imbalance between stimulatory
cept of ‘‘binding dysfunction’’ because of its sim- and inhibitory interactions which allow maladjust-
plicity, for it comes from key concepts in brain ments of cerebral excitability. The systems of neu-
research (‘‘binding problem’’) and also because it rotransmission are clear mediators of neuronal
alludes to a dynamic process that puts the accent excitability. Each one of them is distinguished by
on the interactions more than a static analysis of its more stimulatory or inhibitory action over the
the elements of the system [41]. In this way, we said neuronal excitability, its functional reserve
try to illustrate a generative mechanism capable being conditioned by the expression of numerous
of integrating many factors implicated in Depres- genes. Although it is far from being replicated suf-
sion, none of them necessary or sufficient. ficiently, until now one of the ways of neurotrans-
According to the above, the predisposing factors mission that has been most implicated in genetic
for ‘‘binding dysfunction’’ would be all those that studies about Depression is the serotoninergic. In
contribute to an imbalance in the proportion be- any case, these genetic studies have not provided
tween stimulatory and inhibitory interactions in consistent results and it is thought very improbable
any area of the system (brain/mind) and therefore, a simple mode of transmission is going to be found
modify locally its excitability. Precipitating factors [15]. Serotoninergic neurotransmission is very
would be all those associated to a stimulus of suf- important to modulate neuronal activity and has
ficient intensity and selectivity over a certain area a basically inhibitory action. It is distributed dif-
(cerebral/mental) such as to manifest this imbal- fusely throughout the brain with a light preference
ance. Finally, protective or reparative factors for the right hemisphere (that has been indicated
would be all those which, on the contrary, rebal- to be more involved in the neurobiological substra-
ance the percentage of interactions or correct tum of negative emotions and withdrawal behav-
the imbalance in the levels of stimulation over iours) when it is compared with the left
the areas of the system (brain/mind) involved. hemisphere. If a person has a lesser functional
How do we apply this approach to the specific field genetically conditioned serotoninergic reserve, it
of Depression? Our hypothesis is that the person is plausible to assume that there are more proba-
with Depression will suffer at a cerebral level a bilities that its right hemisphere is comparatively
functional dissociation in neural dominions (some more excitable, due to the decrease in the seroto-
rigidly hyperactive and others rigidly hypoactive) ninergic inhibition. Therefore this person has more
in determined locations, which would be a differ- risk of binding dysfunction in the right hemisphere,
ent combination from those found in other mental where over activated areas will appear more fre-
disorders. At a mental level, this would correlate quently together with a compensatory hypoactiva-
with a functional dissociation in two cognitive– tion in the left hemisphere. This agrees with some
Biopsychosocial model in Depression revisited 687
functional neuroimaging findings found in patients inhibitory imbalance. In another study, we have
with Depression, although it must be said that developed in more detail how each antidepressant
there is very variable and contradictory data [42]. treatment would work, so in this study we will only
focus on transcranial magnetic stimulation [45].
Predisposition due to early cerebral damage This new technique is a neurobiological tool that
has proved effective in most of the studies in which
Cerebral damage invisible macroscopically is capa- it has been tested with depressive patients, but
ble of altering the excitability of the brain through which clinical relevance is not yet established
distortions in the process of cellular migration or [46]. Its has been possible to verify its capacity to
through any other way of generating cytoarchitec- modulate cortical excitability in a focal way,
tonic changes which affect in different measure increasing or decreasing it depending on the high
excitatory and inhibitory neurotransmission. For or low stimulation frequency administered. This
example, GABAergic inhibitory neurons migrate agrees with the finding of good antidepressant re-
after glutamatergic excitatory neurons. If any early sults when a high frequency is applied in the left
cerebral damage modifies this process, the result prefrontal area and a low frequency is applied in
can be that a part of these neurons do not arrive the right prefrontal area, although not all the data
to their destination, generating cerebral areas with are concordant [47].
an altered balance of excitatory–inhibitory neuro-
transmission, and for that reason hyper or hypoex- Neuroimaging findings
citable [43]. On the other hand, the GABAergic
neurons are much more sensitive than the glutama- In patients with Depression greater frequency of
tergic to the anoxia and ischemia that can damage loss of focal volume in medial and ventral frontal
them [44]. Therefore, both factors also imply a cortex and also in the hippocampus has been de-
change in the balance of neurotransmission sys- scribed [18,48]. These findings in structural neuro-
tems towards an abnormal excitability of the cere- imaging have been associated with early cerebral
bral areas where they act, and depending on where damage or alterations in the embryogenesis.
they are localized can predispose to Depression or Therefore, they could be indicators of alterations
other mental disturbance. in the excitatory–inhibitory neuronal balance.
The typical findings in the studies of functional
Multiplicity of inducing biological factors neuroimaging in depressive patients are cortical
hypoactivity, more at the left prefrontal area and
It has been demonstrated that a great variety of so- the frequent finding of some areas of limbic and
matic illnesses, medicines, toxic substances and paralimbic over activation, above all of the amyg-
drugs are capable of increasing the incidence of dala and the anterior cingulate [49]. A neurobio-
Depression. Some of them can increase vulnerabil- logical model of Depression has been proposed
ity or predisposition by altering the excitatory/ that is able to explain these findings bearing in
inhibitory balance in cerebral neurotransmission mind that there is a dysfunction of limbic-cortical
(drugs, toxic substances or psychoactive medi- circuits, in which both cerebral dominions would
cines). Others can suggest an increase in the level maintain reciprocally their different activation
of activation of a cerebral area that exceeds the patterns [50]. The improvement in Depression asso-
vulnerability threshold. For example, a vascular ciated with different types of treatment, whether
accident, a space-occupying lesion, or any other biological or psychosocial; tend to normalize such
kind of significant cerebral damage could cause a patterns [42].
functional block of a cerebral area that needs to
be compensated with an over activation in another
Predisposing early psychological stress
area, in which the risk of associative dysfunction
increases.
Freud emphasized the importance of early experi-
ences for the development of the psyche and pro-
Effective biological treatments posed the theory of internalized conflict to
explain Depression. This theory assumed that the
Antidepressants and other methods of cerebral presence of strong and repetitive stressors in cer-
stimulation might be effective insofar as they man- tain circumstances led to stable connections be-
age to restore the balance in the activity patterns tween certain emotions and cognitions that
in different neurotransmission systems, and pre- afterwards tend to repeat themselves together
ventive insofar as they correct the excitatory/ more frequently [31]. Therefore it is widely
688 Garcia-Toro and Aguirre
Freud in ‘‘Mourning and Melancholy’’ looked for a Psychotherapeutic work with cognitions, emotions
common explication to all forms of Depression. Be- and behaviours improves Depression. Each school
sides recognizing his suspicion that biological as- of psychotherapy has developed its methods to pro-
pects unknown at the time played a role, he mote channels of communication between hyper
arrived at the well known conclusion that Depres- and hypoactive mental schemes, facilitating its
sion is a frequent reaction to loss, or the threat integration with the rest of the mind and the adap-
of loss, of a real or imaginary object [58]. In ‘‘Inhi- tation to the environment [67]. Therefore the rup-
bition, Symptoms and Anguish’’ he described how ture between certain psychosocial stressors and
the loss of the object is usually accompanied by rigid cognitive-affective patterns is essential
an intense desire for it, and also by negative emo- [56,68]. This is equivalent at a cerebral level to
tions (sadness, anger, etc.) and the recognition the neuronal networks which are habitually over
that the desire is unattainable [59]. Freud proposed activated or inhibited in the depressive patient
that when depressive emotions and cognitions form being able to be integrated during psychotherapy
a vicious circle that feeds itself, the person enters [69,70]. Therefore it is not strange that the use
a depressive state, something accepted by other of psychotherapy should have demonstrated
psychotherapeutic schools [60]. Therefore, some- changes in the activation of cerebral areas related
how he proposed that psychological stress is a fun- to Depression similar to the areas observed with
damental precipitating factor in Depression, antidepressants [71,72].
Biopsychosocial model in Depression revisited 689
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