Glannon, W - Depression As Mind-Body Problem (Plus Comments), (2002) 9 PPP 243

GLANNON / DEPRESSION AS A MINDBODY PROBLEM
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Depression as a
MindBody Problem
Walter Glannon
ABSTRACT: Major depression is a disorder of the mind

caused by dysfunction of both the body and the brain.
Because it is a psychiatric illness and psychiatry is a
branch of medicine, the question of how mind and
body interact in depression should be treated as a
medical rather than metaphysical mindbody problem. The relation between mind and body as it pertains to this illness should be construed in teleological
rather than causal terms. Mental states like beliefs
and emotions serve an adaptive purpose by constraining the physiologic systems involved in the bodys
stress response, thus preserving homeostasis and protecting us from various disorders. Depression results
when the mind fails it its constraining role.
KEYWORDS: Depression, mind, body, teleology, constraint, homeostasis.
ANY PSYCHIATRISTS CONCEPTUALIZE severe
mental illnesses like schizophrenia,

bipolar disorder, and severe depression as disorders of the mind arising from dysfunctions in the brain (Andreasen 1997; APA
1994, 273392). Schizophrenia is characterized
as a disorder of cognition (hallucinations, delirium), emotion (affective blunting), and volition
(inability to initiate and complete goal-directed
behavior); bipolar disorder as an affective disorder involving radical swings between mania and
depression; and chronic depression as an affective disorder involving negative moods such as
sadness, hopelessness, and listlessness. Most neurobiologists believe that some varieties of brain
dysfunction underlie serious mental illnesses.

Whereas neurotransmitters such as acetylcholine, dopamine, noradrenaline, and serotonin may
play a role in these illnesses, there are additional
factors that may account for them as well.
The mind consists in the capacity for cognitive
states like beliefs and affective states like emotions,
as well as unconscious affective states like emotional memories that can cause conditioned fear and
physiologic responses when triggered by external
events.1 Our mental states are generated and
sustained by the brain. In their conscious mode,
however, there are qualitative and intentional
aspects of our beliefs, emotions, and memories.
Neither the subjective nature of these mental states
nor their representational content (what they are
about) can be explained in terms of the brain
alone. Diagnostic measures such as functional
magnetic resonance imaging and positron emission tomography scans can reveal the underlying
pathophysiology of a mental disorder by showing
reduced glucose metabolism, reduced blood flow,
and structural abnormalities in the cortex. But
these objective measures cannot explain what it
feels like to hear voices or to have negative moods.
Nor can they account for the contents of these
mental states. In these respects, the first-person
perspective of being schizophrenic or depressed
is ontologically distinct from and irreducible to
the third-person perspective of brain science.
These considerations invite the two main questions at the core of the mindbody problem: (1)
2003 by The Johns Hopkins University Press
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244 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002
How can conscious mental states like beliefs and

emotions arise from physical processes in the
body and brain? (2) If the mental and the physical are ontologically distinct domains, then how
can there be causal interaction between the mind
and the body? These metaphysical questions have
vexed philosophers since antiquity. Yet, even if
the metaphysical mindbody problem remains
insoluble, it does not follow that we cannot make
progress in coming to a better understanding of
the medical mindbody problem: how mind and
body interact in maintaining health or causing
disease. It is the second question raised above
that is germane to psychiatry in general and
depression in particular, especially regarding the
idea that the mind can affect the brain and body,
and vice versa. By analyzing depression as a
medical rather than a metaphysical mindbody
problem, we can gain a better understanding of
how psychological and physiologic processes interact. This can shed light on the etiology of
depression and other mental disorders and lead
to more effective therapies to alleviate the suffering of the people who experience them. Metaphysics is inadequate in this regard because it
tends to locate the mind in the brain. The medical model more closely captures the idea that the
mind is not located in any one place but is distributed among the brain, the body, and the
environment.
Depression results not only from dysfunction
of the brain but from mental states as well. Because the mental states that figure in its etiology
have a subjective quality and representational content that reflect the social and natural environment, factors external to the brain must be considered to properly diagnose and treat the disorder.
Indeed, in physiologic terms alone it is not only
the brain or central nervous system that play a role
in depression, but endocrine and immune systems as well. By explaining how these physiologic systems are interconnected, and how mental
states can influence and be influenced by them, I
will show that depression is a psychoneuroimmunologic disorder consisting of four dimensions, one psychological and three physiologic.
Furthermore, because the mind serves an adaptive purpose by enabling a human organism to
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process sensory information more accurately and

efficiently and thus enhance its survival, it is
more plausible to construe the relation between
mind and brain (and body) in teleological terms.
The causal question of how brain and mind interact should be subsumed under the teleological
question of why they interact. From the perspective of evolutionary medicine, I will take issue
with the idea that depression can be an evolutionary tool for human survival. On the basis of
a teleological model, I will explore the ethical
implications of the mindbody relation for treatment of depressed patients by psychiatrists. Because depression is a disorder with interdependent physiologic and psychological dimensions,
it requires both pharmacology and psychotherapy as complementary forms of treatment.
Theories of Mind
In addressing a mental disorder like depression, it is necessary to frame it by a satisfactory
theory of the relation between mind and body.
Descartes raised the problem of causal interaction between the mind and body by arguing that
they were ontologically distinct substances. His
legacy of substance dualism says that, although
mind and body causally interact through the
pineal gland in the brain, the metaphysical relation between these substances is contingent rather than necessary. It is possible for the mind to
exist and function independently of the body and
brain. Few philosophers today defend substance
dualism; most agree that the mind necessarily
depends on the body and brain to generate and
sustain it. Instead, many philosophers defend
reductive materialism. This theory says that consciousness and other forms of mentality are not
simply caused by neural processes in the brain;
mental states just are neural processes or neural
states (Dennett 1991; Churchland 1995; Churchland 1989). This form of materialism is reductionist because it says that mental states can be
explained entirely in terms of the material or
physical structures and functions of the brain.
But insofar as our mental states have a subjective phenomenology, and insofar as their content
involves features of the social and natural environment, the mind cannot be explained entirely
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in terms of the objective physical properties of

the brain and body. The qualitative experience of
pain underscores the inadequacy of materialism.
There is something that it is like to feel pain that
cannot be explained away by neurophysiology.
As neurologist Todd Feinberg puts it, From the
outside, we cannot ultimately reduce the experience of pain to the neural state that creates it
because there is nothing material from the outside perspective to reduce . . . Our visions, our
minds, our pains, are personal and have no material existence for anyone but ourselves (Feinberg 2001, 146). The first-person ontology of
the mind is irreducible to the third-person ontology of the physical structure and functions of the
brain (Feinberg 2001; Searle 1992, 122).
This seems to introduce another version of
dualism, however. The distinction is not between
mental and physical substances, but between
mental and physical properties that are related
contingently rather than necessarily. It still leaves
us with the problem of explaining how the mind
can interact with the brain if it is ontologically
distinct from it. The nonreducibility of the mental to the physical seems to entail epiphenomenalism, the view that the physical affects the
mental but not vice versa. The mind does not
cause our behavior and makes no difference to
what happens in the world. Jaegwon Kim spells
out the problem of the explanatory exclusion of
the mental thus: If mental properties are physically irreducible and remain outside the physical
domain, then, given that the physical domain is
causally closed, how can they exercise causal
powers, or enjoy any kind of causal relevance, in
the physical domain? (Kim 1998, 58).
The main metaphysical theory advanced to
solve this problem is supervenience, which specifies a relation of dependence of mental properties on physical properties. Every mental property has a physical base in the brain that guarantees
its instantiation. For example, if a person experiences pain, then the mental property of having
the experience is an instantiation of some underlying physical property in the brain and nervous
system that regulates pain (Kim 1998, Chapter
1). But there are at least two problems with
supervenience.
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First, it suggests the idea of linear causation

between particular physical events or states in
the brain and particular mental events or states.
But this is based on a mistaken view of how the
mind arises from the brain. The conscious mental state of fear, for example, may be triggered by
a belief about an environmental stimulus. Fear
and belief are mental states generated by populations of neurons in many different brain regions.
These neurons are regulated by feedback loops
between the amygdala and thalamus on a lower
level, and between the prefrontal cortex and the
amygdala on a higher level. In addition, the phenomenological quality of the mental state depends partly on physical processes in the hippocampus, brain stem, hypothalamus, and limbic
system. Because so many neurons and brain regions are involved in generating and sustaining
mental states and events, it is implausible to
think that there can be a one-to-one correspondence between a particular physical event in the
brain and a particular mental event. Instead,
there is a stream of neural activity with diverse
relations to moments of conscious experience
(Gillett 1999, 288 ff.).
Second, like any other metaphysical theory,
supervenience locates the mind in the brain. Even
if it does not limit it to one brain region, it
ignores the interaction of the brain with the body
as well as with the environment in explaining the
nature of the mind.2 As Antonio Damasio (1994,
1999) and others (Clark 1997; Schechtman 1997)
have argued, the mind is a function of the interaction of the entire organism, not of the body alone
or the brain alone, with the environment. Damasio
says that, for the mental state of the self to occur:
numerous brain systems must be in full swing, as
must numerous body-proper systems. If you were to
cut all the nerves that bring brain signals to the body
proper, your body state would changes radically, and
so consequently would your mind. Were you to cut
only the signals from the body proper to the brain, your
mind would change too. Even partial blocking of
brainbody traffic, as happens in patients with spinal
cord injury, causes changes in mind state. (1994, 227).
A more promising theory consistent with the

distributed view of mind is emergentism. On this
theory, mental states emerge as higher-level prop-
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erties from lower-level physical properties in the

brain and body. There are two distinct types of
hierarchy that explain how mentality emerges
from the brain: nested and non-nested. In a nonnested hierarchy, although successive levels of
properties causally interact, each emerging level
is independent of the others. And once it emerges
at the top of the hierarchy, the mind is independent of the lower physical levels that generate it.
In what Feinberg (2001, Chapter 8, Eccles 1966)
calls a compositional or, nested, hierarchy, the
properties comprising the lower physical levels
are inextricably intertwined with, or nested within, the properties of the higher mental level.3
This theory best captures the medical model of
the mindbody relation. By holding that lowerlevel physical properties and higher-level mental
properties are interdependent, the nested view
avoids the problem of property dualism in the
non-nested view. It does not have to explain how
mental properties can be self-sustaining and can
interact with physical properties if they are only
contingently related to them.
Feinbergs position is similar to what John
Searle (1992, 1999) calls biological naturalism.
Consciousness is a biological phenomenon. It
does have subjective features, and unlike the neurons from which it arises, it is intentional, directed toward states of affairs external to the brain.
But it is a higher-level feature of the brain in the
same way that digestion is a higher-level feature
of the stomach, or liquidity is a higher-level feature of the system of molecules that constitutes
our blood. The mental and the physical are not
independent categories, but two interdependent
aspects of one biological system of a human
organism interacting with the environment.
A critical notion in the nested hierarchy model
of mind is constraint. Feinberg explains mental
constraint on the brain and body by analogy
with the human lung. At a higher level, the lung
displays emergent features not possessed by and
thus not reducible to the mitochondria in its
cells. If the lung did not breathe, the body would
not have oxygen, and if it did not have oxygen,
the mitochondria would not be able to carry on
cellular respiration. In this manner, the higherlevel property of breathing constrains the activi-
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ty of the mitochondria. When the system is considered as a whole, the mitochondria contribute
to the emergence of the lung. And the lung in
turn constrains the mitochondria. (Feinberg
2001, 1289)
Similarly, the higher-level properties of the
mind constrain the lower-level properties of the
brain and body. But this relation can be understood only in terms of the purpose the mind
serves for a human organism as a whole. In
evolutionary terms, the mind serves an adaptive
purpose by enhancing the survival of the organism by protecting it from external threats and
preventing various physiologic disorders. Strictly
speaking, the mind as such is not adaptive.4 Rather, mental states like beliefs and emotions are
adaptive when they enable the organism to discriminate between threatening and benign events
by processing sensory information from the environment accurately and efficiently. When they
accurately represent these events to the organism, the relevant mental states modulate physiologic systems in the body so that they are neither
understimulated nor overstimulated. By constraining or modulating bodily systems, the mind plays
a critical role in maintaining homeostasis of the
systems that constitute the organism. Consistent
with this role, the mind cannot be so inattentive
to environmental stimuli that it renders the brain
and body unable to sense and respond appropriately to real threats. At the same time, the mind
cannot be so overly attentive to external events
that beliefs misrepresent benign situations as
threats and emotions are out of proportion to
the problems at hand. In these instances, the
mind becomes maladaptive and can trigger pathologic processes in the brain and body.
The model of the mind as an emergent feature
of a nested hierarchy serving an adaptive purpose has several advantages over both supervenience and non-nested models. First, because it
specifies interdependence among different levels
and different regions of physical and mental organization, it provides a more accurate picture of
mindbrain interaction than the linear causation
in supervenience, which treats this interaction as
a one-to-one relation between particular physical events and particular mental events. Second,
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it assumes that the mind emerges from the interaction of the body and brain of the entire organism in interaction with the environment. Third,
as a teleological rather than causal model, it
offers a more helpful way of understanding how
the mind plays a role in preserving bodily homeostasis and maintaining health or generating
disease in human organisms. Fourth, by focusing
on purposive rather than causal processes, and
thus on evolutionary biology rather than physics, the nested hierarchy model sidesteps worries
about physical events causally determining mental events in accord with psychophysical laws. It
also sidesteps worries about how the mind in a
non-nested hierarchy could interact with physical properties from which it emerges but of which
it presumably becomes independent. Given that
mind and brain are two aspects of one biological
system, we can account for interaction between
them. But we can only do this provided that any
causal explanation of the interaction between
physical and mental events is subsumed under a
more general teleological explanation specifying
their role in terms of the organism as a whole in
interaction with the environment.
MindBrain Interaction and

the Etiology of Depression
Let us focus on psychological and physiologic
stress responses to environmental stimuli as causes
of chronic depression. Strictly speaking, mood
disorders like chronic depression and anxiety
disorders are differentiated in psychiatry. But
because both are emotional disorders tied to excessive fear, involve a stress response, and implicate many of the same brain structures, pathways, and processes, I will speak of anxiety as
one of the emotions that can trigger depression.
PTSD should be treated separately. Unlike most
cases of depression, which involve a chronic stress
response, PTSD can result from a single severe
traumatic experience. The severity of the trauma
can cause different physiologic reactions from
those implicated in depression.
A psychological stress response can occur in
the form of fear or anxiety activated by trauma
or a belief about a real or imagined threat from
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the environment. This can initiate a physiologic

stress response by first triggering the amygdala
in the limbic system, which controls emotions.
The amygdala activates one subsystem of the
bodys autonomic nervous system, the sympathetic nervous system. This subsystem prepares
the body for action to protect it against external
threats, while the other subsystem, the parasympathetic nervous system, counteracts this response
once the perceived threat has passed. In this
balanced way, these two subsystems contribute
to bodily homeostasis. The amygdala activates
the hypothalamus, which controls the autonomic nervous system and prepares the body for a
sustained stress response. The hypothalamus does
this by producing corticotropin-releasing hormone (CRH), which then stimulates the pituitary
gland to secrete adrenocorticotropin hormone
(ACTH), which in turn stimulates the adrenal
glands to secrete cortisol. Now the hypothalamicpituitaryadrenal (HPA) axis is in a full physiologic stress response: the fight-or-flight response (Conlan 1999, McEwen 1999; Sternberg
1999, 2000; LeDoux 1996, 1999).
Under ordinary circumstances, when a real
threat to the organism has ended, the bodys
sensory processing system relays this information from beliefs and conscious emotions to the
parasympathetic nervous system, which shuts
down the production of the stress hormones.
Cortisol acts as a complex feedback loop regulating production of CRH. But when the perception of real or imagined danger is constant, and
there is a psychological stress response in the
form of chronic fear or anxiety, this signals the
body, specifically the adrenal glands, to continue
producing cortisol. The HPA axis also functions
abnormally in people with PTSD, although for
some unknown reason they tend to exhibit unusually low cortisol levels. It may be due to the
strength of the original unconditioned stimulus,
such as the acute stress of a military battle or an
automobile accident (Hobson and Leonard 2001,
1445). Perhaps the less severe stress of chronic
fear and anxiety has the opposite effect on cortisol. In any case, with our mental states telling the
sympathetic nervous system and its auxiliary
structures that there is a persistent threat to the
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organism, the body is put on the constant defensive. As a consequence, the feedback loop between cortisol and CRH is disrupted. The mind
fails to constrain the central nervous, endocrine,
and immune systems, disrupting homeostasis and
thereby working against the adaptive purpose
for which it is designed. An adaptive mechanism
turns into a maladaptive response. The psychological and physiologic stress responses persist
beyond the point where they are useful in enhancing the survival of the organism.
Overproduction of cortisol adversely affects
levels of the neurotransmitters noradrenaline and
serotonin by disrupting the presynaptic reuptake
of them. This appears to be the major physiologic cause of chronic depression. In addition, overproduction of cortisol can prompt the immune
system to release cytokines and immune molecules such as interleukin I and II, which can also
adversely affect the relevant neurotransmitters
and contribute to or exacerbate depression. Although the underlying mechanisms are still unclear, research suggests that impaired feedback
regulation of the HPA axis found in many depressed patients is positively correlated with immune activation of cytokines (Krionfel and
Remick 2000; Ader et al., 2001). Chronic psychological and physiologic stress responses can
trigger the release of cytokines from leukocytes
in the blood circulation, which can penetrate the
bloodbrain barrier and combine with cytokine
receptors in the hypothalamus and pituitary. By
altering normal hormone secretion in these two
structures, cytokines can disrupt modulation of
noradrenaline and serotonin, leading to depression. The links among nervous, endocrine, and
immune systems may help to explain why depression is often correlated with suppressed immune function and increased susceptibility to
infectious diseases in patients who have the disorder. Too much cortisol suppresses the immune
system and increases susceptibility to infection.
Too little cortisol overstimulates the immune system and increases susceptibility to autoimmune
diseases like rheumatoid arthritis. This illustrates
how an imbalance in or between bodily systems
involved in the stress response can disrupt homeostasis and lead to disease.
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All of these points suggest that the mind is one

of four interrelated systems in human organisms
designed to preserve homeostasis. The other three
are the nervous, endocrine, and immune systems.
As an emergent feature of lower-level physiologic systems in a human organism, the mind is
neither independent of nor reducible to, but rather
interdependent with these three other systems. In
its role as a highly refined sensory processor of
information from the external world, the mind is
naturally designed to constrain these systems so
that they are not over- or understimulated. In
this way, the mind contributes to the preservation of homeostasis and the survival of the organism by protecting it from various disorders.
In depression, overstimulated cognitive and affective mental states in the psychological stress
response to external events can initiate a prolonged physiologic stress response. This in turn
can manifest in the negative moods that are symptomatic of the disorder. The pathway goes from
mind, to brain and body, then back to mind. It is
important to emphasize that the mind cannot be
reduced to the brain and body in accounting for
this sequence of events; the intentional and qualitative aspects of beliefs and emotions cannot be
explained in terms of physical processes in the
brain and body alone. In particular, the events
toward which these mental states are directed, as
well as the phenomenological quality of these
states, are critical to the initiation of the stress
response.
The fourfold psychoneuroimmunologic model that I have described has important medical
and ethical implications for antidepressant therapy. It points to the combination of biomedicine
and psychotherapy as the most effective means
of treating depression. It also suggests that psychiatrists should treat their depressed patients
with different varieties of these interventions,
depending on the extent to which the one psychological and the three physiologic systems figure in the way that depression affects each patient.
An Adaptive Response?
There are fewer stressors on humans from the
natural environment now than there were centuries ago, largely because we are better able to
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control its effects on us. Arguably, there are now

more stressors from the social environment. Given a higher standard of living than what our
remote ancestors enjoyed, there are greater social expectations to achieve more in life. Correspondingly, there is increased pressure to set higher goals for ourselves. The gap between these
expectations and the failure to meet them may
lead to the perception of expectations as stressors and to negative beliefs about ones abilities,
both of which can contribute to depression. Depression thus can be characterized as an adaptive
disorder. The problem is not with adapting to the
natural environment, but instead to the social
environment.
Some psychiatrists consider certain forms of
depression as an evolutionary tool for survival
that may have developed as a useful human response to situations in which a desired goal is
unattainable (Nesse 1999, 2000; Stevens and Price
2000). In some cases, depression as a limiting
condition may help one to disengage from projects
in which one puts considerable effort but through
which one achieves nothing. In other cases, it
may protect one from taking on or abandoning
projects too impulsively, making one deliberate
more carefully before acting. Understood in this
way, depression is a defense mechanism that can
protect us from harming ourselves and others
and thereby enhancing our ability to adapt to
and survive in the social environment. If this is
correct, then, contrary to what I have claimed,
depression is not an adaptive disorder but an
ordered, adaptive, response to social circumstances.
Those who endorse this view see depression as
analogous to certain physical responses in the
body that should be described as defense mechanisms protecting the organism, rather than as
disorders. Coughing is not a disorder, but the
bodys way of ridding itself of bacteria in the
lungs and bronchial tubes. Diarrhea and vomiting serve as defenses in eliminating potential
pathogens from the stomach and intestine. Pain
protects the body from injury by acting as a
mechanism alerting it to objects that can damage
it. This is borne out in the limb deformities of
people with leprosy (Hansens disease), where
peripheral neuropathy caused by the bacterium
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Mycobacterium leprae destroys nerve endings that

ordinarily enable us to feel pain in our limbs.
There are important disanalogies between these
conditions and depression, however. Depression
involves both psychological and physiologic responses, not just a physiologic one. The process
of perceiving and internalizing social expectations is much more complicated than coughing
or vomiting. Moreover, unlike the acute physiologic responses of coughing and vomiting, which
end once the threat to the organism has been
removed, the stress that results in depression is a
chronic response setting off a cascade of events
that disrupt bodily homeostasis. Once the process begins, it is difficult to reverse it and the
damage that has already been done. As I will
explain in the next section, this is because depression and other mental disorders often involve emotional memories embedded in an overactive amygdala, which is difficult to modify
because it is such a hard-wired feature of the
human brain. Although it may be plausible to
think of depression as a limiting condition on
goals that are unattainable, there is no single
event or set of events leading to the condition
that can alert us to when that limit has been
reached. Many people go beyond the limit and
only realize it once they have the full-blown
symptoms of the condition.
In the light of these considerations, we should
uphold the claim that depression is an adaptive
disorder consisting in an individuals inability to
adjust to the social environment. It is not a defense mechanism serving an adaptive purpose for
the survival of the organism. Ordinarily, the mind
does serve such a purpose. But when the mind is
disordered, as in chronic depression, it works
against this purpose. Depression results when an
adaptive mechanism turns into a maladaptive
response. The key to treating depression may be
in adjusting ones perception of and relation to
the environment so that ones goals and expectations from others are set within reasonable limits.
Treatment Modalities:
Biomedicine and Psychotherapy
Antidepressant therapy should be tailored to
fit the relative causal roles that the four systems I
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have discussed play in depression. For example,

if the immune system and cytokines have a major
role in the disorder, then tricyclic antidepressants
or monoamine oxidase inhibitors (MAOIs) may
be indicated as appropriate drug therapy. This is
because these classes of drugs have been shown
to modulate immune response and the release of
cytokines more effectively than other classes. Still,
this point must be weighed against the fact that
the drugs can have adverse side effects. In particular, people who take MAOIs must adhere to a
number of dietary restrictions to prevent potentially life-threatening hypertension from the drugs.
On the other hand, the newer class of selective
serotonin reuptake inhibitors (SSRIs) can boost
serotonin levels and moderate mood to a normal
level or even elevate it. SSRIs are important because they allow the prefrontal lobes to have
more control over the amygdala. This is the region of the brain where the negative conscious
emotions and unconscious emotional memories
that figure prominently in the cascade of events
leading to depression are generated or embedded. These drugs can enhance the effect of cognitive psychotherapy, for example, because the beliefs that are altered or moderated to break a
chronic stress response are generated from the
prefrontal lobes and relay sensory information
back to them (Hobson and Leonard 2001, 156ff.).
As the probable role of the immune and endocrine systems in depression indicates, though,
proper treatment of the disorder requires an understanding of more than the brain or central
nervous system. Restoring normal levels of serotonin and noradrenaline requires ensuring the
proper balance of the endocrine and immune
systems that also modulate these neurotransmitters. In PTSD, for example, overproduction of
adrenaline may serve to embed the emotional
memory of a traumatic event in the amygdala.
Biomedicine is limited in its therapeutic value
in treating chronic depression, however. It is a
necessary but not a sufficient intervention. Psychiatric drugs like SSRIs only treat the symptoms
of mental disorders; they do not treat the underlying causes. Furthermore, psychiatric drugs are
not always specific enough to precisely target the
critical neuronal receptors in the brain that regu-
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late neurotransmitter levels in each patient. Owing to this lack of precision, they do not always
effectively stabilize mood in all patients, and
they may cause debilitating side effects. Each
persons brain has a great degree of plasticity and
develops uniquely in response to the social and
natural environment as the person develops over
the course of his or her life. Our brains are
systems that are in dynamic interaction with the
environment and as such facilitate our relatedness to it (Edelman 1992; Gillett 1999). Also,
antidepressants can positively modulate neurotransmitters and the qualitative aspects of beliefs and emotions and thereby influence how we
perceive their representational content. But antidepressants cannot completely determine this content. The nature of the states of affairs toward
which our mental states are directed is independent of our minds and brains. Because this content can elicit a psychological stress response in
our beliefs and emotions, there are causes of
depression that are not located in the brain and
body.
Given the role that beliefs and emotions play
in the sequence of events leading to depression,
biomedicine is insufficient because therapeutic
intervention must also take place at the mental
level where the sequence is initiated. Behavior
therapy, for example, can help to block stimuli
that prompt a conditioned response involving an
unconscious memory that can generate conscious
fear or anxiety out of proportion to the problem
at hand (McCullough 2000). In constructive
avoidance, patients are taught to develop appropriate responses to stimuli by working through
harmless to gradually more difficult stimuli until
the stimuli become manageable. Ideally, the conditioned signals that prompt attacks will be eliminated. This is difficult to achieve in practice,
though, because it is extremely difficult to rewire the amygdala, where unconscious emotional memory is entrenched. Emotional memory is distinct from conscious memory of emotion,
which is controlled by the hippocampus. Because
the amygdala is hard-wired as a defense mechanism that responds automatically to stimuli as
potential threats to the organism, psychotherapy
that utilizes more recently evolved (soft-wired)
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brain regions such as the cerebral cortex is likely

to have only limited success. It is much more
difficult to work backward and alter the pathway between the cortex and the amygdala because of the more primitive role that the thalamusamygdala pathway plays in sensory
processing. Once a fear- or anxiety-inducing emotional memory becomes embedded in the amygdala, it cannot be easily dislodged (LeDoux 1996).
This problem is even more acute in PTSD. Yet, it
is now believed that administering beta-blockers
immediately after a traumatic incident to block
the excessive release of adrenaline may prevent
the emotional memory from becoming locked
into this region of the brain.
Cognitive therapy operates on the level of the
subjects beliefs about him- or herself or about
events he experiences in the social and natural
environment. The therapy aims to enable the
subject to become more consciously aware of his
or her beliefs and thereby achieve a better match
between the qualitative features of the beliefs
and their actual contents. This can give one more
control over events or situations that otherwise
would be perceived as stressors or threats. If
ones beliefs are such that an event is not perceived as a threat, then the cerebral cortex sustaining the belief will not relay the information
to the thalamusamygdala pathway in threatening terms. This can prevent a psychological and
physiologic stress response that would be out of
proportion to the real nature of the event.
Yet the same problem that plagues behavior
therapy plagues cognitive therapy as well. In
depression and anxiety disorders, the force of the
amygdala outweighs the force of the cerebral
cortex. Unconscious emotions are more recalcitrant than conscious beliefs because, in evolutionary terms, the amygdala and the emotions it
sustains (fear, anxiety) are more crucial to the
survival of the organism than the cerebral cortex
that sustains beliefs. Moreover, our minds are
unconscious to a much greater extent than they
are conscious; most of our emotions occur outside of our conscious awareness. So, developing
conscious control over unconscious emotions is
no easy task. The role of transference in a neurodynamic approach might be one way of reconfig-
9.3glannon01
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251
uring the unconscious. But it is unclear how this

could modify the most hard-wired regions of the
brain. Although the precise mechanism is still
not completely understood, research suggests that
trauma, grief, and other forms of prolonged stress
can prompt depression by causing the amygdala
to overbalance the prefrontal lobes and consequently lower levels of the critical neurotransmitters. Nevertheless, the prefrontal lobes of the
cerebral cortex can serve as a counterweight to
the amygdala and its role in depression and anxiety because it is through the former that the
latter receives sensory information.
Beliefs are not just generated and sustained by
the prefrontal lobes; beliefs also relay sensory
information, which is then relayed to the amygdala. Recall that there are two levels of sensory
information processing: from the thalamus to
the amygdala at a lower level, and from the
cortex to the amygdala at a higher level. It is at
the higher level that beliefs are critical. If the
content of ones beliefs is perceived in a positive
or benign way, then it is less likely that the cortex
sustaining these beliefs will cause the amygdala
to interpret their content as a threat to the organism. By focusing on positive intentional and qualitative aspects of a patients beliefs, cognitive
therapy may help to restore the balance between
the two regions of the brain at issue and the
cognitive and affective states that depend on them.
But cognitive therapy is not likely to accomplish this on its own. Indeed, research points to
the efficacy of combining pharmacologic use of
antidepressants with psychotherapy as complementary treatment modalities (Keller et al. 2000).
It is worth noting, however, that although this
combination treatment makes the most sense for
depression, it may not be generalized to all psychiatric conditions. It is not proven for schizophrenia and bipolar disorder, for which drugs
such as clozapine and lithium are much more
effective. For depression, SSRIs can increase the
activity of the prefrontal lobes in the cerebral
cortex, which in turn can enhance the ability of
the cortex to modulate the functions of the
amygdala. At the mental level, antidepressants
can enable conscious beliefs to more effectively
control unconscious emotional memories that
6/24/03, 2:54 PM
otherwise might prompt a conditioned fear or

anxiety response. The functional relation between
the cortex and beliefs, on the one hand, and the
amygdala and emotions, on the other, is a good
example of mindbody interaction in preserving
homeostasis.
Earlier, I said that psychiatrists should treat
depression as a physiologic disorder involving
not only the brain and central nervous system,
but endocrine and immune systems as well. Antidepressant medication should be tailored to fit
the role that each of these systems plays in the
disorder, depending on the extent to which CRH,
ACTH, cortisol, and cytokines are implicated.
As a mental disorder, psychiatrists also have an
obligation to address the qualitative and intentional aspects of the depressed patients psychology. These include the patients feeling of helplessness, dread, or fear, and the states of affairs
toward which these emotions and associated beliefs are directed. This requires helping the patient to reestablish a more salutary relationship
with the environment, enabling him or her to
normalize his or her perception of it and eliminating or neutralizing any real or potential stressors. Psychiatrists also have an obligation to explore the history of a patients beliefs and emotions
to gain a better understanding of the role these
mental states play in the etiology of depression.
It is these mental states, and the environmental
stressors that are their contents, that often trigger the cascade of events resulting in brain dysfunction and mood disturbance. This means allowing the patient to express his or her unique
first-person experience of past and present events,
and listening to this narrative and interpreting it
in terms of the patients life as a whole (McHugh
and Slavney 1986). Attention to these features of
the patients psychology can yield clues into how
the pathologic sequence of events began. Moreover, it can point toward ways of reestablishing
the balance between the patients cognitive and
affective mental states and the balance between
the brain and body that ultimately will restore
the patient to mental and physical health.
To be sure, psychotherapy is labor intensive,
time consuming, and expensive and therefore
not likely to be looked upon favorably by any
9.3glannon01
252
health care system. Pharmacologic intervention

is comparatively much more cost efficient; but
by itself it is not more cost effective. Failure to
combine biomedicine with psychotherapy can be
quite costly, especially when one considers the
social and economic consequences of the homelessness, crime, and suicide that all too often
result from inadequately treated mental illness.
A neurodynamic approach, combining biomedicine and psychotherapy, may be the most medically and economically effective long-term course
of treatment (Hobson and Leonard 2001, Chapter 12). Accordingly, psychiatrists may have a
medical and ethical obligation to adopt this approach in treating their depressed patients, and
health care systems may have an ethical obligation to support it.
Conclusion
Mind and body (and brain) are not independent substances. The mind is generated and sustained by the body and brain and could not exist
without them. Nor is the mind reducible to them.
For the qualitative and intentional aspects of
mental states cannot be explained entirely in
terms of physical processes in the body and brain.
Mind and body are interdependent higher- and
lower-level features of a nested hierarchy in a
biological system that is a human organism. Mind
and body interact as part of an adaptive purpose,
which is to maintain homeostasis of bodily systems and thereby enhance the survival of the
organism by protecting it from disease.
With the help of the cerebral cortex that sustains it, the minds role is to process sensory
information in a more refined way than the comparatively primitive processing of the thalamus
and amygdala in the brain. By distinguishing
between threatening and benign events and relaying this information to the relevant bodily
systems, the mind constrains these systems and
prevents the body from undergoing a chronic
stress response that can lead to physical and
mental disorders. Chronic depression is a psychoneuroimmunologic disorder that results when
the mind fails in its constraining role. Negative
beliefs or emotions relay information to the nervous, endocrine, and immune systems in such a
6/24/03, 2:54 PM
way as to trigger a stress response with pathologic consequences for these systems and the organism as a whole. Against the evolutionary hypothesis that depression is a defense mechanism
preventing us from pursuing unattainable goals,
I have argued that it is an adaptive disorder.
Mental states that are designed to serve as an
adaptive mechanism become part of a maladaptive response to the social environment.
We do not know, and perhaps never will know,
precisely how the mind arises from the brain. Yet
by explaining mindbody interaction in terms of
a medical rather than metaphysical model,
progress can be made toward achieving a better
understanding the psychological and physiologic
mechanisms of depression and other mental and
physical disorders. Psychiatrists treating patients
with this disorder must try to enable them to
reestablish a normal connection between mind
and environment. Ultimately, the aim of all psychiatric interventions is to restore the balance
between the mind and the body so that they
interact in accord with the adaptive purpose for
which they are naturally designed in preserving
the health and life of human organisms.
Acknowledgment
I am grateful to George Graham and two
anonymous reviewers for this journal for very
helpful comments on earlier versions of this paper.
Notes
1. Damasio (1994, 1999) and LeDoux (1996, 1999)
distinguish between feelings and emotions. Feelings are
the conscious manifestations of emotions, which are
largely unconscious. I ignore this complication for the
issue at hand and simply distinguish between conscious and unconscious emotions.
2. Most philosophers in the analytic tradition defend the localized view of mind, especially Dennett
(1991) and Kim (1998), as do most cognitive scientists.
3. According to the non-nested view, once higherlevel mental properties emerge at the top of the hierarchy, they become independent of lower-level physical
properties. This is a form of property dualism. It is
defended by, among others, Sperry (1966) and Scott
(1995).
4. There has been much discussion of whether the
mind is or is not adaptive, as well as of the different
9.3glannon01
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253
senses in which it might be adaptive. For a good critical

discussion of this idea, see Buller and Hardcastle (2000).
References
Ader, R., Felten, D., Cohen, N. 2001. Psychoneuroimmunology, 3rd ed, 2 vols. San Diego: Academic
Press.
Andreasen, N. 1997. Linking mind and brain in the
study of mental illnesses: A project for scientific
psychopathology. Science 275, 158693.
Buller, T., and Hardcastle, V. G. 2000. Evolutionary
psychology, meet developmental neurobiology:
Against promiscuous modularity. Brain and Mind
1, 30725.
Churchland, P. 1995. The engine of reason: The seat
of the soul. Cambridge, Mass.: MIT Press.
Churchland, P. S. 1989. Neurophilosophy: Toward a
unified science of the mind/brain. Cambridge,
Mass.: MIT Press.
Clark, A. 1997. Being there: Putting brain, body, and
world together again. Cambridge, Mass.: MIT Press.
Conlan, R., ed. 1999. States of mind. New York:
Wiley.
Damasio, A. 1994. Descartes error: Reason, emotion, and the human brain. New York: Grosset/
Putnam.
Damasio, A. 1999. The feeling of what happens: Body
and emotion in the making of consciousness. New
York: Harcourt Brace.
Dennett, D. 1991. Consciousness explained. Boston:
Little Brown.
Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). 1994. Washington, D.C.:
American Psychiatric Association.
Eccles, J. C. 1966. Brain and conscious experience.
New York: Springer-Verlag.
Edelman, G. 1992. Bright air, brilliant fire: On the
matter of the mind. New York: Basic Books.
Feinberg, T. 2001. Altered egos: How the brain creates the self. New York: Oxford University Press.
Gillett, G. 1999. The mind and its discontents: An
essay in discursive psychiatry. Oxford: Oxford University Press.
Gillett, G. 1999. Philosophy, neuroscience, and the
human soul. Unpublished.
Hobson, J. A., and Leonard, J. 2001. Out of its mind:
Psychiatry in crisis. Cambridge, Mass.: Prometheus.
Keller, M., McCullough, J. P., Klein, D. N., Arnow, B.,
Dunner, D. L., Gelenberg, A., Markowitz, J. C.,
Nemeroff, C. B., Russell, J. M., Thase, M. E.,
Trivedi, M. H., and Zajecka, J. 2000. A comparison of nefazodone, the cognitive behavioral analysis system of psychotherapy, and their combination
for the treatment of chronic depression. New England Journal of Medicine 342:146270.
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Kim, J. 1998. Mind in a physical world: An essay on

the mindbody problem and mental causation.
Cambridge, Mass.: MIT Press.
Krionfel, Z., and Remick, D. 2000. Cytokines and the
brain: Implications for clinical psychiatry. American Journal of Psychiatry 157:68394.
LeDoux, J. 1996. The emotional brain. New York:
Simon & Schuster.
LeDoux, J. 1999. The power of emotions. In States of
Mind (pp. 12349), ed. R. Conlan. New York:
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Nesse, R. 1999. What Darwinian medicine offers psychiatry. In Evolutionary medicine (pp. 35174),
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New York: Oxford University Press.
Nesse, R. 2000. Is depression an adaptation? Archives
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McCullough, J. P. 2000. Treatment for chronic depression: Cognitive behavioral Analysis systems of
psychotherapy. New York: Guilford.
McEwen, B. 1999. Stress and the brain. In R. Conlan,
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Schechtman, M. 1997. The brain/body problem. Philosophical Psychology 10:14963.

Scott, A. 1995. Stairway to the mind: The controversial new science of consciousness. New York:
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Sperry, R. 1966. Brain Bisection and the Mechanisms
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Sternberg, E. 2000. The balance within: The science
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Stevens, J., and Price, J. 2000. Evolutionary psychiatry, 2nd ed. London: Routledge.
Travathan, W. R., Smith, E., and McKenna J. 1999.
Evolutionary medicine. New York: Oxford University Press.
6/24/03, 2:54 PM
MARTIN / THE EVOLUTION OF DEPRESSION
255
On the Evolution of
Depression
Mike W. Martin
KEYWORDS: Depression, morality, mental disorders, psychobiology, evolutionary psychiatry.
DEPRESSION AS A MINDBODY PROBLEM,

Walter Glannon outlines a psychosocial-physiological explanation of depression as a psychological response to chronic stresstoday, especially social stressin which cortisol imbalances
disrupt neurotransmitters. Accordingly, treatment
for depression should combine psychopharmacology and psychotherapya valuable reminder
in light of the current restrictions on funding for
health care (Hobson and Leonard 2001). My
comments focus, however, on Glannons objections to evolutionary theorists who explain our
capacity for depression as adaptive to the natural
and social environment. His objections are implausible because he fails to distinguish depression as a mood and a disorder.
N
What Is Depression?
Explaining the psychology, sociology, physiology, and evolution of depression presupposes
knowing what depression is and hence what is
being explained. As a blunt but important distinction, let us contrast depression as a mood
and as a mood disorder.
As a mood, depression is a state of low spirits,
typically involving painful and low affect (of a
kind needing further specification). Not all negative low moods are depressions. It is notoriously
difficult to distinguish depression from grief, sadness, gloom, and a host of additional ways to feel
downespecially because today many people use
Im depressed as a blanket expression for virtually any low mood. For the purposes of this
paper, it is not necessary to attempt a full-blown
analysis of depressed moods (and emotions). I
would emphasize, however, that depressed moods
involve values. They involve negative evaluations
of ourselves, major events in our lives, life in its
entirety, or the values that have been guiding us.
Typically, to be depressed is to experience such
things as feelings of worthlessness, dejection about
failures, despair and hopelessness, and loss of
caring and commitment. Thus, we might be sad
or grieving but not depressed because we retain a
solid grip on what is valuable and worthwhile. In
any case, there should be no general presumption that depressed moods are all bad or undesirable. Instead, we should be prepared to appreciate the importance of depressed moods in
connection with questions of value, identity, and
even moral insight (Martin 2000). Depressed persons are not necessarily sick.
In contrast, depression as a mood disorder is,
by definition, pathologic. Moreover, usually it is
not a depressed mood, although it involves depressed moods. On the one hand, depression as a
disorder is defined as pathologic, a notion that is
itself understood in terms of valuesthe values
of health and, indirectly, moral values that define
what is culturally acceptable. Thus, even severe
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6/16/03, 10:51 AM
grief can be nonpathologic, even though it involves depressed moods, when it is within the
range of culturally-sanctioned responses (APA
2000, xxxi). On the other hand, only sometimes
is depression a single pathologic mood, as in
major depressive episodes that can strike with a
terrifying and suicidal severity (APA 2000, 375).
Usually, however, the pathology is not a single
depressed mood, but instead a longer-term state
involving recurring depressed moods and additional features, such as poor concentration, insomnia, poor appetite or overeating, and so on.
For some purposes, such as research funding and
billing insurance companies and government
health providers, these pathologies can be equated with what is currently in the DSM. Yet, there
are many additional states of suboptimal health,
in which the DSM criteria are only partly met.
What does Glannon mean by depression? He
does not define it, but he makes it perfectly clear
that he intends depression as a disorder. Or rather, it is a set of mental disorders, including the
depressive disorders of major depressive disorder, dysthymic disorder, depressive disorder
not otherwise specified, and a variety of bipolar
disorders and some anxiety disorders. Glannon
sometimes indicates his primary topic is severe
depression, which of course is not a DSM category (nor always a mark of pathology). For the
most part, however, he says his topic is chronic
depression, which might suggest dysthymia, a
chronically depressed mood for most of the day,
for more days than not, as indicated either by
subjective account or observation by others, for
at least 2 years (APA 2000, 380). I suspect,
however, that Glannon intends something broader
than dysthymia, perhaps including most pathologic states that significantly involve depression that
is severe and recurrent. Such a broader conception
would allow him to bypass the vagaries of the
DSM classifications, which fluctuate as its editions
change. Nevertheless, he seems to target disorders that involve primarily depressed moods, rather than bipolar disorders, and he explicitly sets
aside posttraumatic stress disorder. In any case,
because parts of his paper are concerned with the
physiology of depression, it might be helpful to
more fully specify the disorders being explained.
9.3martin
256
My main concern, however, lies elsewhere. In

a brief section titled An Adaptive Response?
Glannon calls for a sweeping rejection of explanations developed by evolutionary psychiatrists and
psychobiologists to explain why we have evolved
as creatures who suffer depression (and lots of it).
According to these evolution theorists, depression serves various adaptive purposes. Glannon
argues that these theorists are mistaken because
depression is a set of maladaptive disorders: depression is an adaptive disorder consisting in an
individuals inability to adjust to the social environment. It is not a defense mechanism serving
an adaptive purpose for the survival of the organism. In making this claim, he assumes that
the evolution theorists mean what he means by
depressionnamely, mental disorders. Do they?
Maladaptive Disorders Versus

Adaptive Defenses
Are the evolutionary theorists trying to explain (a) the evolutionary purposes of depressed
moods (both healthy and unhealthy ones) or (b)
the evolutionary purposes of depression as a mood
disorder only? Glannon assumes (b), but (a) is
closer to the truth. I say closer to the truth
because evolutionary psychiatrists also sometimes
fail to distinguish (a) and (b). Even so, Glannon
fails to engage the evolutionary theorists on their
own terms, and sometimes he seems to attack a
straw man.
As an example of someone who clearly intends (a) rather than (b), consider Randolph M.
Neeses Is depression an adaptation? (2000),
an essay that Glannon explicitly targets. After
noting the unclarity about what depression means,
Neese stipulates that for his purposes depression will refer to severe states of negative affect
that are often but not necessarily pathologic, and
low mood will refer to states in the common
range of normal experience (Nesse 2000, 15).
He notes the intuitive starting point that much
low mood and depression are normal and become pathologic only in some forms and under
some conditions. Then he seeks an explanation
of both depression and low mood, concluding
that although many depressions are pathologic
(maladaptive), many other depressions and low
6/16/03, 10:51 AM
moods are adaptive in helping us deal with defeat and danger.

It seems likely that low mood and related
negative affects were shaped to help organisms
cope with unpropitious situations. Some negative and passive aspects of depression may be
useful because they inhibit dangerous or wasteful actions in situations characterized by committed pursuit of an unreachable goal, temptations to challenge authority, insufficient internal
reserves to allow action without damage, or lack
of a viable life strategy (Neese 2000, 18).
In Evolutionary Psychiatry, another work targeted by Glannon, Anthony Stevens and John
Price (2000) give credence to attachment theory
explanations of depression, as well as to Neeses
escape-and-avoidance theory that focuses on competition and rank conflicts. Attachment theory
emphasizes that love and other deep bonds of
affection involve (as one mark of depth) grief,
sadness, guilt, shame, and other forms of distress
when the love is lost or threatened. These emotions can easily degrade into pathologic states.
Stevens and Price are less careful than Neese in
defining depression, but it is clear they are explaining a wider range of low-mood states and
then subsuming pathology as a maladaptive distortion. Depressive disorders, they tell us, are
best understood as chronic exaggerations of
innate behavioural potentials with which all human beings are equipped by virtue of their humanity (2000, 48).
Glannon is not accurate, then, when he says,
tout court, that evolutionary theorists portray
and explain pathologic depression as adaptive.
The theorists are not saying there is pathology in
every depressed-mood withdrawal from competition and response to the loss of love. Instead,
the theorists are explaining how humans came to
possess general capacities for depressed moods
that enter into a continuum from adaptive to
maladaptive. These general types of explanations
have great interest and promise, in my view, and
Glannon provides no reason to reject them. Stated more positively, Glannons psychophysiologic
explanation of depression as a disorder is compatible with the work of the evolutionary theorists.
9.3martin
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257
To confuse (or clarify?) matters further, let me

suggest that evolutionary psychiatrists often interweave two different types of explanation of
mood disorders, what I will call adaptive-sickness explanations and malfunctioning-defense
explanations. Adaptive-sickness explanations
explain why mood disorders sometimes serve
purposes beneficial to individuals and groups.
These explanations seem paradoxical, because
by definition disorders are maladaptive or dysfunctional. In fact, the paradox is superficial. A
disorder can be maladaptive in some ways (indicated in its defining criteria) and adaptive in
other ways (given serendipitous circumstances).
It is commonplace, but interesting, that maladies
of many kinds can have good side effects (Sandblom 1995). For example, the maladies that take
away a writers ability to walk might provoke the
writer into greater commitment and concentration that result in an explosion of creativity (Price
1995). Similarly, it is amply documented that
mood disorders sometimes play creative roles in
the lives of artists (e.g., Lord Byron), leaders
(e.g., Abraham Lincoln), and others (Jamison
1993).
Malfunctioning-defense explanations seek to
explain a broader category of moods (or other
mental states) as frequently adaptive psychological defenses against stress and anxiety, and then
they portray mood disorders as breakdowns or
distortions of those defenses. That is, they do not
portray pathologies as adaptive; on the contrary,
the disorders are maladaptive perversions of processes and states that normally functions adaptively. Glannon, too, provides explanations of
this sort. (In doing so, I might add, he distinguishes psychological defense mechanisms, which
he says help us to avoid harm and social realities,
and disorders. Yet, defense mechanisms, the idea
introduced by Freud and refined by neo-Freudians, can serve healthy or unhealthy purposes.)
One Cheer for Depression

Clarity about definitions and distinctions, I
have suggested, is essential in gaining clarity about
what is being explained and assessed in evolutionary psychiatry and psychobiology. It is also
important in connection with therapy and self-
6/16/03, 10:51 AM
understanding, in determining what is unhealthy

or not, and in understanding the continuum between health, suboptimal health, and full-blown
disorders. Indeed, our choice of terminology already reflects our attitudes. If we think of negative low moods as inherently undesirable then
we will tend to use the word depression to connote sickness. If we discern value in many negative low moods we will be more likely to use the
word depression to refer to a broad range of
moods, most of which are normal and some of
which are pathologic (Neese 2000, 15).
Furthermore, if we view all depressed moods
as bad, we will have to usurp some other term to
connote the wider range of healthy emotions.
For example, Lewis Wolpert (1999) stipulates
that (all) depression is pathologic and then uses
sadness for wider range of emotions: depression
is malignant sadness. For reasons I gave earlier, I
think we should keep the broader sense of depression, and not equate depressed moods with
sadness. No doubt that reflects both my attitudes
and my idiolect.
Historically, attitudes toward depression (melancholy, acedia, etc.) have varied greatly (Radden 2000). At one extreme, much everyday depression is defended and even celebrated, a view
associated with Romanticism. (I still remember
that in an undergraduate course on English Romanticism I was graded down for failing to appreciate how much the Romantics value states
that today we pathologize.) Some philosophers
continue that positive emphasis on the desirable
aspects of depression as part of a value-guided
life (Solomon 1976). At the other extreme are
the pathologizers, not just some Prozac-profligate psychiatrists but also many up-beat Americans who require steady and ever-increasing states
of augmented cheerfulness to get through the
week. In between are a variety of nuanced attitudes, including Susanna Kaysens (2001) aptly
expressed realism in giving one cheer for melancholy as unpleasant but often useful.
Evolutionary explanations of depression blur
over most of the nuanced roles of depression in
individual lives and cultures. Their broad-brushed
explanations focus on only one value, however
important: survival. Evolutionary theory is tele-
9.3martin
258
scopic: it observes big and complicated terrain from

a great distance. In contrast, physiology is microscopic: it sees big and complicated terrain from
close up. Telescopes and microscopes reveal much,
but they also neglect much that is important in
appreciating the nuances of the value-permeated
world of human beings. Worse, they carry the
danger of reducing complex value dimensions of
human life to something simplera danger to
which sociobiology fell prey (Midgley 1995).
Glannons interest is mental health, but even
our conceptions of mental health are immersed
in a broader set of values than survivalvalues
about morality and meaningful life. Furthermore,
many psychologists have come to appreciate the
need for focusing not only on disorders and
threats to survival, but also on positive conceptions of health as well-being beyond the mere
absence of disease (Snyder and Lopez 2002). I
suspect that psychologists current explorations
in positive health will yield new insights into the
positive contributions of depressed moods to
meaningful life. In any case, depression as a mood
raises important questions about moral values at
several junctures: the value judgments internal to
the mood (e.g., self- or world-denigration); the
values under assault by the mood (e.g., loss of
caring); defining the line (blurry) line between
healthy moods and depressive disorders; therapeutic judgments about the best course of treatment for depressive disorders and suboptimal health.
References
American Psychiatric Association (APA). 2000. Diagnostic and statistical manual of mental disorders.
4th ed. Text Revision. Washington, DC: Author.
Edwards, R. B. 1997. Value dimensions of mental
illness and mental health. Ed. R. B. Edwards.
Ethics of psychiatry (pp. 1721). Amherst, NY:
Prometheus Books.
Hobson, J. A., and Leonard, J. A. 2001. Out of its
mind: Psychiatry in crisis. Cambridge, Mass: Perseus Publishing.
Jamison, K. R. 1993. Touched with fire: Manic-depressive illness and the artistic temperament. New
York: Free Press.
Kaysen, S. 2001. One cheer for melancholy. Ed. N.
Casey. Unholy ghost: Writers on depression. New
York: William Morrow.
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Martin, M. W. 2000. Depression: Illness, insight, and

identity. Philosophy, Psychiatry, and Psychology
6:27186.
Midgley, M. 1995. Beast and man. Revised ed. New
York: Routledge.
Nesse, R. M. 2000. Is depression an adaptation? Archives of General Psychiatry 57:1420.
Price, R. 1995. A whole new life: An illness and a
healing. New York: Plume.
Radden, J. (ed.). 2000. The nature of melancholy:
From Aristotle to Kristeva. New York: Oxford
University Press.
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259
Sandblom, P. 1995. Creativity and disease: How illness affects literature, art and music. New York:
Marion Boyars.
Snyder, C. R., and Lopez, J. S., eds. 2002. Handbook
of positive psychology. New York: Oxford.
Solomon, R. C. 1976. The passions. Notre Dame, IN:
University of Notre Dame Press.
Stevens, A., and Price, J. 2000. Evolutionary psychiatry: A new beginning, 2d ed. London: Routledge.
Wolpert, L. 1999. Malignant sadness: The anatomy of
depression. New York: Free Press.
6/16/03, 10:51 AM
FUCHS / MIND, MEANING, AND THE BRAIN
261
Mind, Meaning, and

the Brain
Thomas Fuchs, MD, PhD
KEYWORDS: Mind, brain, meaning, translation, depression.
A Systemic View of the Mind
over the past

two decades demonstrates the power of
the neurobiological paradigm. However,
this progress is connected with a restricted field
of vision typical of any scientific paradigm. The
psychiatrist should be aware of this restriction,
because, unlike the brain scientist, he deals with
patients, not with brains. The restricted view
may be described by the terms of (1) reductionism, (2) reification, and (3) isolation.
ROGRESS IN BRAIN RESEARCH
Reductionism: Neurobiology tends to regard subjectivity as a mere by-product of the brains activity as a symbol-manipulating machine or an
information processor. Consciousness becomes
an epiphenomon of the neuronal machinery that,
operating behind our back, creates the illusion of
a continuous self and of an autonomous will
(Churchland 1995; Roth 1996).
Reification: Mental or subjective states seem to
be localizable in the brain; thoughts or feelings,
it appears, may be observed in the colored illumination of cortical and subcortical structures.
This results in the belief that brain images could
also show the cause of a mental illness, or even
the illness itself, which then manifests, for instance, in a reduced metabolic activity in certain
areas of the cortex.
Isolation: As a further consequence, this view

isolates the individual patient and considers his
illness separated from the interconnections with
his environment. However, on these interconnections his personal experiences and dispositions
are founded, and it is the actual interpersonal
situation that has triggered his present illness.
Walter Glannons paper successfully counters
these tendencies toward a neurobiological reductionism with an extended view of the mind: . . .
the mind is not located in any one place but is
distributed among the brain, the body, and the
environment. Of course, who observes someones brain will never see his thoughts, his pain,
or his anxiety. For consciousness is not a localizable object or state at all but a process of relating
to something: a perceiving of, remembering of ,
wishing for, aiming at, and so on. Thus on the
phenomenological level, there is nothing like a
mental event that could be isolated from the
world and from the stream of conscious experiences. The mind exists only embedded in the
world and in the temporal process of life.
The same applies to the biological level: Consciousness is based on the continuous interaction
of the brain with the organism, and of the organism as a whole with the environment. The role of
the brain for mental phenomena is thus comparable to the role of the heart in the circulatory
system or of the lung in the respiratory system.
Of course, the lung is the central organ of breathing, but respiration may not be restricted to the
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6/24/03, 2:57 PM
lung, nor to the organism as a whole. It means

constant exchange with the environment, and
there is no sense in asking whether the air taken
in still belongs to the surroundings or already to
the organism. The same systemic unity is found
in the circle of perception and action mediated
by the brain: When I am writing a letter, there is
no place in the unity of action where my self
ends and the world begins, no border that
separates inner and outer worlds.
There is another argument to be raised against
the reification of the mind if we consider the
aspect of a historical biology. From birth on, our
mind as well as the correlated brain structures
are essentially formed by social and cultural influences. The brain is not inserted into the world
as a prefabricated apparatus but through its plastic development in and from the world. Thus it
adapts epigenetically to its specific natural and
social environment like a key to a lock. This
complementarity makes it impossible to restrict
ones view to the anatomic organ and requires an
interdisciplinary approach to brain-environment
investigation, as for example, under the heading
of a social cognitive neuroscience (Ochsner
and Lieberman 2001).
As Glannon goes on to argue, to overcome
neurobiological reductionism, more is required
than a defense of subjective consciousness and its
irreducible intentional or qualitative aspects; for
this impregnable refuge of subjectivity would
also remain sterile. An adequate theory of mind
rather ought to grasp its function in the systemic
unity of organism and environment; and an adequate theory of the brain should be able to represent not single objects, events, or states but relations and interactions.
However, Glannons teleological explanation
of the mind seems not quite sufficient. Certainly
its adaptive function amounts to more than the
mere enhancement of survival by adequately reacting to threatening stimuli, triggering a fightor-flight response, and so on. The decisive
progress brought about by the evolution of the
mind is not just an improved reaction to stimuli
(this could better be performed by a mindless
brain alone) but gestalt formation; that is, the
grasping of complex wholes or situations. Be-
9.3fuchs
262
cause the human organism itself is an integrated

whole, it has to act and react as such, which
presupposes an integrated or gestalt-like representation of itself (the body), the environment
(the world), and its own relation to the environment (meaning). This is mainly brought about
(1) by a synthesis of sense experiences, creating
our embodied being in the world; (2) by an
integrated evaluation of the meaning and the
options of a given situation, which we experience as emotion; and (3) by the iconic and symbolic representation of the world, that is, by
ideas and language. The mind creates wholes,
such as body, feeling, self, ideas, and concepts.
This allows the human organism to internally
model its relation to the environment, and thus
to act not merely in an automatic, but in a meaningful way.
The Brain as an Organ of Translation

If we now try to describe the role of the brain
on this systemic basis, we may conceive it as an
organ of transformation or translation, which
translates the relations between single elements
of a given situation (stimuli) into wholes or gestalt units. The constantly changing patterns of
synchronized neuronal excitations correspond to
the wholes emerging in subjective experience.
We may illustrate this transformation by the synthesis of single letters to a word (such as book),
which we grasp immediately through its components, without even being aware of the letters.
Of course, we once had to learn this word letter
by letter (b-o-o-k), but by stabilizing the pattern
or picture in our subjective experience, our brain
was induced to form a corresponding neuronal
pattern (in systems theory, an attractor) in such a
way that the constellation of single letters received the new meaning of book.
Following this line, we cannot regard subjective experience as a merely epiphenomenal picturing of underlying neuronal processes. On the
contrary, it plays an essential role in the systemic
interaction of organism and environment. For it
is only by conscious experience that the organism is able to enter into a relationship with the
environment on the higher level of meaning, of
integrated perceptive and cognitive units or ge-
6/24/03, 2:57 PM
FUCHS / MIND, MEANING, AND THE BRAIN
stalten; and these subjective, meaningful units in

turn influence the plasticity, the structuring and
functioning of the brain. A historical biology
implies the continuous formation and reconstruction of the brain via subjective experience. The
constraint that the mind in a nested hierarchy
(Feinberg 2001) exerts on the lower-level properties of the brain and the body consists mainly in
forming, maintaining, and connecting meaningful units of experience that stabilize corresponding
neuronal activity patterns and thus trigger, accordingly, physiologic reactions of the organism
as a whole.
As Glannon rightly points out, there is no
dualistic causality involved here: The brain transforms configurations of single elements or events
into higher-order patterns or units, and vice versa. It may be addressed by input on the different
hierarchical levels and translates them into each
other. This means that any process concerning
the etiology and symptoms of mental illness is of
a biological as well as psychological nature. The
translation only runs top-down in the one case
from subjective experience (e.g., a perceived social situation, a psychotherapeutic intervention)
to the level of neuronal and biochemical processes,
and it runs bottom-up in the other case, for example, from pharmacologic effects on transmitter
metabolism to a change in emotional experience.
Depression and Subjectivity

Obviously this systemic concept of the brain is
opposed to any biomedical reductionism operating in claims like depression really is a chemical
imbalance, or responsible psychiatrists should
focus on the real causes of psychiatric illness, i.e.,
damaged brains. The bottom-up explanation of
mental disorders as products of specific genetic
or physiologic etiologies is inadequate to the
causal complexity of most disorders. Whatever
the genetic basis of, as an example depression is,
it can be only one precondition of a complex,
interactive process that ends up as a psychiatric
disorder. The final disorder is the product of a
cascade of subjective, neuronal, social, and environmental interactions in which the brain acts as
a mediating, translating, and amplifying relay
station, but not as the cause.
9.3fuchs
263
263
Glannon regards depression as a psychoneuroimmunologic disease involving psychological as well as physiologic stress responses. In a
similar approach, I have described depression as
a psychophysiologic desynchronization (Fuchs
2001): a perceived backlog or gap between ones
expectations and achievements is translated by
the brain into a neurobiochemical pattern associated with depressed mood. It also entails an
uncoupling of rhythmic physiologic (e.g., endocrine) processes otherwise synchronized to each
other and to the environment. In the course of
this desynchronization, the production of stress
hormones and, subsequently, immunologic processes may become autonomous and inadequate,
resulting in negative feedback loops and, in turn,
increasing depressed mood. Thus the subjective
reactions to the disorder become intertwined with
the disorder itself. Psychosocial and physiological desynchronization influence each other.
As we can see, subjective experience is more
than a mere by-product of an underlying real or
brain depression. Depressed mood, distorted
thinking, or perceived insufficiency, are not just
accidental or epiphenomenal symptoms whose
only importance is to give cause to consult a
psychiatrist (who actually is rather a brain doctor). Depression, on the contrary, is triggered by
the subjective perception of meaningful, mainly
interpersonal situations, and it is also to a high
degree maintained or worsened by negative feeling, thinking, and interacting with others.
Finally, given the inadequacy of monocausal
accounts that invoke specific brain abnormalities, it would be inappropriate for the psychiatrist to treat the brain exclusively. Instead, a
therapeutic pluralism is required. One could argue here that because the brain translates input
in both directions, a biochemical or bottom-up
treatment suffices to attain the desired purpose.
However, in view of the limited effectiveness of
pharmacologic treatment, it would be imprudent
to neglect the top-down options on the psychotherapeutic level. But what is more important,
we do not have any biochemical means to change
the maladaptive dispositions of perception and
behavior that have led to depression and may
lead to relapse in the future. Such dispositions
6/24/03, 2:57 PM
are only accessible to change by new and repeated subjective experiencesemotional, verbal, and
interpersonal processes of learning that stabilize
new attractors of perception and behavior in the
brain. Only conscious experience is able to correct the corresponding dysfunctional patterns of
neuronal activity. Because the brain is a historical organ, there will probablyand hopefully
never be a way to create new views of the self
and the world by brain manipulation.
Conclusion
I have briefly outlined a systemic view of mind
and brain as embedded in the relation of organism and environment. There is no such thing as a
brain for itself, as long as it is not separated from
the living organism by autopsy. Its role may be
seen in the mutual translation of single elements
of a given situation into higher-order units that
are experienced as meaningful wholes and vice
versa. Only subjectivity contains the gestalt-like
wholes that for the organism represent an integrated model of reality. And it is only subjective
experience that is capable of gradually changing
the dysfunctional patterns of perception and behavior that may lead to mental disorders.
9.3fuchs
264
A psychiatry of the brain, when adequately

understood, would have to become a systemic
or ecological psychiatry (Fuchs 2002). Psychiatry needs an ecology of the brain to better
grasp the interconnection of psychological, social, and pharmacologic approaches adequate for
its subject. For this subject is not the brain, but
the mentally ill patient.
References
Churchland, P. M. 1995. The Engine of Reason, the
Seat of the Soul. Cambridge, Mass: The MIT Press.
Feinberg, T. 2001. Altered Egos: How the Brain Creates the Self. New York: Oxford University Press.
Fuchs, T. 2001. Melancholia as a desynchronization.
Towards a psychopathology of interpersonal time.
Psychopathology 34:17986.
Fuchs, T. 2002. The Challenge of Neuroscience. Psychiatry and Phenomenology today. Psychopathology 35:319326.
Ochsner, K. N., and Lieberman, M. D. 2001. The
Emergence of Social Cognitive Neuroscience. American Psychologist 56:71734.
Roth, G. 1996. Das Gehirn und seine Wirklichkeit.
Frankfurt: Suhrkamp.
6/24/03, 2:57 PM
GLANNON / THE PSYCHOLOGY AND PHYSIOLOGY OF DEPRESSION
265
The Psychology and

Physiology of
Depression
Walter Glannon
RAUMA AND STRESSFUL EVENTS can disrupt

the physiologic homeostasis of our bodies and brains. The physiologic stress response consists of neural and endocrine mechanisms whose function is to reestablish homeostasis.
These mechanisms include the secretion of glucocorticoids (cortisol) and catecholemines (epinephrine and norepinephrine). Once an external
event has ceased to be a stressor or threat to a
human organism, an integrated system of negative feedback loops inhibits the continued production of these hormones and effectively shuts
down the stress response. These mechanisms are
adaptive in the sense that they ensure the survival of the organism by reestablishing homeostasis.
But prolonged exposure to real or perceived stressors can trigger prolonged secretion of stress
hormones, thereby disrupting the feedback systems and causing a cascade of pathogenic events.
The stress response is a double-edged sword. An
acute stress response can protect an organism
from external threats and reestablish homeostasis. But a chronic stress response can cause the
bodys defenses to become damaging rather than
protective and to result in various disorders. Acute
stress responses are adaptive. Chronic stress responses are often maladaptive and pathogenic.
In Depression as a MindBody Problem, I
characterized major clinical depression as a disorder resulting from a maladaptive chronic stress
response (Glannon 2003). Specifically, I argued

that depression often results when our beliefs
and emotions are out of proportion to the true
nature of external events. The mind prolongs
rather than constrains the physiologic stress response. Depression is not a disorder of the brain
alone or the mind alone, however. Endocrine and
immune dysfunction can contribute to the dysfunction in the brain and central nervous system
that are involved in depression. Moreover, the
contents of the mental states that initiate the
sequence of events leading to depression are reflections of the persons natural and social environment. Thus, a satisfactory account of depression requires an analysis of the interconnections
among the central nervous, endocrine, and immune systems, as well as the mind and the environment. All of these factors support the description of depression as a psychoneuroimmunologic
disorder.
Mike Martin (Martin 2003) and Thomas Fuchs
(Fuchs 2003) discuss important aspects of depression that I did not elaborate in my paper.
Martin argues that I fail to distinguish between
depression as a mood and depression as a disorder. This is pertinent to the distinction evolutionary psychiatrists draw between moods that are
adaptive and moods that are maladaptive. In
contrast to my negative characterization of depression, Martin also makes a case for the posi-
9.3glannon02
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6/24/03, 3:39 PM
tive contributions of depression to meaningful

life. Fuchs explores the notion of the brain as an
organ of translation enabling patients to have
meaningful subjective experience. The emphasis
on subjectivity has important implications for
potential preventive and therapeutic interventions
for depression. For whether a person perceives
an external event as a stressor may play a crucial
role in the physiologic stress response. I will
address the main points of these two authors in
turn.
Contrary to what Martin claims, I explicitly
defined chronic depression as an affective (mood)
disorder. My focus was on the clinical definition
of major depression as a moderately severe to
severe chronic disorder. It consists of affective,
cognitive, and even physical dysfunction that interferes with a persons ability to carry out the
normal tasks of daily life. This characterization
of major chronic depression distinguishes it from
milder forms of depression, such as dysthymia.
Because these milder forms do not involve the
same type or degree of dysfunction as more severe forms, they are not appropriately characterized as pathologies. For this reason, I focused on
Nesses (2000) discussion of depression rather
than on his discussion of low mood. In fairness
to Nesse and Stevens and Price (2000), not all
forms of depression are pathologic according to
the evolutionary view they defend. Some passive
aspects of mild depression may be useful in alerting us to dangerous or wasteful behavior. It does
seem plausible to describe depressed moods as
falling along a continuum from those that are
adaptive to those that are maladaptive. Yet most
cases of chronic depression are pathologic rather
than useful or adaptive precisely because of the
mental and physical dysfunctions that are symptomatic of them. Moreover, it is difficult to know
when one has crossed the threshold separating
moods that are useful from those that are pathologic.
As I explained in my earlier paper, this difficulty is due to the fact that the mental states
involved in the psychological stress response are
largely nonconscious. Emotions such as fear and
anxiety, as well as the physiologic processes that
underlie them, occur to a considerable extent
9.3glannon02
266
outside of our conscious awareness. The slide

from adaptive to maladaptive beliefs and emotions cannot be easily controlled because we cannot always be aware of the process. Joseph
Ledoux explains the problem with implicit
(nonconscious) memory of stored information
about stressful or traumatic situations as follows: If we dont know what it is we are learning about, those stimuli might on later occasions
trigger fear responses that will be difficult to
understand and control, and can lead to pathologic rather than adaptive consequences (Ledoux
2002, 225). In evolutionary terms, perhaps our
psychological and physiologic stress responses
have not yet adjusted to the noise and air pollution in the modern natural environment, or to
the crime and higher expectations in the modern
social environment. These chronic stressors are
very different from the more acute stressors of
temporary food shortages and threats from animals that typified the environment of our ancestors.
Martin maintains that mood disorders can
have good side effects. He cites the creative role
that mood disorders have played in the lives of
artists. Although there may be a correlation between bipolar disorder and artistic creativity, a
similar correlation between depression and creativity is questionable. Even in bipolar disorder,
it is during the manic, not depressed, phase that
artists and writers with this condition do their
creative work. More importantly, the lost opportunities and suffering of people afflicted with
these and other mental illnesses far outweigh any
positive effects they might have. Martins romanticized view of depression applies to a very small
subset of people with depression and ignores the
magnitude of the deleterious consequences of the
disorder.
For example, prolonged secretion of glucocorticoids in the cascade of events leading to major
depression can damage hippocampal neurons (Sapolsky 1992; McEwen 1999). This can adversely
affect memory formation because the hippocampus is one of the regions of the brain that control
the formation and processing of memory. Damage to the hippocampus can impair the capacity
for planning and decision making, which rely on
6/24/03, 3:39 PM
the capacity to form new memories. In severe

cases, memory impairment can result in the loss
of conscious awareness of oneself as a person
persisting through time. Because severe depression can have this effect on cognition, as well as
an equally destructive effect on mood, it can
undermine a persons sense of self. In this respect, depression threatens rather than contributes to meaningful life. Ordinarily, the hippocampus modulates glucocorticoid feedback
inhibition between the brain and the adrenal
cortex. But hypersecretion of hormones such as
cortisol disrupts this feedback loop and accelerates damage to hippocampal neurons. In fact,
the impairment of reasoning resulting from this
damage can amplify fear reactions and thus exacerbate depression. The view that depression
can be useful and indeed even desirable makes
light of the fact that most forms of depression
involve significant cognitive, affective, and physical dysfunction. It also fails to appreciate that
the purpose of antidepressants is not to enhance
cheerfulness, but to restore people to a normal
level of functioning in their lives.
Martin suspects that psychologists explorations will yield new insights into the positive
contributions of depressed moods to meaningful
life. Yet this misleadingly suggests that major
chronic depression is exclusively a psychological
disorder. It oversimplifies the nature of the disorder by ignoring the physiologic and environmental factors with which the mind interacts. A better understanding of how these consequences
can be prevented or alleviated will only come by
attention to the interactions among all of these
factors.
Fuchs offers a more accurate and insightful
explanation of depression in terms of mind as
distributed among the brain, body, and environment. This involves what he aptly calls an ecological psychiatry. Fuchs rightly points out the
inadequacy of my teleological explanation of the
mind. He says that my account is too automatic
and fails to appreciate the dynamic aspect of the
mind. This hinges on the idea of the plasticity of
the brain as an organ of translation, one that is
in constant interaction with the environment.
The process of translation enables a human or-
9.3glannon02
267
267
ganism to model its relation to the environment

in a meaningful way. The subjective units of
meaning in turn influence the plasticity, structuring, and functioning of the brain. Fuchs model is
significant because it suggests that mental states
can influence brain states. It suggests that attention to a persons subjective interpretation of
events over time can elucidate the causal role of a
persons psychology in the pathogenesis of depression.
The idea of a historical biology consists in the
continuous formation and reconstruction of the
brain via subjective experience. This idea may
help us to understand how beliefs and emotions
can go from being adaptive to pathologic. Such a
model may also provide a way of reframing these
mental states. It offers potentially effective forms
of prevention or treatment of depression through
psychotherapy so that the mind represents the
environment in a more salutary way. Fuchs says
that only subjective experience is capable of gradually changing the dysfunctional patterns of perception and behavior that may lead to mental
disorders. Indeed, perception may be the key to
understanding the chronic psychological and
physiologic stress responses resulting in major
depression.
Different people may respond differently to
the same stressor. The critical question is why
some people but not others perceive an event as
stressful in the first place. Such a negative perception may be a function of underlying emotions such as excessive fear or anxiety, which are
absent when the perception of the event is more
positive or neutral. Either way, a physiologic
stress response can be modulated by the perception of the stressor. In more extreme cases, a
physiologic stress response can be provoked in
the absence of a stressor. This occurs when ones
beliefs and emotions are way out of proportion
to the real nature of the external event. Genetics
may play some role in this. But a more likely
explanation is that a diachronic pattern of subjective interpretations of situations as threatening or as being beyond ones control can condition one to have beliefs and emotions whose
contents will be interpreted as stressful. Psychotherapeutic intervention that explores the pa-
6/24/03, 3:39 PM
tients experiential history may be able to correct

these pathologic patterns of belief and emotion,
enabling the patent to reframe them in a way
that is more consonant with events in the natural
and social environment.
Nevertheless, whereas psychological interventions may be able to prevent depression, they
alone will not be effective therapies once depression has become full-blown. Reiterating an earlier point, this is because the emotions involved in
depression are largely nonconscious. Although
Fuchs rightly advocates a therapeutic pluralism for the treatment of depression, he overstates the case for psychological intervention in
saying that only conscious experience can correct the corresponding dysfunctional patterns of
neuronal activity.
The storing of nonconscious emotional memory of fear about a threatening situation in the
amygdala is critical for an organisms survival.
For this reason, the capacity for fear is hardwired into this subcortical region of the brain. In
contrast, psychological states like beliefs and conscious emotions (feelings) are in the more recently evolved, or soft-wired, cortical regions of the
brain. They enable us to differentiate between
threatening and benign situations. Depression
can result from a dysfunctional pattern of beliefs
and emotions that interpret most situations as
though they were threatening. Once the excessive fear and anxiety that lead to depression
become firmly embedded in the amygdala, it can
be difficult to dislodge them. With the negative
feedback mechanism between the prefrontal cortex and the amygdala disrupted, the beliefs regulated by the prefrontal cortex cease to influence
the amygdala and instead are only negatively
influenced by it. This dysfunction between these
two brain systems makes it difficult to reframe
the beliefs and emotions so that they are consonant with the real nature of external events. It
may be one explanation for the high incidence of
relapse among depressed patients.
I noted in my paper that selective serotonin
reuptake inhibitors (SSRIs) and other antidepressants facilitate positive feedback in the pathway
between the beliefs in the prefrontal cortex and
the emotions in the amygdala. These and other
9.3glannon02
268
pharmacologic interventions can do the necessary work at the nonconscious neural level that
cannot be done at the conscious level of beliefs
and feelings. The fact that the emotions involved
in depression function outside of our conscious
control is what makes combined psychotherapy
and pharmacotherapy necessary and sufficient
interventions. Still, in more severe forms of depression, the dysfunctions in the underlying brain
mechanisms may be so deep-seated that they are
completely refractory to any intervention at the
psychological level. Trying to reframe the dysfunctional beliefs and emotions that led to major
or severe depression may be of limited therapeutic value. Beyond a certain point, the dysfunction
in the neural and endocrine mechanisms involved
in depression may be too advanced to be corrected by working through the mind alone. In these
cases, the critical pathway is not between the
prefrontal cortex and the amygdala, but instead
between the adrenal cortex and the amygdala.
And the main culprits are not neurotransmitters,
but stress hormones such as cortisol.
To be sure, it is not the brain but the mentally
ill patient who suffers from a mental disorder
like depression. Because the patient is a psychological subject, we need to attend to his or her
subjective experience in understanding depression. This includes the contents of the experience
as a subject in the natural and social environment. Yet, even if we can alter the environment,
some people will still perceive events as stressors.
In these and other cases, we need to explore the
role that neural and endocrine mechanisms play
in sustaining pathologic states of body and mind.
Pharmacologic interventions may be the only
way to reverse dysfunctional neural and endocrine mechanisms underlying these states.
A good example of the therapeutic value of
drug intervention for severe depression is a recent study showing the effectiveness of the antiglucocorticoid mifepristone in treating psychotic
depression (Belanoff et al. 2002; Gold et al. 2002).
Researchers have found that mifepristone can
mitigate the pathophysiologic effects of amygdala activation in severe depression by blocking the
action of cortisol from the adrenal cortex on
glucocorticoid receptors in the amygdala. This
6/24/03, 3:39 PM
blockade can reset dysfunctional negative feedback mechanisms in the hypothalamuspituitary

adrenal (HPA) axis and reestablish stress homeostasis. Consequently, this action can reduce the
deleterious effects of depression on the hippocampus, brain stem, and other brain regions that
are implicated in psychotic depression. Admittedly, this treatment is indicated for only a subclass of patients with depression. Yet it illustrates
that interacting systems in the body and brain
are involved in this disorder. Because neural and
endocrine systems underlie the psychological
symptoms of depression, effective treatment in
more serious forms of the disorder requires drug
therapies that more precisely target both serotonergic and noradrenergic neuronal receptors.
Cortisol and CRH-receptor antagonists may be
helpful as well. In less severe forms of depression, however, combined psychotherapy and pharmacology will likely continue to be the most
effective course of treatment.
Prevention and treatment of major depression
require attention to the interaction among mind,
brain, body, and environment. We need to further explore why some people perceive events in
the natural and physical environment as stressors. In addition, we need to further examine
how beliefs and emotions can modulate physiologic stress responses in the endocrine and central nervous systems, and how these in turn can
modulate immune responses. Only by studying
9.3glannon02
269
269
psychological and physiologic stress responses in

an integrated way will we be able to prevent or
reverse the dysfunction in these responses that
causes major depression.
References
Belanoff, J. K., Rothschild, A. J., Cassidy, F., DeBattista, C., Baulieu, E. E., Schold, , and Schatzberg,
A. F. 2002. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biological Psychiatry 52:38692.
Fuchs, T. 2003. Mind, meaning, and the brain. Philosophy, Psychiatry, and Psychology This issue.
Glannon, W. 2003. Depression as a mind-body problem. Philosophy, Psychiatry, and Psychology. This
issue.
Gold, P., Drevets, W. C., and Charney, D. S. 2002.
New insights into the role of cortisol and the glucocorticoid receptor in severe depression. Biological Psychiatry 52: 3815.
LeDoux, J. 2002. The synaptic self. New York: Viking
Penguin.
Martin, M. 2003. On the evolution of depression.
Philosophy, Psychiatry, and Psychology This issue.
McEwen, B. S. 1999. Stress and hippocampal plasticity. Annual Review of Neuroscience 22: 10522.
Nesse, R. 2000. Is depression an adaptation? Archives
of General Psychiatry 57:1420.
Sapolsky, R. M. 1992. Stress, the Aging Brain, and the
Mechanisms of Neuron Death. Cambridge, Mass:
MIT Press.
Stevens, J., and Price, J. 2000. Evolutionary psychiatry, 2nd ed. London: Routledge.
6/24/03, 3:39 PM

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GLANNON / DEPRESSION AS A MINDBODY PROBLEM

ABSTRACT: Major depression is a disorder of the mind

ANY PSYCHIATRISTS CONCEPTUALIZE severe

mental illnesses like schizophrenia,

dysfunction underlie serious mental illnesses.

2003 by The Johns Hopkins University Press

244 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

How can conscious mental states like beliefs and

process sensory information more accurately and

GLANNON / DEPRESSION AS A MINDBODY PROBLEM

in terms of the objective physical properties of

First, it suggests the idea of linear causation

A more promising theory consistent with the

246 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

erties from lower-level physical properties in the

GLANNON / DEPRESSION AS A MINDBODY PROBLEM

MindBrain Interaction and

the environment. This can initiate a physiologic

248 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

All of these points suggest that the mind is one

GLANNON / DEPRESSION AS A MINDBODY PROBLEM

control its effects on us. Arguably, there are now

Mycobacterium leprae destroys nerve endings that

250 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

have discussed play in depression. For example,

GLANNON / DEPRESSION AS A MINDBODY PROBLEM

brain regions such as the cerebral cortex is likely

uring the unconscious. But it is unclear how this

252 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

otherwise might prompt a conditioned fear or

health care system. Pharmacologic intervention

GLANNON / DEPRESSION AS A MINDBODY PROBLEM

senses in which it might be adaptive. For a good critical

254 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

Kim, J. 1998. Mind in a physical world: An essay on

Schechtman, M. 1997. The brain/body problem. Philosophical Psychology 10:14963.

MARTIN / THE EVOLUTION OF DEPRESSION

KEYWORDS: Depression, morality, mental disorders, psychobiology, evolutionary psychiatry.

DEPRESSION AS A MINDBODY PROBLEM,

2003 by The Johns Hopkins University Press

256 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

My main concern, however, lies elsewhere. In

Maladaptive Disorders Versus

MARTIN / THE EVOLUTION OF DEPRESSION

moods are adaptive in helping us deal with defeat and danger.

To confuse (or clarify?) matters further, let me

One Cheer for Depression

258 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

understanding, in determining what is unhealthy

scopic: it observes big and complicated terrain from

MARTIN / THE EVOLUTION OF DEPRESSION

Martin, M. W. 2000. Depression: Illness, insight, and

FUCHS / MIND, MEANING, AND THE BRAIN

Mind, Meaning, and

KEYWORDS: Mind, brain, meaning, translation, depression.

A Systemic View of the Mind

over the past

Isolation: As a further consequence, this view

2003 by The Johns Hopkins University Press

262 PPP / VOL. 9, NO. 3 / SEPTEMBER 2002

lung, nor to the organism as a whole. It means

cause the human organism itself is an integrated

The Brain as an Organ of Translation