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Psychological Theories of Depression: Potential Application for the

Prevention of Acute Coronary Syndrome Recurrence




Objective: The natural course of elevated depressive symptoms or subthreshold depression in patients with an acute coronary
syndrome (ACS) is presented, as is the prognostic impact. Safe and effective psychological treatment options are desirable for
subthreshold depression in patients with ACS, should they prove tolerable, efficacious, and cost-effective to cardiologists and their
patients. To achieve this long-term goal, we propose focusing on 3 intermediate goals. First, we need to understand which symptoms
or patterns of symptoms (eg, fatigue, anhedonia, guilt feelings) are specifically predictive of ACS recurrence. Second, the
prevalence of known psychosocial vulnerabilities (proximal causes) of depressive disorders should be assessed in patients with
ACS, to understand better the etiology of these symptoms in these patients. Third, randomized controlled trials of vulnerabilityrelated, evidence-based psychological depression interventions in cardiac patients are needed. The ways in which psychological
proximal cause theories are relevant or irrelevantfor both the treatment of depressive symptoms in post-ACS patients and the
prevention of ACS recurrence are discussed. Key words: depression, acute coronary syndromes, psychosocial intervention.
CHD coronary heart disease; ACS acute coronary syndrome;
BDI Beck Depression Inventory.

ven minor elevations in depressive symptoms (subthreshold depression, defined to include mood, somatic, and
interpersonal symptoms of depression, but not necessarily a
diagnosable depressive disorder) significantly increase the
risk of incidence of coronary heart disease (CHD) among
previously healthy participants or worsen the cardiac prognosis in patients with established CHD. The scientific evidence
is strongest for patients who have been hospitalized for an
acute coronary syndrome (ACS)that is, myocardial infarction or unstable angina (115).
Well-established theories of the psychosocial causes of
depression and their theory-related, evidence-based treatments
exist (16 20). However, these theories were formulated and
tested primarily on younger, psychiatric (depressive disordered), and treatment-seeking people rather than older, subthreshold depressed, post-ACS patients. Furthermore, as has
been previously found in psychiatric populations, there is
likely no single proximal depression cause that is inevitably or
necessarily present in post-ACS patients with depressive
symptoms. We suggest that the usefulness of various psychological depression treatments for post-ACS subthreshold depression will differ depending on the extent to which each of
these proximal causes presents in this specific population.
In this article, we outline current evidence for the natural
course of depressive symptoms after an ACS event and their
prognostic impact for ACS recurrence and cardiac death. We
then review 3 accepted depression etiologic theories (cognitive theory, behavioral theory, and interpersonal theory) that

From the Columbia College of Physicians and Surgeons, New York, NY

(K.W.D.); the Cardiovascular Institute, Mount Sinai School of Medicine, New
York, NY (K.W.D.); the Department of Psychiatry, Mount Sinai School of
Medicine, New York, NY (N.R.); and the Department of Psychiatry, University of Montreal, Montreal, Canada (F.L.).
Address reprint requests to: Karina W. Davidson, PhD, Medicine, Columbia University College of Physicians and Surgeons, 622 W. 168th St, PH9
Center, Room 941, New York, NY 10032. E-mail:
Received for publication May 12, 2003; revision received October 26,
Preparation of this article was financially supported by #HC-25197 and
#HL-04458 from the National Heart, Lung, and Blood Institute.
DOI: 10.1097/01.psy.0000116716.19848.65
Psychosomatic Medicine 66:165173 (2004)
Copyright 2004 by the American Psychosomatic Society

all fulfill the following criteria: they have been tested for the
presence of their putative depression proximal cause in depressed patients, they have an associated evidence-based treatment protocol (2124), and they have been tested in elderly
patients of relevance for the majority of patients with ACS.
Each theory asserts that their proximal causes should apply
only to a subset of people with depression symptoms, because
depression itself is a heterogeneous disease (25). The applicability of the existing psychosocial depression theories and
their established treatment protocols to the population of ACS
patients is then discussed in light of the effects that such
treatments may have on preventing ACS recurrence and cardiac death, in addition to the effects on a general reduction in
depressive symptoms and related functional impairments (26).
Finally, alternative conceptualizations of subthreshold depressive symptoms in this patient population are discussed.
Numerous studies have established that depression predicts
the incidence of CHD in previously healthy people. A recent
meta-analysis by Rugulies (15) reported that depression increases the risk of myocardial infarction or coronary death
(relative risk 1.64, 95% confidence interval 1.29 2.08,
p .001) and that the risk is not limited to patients with
clinical depression.
Similar findings have been reported in patients with established CHD. It appears that not only a psychiatric disorder
history but also the presence of mildly elevated depressive
symptoms, such as a Beck Depression Inventory (BDI) score
of 10 or higher, are associated with worse prognosis in patients recovering from ACS (9, 27). Indeed, there appears to
be a linear association between depressive symptoms at the
time of a myocardial infarction and the risk of subsequent
cardiac morbidity and mortality (6, 13). However, when accounting for naturalistic changes in the course of depressive
symptoms after the ACS event, the prognostic importance of
mild vs. severe depressive symptoms differs. A recent follow-up study by Lesperance et al. (14) reported the prognostic
importance of naturalistic improvement or deterioration of
depression symptoms over the period of 1 year postmyocardial infarction. In this study, improvements in depressive

K. W. DAVIDSON et al.
symptoms had only an independent positive impact on prognosis (5-year cardiac morbidity, and cardiac and noncardiac
mortality) in patients with initial BDI scores from 10 to 18
(mild depression symptoms). Among these patients, the
greater the improvement in depression symptoms, the better
the long-term prognosis. However, 1-year depression symptom improvement in those with higher initial depressive
symptoms (BDI 18) did not result in decreased 5-year cardiac
outcome risk. This finding provides preliminary evidence for
the potential cardiac benefit of reducing depressive symptoms
in a substantial proportion of patientsthose with subthreshold depression.
To conclude, even minor symptoms of depression at the
time of admission to the hospital predict post-ACS morbidity
and mortality. Furthermore, there is some suggestion that
previous history of major depressive episodes may further
enhance the strong prognostic impact of these symptoms (28).
Clearly, further studies should examine factors that potentially
moderate the impact of depression besides its severity at
baseline, such as the number, the timing and duration of
previous episodes, and previous depression treatment history.
Although an enticing prognostic prediction is available
from depression inventories, what is assessed by a depressive
symptom inventory in post-ACS patients is not entirely clear.
Some have argued that the symptoms endorsed by these
patients (fatigue, loss of concentration, sadness, pessimism)
may result from more severe cardiac illness that is not properly controlled for by assessing the number of diseased vessels
or other medical severity measures in published studies (29).
The meaning of depressive symptoms and depressive disorder
diagnosis post-ACS and possible treatments are presented
after reviewing the course of depressive symptoms in this
patient population.
The course of elevated depressive symptoms in postmyocardial infarction patients has been characterized by Schleifer
et al. (30). Of those admitted to the cardiology unit, 27% met
criteria for minor depression as assessed by the Schedule for
Affective Disorders and Schizophrenia (31), and an additional
18% met criteria for major depression when all were assessed
within 10 days of their event. Schleifer et al. (30) reassessed
their patients 3 to 4 months after admission. Seventy-seven
percent of those with major depression still met criteria for
this disorder, but only 35% of those with minor depression
continued to have elevated depressive symptoms.
Another study examined the natural course of depressive
symptoms in patients with CHD who had not experienced a
recent major cardiac event (32). At baseline, 17% of 200
patients met the DSM-IV criteria for major depression, and an
additional 17% met the DSM-IV criteria for minor depression.
Seventy-five percent of the depressed patients were followed
up over a period of 1 year. Of these, 42% of patients with
initial minor depression had progressed to major depression 1

year later, and 31% of patients with initial major depression

persisted in that category. Full remission was observed in 23%
of the major depression group and 50% in the minor depression group. A similar pattern of naturalistic waning of postmyocardial infarction depressive symptoms was reported by
Lespe rance et al. (28).
Thus, a substantial portion of post-ACS patients may show
spontaneous depression symptom remission, especially those
who did not initially meet criteria for major depression. Moreover, patients who do remit spontaneously from subthreshold
depression have a better cardiac prognosis (14). Consequently,
the identification of predictors that are able to differentiate
sensitively and specifically between the remitting and the
nonremitting subthreshold depressed patients will be a crucial
component for successfully identifying those most at risk and
those most in need of depression treatment. This intermediate
goal can be accomplished in 2 very different ways. First, it is
critical to examine the types or patterns of depressive symptoms that predict whose subthreshold depression will remit
spontaneously. Irvine et al. (33) examined somatic and cognitive-affective depressive symptoms separately for ACS recurrence prognosis, and only the latter were (marginally significantly) predictive for sudden cardiac death in a sample of
671 postmyocardial infarction patients. This kind of disentanglement of the different types of depressive symptoms typically surveyed within self-report instruments may aid us in
identifying patients with ACS at risk for recurrence, and those
whose depressive symptoms will persist.
Second, we believe that cognitive, interpersonal, and behavioral proximal depression causes are potential candidates
for the differentiation of subthreshold depression remitters
from nonremitters. These proximal causes have been shown to
increase the likelihood of depressive episode presence, they
may differentiate the less and more depressed patients from
each other, and they have theoretically derived, evidencebased treatments. However, their prevalence and predictive
value in the ACS population remain unknown.
The cognitive theory described by Beck (16, 34) evolved
from his empirical observation of depressed patients descriptions of their thought content through verbalization. Cognitive
psychotherapy takes the form of helping patients become
aware of their cognitive distortions or cognitive errors and the
underlying assumptions of these thoughts. The patient is then
encouraged to seek evidence by which to support or refute
these cognitive assumptions and to modify assumptions based
on a more balanced view of all available information. There is
a well-operationalized, manualized treatment procedure designed to replace maladaptive cognitive processes with more
adaptive cognitions (18). Cognitive therapy of depression has
been widely studied, and meta-analyses of its efficacy have
found it to satisfy clearly the criteria for evidence-based
treatment (35, 36). Several randomized controlled trials have
shown that, when implemented by experienced therapists, it is
as effective as pharmacotherapy (37), regardless of the severPsychosomatic Medicine 66:165173 (2004)


ity of depressive symptoms, and may be even more effective
than pharmacotherapy in preventing relapse of depressive
episodes (38). The cognitive theory underlying this treatment,
however, has been less well studied (39). Although there are
many components of cognition that are important to cognitive
depression theory, we focus on the 2 cognitive constructs with
well-validated measures: cognitive errors and dysfunctional
attitudes. Jointly, we label these cognitive distortions.

Cognitive Distortions in the Etiology of Depression

Cognitive distortions in the absence of a major life stressor
are thought to be quiescent. Without specific cognitive intervention, they are also thought to be relatively stable. The
conjoint presence of cognitive distortions and a major life
stressor, however, is expected to increase the likelihood of a
depressive episode. Following from this conceptualization,
cognitive distortions should be higher in depressed compared
with normal control post-ACS patients, both when a depressive episode is present and when it is absent. This latter point
has not yet been established in the literature.
For cognitive distortions to be proximal causes for depression, they must precede the depressive episode; otherwise,
they would be better conceptualized as epiphenomena. To
address this question, Smith et al. (40) conducted a prospective study with a sample of 72 (nondepressed) patients with
rheumatoid arthritis followed for 4 years. Cognitive distortions assessed at baseline by the Cognitive Error Questionnaire predicted significant increases in depressive symptoms 4
years later, controlling for baseline depressive symptoms.
Moreover, baseline depressive symptoms did not predict
changes in cognitive distortions across the study. Interestingly, increased helplessness (41) was also assessed at baseline and did not predict depressive symptom increase across
the 4 years, suggesting that helplessness was not a depression
proximal cause in this sample.
Support for the cognitive theory of depression would also
be bolstered if cognitive depression interventions led to less
cognitive distortion, such that the level of distortion for successfully treated patients were normalized or closer to the
level of nondepressed people. Using the Dysfunctional Attitude Scale, depressed patients have been found to have significantly higher initial levels of dysfunctional attitudes than
normal controls, and after cognitive therapy, those whose
depression remitted had Dysfunctional Attitude Scale scores
close to the levels of normal controls in 1 study (42). In
contrast, the National Institute of Mental Health Treatment of
Depression Collaborative Research Program did not find that
cognitive distortions were lowered most by cognitive (behavioral) therapy (43 45) compared with a drug or interpersonal
therapy arm.
Beck (46) and Ruehlman et al. (47) have cautioned that the
correlates and causes of mildly elevated depressive symptoms
or dysphoria cannot be safely assumed to be the same as those
for major depression. Specifically, people with subthreshold
depression are generally thought to have accurate cognitive
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perceptions of the stressful life event, resembling adjustment

disorder, whereas those with major depression are not (48).
Cognitive theory would predict that post-ACS patients with
high dysfunctional attitude scores are more likely to have
more severe depressive symptoms compared with post-ACS
patients with low dysfunctional attitudes. Furthermore, given
that cognitive distortions appear relatively stable and increase
a persons vulnerability to a major depressive episode when
combined with a major life event, depressive symptoms in the
presence of cognitive distortions would not be expected to
spontaneously remit in this patient population.
In summary, there is some evidence from a number of
different designs suggesting the possibility that cognitive distortions may be a proximal cause of depression, but there is
other evidence such as that from the National Institute of
Mental Health trial that is troubling. From the lack of convincing empirical data on the postulates of cognitive theory,
some have expressed more global concerns about the theory;
they propose that all diathesis-stress models of depression
have formidable conceptual and methodological challenges
that have not yet been met (49). These challenges compromise
the potential usefulness of these theories to depression treatment. However, the presence of cognitive distortions in postACS patients, regardless of current depressive episode status,
could be 1 of the markers of excess ACS and depression
nonremittance risk, because in theory it should mark previous
and future vulnerability to depression.
The interpersonal theory of depression is based on theories
emanating from the interpersonal school of psychiatry (50)
and empirical data related to attachment theory and social
roles (51). Interpersonal psychotherapy, developed by Klerman et al. (19), is a focused, short-term, time-limited therapy
that emphasizes the current interpersonal relations of the depressed patient. The efficacy of interpersonal psychotherapy
treatment for major depression has been demonstrated in several controlled comparative depression treatment trials (45).
For example, in a depressed geriatric population, interpersonal
psychotherapy has shown some advantages over tricyclic antidepressant therapy because of attrition in the latter intervention, in part because of medication side effects (52). A brief
psychosocial intervention, based on interpersonal psychotherapy, to treat medical patients in primary care has also demonstrated a reduction in depressive symptoms (19). Interpersonal psychotherapy has been successfully modified and used
with older patients (53) and with subsyndromally depressed
hospitalized elderly patients (54). Frank et al. (55) also demonstrated the efficacy of maintenance interpersonal psychotherapy, a modified interpersonal psychotherapy version focusing on the prevention of depression in remitted patients, in
a long-term randomized controlled trial. Interestingly, they
also showed that treatment specificity (the ability of patients
and therapists to focus consistently on interpersonal concerns
and the techniques of interpersonal psychotherapy to the ex167

K. W. DAVIDSON et al.
clusion of other treatment elements) was essential for successful depression relapse prevention.
Interpersonal psychotherapy focuses on the intuitively appealing concept that events in ones psychosocial environment
affect ones mood and vice versa. When major events occur,
mood worsens, and depression may result. Conversely, depressed mood compromises ones ability to handle ones social roles, generally leading to further negative events and
ongoing interpersonal distress (56). The crux of interpersonal
psychotherapy is to demonstrate empirically a link between
mood and interpersonal issues that appear temporally and
thematically related to the onset and maintenance of depression (19). Once a patient understands this link and identifies
the specific interpersonal area that is currently problematic,
the therapist and patient work together to alter the interpersonal environment so that the depression will lift (56). The
patient and therapist agree on 1 of the following 4 interpersonal problem areas that will be the focus of the depression
treatment: a) grief or complicated bereavement, b) role dispute
or ongoing disagreements with a significant person in the
patients life, c) a recent role transition that results in major
interpersonal role changes or alterations (eg, retirement, moving, being diagnosed with a major medical illness), and d)
interpersonal deficits (recurrent difficulties in social interactions, in their extreme form classified as personality disorders). Although depressed patients may fit into several or all
of the 4 interpersonal problem areas, the treatment demands
that 1 area (or occasionally 2) be chosen as the primary target
for intervention.
Presence of Interpersonal Problems in the Etiology of
Numerous studies have found interpersonal problems as
reflected in divorce, marital problems, and negative partner
and child interactions to be significantly more prevalent or
elevated in depressed people (57, 58). However, it is still
unclear whether interpersonal problems precede depressive
episodes rather than co-occur with or even result from depressive mood states. On a variety of interpersonal functioning
indicators, Hammen and Brennan (58) compared 83 women
with unipolar major depression or dysthymic disorder, 271
women who were not currently in a depressive episode but
who had past histories of either DSM-IV depression diagnosis,
and 458 never-depressed women. As expected, the currently
depressed women had the worst scores on all interpersonal
indicators. Compared with the never-depressed group, and
controlling for current subclinical depressive symptoms and
socioeconomic status, the past depression women reported a
more frequent use of coercive interpersonal tactics, more
interpersonal conflicts, less secure attachment representations
of relationships, and more dysfunctional personality traits.
Moreover, their close relationship functioning was found to be
more dysfunctional by interviewers, and the marital satisfaction of the womens spouses was worse. Although crosssectional, at least this 1 set of results suggests that impoverished relational skills and dysfunctional representations of

relationships are proximal causes of depression that persist

even in the absence of clinically relevant depressed mood.
Interpersonal psychotherapy explicitly focuses on the here
and now of these interpersonal problems, and thus appears
applicable to a wide range of patient populations with interpersonal problems. However, little research is available demonstrating that the tenets and postulates of interpersonal theory
are supported. For example, it is not yet clear that the reduction or prevention of depressive symptoms is mediated
through changes in 1 of the 4 interpersonal problem areas,
such as relational functioning. Finally, the efficacy of this
therapy in medically ill, mildly depressed patients has yet to
be clearly established.
To conclude, the interpersonal theory has not been extensively tested for either increased presence of interpersonal
problems before the depressive symptoms or for evidence that
interpersonal psychotherapy reduces the identified interpersonal problem. The beneficial effect of interpersonal psychotherapy on depressive symptomatology is well established.
Based on this theory, post-ACS patients with the presence of
a role transition, or loss, or interpersonal deficits will be more
likely to show elevated depressive symptoms. A second group
at risk may be patients for whom the cardiac event itself
represents a major loss or role transition. Patients with this
depressogenic vulnerability may not be as severely depressed
as those with cognitive distortions, but their depressive symptoms are also unlikely to remit spontaneously without intervention, because the defined interpersonal problems and interpersonal functioning deficits are considered relatively
The predominant behavioral theory of depression postulates that major life stressors can result in a depressive episode
because they disrupt normal behavior reinforcement patterns
(59). Originating from an operant conditioning paradigm, this
theory views depression as the consequence of a lack of or
decrease in the efficiency of positively reinforced behavior
and perhaps overt punishment for behavioral initiation. This
may be a result of a decrease in the availability of reinforcing
events, ones personal skills to act on the environment, the
impact of certain types of events, or a combination of these. In
addition, the mobilization of support from family and other
social networks may result in a negative feedback loop of
social reinforcement for depressive behaviors (eg, social withdrawal, positive social reinforcement for withdrawal, further
withdrawal). In other words, in times of major stress from
unexpected events, people may experience a low rate of positive reinforcement for mood-enhancing behavior and a higher
rate of positive reinforcement for depressive behavior.
The behavioral treatment that derives from this theory of
depression involves helping patients increase their frequency
and quality of pleasant activities. It has been found that
depressed patients have low rates of pleasant activities and
obtained pleasure; their mood covaries positively with rates of
pleasant activities and inversely with rates of aversive activPsychosomatic Medicine 66:165173 (2004)


ities (60). Finally, behavioral treatment for depression has
been shown to be efficaciousto reduce depressionin multiple randomized controlled trials (59, 61).
Lewinsohn (20) discussed dysphoria (defined by him as the
presence of low levels of negative mood symptoms) as the
affective state that results when few environmental positive
reinforcers are available for a persons behavior. Older people,
and particularly patients hospitalized for a life-threatening
event, are at greater risk than people at other points in the life
cycle, with the possible exception of children, for being placed
in situations in which their own behavior has little effect on
the environment or the behavior of others (62). Thus, the
disruption of the pattern of reinforcement for self-initiated
behaviors that occurs when a patient experiences an ACS
event is pertinent to the behavioral theory of depression.
Frequently, ACS risk factor management recommendations
compound this problematic behavior pattern. For example,
patients who experience smoking or eating a saturated fat-rich
meal as positively reinforcing frequently report that most of
the pleasant or pleasurable activities in their lives have now
been restricted or removed because of their health-damaging
Although therapeutic approaches to depression more often
involve both cognitive and behavioral components than either
1 alone, component analyses have shown that behavioral
activation appears to be as effective as cognitive therapy for
altering negative thinking and dysfunctional attributional
styles and for producing change in depressive symptoms and
course of relapse (63).

Lack of Pleasant Events in the Etiology of Depression

The behavioral theory of depression posits that the specific
proximal cause for depression is the interaction of the patient
behavior and the reinforcement schedule of the environment.
The frequency of pleasant events is lower in depressed compared with normal controls (64, 65), mood covaries with this
frequency (60), and behavioral depression treatment increases
pleasant event occurrence in those who have their depression
successfully treated. For example, Wierzbicki and Rexford
(65) studied the frequency and pleasantness or unpleasantness
of positive and negative events (assessed with the Pleasant
Events Schedule and the Unpleasant Events Schedule) in a
clinical sample of 60 people diagnosed with any DSM-III
depressive disorder (major affective disorder, dysthymic depression, or atypical depression), and in a nonclinical sample
of 143 undergraduate students. They found that in both samples, depression scores on the BDI were negatively related to
the frequency and pleasantness of pleasant events and were
positively related to the frequency of unpleasant events. Importantly, Grosscup and Lewinsohn (60) demonstrated in depressed patients that scores on daily ratings of the Unpleasant
Events Schedule and Pleasant Events Schedule were associated with daily fluctuations in mood level. Moreover, during
the course of a specific treatment targeted at increasing pleasant activities, a decrease in the subjective aversiveness of
Psychosomatic Medicine 66:165173 (2004)

events was associated with clinical improvement in depression

In summary, the behavioral theory of depression postulates
that low rates of positive events and therefore the absence of
positive reinforcement are central to the induction and maintenance of depressive symptoms. Depressed people compared
with nondepressed people have fewer pleasant events, and
behavioral treatment aimed at increasing pleasant events successfully decreases depression. It is less clear whether the
behavioral theory has a prediction about the course of depression in patients with ACS. One possibility is that as the time
from the ACS event lengthens, the frequency of pleasant
events occurrence and behavior reinforcement will naturalistically increase, and depressive symptoms will decrease. As a
consequence, post-ACS patients with a behavioral reinforcement disruption as the proximal cause for their depressive
symptoms will be more likely to remit spontaneously than
those with the other 2 depression proximal causes.
In real-life clinical settings, the specific proximal causes
that each theory focuses on are not treated as distinct dimensions of functioning, but rather as interrelated domains. This is
supported by empirical evidence. For example, Whisman and
Friedman (66) demonstrated that in a sample of 390 undergraduate students, higher levels of dysfunctional attitudes
were associated with higher levels of interpersonal problems,
even when controlling for negative affect. In the study of
Wierzbicki and Rexford (65), higher dysfunctional attitude
scores were related to less positive behavioral events and more
unpleasant behavioral events in both a clinical, treatmentseeking sample and an undergraduate student sample. More
importantly, both pleasant events and dysfunctional attitudes
were independently associated with depressive symptoms in
both samples. Although not directly tested in the Wierzbicki
study, this also suggests an independent, additive effect of the
presence of more than 1 proximal cause on depressive levels.
For the specific population of post-ACS patients, the prevalence of the proposed proximal causes and their relationship
with depressive symptoms has yet to be determined. Theoretically, one would expect a higher incidence of depressogenic
vulnerabilities in this population in comparison with the normal population, given that the overall rate of subthreshold and
clinically diagnosed depressive disorder is higher (1, 4, 9).
Furthermore, an ACS constitutes a severe life event with
considerable threat potential and disruptiveness in peoples
daily routines and social lives. Under these circumstances, all
3 vulnerabilities are likely to elicit depressive symptoms temporarily, exacerbate existing subthreshold depression, and
even provoke the onset of a new episode of major depression.
Interpersonal problems may arise from major lifestyle changes
that are prescribed to the patients (eg, abstaining from shared
activities, engaging in special diets). In the case that physi169

K. W. DAVIDSON et al.
cally demanding activities have to be restricted (eg, caregiving
for other family members), or partial or full work retirement is
recommended, the ACS event coincides with a major, irreversible role transition. Pre-existing, quiescent cognitive distortions may be reinforced or activated through the experience
of the uncontrollable, adverse, life-threatening event (eg, bad
things always happen to me, I will never be able to lead a
fulfilling life again). Because of the restrictions and demands
of lifestyle changes, patients may experience a decrease of
pleasant activities and increase of unpleasant activities (eg,
abstaining from smoking, drinking, adherence to aversive
medication and attendance at routine, but anxiety-provoking
medical checkups).
For the application of existing psychosocial depression
treatments to post-ACS patients, a number of parameters on
which this population differs from psychiatric populations
studied by the major depression theories must be considered.
The original populations were generally self-identified; they
were usually without major medical comorbidity; they were
mostly young or middle-aged; they met full criteria for formal
psychiatric or depressive disorders; and finally and importantly, they sought and accepted psychological treatment. In
contrast, the majority of patients with ACS will not selfidentify as being depressed, they all have an acute medical
disease, many do not meet full criteria for a depressive disorder, and they may be unwilling to seek or accept depression
treatment. Moreover, most of these patients are older than 50
years, with a substantial proportion of these patients elderly or
very old.
These characteristics pose specific challenges for the implementation of psychosocial depression treatments. In patients with medical comorbidity, depressive symptoms are
typically underdiagnosed (67). This applies especially to subthreshold depression (68) and depressive symptoms in the
elderly population (69). Although depression is the most common mental health problem from which older adults suffer
(69), they underutilize mental health services, they are less
likely to self-identify as being depressed, and, once interested
in seeking treatment, they must overcome many practical
barriers to obtain mental health treatment (70). Even when
referred to a mental health professional, older patients are less
likely than younger patients to seek specialized mental health
care (71); this is probably in part because of the stigma
perceived by this patient population in seeking mental health
treatment (72).
As Coyne and Thompson (73) have pointed out, evidence
for successful treatment of depressive symptoms in populations of primary care patients is sparse and based on heterogeneous populations and interventions. Further, even when
treatments reduce depressive symptoms, improvements in
event-free survival rates are not necessarily achieved, as recent results of 1 medium-sized antidepressant and 1 large170

sized cognitive-behavioral intervention trial suggest (74, 75).

For women, psychosocial interventions targeted at loneliness
or distress reduction even showed a trend toward higher
post-ACS event risk (75, 76). Coyne and Thompson (73)
argue that, when implementing and evaluating psychological
interventions in primary care settings, the specificity of the
conditions to be treated (eg, general distress, subthreshold
depression, dysthymia, or major depression) and the specificity of the treatment protocols must be considered (73). These
concerns clearly extend to post-ACS, subthreshold depressed
For all of these reasons, it would be premature to introduce
a theoretically derived treatment intervention to post-ACS
dysphoric patients without first demonstrating that the presumed proximal causes (for example, cognitive distortions)
occur at relatively high rates in this population. That is, given
the differences between the population on which these theories were derived and tested and the post-ACS patient population, we need to test the generalizability of these depression
theories by determining whether their postulated proximal
causes are useful for characterizing the subthreshold depressed ACS population.
Should that be the case, the evidence-based depression
treatment protocols will have to be tested for their acceptability, safety, and efficacy in this population. We hypothesize
that a better matching between the primary proximal cause of
depressive symptoms for each patient to the evidence-based
treatment specifically designed to modify that proximal cause
will improve patient and cardiologist acceptance of the treatment. Further documentation of sufficient efficacy in reducing
subthreshold depressive symptoms in post-ACS patientsa
desirable outcome in itselfalong with a demonstration of
pathophysiological risk reduction will aid in the planning of
the next outcome-based depression intervention trial in this
population. If typical depressogenic proximal causes appear to
be absent or only minimally present in this patient population,
alternative depression theories and alternative depression
treatments must be explored for their potential application.
Finally, the reasons why these types of symptoms may exist in
these patients and the meaning of these symptoms must also
be carefully considered. Thus, it may be that a third common
factorsuch as geneticsis driving the association noted
between depressive symptoms and ACS recurrence.
Link Between Subthreshold Depression and Acute
Coronary Syndrome Recurrence Risk Factors Is
Based on Common Genetic Factors
Both depression and coronary artery disease are highly
prevalent, heterogeneous chronic conditions that are the product of multiple gene by environment and gene by gene interactions. That is, these conditions tend to run in families, but no
single gene causes depression or coronary artery disease. For
depression and coronary artery disease, a gene could be a risk
Psychosomatic Medicine 66:165173 (2004)


factor, similar to an environmental factor such as diet or
smoking. The pathophysiology of these conditions involves
many interconnected pathways of otherwise distinct regulatory systems. For example, dysregulation of the coagulation,
inflammatory, hormonal, metabolic (lipid and carbohydrate),
autonomic, or endothelial systems may contribute to CHD.
Interestingly, the genetic information coding for some basic
element (ie, a protein) is used in different organs for different
functions. For example, the serotonin transporter protein in the
brain is thought to be involved in the regulation of mood, and
the same protein on blood platelets participates in blood clot
formation. The glucocorticoid receptors regulating the corticotropin-releasing factor in the brain are also present on
lymphocytes to downregulate the inflammatory response.
Therefore, it is reasonable to argue that frequent and normal
variation of a gene, whether or not necessitating the interaction of an environmental factor or another gene, could be
associated with an increased risk of depression and CHD (77).
However, data confirming a specific genetic contribution
common to both conditions are lacking. For example, for the
serotonin transporter-linked promoter region polymorphism,
the data are so far inconclusive. Research suggests that patients with the long allele (l/l) have a more efficacious serotonin transporter, leading to better reuptake of serotonin inside
platelets, higher secretion of platelet factor 4 (78), and heightened platelet activation (79). Interestingly, a large study has
found that the l/l allele predicts the incidence of myocardial
infarction among previously healthy participants (80). In addition, the l/l allele is associated with a better (81) or a more
rapid (82) antidepressant response to selective serotonin reuptake inhibitor. In contrast, it is the short allele (s/s), interacting with stressful life events, that predicts the incidence and
the severity of depression (83). Clearly, a further explication is
needed for the interaction between this allele and the environment, and this allele and pathophysiological mechanisms implicated in both depression and CHD.
Subthreshold Depression Is an Index of Illness
Even though empirical data strongly support the notion that
subthreshold depression contributes to post-ACS recurrence
and mortality risk independent of other known risk factors, we
cannot rule out the possibility that these symptoms are merely
an expression of more severe underlying medical problems.
One possibility is that patients reporting minor depressive
symptoms are actually reporting feeling more medically ill
than nondepressed patients as a result of more severe underlying disease processes that are not captured by the known
medical risk factors.
Link Between Subthreshold Depression and Acute
Coronary Syndrome Recurrence Risk Factors Is
Based on Common Inflammatory Processes
Another third variable or confounder possibility that has
received much attention recently focuses on inflammatory
processes, which are known to promote the progression of
atherosclerosis (84) and also cause depressive symptoms.
Psychosomatic Medicine 66:165173 (2004)

Studies of cell-mediated immunity have frequently (although

not uniformly) demonstrated immunosuppression in depressed
patients compared with normal controls (85). In animals, the
experimental induction of infection and inflammation through
the administration of proinflammatory cytokines results in a
pattern of depression-resembling sickness behaviors (eg, reductions in activity, social and sexual interaction, and food
and water intake; increasing anhedonia; and altered sleep; 86).
In humans, there is some evidence that immune activation
through viral infections may precede depressive symptoms,
and the administration of proinflammatory cytokines has been
shown to produce depressive symptoms in healthy, nondepressed adults (87). However, a recent study comparing markers of systemic inflammation and severity of depressive symptoms in clinically depressed and nondepressed healthy adults
failed to find evidence for the sickness behavior model (88).
Also, successful treatment of depressive symptoms is associated with reductions in the magnitude of inflammation (89),
suggesting that the relationship between depressive symptoms
and inflammation may be bidirectional. It has yet to be determined whether the higher risk associated with elevated depressive symptoms in post-ACS patients is epiphenomenal
because proinflammatory processes are driving the excess
risk, or whether inflammation is the mediator of the causal
effect of depressive symptoms on ACS recurrence.
From the available evidence, it appears safe to conclude
that the more symptoms of what is commonly thought to be
depression patients have at the time of their ACS hospital
admission, the greater their risk for subsequent cardiac events.
However, the meaning of these symptomswhether they
indicate a subclinical depressive episode, a history of depressive illness, or a chronic untreated inflammatory state, or
reflect a more severe medical illness has not yet been established, and clarification is sorely needed. Most studies have
not considered the role of a previous history of depression, and
this also needs to be considered carefully in determining the
meaning of these depressive symptoms during a medical crisis. Before we know the meaning of these symptoms, treatment both for the relief of suffering and for the possible
prevention of additional ACS events remains a formidable
Post-ACS patients with a BDI of 10 or greater assessed
during their cardiac event hospitalization are at independent,
increased risk for sudden cardiac mortality and ACS recurrence. Unknown are the levels or rates of psychosocial depression proximal causes present in these patients and whether
the proximal causes predict distinct courses (remittance vs.
nonremittance) of depressive symptoms. Cognitive distortions
and role transitions or losses are predicted to identify those
who do not show depressive symptom improvement naturalistically, whereas absence of positive events may identify

K. W. DAVIDSON et al.
those who will be more likely to remit spontaneously. Studying the point prevalence of the differing depression theory
proximal causes will allow us a window into the meaning of
these elevated depression symptoms in post-ACS patients.
Should depressogenic vulnerabilities be highly prevalent and
predictive of nonremission and ACS recurrence, the selection
of evidence-based depression treatments most likely to treat
depressive symptoms successfullyand possibly prevent
ACS recurrencein these patients becomes clear. Alternatively, should the commonly studied depressogenic vulnerabilities be rare or nonpredictive in these patients, pursuing
alternative conceptualizations of subthreshold depression
symptoms becomes urgent.
1. Glassman AH, Shapiro PA. Depression and the course of coronary artery
disease. Am J Psychiatry 1998;155:4 11.
2. Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, Marks
J. Depressed affect, hopelessness, and the risk of ischemic heart disease
in a cohort of U. S. adults. Epidemiology 1993;4:28594.
3. Aromaa A, Raitasalo R, Reunanen A, Impivaara O, Heliovaara M, Knekt
P, Lehtinen V, Joukamaa M, Maatela J. Depression and cardiovascular
diseases. Acta Psychiatr Scand 1994;377(suppl):77 82.
4. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial
infarction, and total mortality in a community sample. Circulation 1996;
93:1976 80.
5. Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ.
Depression is a risk factor for coronary artery disease in men: the
precursors study. Arch Intern Med 1998;158:1422 6.
6. Bush DE, Ziegelstein RC, Tayback M, Richter D, Stevens S, Zahalsky H,
Fauerbach JA. Even minimal symptoms of depression increase mortality
risk after acute myocardial infarction. Am J Cardiol 2001;88:337 41.
7. Carney RM, Freedland KE, Rich MW, Jaffe AS. Depression as a risk
factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002;53:897902.
8. Denollet J, Sys SU, Brutsaert DL. Personality and mortality after myocardial infarction. Psychosom Med 1995;57:58291.
9. Frasure-Smith N, Lespe rance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA 1993;270:
1819 25.
10. Frasure-Smith N, Lespe rance F, Juneau M. Differential long-term impact
of in-hospital symptoms of psychological stress after non-q-wave and
q-wave acute myocardial infarction [published erratum]. Am J Cardiol
11. Frasure-Smith N, Lespe rance F, Talajic M. Depression and 18-month
prognosis after myocardial infarction. Circulation 1995;91:999 1005.
12. Ladwig KH, Roll G, Breithardt G, Budde T, Borggrefe M. Post-infarction
depression and incomplete recovery 6 months after acute myocardial
infarction. Lancet 1994;343:20 3.
13. Lespe rance F, Frasure-Smith N, Juneau M, Theroux P. Depression and
1-year prognosis in unstable angina. Arch Intern Med 2000;160:
1354 60.
14. Lespe rance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk
of cardiac mortality in relation to initial severity and 1-year changes in
depression symptoms after myocardial infarction. Circulation 2002;105:
1049 53.
15. Rugulies R. Depression as a predictor for coronary heart disease: a review
and meta-analysis. Am J Prev Med 2002;23:51 61.
16. Beck AT. Cognitive therapy: past, present, and future. J Consult Clin
Psychol 1993;61:194 8.
17. Beck AT, Rush AJ, Saw BF, Emery G. Cognitive therapy of depression.
New York: Guilford; 1979.
18. Beck JS. Cognitive therapy: basics and beyond. New York: Guilford;
19. Klerman G, Weissman M, Rounseville B, Chevron E. Interpersonal
psychotherapy of depression. New York: Basic Books; 1984.
20. Lewinsohn PM, Antonuccio DO, Steinmetz-Breckenridge JL, Teri L. The
coping with depression course: a psychoeducational intervention for
unipolar depression. Eugene, OR: Castalia Publishing; 1984.

21. Beutler LE. Identifying empirically supported treatments: what if we

didnt? J Consult Clin Psychol 1998;66:11320.
22. Chambless DL, Hollon SD. Defining empirically supported therapies. J
Consult Clin Psychol 1998;66:718.
23. Chambless DL, Ollendick TH. Empirically supported psychological
interventions: controversies and evidence. Annu Rev Psychol 2001;52:
24. Chambless DL. In defense of dissemination of empirically supported
psychological interventions. Clin Psychol 1996;3:230 5.
25. Spangler DL, Simons AD, Monroe SM, Thase ME. Comparison of
cognitive model of depression: relationship between cognitive constructs
and cognitive diathesis-stress match. J Abnorm Psychol 1997;106:
395 403.
26. Carney RM, Freedland KE, Veith RC, Jaffe AS. Can treating depression
reduce mortality after an acute myocardial infarction? Psychosom Med
1999;61:666 75.
27. Kop WJ, Ader DN. Assessment and treatment of depression in coronary
artery disease patients. Ital Heart J 2001;2:890 4.
28. Lespe rance F, Frasure-Smith N, Talajic M. Major depression before and
after myocardial infarction: its nature and consequences. Psychosom Med
1996;58:99 110.
29. Carney RM, Freedland KE. Depression, mortality, and medical morbidity
in patients with coronary heart disease. Biol Psychiatry 2003;54:2417.
30. Schleifer SJ, Macari-Hinson MM, Coyle DA, Slater WR, Kahn M, Gorlin
R, Zucker HD. The nature and course of depression following myocardial
infarction. Arch Intern Med 1989;149:17859.
31. Endicott J, Spitzer TL. Schedule for affective disorders and schizophrenia
(SADS). Acta Psychiatr Belg 1987;87:361516.
32. Hance M, Carney RM, Freedland KE, Skala J. Depression in patients
with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry
33. Irvine J, Basinski A, Baker B, Jandciu S, Pauette M, Cairns J, Connolly
S, Roberts R, Gent M, Dorian P. Depression and risk of sudden cardiac
death after acute myocardial infarction: testing for the confounding
effects of fatigue. Psychosom Med 1999;61:729 37.
34. Beck AT. Depression: clinical, experimental, and theoretical aspects.
New York: Haper & Row; 1967.
35. DeRubeis RJ, Crits-Christoph P. Empirically supported individual and
group psychological treatments for adult mental disorders. J Consult Clin
Psychol 1998;66:3752.
36. Dobson KS. A meta-analysis of the efficacy of cognitive therapy for
depression. J Consult Clin Psychol 1989;57:414 9.
37. Hollon SD, Haman KL, Brown LL. Cognitive-behavioral treatment of
depression. In: Gotlib I, Hammen CL, editors. Handbook of depression.
New York: Guilford Press; 2002. p. 383 403.
38. Evans MD, Hollon SD, DeRubeis RJ, Piasecki JM, Grove WM, Garey
MJ, Tuason V. Differential relapse following cognitive therapy and
pharmacotherapy for depression. Arch Gen Psychiatry 1992;49:802 8.
39. Haaga DA, Dyck MJ, Ernst D. Empirical status of cognitive theory of
depression. Psychol Bull 1991;110:21536.
40. Smith TW, Christensen AJ, Peck JR, Ward JR. Cognitive distortion,
helplessness, and depressed mood in rheumatoid arthritis: a 4 year longitudinal analysis. Health Psychol 1994;13:2137.
41. Seligman MEP. Helplessness: on depression, development, and death.
2nd ed. New York: WH Freeman; 1991.
42. Peselow ED, Robins C, Block P, Barouche F, Fieve RR. Dysfunctional
attitudes in depressed patients before and after clinical treatment and in
normal control subjects. Am J Psychiatry 1990;147:439 44.
43. Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF, Elkin I,
Watkins JT, Imber SD, Leber WR, Moyer J, Oliveri ME. Patient predictors of response to psychotherapy and pharmacotherapy: findings in the
NIMH Treatment of Depression Collaborative Research Program. Am J
Psychiatry 1991;148:9971008.
44. Elkin I, Parloff MB, Hadley SW, Autry JH. NIMH Treatment of Depression Collaborative Research Program: background and research plan.
Arch Gen Psychiatry 1985;42:30516.
45. Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM, Collins JF, Glass
DR, Pilkonis PA, Leber WR, Docherty JP. National Institute of Mental
Health Treatment of Depression Collaborative Research Program: general effectiveness of treatments. Arch Gen Psychiatry 1989;46:971 82.
46. Beck AT. Cognition, affect, and psychopathology. Arch Gen Psychiatry
47. Ruehlman LS, West SG, Pasahow RJ. Depression and evaluative schemata. J Pers 1985;53:46 92.
Psychosomatic Medicine 66:165173 (2004)


48. Flett GL, Hewitt PL. Clinical depression and attributional complexity.
Br J Clin Psychol 1990;29:339 40.
49. Coyne JC, Whiffen VE. Issues in personality as diathesis for depression:
the case of sociotropy-dependency and autonomy-self-criticism. Psychol
Bull 1995;118:358 78.
50. Sullivan HS. The interpersonal theory of psychiatry. New York: Norton;
51. Bowlby J. Attachment. New York: Basic Books; 1969.
52. Sloane RB, Staples FR, Schneider LS. Interpersonal therapy versus
nortriptyline for depression in elderly. In: Clinical and pharmacological
studies in psychiatry disorders. London: John Libbey; 1985.
53. Miller MD, Cornes C, Frank E, Ehrenpreis L, Silberman R, Schlernitzauer MA, Tracey B, Richards V, Wolfson L, Zaltman J, Bensasi S,
Reynolds CF. Interpersonal psychotherapy for late-life depression. J Psychother Pract Res 2001;10:231 8.
54. Mossey JM, Knott KA, Higgins M, Talerico K. Effectiveness of a
psychosocial intervention, interpersonal counseling, for subdysthymic
depression in medically ill elderly. J Gerontol A Biol Sci Med Sci
1996;51:172 8.
55. Frank E, Kupfer DJ, Wagner EF, McEachran AB, Cornes C. Efficacy of
interpersonal psychotherapy as a maintenance treatment of recurrent
depression: contributing factors. Arch Gen Psychiatry 1991;48:10539.
56. Weissman MM, Markowitz JC. Interpersonal psychotherapy: current
status. Arch Gen Psychiatry 1994;51:599 606.
57. Gotlib I, Hammen C. Psychological aspects of depression: toward a
cognitive-interpersonal integration. Chichester: Wiley; 1992.
58. Hammen C, Brennan PA. Interpersonal dysfunction in depressed women:
impairments independent of depressive symptoms. J Affect Disord 2002;
59. Antonuccio DO. The coping with depression course: a behavioral treatment for depression. Clin Psychol 1998;51:35.
60. Grosscup SJ, Lewinsohn PM. Unpleasant and pleasant events, and mood.
J Clin Psychol 1980;36:2529.
61. Teri L, Logsdon RG. The future of psychotherapy with older adults.
Psychotherapy 1992;29:8197.
62. Blazer DG. Depression in late life. 2nd ed. St. Louis, MO: Mosby; 1993.
63. Jacobson NS, Dobson KS, Truax PA, Addis ME, Koerner K, Gollan JK,
Gortner E, Prince SE. A component analysis of cognitive-behavioral
treatment for depression. J Consult Clin Psychol 1996;64:295304.
64. MacPhillamy DJ, Lewinsohn PM. Depression as a function of levels of
desired and obtained pleasure. J Abnorm Psychol 1974;83:6517.
65. Wierzbicki M, Rexford L. Cognitive and behavioral correlates of depression in clinical and nonclinical Populations. J Clin Psychol 1989;45:
66. Whisman MA, Friedman MA. Interpersonal problem behaviors associated with dysfunctional attitudes. Cognit Ther Res 1998;22:149 60.
67. Wittchen HU, Hofler M, Meister W. Prevalence and recognition of
depressive syndromes in German primary care settings: poorly recognized and treated? Int Clin Psychopharmacol 2001;16:12135.
68. Pincus HA, Davis WW, McQueen LE. Subthreshold mental disorders:
a review and synthesis of studies on minor depression and other brand
names. Br J Psychiatry 1999;174:288 96.
69. Friedhoff AJ. Consensus panel report. In: Schneider LS, Reynolds CF,
Lebowitz BD, Friedhoff AJ, editors. Diagnosis and treatment of depression in late life: results of the NIH Consensus Development Conference.
Washington, DC: American Psychiatric Press; 1994.
70. George KL. Community and home care for mentally ill older adults. In:
Birren J, Slone RB, Cohen GD, editors. Handbook of mental health and
aging. 2nd ed. San Diego, CA: Academic Press; 1992.
71. Robinson P. Living life well: new strategies for hard times. Reno, NV:
Context Press; 1996.
72. Smith M, Buckwalter KC. Metal health care for rural seniors. Health Prog

Psychosomatic Medicine 66:165173 (2004)

73. Coyne JC, Thompson R. Psychologists entering primary care: Manhattan

can not be bought for $24 worth of beads. Clin Psychol 2003;10:102 8.
74. Glassman AH, OConnor CM, Califf RM, Swedberg K, Schwartz P,
Bigger JT Jr, Krishnan KR, van Zyl LT, Swenson JR, Finkel MS, Landau
C, Shapiro PA, Pepine CJ, Mardekian J, Harrison WM, Barton D, Mclvor
M. Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with
acute myocardial infarction or unstable angina. JAMA 2002;288:7019.
75. Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan
MJ, Czajkowski SM, DeBusk R, Hosking J, Jaffe A, Kaufmann PG,
Mitchell P, Norman J, Powell LH, Raczynski JM, Schneiderman N.
Enhancing Recovery in Coronary Heart Disease Patients Investigators
(ENRICHD). Effects of treating depression and low perceived social
support on clinical events after myocardial infarction: the Enhancing
Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized
Trial. JAMA 2003;289:3106 16.
76. Frasure-Smith N, Lesperance F, Prince RH, Verrier P, Garber RA, Juneau
M, Wolfson C, Bourassa MG. Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet 1997;16:4739.
77. Lespe rance F, Frasure-Smith N. The seduction of death. Psychosom Med
1999;61:18 20.
78. Whyte EM, Pollock BG, Wagner WR, Mulsant BH, Ferrell RE, Mazumdar S, Reynolds CF III. Influence of serotonin-transporter-linked promoter region polymorphism on platelet activation in geriatric depression.
Am J Psychiatry 2001;158:2074 6.
79. Laghrissi-Thode F, Finkel MS, Johnson PC, Pollock BG. Elevated platelet factor 4 and -thromboglobulin plasma levels in depressed patients
with ischemic heart disease. Biol Psychiatry 1997;42:290 5.
80. Fumeron F, Betoulle D, Nicaud V, Evans A, Kee F, Ruidavets JB,
Arveiler D, Luc G, Cambien F. Serotonin transporter gene polymorphism
and myocardial infarction: Etude Cas-Temoins de lInfarctus du Myocarde (ECTIM). Circulation 2002;105:29435.
81. Yu YWY, Tsai SJ, Chen TJ, Lin CH, Hong CJ. Association study of the
serotonin transporter promoter polymorphism and symptomatology and
antidepressant response in major depressive disorders. Mol Psychiatry
82. Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA,
Davis S, Kirshner MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ.
Allelic variation in the serotonin transporter promoter affects onset of
paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000;23:58790.
83. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H,
McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life
stress on depression: moderation by a polymorphism in the 5-HTT gene.
Science 2003;301:386 9.
84. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999;
85. Irwin M. Immune correlates of depression. Adv Exp Med Biol 1999;461:
86. Dantzer R. Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci 2001;933:22234.
87. Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R,
Shavit Y, Ovadia H, Weidenfeld J, Morag A, Newman ME, Pollmacher
T. Illness, cytokines, and depression. Ann N Y Acad Sci 2000;917:
478 87.
88. Miller GE, Freedland KE, Carney RM, Stetler CA, Banks WA. Pathways
linking depression, adiposity, and inflammatory markers in healthy young
adults. Brain Behav Immun 2003;17:276 85.
89. Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP. Treatment of
depression is associated with suppression of nonspecific and antigenspecific T(H)1 responses in multiple sclerosis. Arch Neurol 2001;58:
1081 6.