568342
research-article2015
CDPXXX10.1177/0963721414568342Monroe, AndersonDepression: The Shroud of Heterogeneity
Depression: The Shroud of Heterogeneity
Scott M. Monroe and Samantha F. Anderson
Current Directions in Psychological
Science
2015, Vol. 24(3) 227­–231
© The Author(s) 2015
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DOI: 10.1177/0963721414568342
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University of Notre Dame
Abstract
Over the past several decades, depression has emerged as a major public health problem. Yet depression has not
always represented such a prominent psychiatric condition, and the term depression has harbored different meanings
over time. One widely agreed upon way of explaining such variation in what depression implies has been to describe
depression as being heterogeneous. In the present article, depression is examined in relation to different types of
heterogeneity, particularly with regard to the concept of a syndrome. The consequences of various meanings of
heterogeneity for understanding the nature of depression are then explored. Finally, we speculate on the implications
for the future of depression research and practice.
Keywords
depression, classification, diagnosis, heterogeneity, psychological disorders
Over the past few decades, depression has emerged as
one of the most prominent mental disorders and pressing
public health problems. It is currently the leading cause
of disease-related disability worldwide (World Health
Organization, 2012). Long known as one of the most significant contributors to suicide, depression now is recognized to be associated with life-threatening diseases (e.g.,
coronary heart disease and diabetes). Without question,
a strong consensus exists about the importance of this
highly prevalent and destructive condition (Monroe &
Harkness, 2011).
However, depression has not always been viewed as
such a serious problem. Some contend that only 50 years
ago depression was a relatively rare and obscure psychiatric condition, confined largely to the severely afflicted in
the back wards of psychiatric hospitals (Healy, 1997). And
although descriptions approximating what we currently
label depression can be traced far back into history, what
“depression” signifies has also varied considerably over
time and place (Berrios, 1988; Jackson, 1986). This semantic elasticity is detectable in contemporary incarnations of
the term: “Depression” carries with it many connotations,
which in turn contribute to ongoing confusion about its
nature and classification (Cole, McGuffin, & Farmer, 2008;
Parker, 2014).
This problem of multiple meanings is evident in even
the most basic of tasks: defining clinical depression.
According to current practices, two people can be diagnosed with an episode of major depression without
sharing a single symptom. Although patients may have
symptoms in common, there are sundry alternative and
unique constellations of signs and symptoms that can
qualify for a formal diagnosis of major depression
(American Psychiatric Association, 2013). With some lifetime estimates for the prevalence of major depression
exceeding 40% (Moffitt et al., 2010), unprecedented numbers of individuals are becoming depressed, and doing
so in potentially many different ways.
Statistics such as these must give pause to many. The
skeptic might wonder how two people could suffer from
the same underlying disorder but not share any of its core
defining attributes. The cynic might dismiss the situation
as a social construction of contemporary culture. And the
historian might wonder how things could have changed
so dramatically over such a brief period of time—or even
if the construct of depression is becoming so general and
diffuse that it no longer serves a useful purpose and will
return to its putative obscurity of the early 1960s.
Our goal in the present article is to consider how
depression has come to be what it appears to be today,
and to suggest how such an analysis can inform expectations for the future. While inconsistencies and controversies abound, the field approaches unanimity on one
Corresponding Author:
Scott M. Monroe, Department of Psychology, 118 Haggar Hall,
University of Notre Dame, Notre Dame, IN 46556
E-mail: smonroe1@nd.edu
Monroe, Anderson
228
Table 1. DSM-5 Criteria A Symptoms for Major Depressive Disorder
Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from
previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not
include symptoms that are clearly attributable to another medical condition.
1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless)
or observation made by others (e.g., appears tearful).
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated either
by subjective account or observation).
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or
decrease or increase in appetite nearly every day.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or
being slowed down).
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely selfreproach or guilt about being sick).
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by
others).
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or
specific plan for committing suicide.
Note: Adapted and reprinted from the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; pp. 160–161), by the American Psychiatric
Association, 2013, Arlington, VA: American Psychiatric Publishing. Copyright 2013 by the American Psychiatric Association. Reprinted with
permission.
point: Depression, as currently conceived, encompasses
a broad range of mental and physical states. Depression
is heterogeneous. Consequently, we focus on this theme
of heterogeneity and its implications for depression.
Heterogeneity in Depression
Most simply, heterogeneity refers to variation in signs
(observable manifestations), symptoms (subjective
reports), and syndromes (combinations of signs and
symptoms associated with depression). The phenotypic
expression of depression (i.e., presenting signs and
symptoms) can vary substantially from one depressed
person to another. This may be in terms of both the
severity of specific indicators and the range of symptoms.
Heterogeneity in this sense can be expanded, also, to
address variation in clinical course over time. Overall,
this phenotypic or horizontal heterogeneity is confined
to the observable or reportable features of depression.
Heterogeneity also refers to variation in the theoretical
causes, or etiology, of depression. On the one hand, this
can be straightforward: Different causes lead to the
shared phenotype of depression. For example, one person may become depressed in response to life stress,
whereas another may become depressed as a result of a
genetic predisposition. This vertical heterogeneity implies
that there are distinctive subtypes of depression with
their own particular causes.
However, etiologic heterogeneity can be more difficult
to pin down. The causes of depression often are referred
to as “multifactorial.” This position compounds the
heterogeneity problem. First, it means that many factors
contribute to depression. These individual factors,
though, vary in their effects across persons, such that
heterogeneous causal arrangements can bring about
depression. Second, it suggests that there is a “final common pathway” through which these alternative causal
complexes converge, initiate, and ultimately orchestrate
the features of depression (Akiskal & McKinney, 1975).
Thus, although different vulnerabilities might bring about
depression, they eventually do so via common mechanisms and processes.
The critic might begin to wonder why people with so
many phenotypic and etiologic differences are believed
to suffer from the same disorder. To understand this, we
next take a more basic look at the defining features of
major depression.
Heterogeneity and the Defining
Features of Depression
What are the criteria for defining clinical depression, and
how are they brought together to diagnose an episode?
Can an analysis at this level shed further light upon the
heterogeneity problem? Table 1 lists the symptoms of
major depression as specified in the Diagnostic and
Statistical Manual of Mental Disorders, fifth edition
(DSM-5; American Psychiatric Association, 2013).
Most of the individual symptoms of depression are
readily recognizable as extensions of common human
feeling states. These include emotional and physical
responses to everyday life, as well as to the less frequent
Depression: The Shroud of Heterogeneity
major challenges of human existence. It is the unusual
person in the population who does not evidence any of
these symptoms to some degree. To some extent, depression is a part of everyday life.
Depression and its features, then, can be both a part
of normal functioning and a severe psychological disorder. The criteria listed in Table 1 are imperfect indicators
of the clinical meaning of depression. This is yet another
form of heterogeneity, a dimensional one, wherein the
continuum of depression’s symptoms blends normal,
understandable, everyday negative emotions with more
psychopathological states. Although the diagnosis of
depression also requires a number of other criteria be
met (American Psychiatric Association, 2013), there is no
attention to the patterning of the indicators for a primary
diagnosis. All combinations are presumed to be of equal
information value.
Given the symptoms of depression, part of the heterogeneity of depression can be easily explained. This is
because there could be serial dependencies between
some of the symptoms. For example, someone with
“troubles sleeping” will also likely experience “fatigue or
loss of energy” and “diminished ability to think or concentrate.” Some researchers even contend that depression can be explained at this phenotypic or symptom
level, without recourse to assumptions about underlying
mechanisms or disorders (Borsboom & Cramer, 2013).
More generally, many people can be diagnosed with
depression yet exhibit symptoms that vary widely and
whose origins can be traced to very different underpinnings. One might ask, again, why it is assumed that
depressed persons whose symptoms sometimes appear
similar, sometimes rather different—and sometimes
entirely different—suffer from one common disorder. We
suggest that this passive acceptance of heterogeneity
stems from confusion about what a syndrome represents
in science and medicine.
The Premise and the Promise of a
Syndrome
Technically, as defined by the Oxford English Dictionary,
a syndrome is “a concurrence of several symptoms in a
disease” (“Syndrome,” n.d.). The syndrome concept helps
to explain similarities—not perfect likenesses—in the
concurrences and course of symptoms. Not all persons
suffering from the same condition will display the exact
same constellation of signs and symptoms or an identical
clinical course. The general similarities, however, can be
sufficient to suggest a distinctive syndrome, which in turn
can be an indicator of a distinctive disorder.
Distinguishing a specific syndrome has many advantages. It supplies a working definition for a condition of,
229
as yet, unknown origins. Importantly, it also implies a
common underlying pathophysiology (e.g., shared mechanisms and processes), which likely results from the same
etiology. Most importantly, these hypothetical shared
mechanisms provide the meaning and coherence associated with the particular arrangement of signs, symptoms,
and courses: They cohere because of the orchestrating
influences of these underlying mechanisms.
More generally, a syndrome recognizes yet unites
“noisy” variation in the manifestations of a disorder. This
helps to mitigate the larger heterogeneity problem and to
carve out a more homogenous entity; it also enhances
the likelihood of finding a common underlying pathophysiology and possible cause. With a deeper understanding of these matters, treatment and prevention can
be more effectively developed based upon recognized
causes and mechanisms.
But can there be a potential problem with such reasoning? By permitting some degree of heterogeneity in
symptoms, a syndrome helps to identify potentially similar conditions that have variability in their phenotypic
expression. But at what point might heterogeneity
become an unproductive way to think about the matter,
a conceptual carte blanche? The allure of a distinctive
syndrome may blind investigators to the illusions that it
can foster.
The Dark Side of the Syndrome
Concept
The syndrome concept is an integral tool in science and
medicine. But the slippery part of classification and diagnosis is the process of “recognizing things to be alike
when they are not identical,” as well as to be different
when they appear similar (Bronowski, 1978, p. 21). It is
in this vague and imprecise realm that problems can arise
and vague insights based on imperfect similarities and
differences eventually may prove to be clear oversights.
Specifically, when are similarities and differences sufficient to demarcate a distinctive syndrome? With regard to
depression, how can phenotypes that share few, or no,
overlapping features reflect the same syndrome and, in
effect, a common underlying disorder? In essence, what
are the boundaries of the syndrome concept?
Little attention has been paid to this question. In part,
this is because the idea of a syndrome has become such
an entrenched and overpowering premise. In theory, a
syndrome not only carves out a specific condition, it also
presupposes a concrete pathophysiology and cause, simplified down to presumed basic biological mechanisms
and processes. If a syndrome can be distinguished—or
declared, it creates an aura—or an illusion—that the
problem is well on its way to being resolved.
Monroe, Anderson
230
It is this aura surrounding the syndrome premise that is
important to consider. A syndrome confers an air of certainty—scientific, medical, and cultural legitimacy. It
serves as a reassuring placeholder for the eventual and
inexorable discovery of the true disorder and its biological causes. With these extra-theoretical functions, a syndrome begins to reify all conditions that fall under its
patronage. Thus sanctioned, heterogeneity becomes malleable and may potentially be appropriated for misleading
professional, social, economic, and scientific agendas.
No longer are symptoms arranged in some consequential way to signify underlying mechanisms and possible etiology. Rather, they have become a constellation
of symptoms—many rather common over the course of
life—and, as such, perhaps no more intrinsically meaningful than the constellations of stars in the heavens
above (Mirowksy & Ross, 1989).
Depression at a Crossroads?
About 100 years ago, Americans were afflicted with a
mental disorder of epidemic proportions (Schuster, 2011).
Called neurasthenia, and often referred to as the
“American disease,” it began its medical odyssey as a disabling condition, with sundry signs and symptoms, often
overlapping with what today we would call depression,
anxiety, fatigue, and general malaise. It was an attractive
alternative to the more stigmatizing diagnoses of the day
(thought to be degenerative and highly heritable).
Presumed to be firmly anchored in biological origins, initially considered to afflict only society’s elite, and believed
to be treatable, neurasthenia in time caught the attention
of legions. It helped to encapsulate, explain, embody,
and legitimate a multitude of ailments and miseries.
All but unknown in America today, neurasthenia provides a fascinating reference point for thinking about
current-day problems and misconceptions about depression. For some 30 years, neurasthenia was the de facto
explanation for an expanding array of uncomfortable and
overwhelming physical and mental states. But the more
heterogeneous the conditions that neurasthenia came to
subsume and to legitimize, the less useful it became.
Neurasthenia largely faded from medical nomenclature
in America after about 1910. Could such a fate await
depression?
“Major depression” officially entered the psychiatric
nomenclature in 1980 (American Psychiatric Association,
1980; Hirshbein, 2007). Through good intentions over
the intervening 30-plus years, depression has become
increasingly widely recognized through public awareness campaigns, the media, and education programs
for general practitioners. Further, because Americans
live in one of the very few countries in the world allowing direct-to-consumer pharmaceutical advertising, the
American population has become unusually well versed
via television commercials in the warning signs of, and
availability of pharmaceutical treatments for, depression. Arguably, perhaps no other society has ever been
so attuned to, or concerned about, its emotional wellbeing. All of these factors likely have catapulted depression into the psychiatric and social limelight and
expanded its “detection” and diagnosis over time.
We speculate that depression, as we currently know it,
will not be sustained much longer. The point has been
reached where respected spokespersons on the topic are
in stark disagreement. Some lament the “loss of sadness,”
contending that understandable unhappiness has become
overly medicalized as major depression (Horwitz &
Wakefield, 2007). In contrast, others contend that depression has been overly romanticized and, even in its mildest forms, eventually will be eradicated from society
(Kramer, 2005). Should these diametrically opposing
viewpoints be politely shrugged off as additional reflections of “heterogeneity”?
There are good reasons to be optimistic about progress that can come from insights into the heterogeneity
problems in depression. These may be partially resolved
through distinguishing clinically meaningful subtypes,
which in turn could guide investigators toward discovering more substantive syndromes. For instance, recent
research suggests that major depression can be a destructive and highly recurrent disorder or a more benign and
time-limited condition (e.g., Wakefield & Schmitz, 2014).
As yet, little is known about what distinguishes the firstonset cases of depression who will never suffer a recurrence from those who will do so repeatedly—why or
how someone who becomes clinically depressed for the
first time does or does not suffer subsequent recurrences
(Monroe & Harkness, 2011).
The recent National Institutes of Mental Health
Research Domain Criteria (RDoC) initiative, too, holds
promise for tightening our understanding of depression
and its boundaries (Cuthbert & Kozak, 2013). The RDoC
project promotes the identification of syndromes based
upon pathophysiology, with a primary focus on neural
circuitry and its relationships with behavior. Such an
approach could realign the syndrome concept as originally intended, reflecting specific underlying mechanisms—not presupposing them. By removing the shroud
of heterogeneity, advances along lines such as these may
be made to help so many people suffering from such
mysterious and multifarious conditions.
Recommended Reading
Borsboom, D., & Cramer, A. O. J. (2013). (See References).
An interesting article that introduces an alternative way to
conceptualize the interrelations of signs, symptoms, and
syndromes.
Depression: The Shroud of Heterogeneity
Horwitz, A. V., & Wakefield, J. C. (2007). (See References). A
book whose authors provide an in-depth and careful analysis of the challenges involved in distinguishing responses to
adversity and understandable unhappiness from the disorder of major depression.
Kramer, P. D. (2005). (See References). An insightful and very
readable account of the destructive biological aspects of
depression.
Monroe, S. M., & Harkness, K. L. (2011). (See References). A
review article that makes the case that the likelihood of
recurrence of major depression has been overestimated
and that the emphasis on the recurrent forms of depression
has overshadowed the substantial number of people who
have only one episode over the life course.
Wakefield, J. C., & Schmitz, M. F. (2014). (See References). A
recent empirical study that demonstrates the potential for
distinguishing subtypes of depression that have very different clinical implications over the life course.
Acknowledgments
S. M. Monroe gratefully acknowledges support from the John
Simon Guggenheim Memorial Foundation.
Declaration of Conflicting Interests
The authors declared that they had no conflicts of interest with
respect to their authorship or the publication of this article.
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