SPECIAL ARTICLES
Clinically Significant Non-Major Depression
Old Concepts, New Insights
Helen Lavretsky, M.D.
Anand Kumar, M.D.
Clinically significant non-major depression has been underinvestigated despite its
high prevalence and public health impact. Although there is an increasing recognition
of the importance of non-major forms of depression, their nosological boundaries and
neurobiological mechanisms remain largely unknown. The authors discuss the literature pertaining to the current concepts, phenomenology, neurobiology, and treatment approaches to geriatric non-major clinically significant depression. They examine the similarities and differences between various subtypes of depressive
disorders and compare non-major, clinically significant depression in elderly patients
with non-geriatric adult populations. They draw conclusions from the published literature and propose clinical criteria for the diagnosis of clinically significant nonmajor depression in elderly persons. (Am J Geriatr Psychiatry 2002; 10:239–255)
D
epression in later life has serious health consequences, including increased mortality related to
suicide and medical illness and amplification of disability associated with medical and cognitive disorders, often resulting in increased healthcare costs.1,2 Although
major depression is the most studied and well-defined
depressive syndrome, other depressive syndromes and
subsyndromal disorders are also associated with significant functional impairment and disability,3–7 and these
clinical categories have only received scant attention in
the psychiatric literature.
This article focuses on clinically significant depression that does not meet established criteria for Diagnostic and Statistical Manual of Mental Disorders, 4th
Edition (DSM) Major Depressive Disorder (MDD). This
category encompasses several clinical subtypes with
subtle distinctions. We begin by discussing the clinical
heterogeneity and nosological complexities of these disorders as currently described in the literature. (See Table 1.) We highlight the phenomenological, neurobiological, and therapeutic evidence in support of this
category of disorders. Also, we integrate information on
elderly patients with data from non-geriatric adult patients with comparable clinical impairment on domains
such as epidemiology, neurobiology, and treatment. Finally, we draw conclusions about the validity of this
clinical category on the basis of the published literature
and recommend future areas of research.
Nosological and Diagnostic Complexities
In current psychiatric practice and research in both
elderly patients and younger adult populations, two
principal approaches define depression: 1) depressive
Received August 14, 2001; revised September 4, 2001; January 31, 2002; accepted September 6, 2001. From the Department of Psychiatry and
Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, CA. Address correspondence to Dr. Helen Lavretsky, UCLA-Neuropsychiatric
Institute, Room 37-425, 760 Westwood Pl., Los Angeles CA 90095.
Copyright 䉷 2002 American Association for Geriatric Psychiatry
Am J Geriatr Psychiatry 10:3, May-June 2002
239
Area of Research
Epidemiology
1. Community samples
Authors
Beekman et al., (1999)60
Heun et al., (2000)114
Steffens et al., (2000)66
Newman et al., (1998)61
Henderson et al., (1993)58
Am J Geriatr Psychiatry 10:3, May-June 2002
2. Medical illness
Koenig, (1998)72
Lyness et al., (1999)115
Study Design
Sample
Depressive Subtype
Major depression, minor
Review of 16 community
depression, depressive
studies of geriatric
symptoms
depression in 22,794
patients
Community sample; 86
Rates of lifetime prevalence Major, minor, and
subjects age 60 and older
subthreshold depression
Results
Weighted average prevalence of major
depression was 1.8%; minor
depression: 9.8%; depressive
symptoms: 13.5%
4.9% had a lifetime diagnosis of major
depression; 31.8% had either minor
or recurrent brief depression
90% of Cache County
4,559 subjects, ages 65–100 Major, minor, subclinical
Prevalence of major depression was
(Utah) elderly
years
depression
4.4% in women and 2.7% in men;
community sample
lifetime prevalence was 20.4% in
women and 9.6% in men,
decreasing with age; only 35.7%
with major depression were treated
with antidepressants
Community survey in
1,119 community residents Major and minor depression Prevalence of GMS-AGECAT
depression (11.4%) was higher than
Edmonton, Canada
age 65 and older,
the DSM-III-R diagnosis of Major
administered the
(0.86%) or Minor depression (3.6%),
Geriatric Mental State
which was determined mainly by
(GMS) Questionnaire and
proportion of dysphoric symptoms
compared with the DSMon the instrument
III-R diagnoses
Cross-sectional prevalence ICD-10 and DSM-III-R
Depressive disorder vs.
Elderly subjects had many depressive
and clinical-correlates
depressive diagnoses
symptoms
symptoms that did not increase
study of depression
with age; the number of depressive
symptoms correlated with
neuroticism, poor physical health,
disability, and previous depression
Prevalence of depression in 542 consecutive medical
Major and minor depression Rate of major depression was 36.5% in
patients with congestive
patients
patients with CHF, vs. 25.5% in
heart failure (CHF)
patients without CHF; rate of minor
depression was 21.5% in patients
with CHF, vs. 17% in patients
without CHF
Prevalence of depression in 224 outpatients age 60 and Major, minor, subsyndromal 31.7% of patients had a diagnosis of a
older in the Outpatient
depression
mental disorder; major depression:
primary care patients and
Family Medicine and
6.5%; minor depression: 5.2%;
associated functional
Internal Medicine
subsyndromal: 9.9%; and dysthymia:
disability
practices
0.9%; subsyndromal depression is
associated with functional disability
and medical comorbidity, and often
treated with antidepressants
Literature review by level
of “caseness”
Significant Non-Major Depression
240
TABLE 1. Summary of the representative studies of non-major, clinically significant depression
Am J Geriatr Psychiatry 10:3, May-June 2002
TABLE 1. Summary of the representative studies of non-major, clinically significant depression (continued)
Area of Research
3. Neurological illness
Authors
Study Design
83
Outcomes
Results
Major and minor depression 17% had major and 11% minor
depression at 4 months post-stroke;
predictors of depression included
functional impairment, living in a
nursing home, being divorced
33 patients with Alzheimer Depressive symptoms
Frequency ranged from 6%–33%,
disease (AD)
depending on definition of depression
and instruments used
19 patients with PSP and 42 Depressive symptoms
42% of the PSP group had mild-towith PD
moderate depression; 52% of patients
had some degree of dementia
Risk factors for post-stroke
depression in 4-month
follow-up
Cummings and Litvan,
(1995)84
Cross-sectional study
Menza et al., (1995)81
Cross-sectional comparison
of patients with Parkinson
disease (PD) and
progressive supranuclear
palsy (PSP)
Four diagnostic systems for 274 community-dwelling
elderly subjects
dementia and depression
compared by using Latent
Trait Analysis
Geiselmann and Bauer,
(2000)4
Epidemiological Berlin
Aging Study (BASE)
Oxman et al., (1990)116
Cross-sectional comparison 193 outpatients in the
of older and younger adults Internal Medicine and
Family practices
2-year follow-up
20 bereaved elderly
subjects
Pasternak et al., (1994)117
Depressive Subtype
191 first-ever stroke
patients followed for 4
months
Burvill et al., (1997)
Grayson et al., (1987)23
Phenomenology
Sample
Community sample
Cross-sectional association
study of depression and
disability
646 community-dwelling
older adults, age 55–85
years
Penninx et al., (2001)119
Longitudinal follow-up of
the community sample
2,847 community-dwelling
persons age 55–85; 450
subjects with and 2,397
subjects without cardiac
disease
DSM-III, Gurland’s system and
AGECAT and clinician’s ratings were
used; two distinct clusters of
symptoms were identified, and the
level of severity (threshold) was
identified
Subthreshold depression,
Subthreshold depression had fewer
dysthymia, major
symptoms, with less continuity, with
depression
fewer suicidal ideations, thoughts of
guilt, or worthlessness
Minor depression
No differences observed between
older and younger adults with minor
depression
Subsyndromal depression
Subsyndromal depression was
associated with greater functional
impairment, worse sleep quality, less
perceived interpersonal support, and
more intense grieving than
nondepressed bereaved subjects
Major and minor depression Associations of major and minor
depression with disability and wellbeing remained significant after
controlling for chronic disease and
functional limitations; adequate
treatment was often not administered,
even in subjects with major
depression; major and minor
depression were associated with
increased use of non-mental health
services
Major depression (DSM-III) Depression increased risk of cardiac
and minor depression (CES- mortality in subjects with and without
cardiac disease; excess cardiac
Dⱖ16)
mortality was more than twice as high
for major depression than for minor
depression
(continued)
Lavretsky and Kumar
241
Beekman et al., (1997)118
Depression and dementia
TABLE 1. Summary of the representative studies of non-major, clinically significant depression (continued)
Am J Geriatr Psychiatry 10:3, May-June 2002
Longitudinal follow-up of
the community sample
2,847 community-dwelling
persons age 55–85; 450
subjects with and 2,397
subjects without cardiac
disease
Penninx et al., (2000)120
Longitudinal follow-up of a
community sample (4.5
years)
3,107 older persons (age
55–85)
Penninx et al., (1998)71
Epidemiologic follow-up of
community samples (the
established populations for
epidemiologic studies of
elderly subjects)
4,825 persons age 71 years
and older followed up at 3
and 6 years
Neuroimaging
Kumar et al., (1998)102
Genetics
Anderson et al., (1996)121
Cross-sectional, quantitative
MRI study; whole-brain
volumes and normalized
measures of prefrontal and
temporal volumes
Family study of
subaffective, character
spectrum, and primary
dysthymia
18 subjects with minor
depression, 35 patients
with late-onset major
depression, and 30 normalcontrol subjects
97 early-onset dysthymic
outpatients received
diagnostic interview and
family history interviews
Remick et al., (1996)91
Family study
Examined first-degree
relatives of probands with
depressive-spectrum
diagnosis
Probands with minor
depression, major
depression, dysthymia, and
“double” depression
Rosen et al., (2000)44
6-week open-label study of
sertraline treatment of
minor depression
Cognitive-behavioral
intervention for minor
depression
Randomized 11-week
effectiveness trial
12 nursing home residents
Minor depression
Interventions
Dai et al., (1999)122
Williams et al., (2000)45
Major depression (DSM-III) Depression increased risk of cardiac
and minor depression (CES- mortality in subjects with and without
Dⱖ16)
cardiac disease; excess cardiac
mortality was more than twice as high
for major depression than for minor
depression
Major depression (DSM-III) At baseline, 12.8% had minor
and minor depression (CES- depression, and 2% had major
Dⱖ16)
depression; minor depression was
associated with a significantly greater
decline in functional status and
performance, as well as with
increased risk of death in men; major
depression increased risk of functional
decline and death in men and women
Chronic depression (CES-D) When present for at least 6 years,
based on cut-off criteria
depression was associated with a
generally increased risk of cancer,
after controlling for age, sex, race,
disability, hospital admissions, alcohol
intake, and smoking
Major and minor depression Normalized prefrontal lobe volumes
show a significant linear trend with
severity of depression, with volumes
decreasing with depression severity
Dysthymia, subaffective
disorder
Elderly Chinese Americans Minor depression
assigned to intervention vs.
control
Comparing paroxetine with Minor depression,
dysthymia
placebo and problemsolving therapy in primary
care (PST-PC)
Subaffective depression subjects had
higher rates of major depression,
depressive symptoms, and depressive
personality features, as well as higher
rate of alcoholism in families
When morbidity risks were calculated
using the maximum-likelihood
approach for the first-degree relatives,
results showed no significant
differences in morbidity risk to firstdegree relatives
75% achieved remission and all
tolerated medication well
Experimental group showed an
improvement; control group did not
Paroxetine group showed greater
symptom resolution than placebo
group in patient with dysthymia and
minor depression; patients treated
with PST-PC did not show more
improvement than placebo group, but
their symptoms improved more
rapidly than those of placebo patients
Note: The table includes representative studies of late-life major and non-major depression, as well as genetic studies addressing depressive spectrum disorders.
Significant Non-Major Depression
242
Penninx et al., (2001)119
Lavretsky and Kumar
symptoms; and 2) more specific depressive illnesses or
disorders defined in terms of duration, number, and
type of depressive symptoms. Most nonpsychiatrists
typically regard depression in terms of the first construct, whereas psychiatrists apply the second.8 Most
studies demonstrate that patients with depressive symptoms, even in the absence of a specific depressive disorder, experience considerable morbidity and reduced
social functioning.8,9
Only a few of the depressive spectrum disorders
currently have official descriptive definitions in the
DSM-IV.10 An even smaller number have gained the
status of a “syndrome.” These include Major Depression, Dysthymic Disorder, Mood Disorder Due to a General Medical Condition, Substance-Induced Mood Disorder, Adjustment Disorders, and Depressive Disorder,
Not Otherwise Specified (NOS). The last category encompasses several very different and conceptually
evolving subcategories, including Minor Depressive Disorder, Premenstrual Dysphoric Disorder, and Recurrent
Brief Depressive Disorder. According to DSM-IV, Minor
Depression may be subsumed within either Dysthymia,
Adjustment Disorder with Depressed Mood, or Depression, NOS. Recognizing these ambiguities and overlap,
DSM-IV has published tentative criteria sets for Minor
Depressive Disorder, Recurrent Brief Depressive Disorder (RBD), and Mixed Anxiety–Depressive Disorder.
This exhaustive list of mood disorders does not however cover all categories of “clinically significant depression.”
The existing clinical and semantic overlap makes
any assumptions about the true prevalence of nonmajor depression somewhat questionable. For example,
the term “minor” depression is frequently used to denote all clinically significant forms of depression that
fail to meet the criteria for major depression, rather than
to the syndrome described in the DSM-IV. The term
“subthreshold major depression” emerged to classify patients with fewer than five clinically significant depressive symptoms, thereby not meeting the criteria for the
diagnosis of major depression. This patient group was
found, in two epidemiological surveys, to have significant impairment in social and occupational functioning.11,12 Data are sparse on the clinical course and outcome and on the risk of suicide in patients diagnosed
with these conditions.
psychiatry and the behavioral sciences. The basic presumption in medicine—that a classification based on
etiology is the most valid—is not applicable in psychiatry, given the lack of clarity about the etiology of nearly
all mental disorders.13 Descriptive categorization of psychiatric syndromes remains the principal approach to
classifying and understanding mental illnesses.13,14 A
syndrome may be operationally defined as a cluster of
related symptoms and signs with a characteristic time
course.13,14 It may consist of abnormal behaviors, subjective experiences, or a combination of the two.13 By
definition, primary psychiatric disorders are idiopathic
syndromes in which no defined disease processes are
known to cause the manifest symptoms and signs.15
Syndromes are often treated as distinct from one another, and this approach forms the basis of both the
DSM and the International Classification of Diseases
(ICD) for psychiatric disorders. The DSM and ICD systems operationalize diagnostic concepts, standardize
the nomenclature,16,17 and provide the principal dialects for communication in psychiatry and the behavioral sciences around the world.16,17 However, a purely
categorical approach has fundamental limitations, potentially impeding our understanding of the nature of
these disorders. It is based on the assumption that the
psychiatric syndromes are largely distinct from one another and mutually exclusive. This distinction is assumed despite the fact that only a few psychiatric disorders have been adequately validated, and genuine
boundaries or points of rarity between the various clinical syndromes and normality remain nebulous. Currently existing constructs of depression frequently overlap or co-exist and often fail to predict disease course
and/or treatment outcome.18–20 Summarizing this approach to psychiatric classification, Kendell14 eloquently says, “Our ignorance of etiology forces us to
define most disorders by their symptoms, and syndromes merge insensibly into one another and into normal distress with no obvious natural boundaries or
points of rarity to separate them.”
In their classic paper, Robins and Guze21 proposed
criteria for the validation of clinical syndromes. These
comprise the following:
1.
Historical Perspective
The classification of mental disorders has posed a
fundamental challenge to clinicians and researchers in
Am J Geriatr Psychiatry 10:3, May-June 2002
2.
Identification and description of the syndrome, either by “clinical intuition”or by cluster analysis;
Demonstration of the natural boundaries or
“points of rarity” between related syndromes by
243
Significant Non-Major Depression
3.
4.
5.
6.
discriminant-function analysis, latent class analysis, and other statistical approaches;
Follow-up studies establishing a distinctive course
and outcomes;
Therapeutic trials establishing a distinctive treatment response;
Family studies establishing that the syndrome
“breeds true”;
Association with some more fundamental abnormality—histological, psychological, biochemical,
or molecular.
Few, if any, syndromes or disorders in the DSM
classification have been validated with standardized
criteria. The majority of existing clinical studies are
based on narrowly-defined samples that exclude much
of the variability of the affective phenomena under
consideration.15 They include psychiatric patients
with categorically-defined depressive disorders, and
one must be especially cautious when concluding that
different samples of depressed patients are phenomenologically distinct from one another.
The dimensional approach to classifying psychiatric disorders is an alternative described in various research studies.22–28 This approach conceptualizes behavioral syndromes as occurring along more than one
dimension. For example, depression and anxiety may
be conceptualized as two “parallel” dimensions, as opposed to distinct, mutually exclusive categories.23 Also,
the vegetative and “psychic” or cognitive aspects of
mood may be treated as two coexisting dimensions in
patients with clinical depression. Psychometric techniques, such as the latent trait analysis, have been used
to model the relationship between variables and to identify clusters of symptoms forming a dimension.22,24,29–32
The widely used categorical approach is helpful when
considering specific interventions for individual disease
states. The dimensional approach more accurately captures symptoms and syndromes as overlapping clinical
phenomena that reflect underlying traits and core psychopathological processes of mental illnesses.33
Diagnostic Controversies
The instability of psychiatric diagnoses over time
has raised questions about the validity of the contemporary diagnostic classification system of depression.
Angst and colleagues34,35 reported that there is little stability among the specific subtypes of depression expe-
244
rienced by those who continue to manifest depression
during the follow-up period. Changes in clinical presentation and severity of depression are frequently encountered over time. Categories such as “subsyndromal”
(SSD), “subclinical,” or “subthreshold” depression have
been described to denote clinically significant symptoms of depression that linger over a period of time.34–37
The results of the 1996 International College of Neuropsychopharmacology (CINP) President’s Workshop
supported the conclusion that unipolar major depressive disorder is a pleiomorphic mood disorder consisting of a cluster of depressive subtypes existing in a relatively homogeneous, symptomatic clinical continuum.
This extends from subsyndromal depressive symptomatology through minor depressive episode, dysthymic
disorder, major depressive disorder, and “double depression.” The workshop38 argued that subsyndromal
and minor depression represent clinically significant depressive subtypes commonly observed during the
course of illness in patients with unipolar major depressive illness. Similarly, in research on geriatric depression, the emphasis is shifting from studying, almost
exclusively, major depressive syndrome toward studying non-major depressive disorders.39 Whereas the exclusively etiological approach identified only the most
severe cases of depression,40 the inclusive approach to
diagnosing depression predicts outcomes most accurately. It is also supported by the observation that while
the prevalence of MDD decreases with age, the prevalence of minor depression and depressive symptoms appear to actually increase.
It is clear from the emerging literature that clinically
significant depression that does not meet criteria for
MDD is responsible for considerable psychosocial and
functional compromise.35–37,39,41 Also, the relationship
of these categories to MDD is dynamic and tends to
change over time. Prospective longitudinal data from
the studies of young adult patients reveal that subthreshold depression and other forms may be both an
antecedent to and sequela of MDD, thereby providing
evidence for the validity of the spectrum concept of
depression.35 Despite the broad impact and clinical relevance of these factors, information on the natural
course, neurobiological correlates, and treatment response of non-major depression is fragmentary at the
present time. Several nosological entities may be subsumed under the rubric of non-major, clinically significant depression, thereby complicating the overall picture both conceptually and clinically.
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Lavretsky and Kumar
DIFFERENTIAL DIAGNOSIS
Minor Depression
Minor Depressive Disorder is now included in the
DSM-IV as a “potential category,” with a set of diagnostic
research criteria proposed for further studies.10 The essential feature of minor depression is one or more periods of depressive symptoms that are identical to major
depressive episodes in duration (2 weeks or longer), but
which involve fewer symptoms and less impairment. An
episode involves either a depressed mood or loss of interest or pleasure in nearly all activities. In total, at least
two, but fewer than five, additional symptoms must be
present. During the episode, these symptoms cause
clinically significant distress or impairment in social, occupational, or other important areas of functioning. In
some individuals, there may be near-normal functioning, but this is accomplished with significantly increased effort. The diagnosis of Minor Depression is excluded if there is a history of a major unipolar or bipolar
mood disorder or a psychotic illness. Using this construct, minor depression may be conceptualized as part
of a depressive spectrum defined by the number of
symptoms and their severity, as well as the duration of
the episode.
The recommended DSM-IV criteria notwithstanding, definitions of minor depression vary among different investigators, which contributes to the confusion of
dealing with this group of disorders. Broadhead and associates11 defined minor depression with mood disturbance as the presence of 2 weeks of depressed mood
or anhedonia plus one or more other symptoms of depression. Minor depression without mood disturbance
is defined as one or more symptoms of depression for
2 weeks, without depressed mood or anhedonia.5,41 Minor depression without mood disturbance was included
because of a concern that individuals with depressive
symptoms may have a depressive spectrum disorder
without depressed mood or anhedonia. Bruce and colleagues42 defined “dysphoria” as 2 weeks or more of
feeling “sad, blue, depressed, or when you lose all interest and pleasure in things you usually cared about or
enjoyed.” Skodol and colleagues43 defined minor depression as presence of one or more symptoms of depression, one of which must be dysphoria or anhedonia. According to Beck and Koenig,5 diagnoses of
major depression or dysthymia must be excluded.
Little is known of the natural history of minor de-
Am J Geriatr Psychiatry 10:3, May-June 2002
pression. About 20% of those diagnosed with minor depression have had a lifetime diagnosis of major depression.7 As many as one-third to one-half of patients with
major depressions do not have a full recovery and have
residual symptoms consistent with minor depressive
syndrome.5,7 Minor depression is associated with considerable discomfort, disability, and morbidity,44 as well
as with the excessive use of non-mental health services.3 Despite the obvious mental and public health
significance of this group of disorders, only a few studies have focused on minor depression. The existing
studies consistently report undertreatment of depressed
elderly patients in primary care and nursing home settings, a factor that underscores the importance of the
recognition of non-major depression.4,44–48
Subsyndromal “Depressive Spectrum”
The category of subsyndromal “depressive spectrum” disorders (SSD) has been proposed by different
investigators in the course of their conducting longitudinal studies of large populations of adult and geriatric
patients. In a 15-year follow-up, community-based,
cohort-study, Angst and colleagues34 studied the longitudinal course of young adult patients diagnosed with
MDD, dysthymia, recurrent brief depression (RBD), and
minor depression. They found very little stability for the
specific types of depression among those who continued to manifest depression during the follow-up period:
51% of patients with MDD and 44% of those with RBD
met criteria for another subtype of depression. When
stability was observed, the same subtype occurred in
combination with the development of another subtype.
Among subjects with a single subtype, severity was
greatest among those with dysthymia, whereas individuals with combined subtypes had greater severity than
those with a single subtype. Despite the demonstrated
close relationship between subthreshold and threshold
depressive disorders, there was also a need for maintaining the threshold criteria in diagnostic approaches
because of the lack of predictive value of minor depression and depressive symptoms for the illness outcome. They suggested that symptom threshold and recurrence, but not the minimum duration of depressive
episodes, should serve as a basis for classification.
Judd and colleagues36 have observed, in their prospective naturalistic follow-up study of 431 adult patients initially diagnosed with MDD, that depressive
symptoms at threshold for minor depression or dysthy-
245
Significant Non-Major Depression
mia (27%) and subthreshold depressive symptoms
(17%) were more common than MDD (15%). SSD was
operationally defined as any two or more concurrent
symptoms of depression (DSM), present for most or all
of the time, for at least 2 weeks, associated with evidence of social dysfunction, occurring in individuals
who do not meet criteria for the diagnosis of minor
depression, major depression, and/or dysthymia. SSD
was initially subcategorized into SSD with and without
depression. The former overlapped considerably with
the DSM-IV category of Minor Depression. Therefore,
the revised criteria only included patients who did not
meet criteria for Minor Depression; that is, without the
14-day depressed mood/anhedonia requirement. They
suggested that the most common SSD symptoms include insomnia, feeling tired, recurrent thoughts of
death, and trouble concentrating. They also proposed
that the symptomatic course is dynamic and changeable, thus representing a symptomatic continuum of a
single disease category.
Other Diagnostic Categories
A number of mood disorders may be considered in
the differential diagnosis of non-major clinically significant depression (DSM-IV).10 Adjustment Disorder with
Depressed Mood is diagnosed if the depressive symptoms occur in response to a psychosocial stressor. Criteria for Depressive Disorder, Not Otherwise Specified
(NOS) differ from those for MDD in the number of presenting symptoms; that is, fewer than five symptoms
can be present. Depressive symptoms occurring in response to the loss of a loved one are considered bereavement. Substance-Induced Mood Disorder is due to
the direct physiological effects of a drug of abuse or the
side effects of a medication (e.g., steroids). Mood Disorder Due to a General Medical Condition is diagnosed
when depression is considered to be due to the direct
effect of a general medical condition. Recurrent Brief
Depressive Disorder is defined as an episode lasting less
than 2 weeks but longer than 2 days, that recurs at least
once per month for 12 consecutive months. In summary, the same combination of signs and symptoms,
occurring in the context of diverse antecedents (medical and psychosocial) have been classified and categorized as distinct clinical entities in standard psychiatric
nosology.
246
DOES GERIATRIC “NON-MAJOR
DEPRESSION” DIFFER FROM
DEPRESSION IN YOUNGER ADULTS?
Some similarities and differences exist in phenomenology and disease course of depression in elderly patients
and in younger adults.49–51 Unlike major depression,
with its preponderance of biological and melancholic
features, the clinical presentation of minor depression
is variable.52 Blazer and colleagues9 identified a symptom cluster profile unique to people over 60 years old,
characterized by depressed mood, psychomotor retardation, poor concentration, constipation, and poor selfperception of health. This cluster was associated with
cognitive deficits and physical illness and did not correspond to any particular DSM category. The spectrum
of geriatric depression also extends to patients with underlying medical or progressive dementing illnesses
who may develop depression during the course of those
illnesses. In bereavement, subsyndromal and minor
depression stood between major depression and nodepression in terms of their effect on the overall adjustment to widowhood,53 thus, supporting the “spectrum” concept. Prigerson and colleagues54 identified
distinct patterns of symptoms in complicated grief and
bereavement-related depression that were associated
with enduring functional impairment. Similarly, some
investigators have identified clinical features of dysthymia that are clearly different in elderly patients; these
include the late onset, medical comorbidity, cognitive
deterioration, and frequent adverse life events.55–57
Epidemiology and Clinical Features
The nosological status of minor depression, together with the variability in diagnostic criteria, contribute to the variability in prevalence estimates of these
disorders.26,58,59 Relevant factors include differences in
diagnostic systems, severity threshold, and duration of
illness required for the diagnosis of various affective
states/disorders.60,61 Despite these methodological considerations, there is broad consensus on the prevalence
and clinical impact of non-major forms of mood disorders in both the community and more specialized clinical settings.
A. Community samples. Minor and other non-major
forms of clinical depression are more prevalent in adult
and elderly populations than MDD. Re-analyzing the Ep-
Am J Geriatr Psychiatry 10:3, May-June 2002
Lavretsky and Kumar
idemiologic Catchment Area data, Judd and colleagues37
reported a 1-year prevalence of “subsyndromal depression” of 11.8% using the criterion of more than two
symptoms for at least 2 weeks. This figure exceeds the
9.5% 1-year combined prevalence for all the DSMdefined mood disorders. Tannock and Katona8 suggested that depressive symptoms or subsyndromal cases
of minor or mild depression are very common in the
elderly population. Blazer and Williams62 found that
14.7% of their community sample over age 65 had substantial depressive symptoms. Despite methodologic
differences, there is an emerging consensus that the
prevalence of minor depression changes with age: there
is an increase in symptoms in people in their 30s, a
decrease in middle age, a steady increase in old age, and
a very steep increase in people over age 80.5,63 This
phenomenon appears unrelated to the increased mortality, somatization, or increased institutionalization
among depressed elderly persons.5,40 There is also a suggestion of mitigation of severe depression with age.63,64
Caine et al.15 argue that much of the affective spectrum
symptomatology in elderly community populations is
not captured by our current diagnostic entities. Most,
although not all, studies also suggest that prevalence
rates are higher in women and among older people living under adverse socioeconomic circumstances.65,66
B. Long-term care settings. The prevalence rates of
minor depression have been estimated in special populations and settings. For example, it affects up to 50%
of residents in long-term care facilities and up to 25%
of patients in primary care settings.44,67 In all settings,
the prevalence of depressive symptoms is two- to fourfold higher than major depression.48,67 Among institutionalized elderly patients, up to 70% feel “depressed,
sad, or blue” at least enough to cause minor problems
in their day-to-day activities.48 Elderly nursing home and
congregate-apartment residents were screened for
symptoms of depression. Of 708 survey respondents,
12.4% met the DSM-III-R criteria for Major Depression.
Another 30.5% of the total sample reported less severe,
but nonetheless marked, depressive symptoms. Such
“minor” depressive syndromes were much more common among congregate-housing than nursing home residents. Possible major depression was more prevalent
among newly admitted residents of both housing components.
Am J Geriatr Psychiatry 10:3, May-June 2002
C. Medical settings. Most patients with mental illness
are seen exclusively in primary care medicine.5,11,12 Primary care settings have therefore been the recent focus
of studies of minor depression. It is estimated that 3%
to 16% of medical outpatients suffer from minor depression. Up to 64% of medical outpatients will complain of depressed mood.5 Studies of depression in medically ill patients usually report the negative impact of
depression on the rate of recovery, as well as its overall
impact on disability, and increased cost of care.5,47,68–72
D. Geriatric depression in medically ill patients. A
review of the literature from 1965 to 1995 found the
reported prevalence of minor depression in medical
outpatients to be 3% to 16%.5 Up to 64% of medical
inpatients complained of depressed mood. In a study of
542 patients age 60 and older, Koenig72 reported higher
rates of major and minor depression in patients with
congestive heart failure (CHF) than in cardiac patients
without CHF (ratio of 1.5–2:1). Compared with nondepressed CHF patients, those with depression were
more likely to have comorbid psychiatric disorders, severe medical illness, and severe functional impairment.72 Patients often remained depressed for a prolonged period, and more than 40% failed to remit during
the year after their discharge.72 When the major and
minor depression groups were compared directly, no
significant differences were observed between them on
salient clinical and psychosocial measures.
A number of studies evaluated the impact of depression on outcomes. Depression was associated with excess disability in visually-impaired patients,68 poor treatment in elderly patients with non–insulin-dependent
diabetes (Type 2),69 and increased risk of falls and fractures.70 Chronic depression, when present for at least 6
years, may also increase risk for cancer in elderly women,
according to a recent epidemiological study.71
E. Depression in patients with degenerative and neurologic disorders. Many diseases of the central nervous system (CNS) are associated with increased prevalence of depression. Mood disturbances are commonly
observed in neurodegenerative disorders, including
probable Alzheimer disease (AD) and Parkinson disease
(PD) and after ischemic injury to the brain (post-stroke
depression).73–84 However, depression is not invariably
seen in all degenerative disorders, and the prevalence
and profile of the mood and behavioral aberrations are
relatively disease-specific. This suggests that specific
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Significant Non-Major Depression
neurobiological mechanisms and pathways may be responsible for mood disorders in certain conditions.73–75
In AD, both major depression and other clinically
significant forms of depression that do not meet threshold for MDD have been described.75–79 In certain study
samples, clinically significant minor depression and depressive symptoms are more prevalent than MDD and
have been reported in 20% to 40% of patients diagnosed
with AD.76–79 Prevalence estimates of depression in AD
vary widely, from 0% to as high as 86% in some samples.
Estimates of depression in PD also vary widely. Studies
using more stringent criteria for the diagnosis of depression suggest that the true prevalence of depression
in PD may be between 20% and 40%.80 Approximately
half these patients would meet criteria for MDD, and
the rest would show features consistent with minor
depression and dysthymia. Differences in diagnostic instruments and in the clinical methods used to diagnose
depression (patient interviews as opposed to caregiver
reports) probably contribute to these discrepant findings.75 Also, the overlap in clinical features between
AD, PD, and affective disorders also complicates the
diagnosis of depression in these disorders.75 The prevalence of depression is low in patients with frontotemporal dementia (FTD) and progressive supranuclear
palsy (PSP), thereby indicating that mood disturbances
are not a natural consequence of all forms of neurodegeneration.81,82,84 Impairment in neurotransmitter
function and selective atrophy in the forebrain nuclei
have been offered as explanations for the depression in
neurodegenerative disorders.81,82,84
Depression after vascular injury to the cerebral
hemispheres is now a well-recognized clinical entity.
Post-stroke depression may present as minor or major
depression and occur within 12 to 24 months after the
cerebrovascular accident.83 Major as well as less severe
forms of depression occur in patients with neurodegenerative and vascular disease.85 This observation, together with the absence of any biological rationale to
treat these categories as being distinct, lend credence
to the notion that major and other forms of depression
may represent a clinical continuum, rather than distinct
clinical entities.
Genetics
The results of the association studies in behavioral
genetics have been inconsistent. The explanations of
these inconsistencies include the lack of the diagnostic
248
precision in defining phenotypes, as well as biases from
population stratification (the mixture of individuals
from heterogeneous genetic backgrounds).86 These artifacts may occur because population stratification (or
admixture) due to ethnic or other confounding factors
can generate significant population differences in
marker allele frequencies. Sher86 suggested that a major
problem of association studies in psychiatric diseases is
that psychiatric diagnoses are not biologically real disease entities: a syndromal psychiatric diagnosis such as
depression includes etiologically, pathologically, and
prognostically heterogeneous disorders. For this reason,
genetic studies have not yet addressed subsyndromal
depressive-spectrum disorders.
On the “syndromal” level, traditional familial studies, designed to study heritability of depression, find a
relationship between major depression, bipolar depression, schizoaffective disorders, alcoholism, panic
disorder, eating disorders, and personality disorders,
thereby establishing a rather broad range of related
spectrum-disorders.87–90 Remick and colleagues91 examined first-degree relatives of probands with the diagnoses of minor depression, major depression, dysthymia and “double” depression in adults. When
morbidity risks were calculated for the first-degree
relatives using the maximum-likelihood approach, the
results showed comparable risks of depression in firstdegree relatives of probands with MDD, minor depression, and dysthymia. They drew the conclusion that,
from a genetic perspective, major depression, recurrent depression, minor depression, and double depression were indistinguishable.
There are no published genetic studies in elderly
patients examining the relationship of major depression
to other forms of mood disturbances. The few genetic
studies of depression in elderly patients have focused
primarily on the apolipoprotein-E genotype, a known
risk factor for AD,92–95 and its relationship to late-onset
depression96 and cerebrovascular disease in late-life depression.97 However, the results of these studies are inconsistent, and many investigators do not find any relationship between apolipoprotein-E genotype and
behavioral symptoms such as depression in either cognitively intact or impaired patients.98–100 Therefore, genetic studies of affective disorders,92–101 although limited, appear to support the concept of a continuum of
depressive disorders and suggest that further studies
should also include milder forms of clinically significant
depression.
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Lavretsky and Kumar
Neuroimaging, Cognitive,
and Polysomnographic Studies
Most neuroimaging studies in mood disorders are
largely restricted to patients with MDD. Magnetic resonance imaging (MRI) studies demonstrate that patients
with late-life MDD have smaller focal brain volumes and
larger high-intensity lesion volumes in the neocortical
and subcortical regions than control subjects.102,103 The
focal reductions in brain volume have been identified
in the prefrontal region, hippocampus, and the caudate
nucleus. The physiological correlates of MDD in late
life include widespread reductions in glucose metabolism and cerebral blood flow on PET, Xenon-133 inhalation, and single photon emission computed tomography (SPECT).103 Glucose hypometabolism in
MDD occurred in neocortical and subcortical regions.103 Cerebral blood flow and metabolism were reduced in prefrontal cortical regions, superior temporal, and anterior–parietal areas.104
Our recent study102 demonstrated that patients
with late-onset minor depression had smaller prefrontal
lobe volumes than age-matched nondepressed control
subjects. Our findings indicate that patients with minor
depression present with specific neuroanatomical abnormalities that are comparable with the major depression group but significantly different from control subjects.102 Normalized prefrontal lobe volumes showed a
significant linear trend with the severity of depression,
with volumes decreasing with illness severity. Wholebrain volumes did not differ significantly among the
groups. These findings suggest common neurobiological substrates for all clinically significant forms of depression with a late onset and support the “spectrum”
hypothesis of depression. Neuroanatomical abnormalities may represent one aspect of a broader neurobiological diathesis to mood disorders in late life. Although
these findings are intriguing, they clearly need to be
replicated before more definitive conclusions can be
drawn. Additional studies combining neuroimaging
with focused postmortem and other neurochemical
studies are also required to further elucidate the biological basis of late-life mood disorders. Studies are underway to examine the extent to which structural abnormalities of the brain, such as hyperintensities on
MRI, covary with functional deficits.
Preliminary unpublished observations from our laboratory suggest that patients with minor depression
have neuropsychological impairment levels that fall in
Am J Geriatr Psychiatry 10:3, May-June 2002
between patients with MDD and control subjects. In a
study of patients with late-onset major and minor depression and normal-control subjects, we asked
whether cognitive abilities decreased with increasing
severity of depression. Our results indicate that in domains such as verbal recall, executive functioning, processing speed, maintenance of set, and working memory, patients with minor depression (operationally
defined using modified DSM-IV criteria) had scores that
fell between the MDD and control groups. This decline
in cognitive performance parallels a similar group trend
in brain-volume demonstrated with MRI.102
Polysomnographic findings in adult patients with
subthreshold depressive depression demonstrated
shortened REM latency, increased REM sleep, redistribution of REM to the first part of the night, classic diurnality, high rate of family history of mood disorders, and
positive response to antidepressant medication and
sleep deprivation.105 Among primary care referrals to a
sleep disorders center, short REM latency was found in
a large number of patients without subjective mood
change but with somatic manifestation of depression.
Rather than being incidental, the REM disturbances in
the foregoing studies appear consistently in the
subthreshold affective group, which suggests a common neurophysiological substrate for subthreshold and
melancholic depression.105 Functional imaging studies
of subsyndromal mood disorders in late life are lacking,
but they could provide additional information about the
pathophysiology of these conditions as compared with
syndromal depression.
TREATMENT
To date, studies of treatment of non-major depressive
disorders are limited in number. Very little is known
about treatment strategies in clinically significant nonmajor depression. Most existing studies focus on dysthymia and minor depression in primary care.39,46,106,107
Descriptive studies have established that in treating
depression, primary care providers use one or more of
three modalities: watchful waiting, medication, and referral to the specialty sector.108 Used most commonly,
watchful waiting return visits provided sympathetic listening and a show of interest, and, in some cases, brief,
“common sense” counseling and suggestions for tensionreduction.108 Return visits also permitted the provider to
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Significant Non-Major Depression
monitor the patient’s symptom level. In approximately
50% of the instances when a referral to a specialist was
considered, the patient refused to accept it because of
cost, possible stigma, or problems with access.108 The
use of medication is virtually the only active treatment
given by primary care providers, but the evidence of
efficacy of psychopharmacologic interventions in nonmajor depression is currently lacking.
Open-Label Pharmacologic
Trials of Minor Depression
Only a few open-label trials among adult outpatients and nursing home residents find promise in alleviating depressive symptoms. In an open-label study of
fluvoxamine, patients with minor depression and
subthreshold depression associated with dysfunction
and disability demonstrated improvement in depression
and functioning.109 In an open-label trial of sertraline
involving 12 nursing home residents who met the
DSM-IV criteria for Minor Depressive Disorder, 75% of
patients reached remission by Week 6. All patients were
able to tolerate sertraline.44
Treatment of Depression in Neurological
and Degenerative Disorders
Although the high prevalence of clinically significant depression has been reported in many neurological
and neurodegenerative disorders, there have been only
13 relevant placebo-controlled trials of antidepressants,
of which only 3 had more than 10 subjects enrolled.85
Positive results were reported in the trials of citalopram in depressed patients with AD and post-stroke
depression and with use of desipramine in patients
with multiple sclerosis and brain injury.85 Nearly half
of the trials did not report drug–placebo differences.
These studies examined the use of imipramine, maprotiline, or clomipramine for depressed patients with
AD, trazodone for patients with poststroke depression,
and amitriptyline for patients with depression and epilepsy. Beneficial effects of nortriptyline were complicated by significant problems with orthostatic hypotension.85 Likewise, delirium and cardiovascular
morbidity occurred in patients taking nortriptyline for
post-stroke depression.85 Although it is clear that depression comorbid with neurological illness compounds disability and worsens outcomes, clear evidence in support
of effective pharmacological approaches is lacking.85
250
Psychotherapy and Combined Treatments
In the United Kingdom, with its general practicebased healthcare delivery system, attention had been
paid to developing brief, practical psychological treatments that could be provided in the primary care setting itself. Problem-solving therapy (PST) is based on
behavioral medicine principles and teaches a patient
that there can be a relationship between problems experienced and emotional symptoms, particularly in the
case of depression and anxiety.110,111 It is a collaborative
treatment, with the therapist and patient focusing on
regaining a sense of control over life’s problems, which
are likely to be important factors in resolving emotional
symptoms. PST is brief, lasting 4 to 6 sessions, for a total
of 2 to 4 hours, with most sessions fitting into a 30minute clinic visit. Non-mental health practitioners
could provide such treatment. Gath and Catalan110 and
Mynors-Wallis,111 at Oxford, reported a high level of patient acceptance and satisfaction with the treatment, as
patients readily understood and accepted the practical
value of acquiring problem-solving skills. The British investigators concluded that PST in primary care (PST-R)
was an effective alternative to medication treatment in
their primary care patients; it performed better than
placebo and was as effective as amitriptyline.112 In the
recent American randomized 11-week effectiveness
trial comparing paroxetine with placebo and PST in primary care (PST-PC), the paroxetine group showed
greater symptom-resolution than the placebo group.
Paroxetine showed moderate benefit for depressive
symptoms and mental health functioning in elderly patients with dysthymia and more severely impaired elderly patients with minor depression. The benefits of
PST-PC were smaller, had slower onset, and were more
subject to site differences than those of paroxetine. Patients treated with PST-PC did not show more improvement than placebo, but their symptoms improved more
rapidly than those of placebo patients during the latter
treatment weeks. PST-PC/placebo differences were
more pronounced in the minor depression group than
in patients with dysthymia.45
Current Trials of Pharmacological
and Combined Treatment of Depression
in Primary Care Settings
Several ongoing collaborative trials are addressing
the effectiveness of pharmacologic and nonpharmacol-
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Lavretsky and Kumar
ogic treatments of depression in primary care setting.
Two current collaborative trials are the NIMHsupported Prevention of Suicide in the Primary Care
Elderly Collaborative Trial (PROSPECT) study,106 and
the Hartford Foundation-supported Improving Mood:
Promoting Access to Collaborative Treatment for LateLife Depression (IMPACT) study, both are evaluating the
effectiveness of models in practices by nurse health specialists.107 The PROSPECT study was designed to evaluate the extent to which intervention targeting depression in older primary care patients with depression
could reduce risk factors for suicide, including suicidal
ideation, hopelessness, and depression. The Department of Veterans Affairs (the VA Unified Psychogeriatric
Biopsychosocial Evaluation And Treatment program
[UPBEAT]) project on mental health services in primary
care is evaluating the relative effectiveness of integrated
mental health services delivered in the medical care setting versus referral to mental health professionals for
older primary care patients with depression, anxiety
disorders, and alcohol abuse problems.107 All three of
the trials include patients with non-major depression.
At present, treatment approaches to non-major clinically significant depression remain unclear. However,
the results of a large, multi-site trial for minor depression and dysthymia in primary care45 offer some hope
in improving the outcomes of depression. In the absence of evidence to the contrary, antidepressant medications and psychotherapeutic interventions,113 alone
or combined, are currently the recommended course of
treatment.
CONCLUSIONS
There are similarities and differences in the manifestations of clinically significant depressive disorders. There
is an emerging consensus from epidemiological, longitudinal, and genetic studies supporting the idea of a
continuum of depressive disorders, ranging from the
very mild “subthreshold” to major unipolar and bipolar
disorders. Evidence from neuroimaging and neuropsychological studies lends additional support to this thesis. All forms of clinically significant depression are associated with considerable economic and psychosocial
consequences. Current approaches to studying affective illness, which adhere to traditional nosological categories, may no longer be adequate for the next gener-
Am J Geriatr Psychiatry 10:3, May-June 2002
ation of studies into the biological and psychosocial
correlates of this group of disorders. Rigid definitions
of the phenotype, without fully integrating clinical realities, greatly limits the scope of studies aimed at elucidating the true biological basis of mood disorders.
Applying the classical criteria outlined by Robins
and Guze21 for the validity of a diagnostic category, one
would be hard-pressed to draw meaningful distinctions
between major and non-major forms of depression in
elderly patients and non-geriatric adults with depression. Dividing patients with these forms of affective illness into encapsulated categories would require us to
ignore clinical and scientific realities for the sake of nosological simplicity. Mood disorders need to be conceptualized and studied along multiple dimensions, including severity, duration of illness, and treatment response.
Also, although there are similarities between geriatric
and non-geriatric depression with regard to phenomenology and other clinical features, there are also important differences that make the independent study of elderly patients crucial to our understanding of depression
in late life.
Our desire to draw sharp boundaries between serious mental disorders and transient states of distress
has contributed to our neglect of the biological and psychosocial basis of non-major forms of depression.
Clearly, the sustained and more extreme forms of mood
disturbances are easier to conceptualize as clinical disorders. The precise distinction between mood changes,
as a normal emotional response to the vicissitudes of
life, and depression, as a clinical disorder, is more nebulous in mild depressive states. Operationally defining
a condition is often a necessary first step in trying to
establish its clinical and biological correlates and demarcating its boundaries from other conditions and normality. However, any operational definition needs to be
clinically meaningful and should reflect all relevant dimensions of the condition. Defining a minimum “floor
effect” for the severity of depression, duration of symptoms, and overall psychosocial functioning, and integrating these domains cohesively would be an important first step in defining a plausible phenotype. In
elderly patients, cognitive and medical aspects are additional dimensions that need to be considered. A phenotype encompassing all of the relevant dimensions
could then serve as the basis for genetic, neurobiological, and psychoneuropharmacological studies.
We propose clinical criteria for the diagnosis of clinically significant non-major depression (CSNMD) in el-
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Significant Non-Major Depression
derly patients (Table 2). These criteria are consistent
with operational definitions of minor depression used
in other clinical studies but broader in clinical and methodological scope.102,116 We believe this is an important
first step in understanding and elucidating the phenomenological and neurobiological basis of clinically significant mood disorders, especially in elderly patients.
Traditional approaches to classifying psychiatric disorders may no longer be adequate for the next generation of studies into the biological correlates and treatment approaches to patients with these groups of
disorders. As more evidence accumulates from welldesigned multicenter studies, we will be in a position to
make more definitive statements and recommend more
precise guidelines for both the diagnosis and management of this complex group of disorders.
Dr. Kumar is at the UCLA Department of Psychiatry and Biobehavioral Sciences.
This work was supported in part by the NARSAD
Young Investigator Award and K23-MH 01948 to Dr.
Lavretsky, and grants MH55115, MH 61567, and KO2MH02043 (to Dr. Kumar).
TABLE 2. Proposed diagnostic criteria
1) Presence of low mood and/or loss of interest in all activities most of the day, nearly every day, and
2) At least two additional symptoms from the DSM checklist:
a. significant weight loss when not dieting or weight gain (e.g., a change in more than 5% of body weight in 1 month), or decrease or
increase in appetite nearly every day
b. insomnia or hypersomnia nearly every day
c. psychomotor retardation or agitation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed
down)
d. fatigue or loss of energy nearly every day
e. feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt
about being sick)
f. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
g. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific
plan for committing suicide
3) The symptoms cause clinically significant distress or impairment in social and occupational functioning
4) 17-item Hamilton Rating Scale for Depression (Ham-D) score of ⱖ10, or Geriatric Depression Scale Score of ⱖ12123
5) Duration of at least 1 month;
Duration subtypes:
a. Duration from 1–6 months;
b. Duration from 6–24 months;
c. Duration ⬎24 months
6) The symptoms may be associated with precipitating events (e.g., loss of significant other)
7) Organic criteria:
• objective evidence from physical and neurological examination and laboratory tests, and/or history of cerebral disease, damage, or
dysfunction, or of systemic physical disorder known to cause cerebral dysfunction, including hormonal disturbances and drug effects;
• a presumed relationship between the development or exacerbation of the underlying disease and clinically significant depression;
• the disturbance occurs exclusively to the direct psychological effect of alcohol or a substance use;
• recovery or significant improvement of the depressive symptoms following removal or improvement of the underlying presumed cause
8) Exclusion criteria:
There has never been:
an episode of mania or hypomania;
a chronic psychotic disorder, such as schizophrenia or delusional disorder.
Previous history of major depressive episode is not an exclusion criterion.
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