J Head Trauma Rehabil

Vol. 25, No. 2, pp. 99112

c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright 

Clinical Considerations for the

Diagnosis of Major Depression After
Moderate to Severe TBI
Ronald T. Seel, PhD; Stephen Macciocchi, PhD, ABPP; Jeffrey S. Kreutzer, PhD, ABPP, FACRM
Major depression (MD) is the most common psychiatric disorder after traumatic brain injury (TBI). Yet, diagnosing
MD is often challenging because of cognitive, emotional, and somatic symptoms that overlap with TBI and other
psychiatric disorders. Best current evidence suggests that depressed mood is characterized more by irritability, anger,
and aggression than by sadness and tearfulness in persons with TBI. Rumination, self-criticism, and guilt may best
differentiate depressed persons from nondepressed persons. Anxiety, aggression, sleep problems, alcohol use, lowerincome levels, and poor social functioning appear to be primary associated factors to MD. Objective levels of injury
severity, impairment, and functioning do not appear to be related to developing MD. The presence of organic
TBI sequelae that overlap with the Diagnostic and Statistical Manual of Mental DisordersVersion IV MD criteria
does not appear to lead to false-positive MD diagnoses, and anosognosia does not appear to lead to false-negative
MD diagnoses. Only the Patient Health Questionnaire9 and Neurobehavioral Functioning InventoryDepression
demonstrated evidence of acceptably ruling out MD in persons with TBI; the Patient Health Questionnaire9
had the best ability to rule in the presence of MD following TBI. Apathy, anxiety, dysregulation, and emotional
lability require careful clinical consideration when making a differential diagnosis of MD in persons with TBI.
Lastly, recommendations are provided on how clinicians can improve diagnostic accuracy and what future research
is required to improve our understanding of MD in persons with TBI. Keywords: depression, diagnosis, rehabilitation,
traumatic brain injury, validity

SYCHIATRIC DISORDERS are frequently diagnosed following a traumatic brain injury (TBI),
and depression is by far the most common with reported rates ranging from 6% to 77%.118 When established diagnostic criteria are used, persons with moderate to severe TBI evidence major depression (MD) rates
ranging from 26% to 36%.57,15,17 Depression has been
associated with high rates of disability,20,21 impaired
psychosocial functioning,7,9,19,2226 and decreased life
satisfaction.27,28 When depression is chronic, psychosocial disability levels increase and life satisfaction decreases further.23,27
While the negative impact of depression after TBI
is well-recognized, diagnosing depression after TBI remains a significant challenge. The Diagnostic and Statistical Manual of Mental DisordersVersion IV (DSM-IV)29
lists a number of depressive disorders including MD,
dysthymia, depressive disorder not otherwise specified
(NOS), and depressive disorder due to a general medical
condition (GMC) that have overlapping symptoms. Rehabilitation professionals and family members often recAuthor Affiliations: Shepherd Center, Atlanta, Georgia (Drs Seel and
Macciocchi); and Virginia Commonwealth University, Richmond
(Dr Kreutzer).
Corresponding Author: Ronald T. Seel, PhD, Shepherd Center, 2020 Peachtree
Rd, NW Atlanta, GA 30309 (ron seel@shepherd.org).

ognize a mood disturbance (eg, feeling down or blue),

which is a primary feature of all depressive disorders.
However, diagnosing MD after TBI is complicated because of the constellation of cognitive, emotional, and
somatic symptoms, such as slowed thinking, poor concentration, lability, sleep problems, and decreased energy and activity, that can be attributable to TBI, MD,
preinjury functioning, or medication side effects.30,31
These diagnostic challenges highlight the need to synthesize research findings and form an empirical basis to
address key clinical considerations when diagnosing depression after TBI.
Dr Mitchell Rosenthal understood the significance of
these challenges and systematically reviewed incidence,
associated factors, diagnosis, and treatment in his 1998
study, Depression Following Traumatic Brain Injury.10
As part of the Gedankschrift memorial issue honoring Dr Rosenthal, our review synthesizes and highlights
current evidence to assist interdisciplinary professionals with identifying and diagnosing MD in persons who
have sustained moderate to severe TBI. While the DSMIV lists a number of depression diagnoses, we focus on
MD because it is more common, implies a more pervasive disturbance in mood, cognition, and behavior,
and is the most challenging to diagnose. We review empirical evidence related to person characteristics, organic impairment, and environmental interactions as
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well as draw upon evidence from non-TBI populations,

which were cornerstones of Dr Rosenthals research
approach.10,32,33
Our review is organized in a manner similar to
the general outline used to present disorders in the
DSM-IV. We first present primary features of a major
depressive episode supplemented with empirical findings on how these features manifest in the TBI population. Second, we review research on associated psychiatric disorders, neuroimaging and laboratory findings,
and personal, cultural, and social features that are common to MD after TBI. Third, we address the potential
impact of TBI features on the diagnosis of MD including whether greater levels of injury severity and impairment increase the likelihood of depression, whether the
presence of common cognitive and somatic sequelae
that overlap with DSM-IV MD criteria leads to falsepositive diagnoses, and whether anosognosia leads to
false-negative MD diagnoses. We then address the MD
diagnostic process including an evaluation of self-report
depression scales and differential diagnosis of related
disorders. Lastly, we provide recommendations on how
clinicians can improve diagnostic accuracy and what future research is required to improve our understanding
of MD in persons with TBI.
MAJOR DEPRESSIONDIAGNOSTIC FEATURES
MD is a psychiatric diagnosis in which clinicians must
rely on the presence or absence of observed symptoms
because there is no valid physiological, laboratory, or
radiological test to establish a MD diagnosis.34 The
DSM-IV29 is the current clinical and research standard
used to diagnose mood disorders including MD. A person must evidence at least 5 of 9 depressive symptoms
(criterion A). Furthermore, at least 1 of 2 primary criterion A symptoms must be present: (A1) depressed mood
that impacts all or almost all aspects of life or (A2)
markedly diminished interest or pleasure in all or almost all
activities. A brief summary of the 9 criterion A symptoms and features is provided in Table 1. All depressive
symptoms are evaluated relative to their intensity (most
of the day) and duration (2 weeks).
Specific depressive symptoms reported in persons
with TBI appear to be fairly similar to those reported
in the general population. Nonetheless, research highlights some TBI population-specific manifestations of
DSM-IV MD criterion A1A9 symptoms (see column 3,
Table 1). There is consistent evidence that depressed
mood (A1) in persons with TBI is more frequently evidenced by irritability, frustration, anger, and aggression
than by sadness, feeling blue, or tearfulness.15,35,36 High
levels of self-reported somatic and cognitive symptoms
that exceed objective findings also strongly distinguish
persons with and without depressed mood.35 Dimin-

ished interest or pleasure (A2) in persons with TBI commonly centers on difficulty enjoying activities, loss of
interest in sex, and loneliness.15,36 Poor appetite (A3)
is more frequently reported by persons with TBI than
overeating and may be a primary discriminator between
depressed and nondepressed persons with TBI.36 Rumination, self-criticism, and guilt are closely related to feelings of worthlessness (A7) and appear to highly differentiate depressed from nondepressed persons with TBI.34
Lack of confidence, discomfort around others, and social
withdrawal may be indicators of depressed mood and
feelings of worthlessness.35,36 Depressed persons with
TBI are 6 times more likely than nondepressed persons
to threaten self-harm (A9).15 Overall, persons with TBI
have a 4 times higher risk for committing suicide than
persons in the general population (please see Teasdale,37
Simpson,38 Wasserman,39 and Hawton,40 for reviews on
suicide incidence and assessment).
To meet criteria for a DSM-IV MD diagnosis, a person must also meet additional criteria including ruling
out a mixed episode of manic and depressive symptoms
(criterion B), depressive symptoms of sufficient severity to cause impairment in at least one aspect of daily
functioning (criterion C), depressive symptoms not being exclusively due to a GMC or substance use (criterion
D), and depressive symptoms not part of bereavement
(criterion E).
An underappreciated feature of MD that is not directly addressed in the DSM-IV is negative thinking,
which refers to maladaptive cognitions, beliefs, and
processes.41 Negative thinking reflects a tendency to
view ones self as defective or inadequate, a pervasive
and absolute evaluation of ones own life experience
as resulting in loss or failure, and hopelessness regarding the future.4144 Negative thinking primarily arises
from automatic thoughts or rumination,4547 in which
depressed persons focus on symptoms or other selfexperiences, using a negative self-evaluative style. Negative thinking also involves selective attention to and
magnification of negative events and feedback while
minimizing positive events and feedback.41 Becks view
of pervasive and absolute negative evaluations is most
often referred to in the depression research literature as
over general autobiographical memory.47,48
Research on negative thinking and rumination in persons with TBI has been limited, but findings have been
compelling. A large sample study found that rumination,
self-criticism, distress, and guilt were part of a symptom
cluster that most differentiated depressed from nondepressed persons with TBI.35 Another study found that
rumination in depressed persons with brain injury resulted in overgeneralized autobiographical memory and
reduced problem-solving.49 Importantly, injury severity was not related to memory and problem-solving
impairments.

Diagnosing Major Depression in TBI

101

DSM-IV criteria for major depressive episode and practical considerations for
use with TBI population
TABLE 1

DSM-IV criteria
A symptoms
(A1) Depressed mood

(A2) Diminished interest or

pleasure
(A3) Weight change
(A4) Sleep disturbance
(A5) Psychomotor agitation
or retardation
(A6) Decreased energy
(A7) Feelings of
worthlessness

(A8) Diminished thinking

ability
(A9) Recurrent thoughts of
death

DSM-IV features

Empirical findings in TBI population

Sad, discouraged, empty, hopeless,

tearful, increased irritability, somatic
complaints

Irritability, easily angered, frustrated, and

hopelessness are more frequently
reported than sadness
Resentfulness, hostility, and aggression
are frequently reported
In all activities, including social
Loss of interest in sex and loneliness are
withdrawal and diminished libido
reported in addition to difficulty enjoying
activities
5% change in body weight or decrease Loss of appetite is reported more than
or increase of appetite (decrease is
overeating
more typical.)
Typically middle or terminal insomnia
Difficulty falling asleep is most often
(hypersomnia less frequent)
reported
Observable (not subjective feelings)
Agitation and restlessness is more
restlessness or slowed speech or
frequently reported than psychomotor
body movement
retardation
Fatigue, loss of energy, excessive
Feeling weak or tired is most often
tiredness, or reduced efficiency in
reported
completing tasks
Excessive guilt, unrealistic negative
Rumination, self-criticism, guilt, and
evaluations, or delusional self-blame
cannot get mind off thoughts highly
differentiate depressed persons from
nondepressed persons
No confidence, discomfort around others,
and social withdrawal may be indicators
of feeling worthless
Poor concentration, difficulty making
High levels of self-reported attention or
decisions, distractibility, or memory
memory problems that exceed objective
difficulties
findings
Recurrent thoughts of death or
May threaten to harm self
suicide; suicidal behavior
Increased risk compared to general
population

These findings are consistent with research in the

general population, indicating that rumination is prevalent in both the development and maintenance of depression, worsens depressive symptoms over time, and
is a risk factor for developing future major depressive
disorders.41,45,46,50

ASSOCIATED DISORDERS AND FEATURES

A number of disorders, neuroimaging and laboratory
findings, and psychosocial features have been associated
with MD (Table 2). No empirically based etiological
models of MD after TBI were identified in the research
literature. Thus, best current evidence for factors that
increase the risk for depression after TBI is based on
univariate analyses of the TBI population supplemented
with research findings from the general population and
is summarized below.

Associated disorders
Anxiety is a commonly reported co-occurring disorder with both early and late onset depression after TBI
with rates ranging from 41% to 77%.6,19,51 Persons with
both depression and anxiety disorders have longer symptom duration (7.5 months vs 1.5 months) than patients
with depression only.19 Co-occurring anxiety may be related to perceived stress,52 fear of job loss,22 phobias,53
and rumination.35,54 High association rates between anxiety and depression in persons with TBI are consistent
with epidemiological research in the general population that indicates anxiety disorders (57.5%, CI 53.3%
61.7%) are the most common co-occurring disorder with
depression.55 Importantly, MD was found to be a temporal antecedent of anxiety disorders in only 14.6% (CI
10.4%18.8%) of cases.55
Aggression also commonly co-occurs with depression
after TBI.5457 Aggression scores are highly associated
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Best current evidence of psychosocial contributory/risk factors for major depression after moderate to severe traumatic brain injury
TABLE 2

Biological/behavioral
Sleep difficulties
Falling asleep
Early awakening
Reduced sleep time
Hypothalamic-pituitary-adrenal hyperactivity
Serotonergic hypoactivity
Bilateral dorsal prefrontal cortex
Lesions

Psychological/behavioral
Anxiety, panic
Rumination
Physical symptoms
Losses, failures
Fears, harm, danger
Aggression
Substance use
Poor social skills
Problem solving
Social withdrawal
Less than high school
education

with depression scores at 6, 12, and 60 months postinjury

and both were among the highest reported psychiatric
symptoms in a 10- to 20-year postinjury study.25 Persons
who reported irritability and anger soon after injury were
at greater risk for developing post-TBI MD.58 In the
general population, impulse control disorders (16.6%,
CI 13.0%20.2%) were the second most common cooccurring disorder in persons with depression.55 MD in
the general population was a temporal antecedent of impulse control disorders in only 20.8% (CI 14.2%27.3%)
of cases.55
Persons with TBI and a preinjury history of alcohol
abuse have higher rates of postinjury depression than persons without an alcohol abuse history.16,59 An epidemiological study of TBI survivors indicated that a MD diagnosis was highly associated (OR = 1.6, CI 1.12.5) with
concurrent heavy drinking at 1-year postinjury.60 Persons
with TBI who deteriorated after 6 months postinjury
were depressed and hostile and misused alcohol.61 In
the general population, substance use (8.5%, CI 6.4%
10.6%) was the third most common co-occurring disorder with depression, which was a temporal antecedent
of substance use diagnoses in 49.2% (CI 41.6%54.8%)
of cases.55
Sleep disorders are one of 9 core symptoms of MD
and trouble falling asleep was 6 times more likely
to be reported by depressed versus nondepressed persons with TBI.15 Objective laboratory studies have confirmed nighttime sleep disorders and excessive daytime
sleepiness in 25%53% of those self-reporting sleep
difficulties.62,64 Persons with TBI who had objective
findings of sleep maintenance insomnia evidenced moderate to severe Beck Depression Inventory scores64 ; however, no association was found between excessive daytime sleepiness and mood.62 In the general population,
a growing empirical literature suggests that insomnia is
a precipitant of depression.6467 Persons with persistent

Social/environmental
Income
Poverty level
Financial problems
13 poverty level
Personal relationships
Lack of intimate partner
No close friend
Discord in close relationships
Unemployment
Unstable work history
Preinjury
Postinjury job loss

insomnia were significantly more likely to develop depression within 1 year (OR = 39.8, CI 19.880.0) than
persons with no insomnia.64
Apathetic syndrome is a common comorbidity for persons who have sustained TBI and primary apathy
related symptoms such as anhedonia, and lack of energy,
initiative, and social interaction are frequently confused
with depression.68,69 In a study with a predominately
mild TBI cohort, 11% were apathetic, 11% were depressed, 60% were both apathetic and depressed, and
18% were neither apathetic nor depressed.70
Pain is common (32%, CI 29%35%) following moderate to severe TBI71 and both early onset depression and
chronic depression may play mediating roles in higher
levels of self-reported pain.28,51,72 Postinjury onset of
headache and headache density were found to be significantly associated with depression scores.73,74
Associated neuroimaging and laboratory studies
MD in the general and TBI populations is believed
to be related to pathophysiology involving the left dorsal lateral frontal cortex and left basal ganglia and, to a
lesser extent, focal lesions in the right hemisphere and
parieto-occipital region.6,19,59,7578 Imaging studies have
also shown that hypometabolism of the lateral and dorsal frontal cortex, especially the dorsal prefrontal cortex
and cingulate gyrus, as well as increased activation in
ventral limbic and paralimbic structures including the
prelimbic cortex, the amygdale, and the medial thalamus may be associated with depressive symptoms.31,59,79
However, these patterns of anatomical dysfunction are
far from universally observed in persons with MD and
variations between studies are likely attributable to heterogeneity in MD symptoms and the existence of subtypes of depression.31,79 For more detailed reviews of this
topic, please see Drevets,80 Davidson,79 Moldover,31 and
Jorge.59

Diagnosing Major Depression in TBI

Depression has long been associated with serotonergic
hypoactivity and there is a well-documented literature on
the use of SSRIs for the treatment of depression.69 Genetic variation in the form of 1 or 2 short alleles of the
serotonin (5-HTT) transporter gene appears to increase
the likelihood that someone will experience depression
in response to stressful life events.81
In addition to a genetic contribution, elevated activity of the hypothalamic-pituitary-adrenal axis has been
shown to be associated with MD.79 A small sample
study found that 18% of persons with mild complicated, moderate, or severe TBI had growth hormone deficiency or insufficiency at 69 months postinjury and
were 3.7 times more likely to report clinically significant
depression scores.82 In the general population, elevated
cortisol/dehydroepiandrosterone (DHEA) ratios have
been found to be strongly related to persistent depression in community adolescents83,84 and in drugfree depressed adults.85,86 Depressed persons have also
been found to have elevated cortisol levels and lowered
adrenocortecotropic hormone (ACTH) levels than nondepressed controls.87
No polysomnography (PSG) studies have been conducted specific to MD following TBI. PSG findings in
the general population indicate that depression has welldefined associations with sleep architecture, including
increased sleep latency, reduced total sleep time, reduced
sleep efficiency, decreased short wave sleep time, decreased REM latency, and increased REM density.6567,88
Associated personal features (age, gender, and race)
In cross-sectional studies, age has not been significantly related to MD following TBI.6,15,16,19 In contrast,
epidemiological research in the general population indicates that persons aged 1859 years have the highest
lifetime prevalence of depression whereas persons aged
1844 years have the highest 12-month rates.55 With regard to gender, mixed findings have been reported in the
TBI population. In 4 studies of comparable quality using DSM-IV criteria, 3 TBI studies found no relationship
between gender and depression,6,15,19 while one study
found that women were more likely to be depressed.89
Another study reported that men had higher subthreshold depression scores at 12 months postinjury.16 Research in the general population consistently reports that
women have higher lifetime and 12-month depression
rates than men.29,55 There is limited evidence that race is
meaningfully associated with depression after TBI15 or
in the general population.55

103

ies found a significant association between history of

mood and/or anxiety disorders and the development
of post-TBI MD,6,19,90 while 2 studies did not show a
similar association.16,28 In contrast, a population-based
study that assessed presence of TBI and affective disorders found that persons without a prior psychiatric illness
had higher rates of affective disorders at 712 months (OR
4.6, CI 1.811.7) and 1318 months (OR 2.2, CI 1.0
4.9) post-TBI.91 Surrogate markers for a history of psychiatric problems (eg, seeking professional help for emotional problems) or traumatic events (eg, assault, sexual
abuse, combat duty) have been shown to be significant
risk factors for depression in both the TBI and general
populations.58,79
Less education14,16,90 and lower IQ scores92 have been
implicated in higher depression rates after TBI, but 2
studies using DSM MD criteria found no effects for
education.6,19 In the general population, no differences
in lifetime prevalence of MD was found among levels of
education, but persons with 011 years education had
higher 12-month MD rates (OR 1.9, CI 1.32.8).55
Present and past social problems, including perceived lack
of social support or a close confiding relationship, have been
associated with greater levels of early and late onset MD
in persons with TBI.4,6,19,22,28,58,90,93 Current marital
status has not been associated with MD after TBI.6,15,19
In contrast, divorced, separated, or widowed persons in
the general population reported higher lifetime (OR 1.5,
CI 1.21.8) and 12-month (OR 1.4, CI 1.01.9) rates
of MD; persons who have never been married had the
highest 12-month rate of MD (OR 2.3, CI 1.73.2).55
Unemployment and/or unstable work history is consistently associated with higher rates of depression after
TBI.15,16,94,95 These findings are consistent with research
in the general population, which shows that unemployment and disability are significantly associated with lifetime (OR 1.5, CI 1.12.0) and 12-month (OR 2.2, CI
1.63.0) prevalence rates of MD.55 There is compelling
evidence that lower-income levels have a linear association with depression after TBI.15,28,93 In a multicenter
study, persons with income of <$10 000 reported greater
depression than all other income groups, while persons
with incomes of $10 000$19 999 reported more depression than persons with income of $50 000 or more.15
Similarly, persons in the general population whose income was below poverty (OR 3.8, CI 2.46.1) or 13
times the poverty rate (OR 1.8, CI 1.32.4) were more
likely to report a 12-month rate of depression.55
DIAGNOSING DEPRESSION FOLLOWING TBI

Associated psychosocial, educational, and

occupational features

Use of DSM-IV criteria and the risk of false-positive

diagnoses of MD following TBI

Findings have been mixed on the association between

preinjury psychiatric history and MD after TBI. Three stud-

Concern has been expressed regarding the use of the

DSM-IV criteria to diagnose MD in persons with TBI
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due to the overlap of DSM-IV symptoms with organic

symptoms of TBI. For example, persons with TBI frequently exhibit lack of initiative, weight loss, low energy, slow movement, attention problems, and sleep difficulties, which could lead to false-positive diagnoses of
MD.96 DSM-IV MD criterion D directs the clinician to
count the presence of criterion A symptoms toward an
MD diagnosis unless the symptoms are clearly and fully
accounted for by a GMC, which presumes that clinicians can discriminate between medical and psychiatric
causes.
Current research indicates that there is little evidence
that the use of the DSM-IV criteria increases the risk
of false-positive MD diagnoses. First, measures of TBI
severity and postinjury functioning do not appear to
be associated with depression following TBI.97 Acute
care length of stay, acute rehabilitation length of stay,
duration of coma, duration of PTA, acute admission
GCS scores, admission and discharge rehabilitation DRS
scores, and admission and discharge rehabilitation FIM
scores have not been predictors of postrehabilitation
depression.15,16,19,90
Second, persons with TBI who are depressed appear
to self-report greater levels of impairment or difficulty
than can be objectively quantified. A multicenter study
found that persons meeting DSM-IV Criterion A for
MD reported markedly greater proportions of poor
appetite (8:1), trouble falling asleep (6:1), restlessness
(8:1), weakness (8:1), and poor concentration (9:1) than
nondepressed persons.15 Measures of injury severity and
functioning did not differ between the depressed and
nondepressed groups.15 A well-controlled, single-center
study also found that persons with MD were 3.4 times
more likely to report organic symptoms than persons
who were not depressed and that injury severity did
not differ between the depressed and nondepressed
groups.6 Another well-controlled study using regression
analyses found that high levels of self-reported functional impairment and low levels of perceived social
support early after injury were significant predictors
of early and late onset depression.90 Importantly,
neither injury severity nor objective measures of family
functioning differed between persons with or without
depression.90 Other studies provide further support that
persons with TBI who are depressed report significantly
greater concurrent physical, cognitive, and behavioral
symptoms than those who are not depressed28,98 and
that depressed symptoms are not related to objective
measures of cognitive functioning.53 Negative thinking characterized by rumination, self-criticism, and
hopelessness are core features of MD and may precede
or partially account for the markedly higher rates of
somatic and cognitive symptoms reported by depressed
versus nondepressed persons with TBI.90

Lastly, even when organic symptoms from the DSM

MD criteria are not considered in the diagnostic process,
MD is diagnosed at virtually the same rate (sensitivity =
1.00, specificity = 0.94) when compared with standard
DSM diagnostic criteria at 3 months postinjury.6,59 Similarly, in a group of non-TBI, older hospitalized patients,
prevalence rates of MD did not differ when DSM-IV
MD criteria were used with and without potential confounding medical related symptoms.34
Anosognosia and the risk of false-negative MD
diagnoses in persons with TBI
Early research suggested that persons with TBI
underestimated cognitive, emotional, and behavioral
impairment.22,99102 However, scales that used specific
versus abstract item content mediated awareness impairments and improved agreement between patients and
familys perceptions of functioning.103,104 Research comparing depression item ratings between persons with
TBI and significant others have revealed high correlations (r = 0.66 and 0.69) and agreement.4,105,106 In a
multicenter study of persons with moderate to severe
TBI, significant others ratings of survivor depression
were significantly higher than those of persons with
TBI.105 Mean differences though were only 2.6 points
on a 65-point scale and were not associated with injury
severity.105 Using an algorithm for identifying disagreement that had diagnostic implications, persons with
TBI did not demonstrate significant underreporting.105
A large, single-center study found exact agreement or
1-point disagreement on 93% of patient and family responses on 13 specifically worded depression items. Disagreement was equally distributed with patients showing
equivalent under- and overreporting of depressive symptoms compared with family ratings.106 In sum, best current evidence suggests that persons with TBI and significant others do not have clinically meaningful differences
in perceptions of depressive symptoms when specifically
worded depression items are used.
The question of whether anosognosia itself impacts
depression has produced mixed findings. Two studies
found no correlation between inaccurate self-awareness
and lower depression scores.107,108 A study using a brain
injury cohort that was predominately TBI empirically
identified 4 awareness typologies: poor self-awareness,
high defensiveness, high symptom reporting, and good
self-awareness.108 Persons with brain injury who either
had poor self-awareness or were high symptom reporters
had the highest number of depressive symptoms.108
Conversely, a well-controlled study using regression
analyses found that impaired self-awareness early after
injury was associated with lower levels of early and late
onset depression.90

Diagnosing Major Depression in TBI

Use of self-report depression scales in
persons with TBI
Clinicians often use self-report scales to case-find
MD and quantitatively monitor changes in symptom
severity. Scale developers typically define a cutoff score
to reflect clinical depression and then establish diagnostic validity for the defined cutoff score. Ideally, clinical
interviews are conducted to determine the true presence
of MD and then 22 contingency tables are constructed
to identify the number of true-positive, true-negative,
false-positive, and false-negative diagnoses.
A number of scales have been used in clinical practice
and research on depression after TBI. The Beck Depression Inventory2nd Edition (BDI-II), Center for Epidemiological StudiesDepression Scale (CES-D), and
Zung Self-Assessment Depression Scale (SDS) are selfreport measures used in primary care and mental health
treatment settings. The Patient Health Questionnaire
9 (PHQ-9) is a self-report measure that addresses the
9 DSM-IV symptoms of MD. The Hospital Anxiety and Depression Scale (HADS), which is self-rated,
and Hamilton Depression Scale (HAM-D), which is
clinician-rated, are frequently used in inpatient medical
settings. The Neurobehavioral Functioning Inventory
Depression Scale (NFI-D) is designed and validated for
persons with TBI.109
Four studies25,90,109,110 have evaluated depression
scale diagnostic validity with TBI samples. An additional
study111 used a rehabilitation sample that did not include patients with TBI. Findings from 2 meta-analytic
reviews22,112 of primary care studies that evaluated the diagnostic validity of depression scales were also included.
No HAM-D diagnostic validity studies were identified.
When complete calculations of sensitivity, specificity,
and likelihood ratios were not provided but raw data
were available, these validity statistics were calculated.
A review of the findings (Table 3) indicates that the
NFI-D and the PHQ-9 demonstrated excellent ability
to rule out the presence of depression in persons with
TBI on the basis of their high sensitivity and low falsenegative likelihood ratios. The CES-D demonstrated an
excellent ability to rule out depression in 2 small rehabilitation populations. Conversely, the HADS had an
unacceptably high rate of false-negative screens and was
unable to reliably rule out the presence of MD in persons with TBI. In the meta-analytic review of primary
care studies, the BDI-II, CES-D, and PHQ-9 were equivalent and acceptable in their ability to rule out MD. The
SDS demonstrated an unacceptably high likelihood ratio of negative tests indicating a suboptimal ability to
rule out the presence of MD in primary care patients.
The PHQ-9 performed better than all other scales at ruling in the presence of depression (eg, minimizing falsepositive screens).

105

Unfortunately, each of the TBI studies had significant methodological issues including lack of masked
raters,15,110 gold standard not administered to all
screened participants,91,110 and using the same interview
data to score the screening scale and the gold standard.26
The meta-analytic reviews that created summative likelihood ratios generally included both high-quality studies
with low risk of bias and studies with significant methodological problems. The risk of bias in all of these studies
limits our ability to draw definitive conclusions regarding diagnostic validity.
Best current evidence suggests that the BDI-II, CESD, NFI-D, and the PHQ-9 appear to have an acceptable
ability to rule out the presence of MD as a screening
tool. Only the NFI-D and PHQ-9 demonstrated evidence of acceptably ruling out MD in persons with TBI.
The PHQ-9 appears to have a better ability to rule in
the presence of MD in TBI and primary care populations. Both The HADS and the SDS demonstrate high
rates of false-negative screens that limit our ability to
recommend their use at this time.
Differential diagnosis of MD in persons with TBI
Challenges with accurately diagnosing MD are not
unique to the TBI population. In the general population,
questions also arise regarding the most effective and efficient methods for diagnosing MD and how best to distinguish whether symptoms are related to depression versus co-occurring medical or psychiatric illnesses.34 For
example, the National Comorbidity Survey Replication
(NCS-R) studied 9000 Americans and found that 79%
of persons who had MD also had at least 1 comorbid
DSM-IV disorder, and in only 13% of cases was MD the
primary diagnosis.55
The DSM-IV provides diagnostic considerations to
differentiate MD, mood disorder due to a GMC, dementia, mixed episodes, adjustment disorder with depressed
mood, bereavement, and depressive disorder (NOS). Instructions are also provided for classifying MD as either a
single episode or recurrent, and whether severity is mild,
moderate, or severe and occurs with or without psychotic features. Our review supplements this information by presenting 4 psychiatric conditions common to
TBI and MD that require careful clinical consideration
when making a differential diagnosis of MD: apathy,
anxiety, dysregulation, and emotional lability (Table 4).
Apathy refers to primary motivational loss that
includes lack of behavioral activity, cognitive initiative, and emotional engagement in purposeful activity75
and is sometimes confused with depression, particularly in acute rehabilitation settings. A key differential
diagnostic consideration is that persons with postTBI apathy do not evidence cardinal features of depression such as sadness, irritability, hopelessness, and
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135
2204 (7)
667 (4)

SCID
SCID
SCID
SCID
SCID
SCID
BDI-II21
SCID
SCID
SCID

29
10
10
50

Reference
standard

>23
10
16
16
16
8

Cutoff score

0.98 (0.911.00)
0.88 (0.660.98)
0.81 (0.720.88)
NR

1.00 (0.461.00)
NR
1.00 (0.701.00)
1.00 (0.681.00)
NR
0.62 (0.430.77)

SENS (95%CI)

0.40 (0.300.50)
0.90 (0.830.95)
0.92 (0.830.97)
NR

0.59 (0.370.79)
NR
0.57 (0.460.68)
0.36 (0.220.53)
NR
0.92 (0.820.97)

SPEC (95%CI)

1.6 (1.41.9)
8.8 (NR)
11.3 (4.628.0)
3.3 (1.38.1)

2.4 (1.54.0)
4.2 (1.213.6)
2.3 (1.83.0)
1.6 (1.22.0)
3.3 (2.54.4)
8.2 (3.419.7)

LR-P
(95%CI)

0.03 (0.00.3)
0.14 (NR)
0.20 (0.10.3)
0.35 (0.20.8)

0.00
0.17 (0.10.3)
0.00
0.00
0.24 (0.20.3)
0.41 (0.30.6)

LR-N
(95%CI)

Abbreviations: BDI-II, Back Depression InventoryIInd Edition; CES-D, Center for Epidemiological StudiesDepression; HADS, Hospital Anxiety and Depression Scale; LR-P, likelihood ratio
of a positive test; LR-N, likelihood ratio of a negative test; NFI, Neurobehavioral Functioning Inventory; NR, not reported/could not be calculated; sample size, No. of patients tested (No.
of studies comprising summative sample size); PHQ, Patient Health Questionnaire; SCID = Structured Clinical Interview for the DSM-IV; SDS, Self-Assessment Depression Scale; SENS,
sensitivity; SPEC, specificity; TBI, traumatic brain injury.

TBI
TBI
Primary care
Primary care

3038 (10)
100

Williams (2002)
HADS WhelanGoodinson
(2009)
NFI-D Seel (2003)
PHQ-9 Fann (2005)
Gilbody (2007)
SDS Williams (2002)

Population
TBI
Primary care
Rehab-ortho
Rehab-neurol
Primary care
TBI

Sample size

27
852 (4)
101 50

Author (year)

Diagnostic validity of scales used to assess major depression after TBI

BDI-II Homaifar (2009)

Williams (2002)
CES-D Caracciolo (2002)

Scale

TABLE 3

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Diagnosing Major Depression in TBI

107

Symptoms that differentiate core features of major depression from common

cognitive and emotional sequelae in persons with TBI
TABLE 4

Core features
Mood (intensity,
scope)
Activity level
Attitude
Awareness
Cognitions
Physiological
Coping style
Potential DSM-IV
diagnoses

Depression
Sad, irritable,
frustrated
(constant, global)
Low activity
Loss of interest,
pleasure
Overestimates
problems
Rumination on loss,
failures
Under- or
hyperaroused
Avoidance, social
withdrawal
Major depressive
episode
Mood disorder due
to GMC

Apathy

Anxiety

Dysregulation

Flat, unexcited
(constant, global)

Worried, distressed
Angry, tense
(frequent, situational)
(frequent, global)

Lack of initiative,
behavior
Lack of concern

Restless, keyed up
Overconcern

Does not notice

problems
Unresponsive to
events
Underaroused

Overestimates
problems
Rumination on harm,
danger
Hyperaroused

Compliant,
dependent

Avoidance, checking
behaviors

Personality change
due to TBI
apathetic type
Cognitive disorder
NOS

Generalized anxiety
disorder

Adjustment disorder
w/depressed
mood
Dysthymic disorder

Impulsive, physically
aggressive
Argumentative
Underestimates
problems
Rumination on
tension, arousal
Underaroused or
agitated
Uncontrolled
outbursts

Personality change
due to TBI
aggressive type
Specific or social
Personality change
phobia
due to TBI
combined type
Anxiety disorder due to Impulse control
GMC
disorder nos
Adjustment disorder
w/anxiety
Anxiety disorder NOS
(mixed anxietydepressive disorder)

Abbreviations: DSM-IV, Diagnostic and Statistical Manual of Mental DisordersVersion IV; GMC, general medical condition; NOS, not
otherwise specified; TBI, traumatic brain injury.

negativistic thinking. Research in postacute rehabilitation settings indicate that persons with post-TBI apathy are underaroused, cannot fully engage in rehabilitation, and use less approach-oriented and social
supportseeking behaviors.67,113115 Conversely, patients
who are depressed actively resist or withdraw from rehabilitation and use avoidant coping strategies.68,113115
Persons with apathy may be given a DSM-IV diagnosis of personality change due to brain injury
apathetic type or in combination with significant memory and other cognitive impairments, cognitive disorder
NOS.
Anxiety and MD also share overlapping symptoms.
The core presentation of depression tends to be sadness,
irritability, and frustration or lack of interest or pleasure,
while anxiety is primarily marked by worry and distress.
Research in the general population provides strong support that anxiety is differentiated from MD by physiological hyperarousal whereas depression is differentiated by low pleasurable engagement with others.43,116118

Research also suggests that depressive rumination focuses on personal failure and loss in a more general
and global sense, while anxious rumination focuses on
harm and danger in specific situations.41,43 Persons with
TBI may meet full criteria for both depression and anxiety disorders. For persons who present with mixed features that do not meet full criteria for either disorder,
the DSM-IV offers an experimental diagnosis of mixed
anxiety-depression disorder based on the well-supported
tripartite model of depression and anxiety116118 and is
recorded as Anxiety Disorder NOS.
Persons with both dysregulation problems and MD after TBI may present with irritability, resentfulness, hostility, and aggression. Persons with dysregulation are differentiated from MD by impulsivity, physical aggression,
and uncontrolled outbursts, whereas low activity, avoidance, and social withdrawal are more typical of persons
with MD. Persons with TBI may receive dual diagnoses
of MD and a dysregulation disorder. Careful consideration of preinjury behavior is required to differentiate
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JOURNAL OF HEAD TRAUMA REHABILITATION/MARCHAPRIL 2010

a diagnosis of personality change due to brain injury

(aggressive, disinhibited, or combined types) from a preexisting personality or impulse control disorder.
Lability (eg, pathological laughing or crying) refers
to sudden and uncontrollable emotional outbursts that
may or may not be consistent with the persons general mood.17,56 Lability is distinguished from depression
in that crying outbursts occur spontaneously and are
triggered internally or by minor external events. These
episodes also resolve quickly and do not represent prolonged tearfulness with mood congruence. Persons with
postinjury pathological crying are typically given a diagnosis of personality change due to brain injurylabile
type.
Lastly, differentiation of MD from a mood disorder
due to a GMC in persons with TBI should include a
thorough review of preinjury diagnoses and function-

TABLE 5

ing, sensorimotor disorders, medical disorders, adverse

effects of medication, sleep disorders, and finally mood
and anxiety.30 To meet a diagnosis of mood disorder due
to a GMC, depressive symptoms should not have been
present prior to TBI and must begin within 3 months
of injury to potentially be a physiological effect of
TBI.19
Recommendations to improve diagnostic
accuracy of MD after TBI
A summary of considerations for diagnosing MD in
persons with TBI based on our empirical review is provided in Table 5. A number of process-related recommendations for working with persons with TBI are worth
noting. Accurate diagnosis begins with the clinicians
ability to obtain diagnostically relevant information

Summary of clinical considerations to improve MD diagnosis in persons with

TBI
1. While persons with TBI and in the general population experience depression similarly, clinicians should be
aware of a few distinguishing features of MD in persons with TBI:
a. Depressed mood in persons with TBI is more frequently evidenced by irritability, frustration, anger, hostility,
and aggression than by sadness and tearfulness.
b. Diminished interest or pleasure commonly centers on loss of interest in sex and loneliness in addition to
difficulty enjoying activities.
c. Loss of appetite appears to strongly differentiate depressed persons from nondepressed persons with TBI.
d. Lack of confidence, discomfort around others, and social withdrawal may be indicators of underlying
feelings of worthlessness and depression.
2. Persons with TBI are at a higher risk for suicidality than the general population. A diagnostic interview on
mood should include questions regarding suicidal thoughts, behavior, and intent.
3. Rumination, self-criticism, distress, and guilt are a symptom cluster that may best differentiate depressed
persons from nondepressed persons with TBI. Clinicians should carefully assess the presence and extent of
negativistic thinking and rumination, which can both clarify the diagnosis and inform the selection of therapy
interventions targeted for negativistic thinking.
4. Anxiety, aggression, sleep problems, alcohol use, lower-income levels, and poor social functioning appear to
be primary contributing factors to MD. Lacking well-controlled empirical etiological models as the basis for
clinical decision making, it is reasonable for clinicians to infer that persons with a greater number of these
contributory factors may be at greater risk for the development and maintenance of MD after TBI. Persons
with TBI who do not meet criteria for MD but evidence these risk factors should be educated along with their
family members on the signs of an emerging depressive disorder and be clinically followed.
5. Persons with TBI who are depressed self-report markedly greater levels of impairment and/or problems than
can be objectively quantified. Clinicians should consider high levels of self-reported physical, somatic, and
cognitive symptoms as either a prodrome or a strong indicator of the presence of MD.
6. Asking specific, concrete questions of TBI survivors appears to minimize the potential impact of anosognosia
on the validity of self-reported depression symptoms.
7. Self-report depression scales are best used to rule out the presence of depression. For persons who
screen positive for the presence of depression, a formal diagnostic interview using Diagnostic and
Statistical Manual of Mental DisordersVersion IV MD criteria is essential.
8. Psychiatric conditions common to TBI that require careful clinical consideration when making a differential
diagnosis of MD include apathy, anxiety, emotional lability, and dysregulation. It is critical for clinicians to have
working knowledge of specific symptoms that either overlap or distinguish between disorders in order to
conduct a thorough diagnostic interview.
9. For cases with complicated and highly overlapping symptom presentation, the use of the SCID is helping in
establishing a differential diagnosis.
Abbreviations: MD, major depression; TBI, traumatic brain injury; SCID, Structured Clinical Interview for DSM-IV.

Diagnosing Major Depression in TBI

from the person with TBI. Establishing rapport by
demonstrating active, empathic, and reflective listening
is critical to understanding the scope and depth of the
TBI survivors issues, establishing an accurate diagnosis, and initiating a targeted treatment plan. As much as
possible, clinicians should ask questions of the person
with TBI directly, with family members supplying confirmation or raising points for clarification. When discrepancies about levels of depression occur, clinicians
should not assume that differences are due to impaired
awareness in the person with TBI. Internal and external
feedback mechanisms, cultural factors, core features of
depression such as negative thinking, coping strategies
such as denial or avoidance, and the psychological disposition of the significant other can all play a role in
differing perceptions.
Many rehabilitation staff, families, and patients have
difficulty distinguishing MD from TBI disorders with
overlapping symptom presentation. Psychologists and
nonpsychologists who treat persons with TBI should
have a working knowledge of DSM-IV diagnostic criteria for MD. Educating all stakeholders on the primary
symptoms of MD and differential diagnostic considerations may help create shared agreement on diagnoses
and treatment plans.
The Structured Clinical Interview for DSM-IV is a
standardized algorithmic diagnostic interview that may
be used to document symptoms of MD and differentiate
MD from other diagnoses. Use of the Structured Clinical Interview for DSM-IV diagnostic interview is highly
recommended when diagnosing persons with TBI who
have complicated presentations. Conversely, it is important to note that it is normal and appropriate for persons
with TBI to experience periodic sadness as a response to
impairments and life changes resulting from injury.
Lastly, primary care physicians and physiatrists frequently must make determinations on the presence of
depression. Research indicates that medical doctors are
most likely to get the diagnosis correct when they ask
specific questions about depressed mood, loss of interest or pleasure, and psychosocial functioning.34

109

Recommendations for future research to improve the

diagnosis of MD after TBI
Dr Mitchell Rosenthal well understood that coping or successful adaptation is contingent upon a variety of complex personal, environmental, and physiologic variables, which vary from person to person.10
Diagnosing and treating MD in persons with TBI are
challenging and significant research is needed to identify varying MD subtypes and understand etiological pathways and interactions so that we can better
help survivors of TBI and their families. In closing,
a number of research recommendations are provided
below.
1. There is a growing belief that MD after TBI
manifests itself in multiple subtypes, each with
differing biological and psychosocial etiological
pathways. Research is required to identify discrete symptomatic subtypes and etiologies including biopsychosocial determinants.97,98
2. The longitudinal course of MD including temporal antecedents, duration of antecedent symptoms
prior to full onset MD, duration of MD episode,
and the risk and timing of recurrent MD are not
well-understood and require research.
3. Research using complex polysomnography and
multiple sleep latency testing appears essential to
identifying temporal associations and interactions
between sleep disorders, MD, anxiety, substance
use, and pain in the TBI population.
4. Research is needed to evaluate the potential impact
of culture on the experience and self-reporting of
MD following TBI.
5. Prognostic studies that use model building statistics are required to identify a parsimonious set of
independent risk factors for MD during the first 2
years postinjury.
6. Lastly, research methodologies that minimize bias
should be used when examining the reliability, diagnostic validity, and prognostic validity of scales
that measure MD in persons with TBI.119

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