SPECIAL ARTICLE
Neuropsychiatric
Psychiatric disorders frequently complicate recov-
ery and rehabilitation from traumatic brain injury
(TBI). This study reviews the literature from 1978
to 2006 on psychosis, depression, posttraumatic
stress disorder, mania, and aggression following
nonpenetrating TBI. The studies were reviewed
using the American Academy of Neurology’s cri-
teria for classification of articles on diagnostic
methods. No studies were found to be Class I or
II. Of the 66 studies reviewed, the majority were
Class IV. There are significant gaps in the litera-
ture on post-TBI psychiatric conditions with re-
spect to nosology, epidemiology, and risk factors.
Larger multicenter prospective studies using stan-
dardized diagnostic instruments are needed to fur-
ther clarify the nosology, risk factors, and clinical
course of these disorders. Specific directions for re-
search are provided.
(The Journal of Neuropsychiatry and Clinical
Neurosciences 2007; 19:106–127)
106 http://neuro.psychiatryonline.org
Complications of
Traumatic Brain Injury:
A Critical Review of the
Literature (A Report
by the ANPA Committee
on Research)
Edward Kim, M.D.
Edward C. Lauterbach, M.D.
Alya Reeve, M.D.
David B. Arciniegas, M.D.
Kerry L. Coburn, Ph.D.
Mario F. Mendez, M.D., Ph.D.
Teresa A. Rummans, M.D.
Edward C. Coffey, M.D.
T raumatic brain injury is a leading cause of morbid-
ity and mortality, accounting for approximately
2 million emergency room visits annually in the United
States and over 500,000 hospital admissions. Another 5.8
million survivors of traumatic brain injury (TBI) in the
United States have chronic disability due to their inju-
ries. Because the age range of peak TBI incidence is 15
to 24 years, survivors may have relatively long life spans
to cope with their impairments.1 Therefore, community
integration, with social and vocational rehabilitative
Received May 15, 2006; accepted May 19, 2006. Dr. Kim is affiliated
with Bristol-Myers Squibb, Neuroscience Medical Strategy, Plainsboro,
New Jersey. Drs. Lauterbach and Coburn are affiliated with the De-
partments of Psychiatry and Behavioral Science, Mercer University
School of Medicine, Macon, Georgia. Dr. Reeve is affiliated with the
Department of Psychiatry, New Mexico School of Medicine, Albu-
querque, New Mexico. Dr. Arciniegas is affiliated with the Department
of Psychiatry, University of Colorado School of Medicine, Denver, Col-
orado. Dr. Mendez is affiliated with the Department of Psychiatry,
University of California, Los Angeles, School of Medicine, Los Ange-
les, California. Dr. Rummans is affiliated with the Department of Psy-
chiatry, Mayo Clinic College of Medicine, Rochester, Minnesota. Dr.
Coffey is affiliated with the Department of Psychiatry and Neurology,
Henry Ford Health System, Detroit, Michigan. Address correspon-
dence to Dr. Kim, Bristol-Myers Squibb Company, 777 Scudders Mill
Road, Plainsboro, NJ 08536; edward.kim@bms.com (e-mail).
Copyright 䉷 2007 American Psychiatric Publishing, Inc.
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

strategies, is a primary treatment goal following acute
medical stabilization and subacute rehabilitation. Psy-
chiatric complications of TBI interfere with rehabilita-
tive interventions and, more importantly, affect survi-
vors’ abilities to function autonomously following their
discharge from structured medical rehabilitative set-
tings. Though the literature contains a wealth of case
and retrospective studies, there is only a limited body
of prospective studies using clearly defined criteria or
structured instruments.
This report of the American Neuropsychiatric Asso-
ciation (ANPA) Committee on Research reviews the
body of literature on post-TBI psychiatric disorders and
identifies studies that provide information regarding
various TBI-related neuropsychiatric syndromes. In the
process, gaps in the literature are identified, yielding
recommendations for future research. This report is in-
tended to provide an evidence-based review of TBI-re-
lated noncognitive psychiatric disorders and considers
the nosology, epidemiology, and risk factors and assess-
ment of the quality of the evidence in the literature. We
define TBI as any extracranial mechanical force to the
brain that leads to any of the following:
1. Any period of loss of consciousness
2. Any loss of memory for events immediately before
or after the event
3. Any alteration in mental state at the time of the
event
This definition is generally consistent with those used
by the American Congress of Rehabilitation Medicine
(ACRM) and the Centers for Disease Control (CDC).2
Due to the complexity of the topic, references were lim-
ited to those that addressed nonpenetrating TBI. Due to
the breadth of potential post-TBI syndromes and for the
sake of practicality, we elected to confine this review to:
1. Psychosis
2. Depression
3. Mania
4. Posttraumatic stress disorder
5. Agitation and aggression
We excluded personality changes as a specific area of
study because they represent a broad class of syndromes
with an extremely diverse range of symptom presenta-
tions, which were determined to be beyond the scope of
this study. Aggression, however, was included because
of its high prevalence following TBI, clinical signifi-
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
cance, and the Committee’s opinion that its diversity of
presentation was manageable within the scope of this
study. The Committee recognized that though post-TBI
aggression may span several diagnostic entities, such as
personality changes and psychotic and mood disorders,
a discussion of post-TBI aggression represents an op-
portunity to clarify the relationship between neuropa-
thology and psychopathology. The postconcussional
syndrome was excluded because it represents a complex
syndrome with associated pain and cognitive symptom
domains that distinguish it from the syndromes in this
study, which only involves behavioral symptoms.
The decision to exclude a focused review of post-TBI
cognitive deficits in this review was made with the rec-
ognition that cognitive impairments, such as dysexecu-
tive syndromes, amnesias, and perceptual disturbances,
may contribute to, mimic, or alter the clinical presenta-
tion of psychiatric disturbances. The interactions be-
tween cognitive deficits and behavioral disturbances
constitute a broad topic that exceeds the scope of this
study. We have limited this discussion to the role of cog-
nitive impairment as a risk factor for developing the sec-
ondary syndromes, or the impact of these syndromes on
cognitive functioning.
The Committee’s rationale for reviewing neuropsy-
chiatric sequelae of TBI was to assess the quality and
extent of data on the relationship between TBI and psy-
chiatric illness (i.e., what mechanisms and risk factors
contribute to these syndromes, and how reliably the dis-
orders may be identified). It is expected that clarification
of the neural substrates of TBI-related psychiatric illness
may, in turn, lead to a clearer understanding of the neu-
ral substrates of idiopathic psychiatric disease. The cur-
rent DSM-IV-TR classification of mental disorders “sec-
ondary to” a general medical condition, such as TBI,
denotes a causal relationship but lends little symptom-
driven specificity to assist in the diagnosis of such syn-
dromes. Notable exceptions are the diagnosis of “mood
disorder due to a general medical condition with major
depressive-like episode,” in which full criteria for major
depressive disorder are met. However, in other cases the
descriptive criteria lack the specificity demonstrated in
other categories. As a result, their clinical utility is lim-
ited beyond assigning a descriptive label to patients.
METHOD
Relevant articles published between 1978 and 2006 were
identified by searching MEDLINE using the following
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
MeSH search terms for traumatic brain injury: brain in-
juries; brain concussion; craniocerebral trauma; head in-
jury, closed. Each of these terms was cross-referenced
with one of the following MeSH terms: psychosis; de-
pression; mania; agitation; aggression; psychiatric status
rating scales; anxiety. The results were limited to human
studies and English language articles. We then manually
excluded articles that met the following criteria: the
topic of interest was not the central focus; review arti-
cles; letters to the editor. Articles were then reviewed
based on the American Academy of Neurology’s
(AAN’s) criteria for classification of articles on diagnos-
tic methods:3
Class I
Evidence provided by a prospective study of a broad
spectrum of persons with the suspected condition, using
a “gold standard” for case definition where the test is
applied in a blinded evaluation, and enabling the as-
sessment of appropriate tests of diagnostic accuracy.
Class II
Evidence provided by a prospective study of a narrow
spectrum of persons with the suspected condition, or a
well-designed retrospective study of a broad spectrum
of persons with an established condition (diagnosed by
the “gold standard”) compared with a broad spectrum
of comparison subjects, where the test is applied in a
blinded evaluation, and enabling the assessment of ap-
propriate tests of diagnostic accuracy.
Class III
Evidence provided by a retrospective study where ei-
ther persons with the established condition or compar-
ison subjects are of a narrow spectrum, and where the
test is applied in a blinded fashion.
Class IV
Any design where the test is not applied in blinded eval-
uation or evidence is provided by expert opinion alone
or in descriptive case series (without comparison sub-
jects).
One limitation of this approach is that there are cur-
rently no “gold standards” for the diagnosis of psychi-
atric illness in neurological disorders. The best available
approaches are validated and reliable instruments for
the diagnosis of idiopathic psychiatric disorders. In sit-
uations where “gold standard” instruments and criteria
were used, such studies were classified as Class I or II.
108 http://neuro.psychiatryonline.org
This was determined to be the closest approximation to
a reliable test available for the purposes of this study.
Even using such constructs, however, we caution that
these instruments have yet to be validated in popula-
tions with a high propensity for cognitive impairment.
In fact, because of the effects of TBI on somatic, moti-
vational, and cognitive functioning, the use of such in-
struments may result in over- or underdiagnosis of the
syndromes.
RESULTS
We identified 66 studies meeting criteria for review.
General findings included inconsistencies in TBI defi-
nitions, severity criteria, nosological methods, control
for premorbid psychiatric disorders, duration of follow-
up period, and tiered screening approaches. Table 1
summarizes our findings across all disorders reviewed.
Posttraumatic Psychosis
Nosology Definitions of “psychosis” have varied
widely in the literature. Sachdev et al.4 matched partic-
ipants on gender, age at injury, current age, and time
since injury in a case-control study comparing 45 pa-
tients with “schizophrenia-like psychosis following
TBI” (which included meeting DSM-IV criteria for
schizophrenia or schizophreniform disorder) to 45 head-
injured subjects without psychosis. In addition, all had
received a computed tomography (CT) head scan and
neuropsychological testing. The psychoses had a mean
age of onset of 26.3 years, a mean latency of 54.7 months
after head injury, and usually a gradual onset and a sub-
acute or chronic course. Paranoid delusions and audi-
tory hallucinations were present in 55% of patients, with
formal thought disorder, catatonic features, and nega-
tive symptoms being uncommon.
Epidemiology
Incidence of Psychosis Following TBI Thomsen5
followed 40 survivors of severe TBI for 10 to 15 years
after sustaining their injuries. In this sample, 20% de-
veloped psychotic disorders, though diagnostic criteria
were not defined and hallucinations and delusions were
not mentioned. This raises significant questions as to the
validity of this figure.
Prevalence of Psychosis Following TBI Strictly de-
fined, no prevalence studies of psychosis following TBI
were identified meeting search criteria.
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
 KIM et al.

Risk Factors Fujii and Ahmed6 conducted a retrospec- psychotic symptoms. TBI severity was based on Amer-
tive chart review comparing 25 state hospital inpatients ican Congress of Rehabilitation Medicine criteria.2 Re-
meeting DSM-IV criteria for a diagnosis of psychosis gression analysis indicated the posttraumatic psychosis
secondary to TBI to 21 outpatient TBI survivors without group was more likely to have had a previous congenital

TABLE 1. Summary of Findings From Review of the Literature

Issue Findings Data Class
Post-TBI Psychosis
Nosology Paranoid delusions, auditory hallucinations in 55% of patients4 III
Epidemiology Incidence 20%5 IV
Prevalence unknown
Risk Factors Injury prior to adolescence6,8 IV
Left temporal injury4 IV
More severe injuries4 IV
Less severe injuries6 IV
Greater cognitive impairment4,7 IV
Post-TBI Depression
Nosology Beck Depression Inventory 36% sensitivity, 80% specificity12 III
DSM-III-R criteria 100% sensitivity and 94% specificity at initial evaluation; 80% sensitivity and III
100% specificity at 1 year. Depressed mood, reduced energy, feelings of worthlessness, and
suicidal ideation differentiated depressed from non-depressed13
NFI items fatigue, frustration, poor concentration, boredom and distractibility commonly III
associated with DSM-IV depression; feeling sad or blue was not14
NFI items reduced libido and appetite, anhedonia, lack of confidence more predictive of DMS-IV III
major depression; verbal and physical aggression, forgetfulness, fatigue are least important15
Epidemiology Incidence 15.3%–33% using SCID16,17 III
Prevalence 18.5%–61% post-TBI14,18–29 IV
Risk Factors Psychosocial stressors30,32,33 IV
Left anterior hemisphere lesion (major depression)27 IV
Right hemisphere lesion (anxious depression)27 IV
Lateral versus medial lesion location34 IV
Increased age20,31 III
Lack of work/fear of job loss29,32 IV
Post-TBI Mania
Nosology Sleeplessness, impaired judgment, grandiosity, irritability, pressured speech in 80%–100% of IV
cases; hyperactivity in 65% and hypersexuality in 50%39
Epidemiology Incidence 9.1%45 IV
Prevalence 0.83%–22.2%39,44,49 IV
Risk Factors Prolonged postinjury amnesia39 IV
Seizures50 IV
Multifocal lesions45,52 IV
Frontal lesions41,52–54 IV
Orbitofrontal lesions54 IV
Temporal lesions33,45,52 IV
Non-dominant hemispheric lesions54 IV
Post-TBI PTSD
Nosology Emotional reactivity common, intrusive memories rare56,57 III
Intrusive memories present58–60 III
Epidemiology Incidence 13%–27%59–62 III
Prevalence 3%–59%21,64–67 III
Risk Factors Loss of consciousness68 IV
Avoidance coping69 IV
Female gender, early post-injury depression and anxiety63 IV
Left temporal lesions, increased lesion volume70 IV
Recall of injury61 III
Post-TBI Aggression
Nosology None NA
Epidemiology Incidence 33.7%–38%74,76 IV
Prevalence 20%–40%79 IV
Risk Factors Injury severity81,85,86 IV
Frontal lesions74 IV
Pre-injury aggression74,82 IV
Pre-injury substance abuse74,86 IV
More than one injury with loss of consciousness87 IV

NFI⳱Neurobehavioral Functioning Inventory; SCID⳱Structured Clinical Interview–DSM

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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
neurological disorder or to have sustained a head injury
prior to adolescence. No differences were found be-
tween the groups with respect to handedness, highest
education level attained, IQ, socioeconomic status, av-
erage age for sustaining the TBI associated with onset
of psychosis, and type of TBI. More general prior sub-
stance use was present among those who developed
posttraumatic psychosis, but no differences were found
in the use of psychosis-inducing substances (e.g., LSD,
amphetamine, and cocaine). There was also no differ-
ence found in proportion of seizure occurrence between
psychosis and comparison subjects. However, because
subjects were not matched for age or gender, and family
history of psychosis was an exclusion criterion, it could
not be determined whether these factors would have
served as significant predictors of psychotic symptom
development following a TBI. In this study, most sub-
jects with posttraumatic psychosis had a mild head in-
jury, whereas more severe injuries were reported in the
comparison group. This study is limited by its retro-
spective nature and the comparison of severely psy-
chotic state hospital patients with fewer impaired out-
patients.
Sachdev et al.4 found no significant differences be-
tween those with post-TBI psychosis and nonpsychotic
TBI comparison subjects with respect to type of injury,
prior alcohol and drug use, and posttraumatic behav-
ioral and personality changes. Family history of schizo-
phrenia, duration of loss of consciousness, language im-
pairment, and frontal and parietal lobe deficits were
more common in patients with posttraumatic psychosis.
Preinjury neurological or developmental abnormalities
were not significantly different between the two groups.
The schizophrenia-like psychosis group had more wide-
spread brain damage on neuroimaging, especially in the
left temporal and right parietal regions, and was more
impaired cognitively. On regression analysis, a positive
family history of psychosis and duration of loss of con-
sciousness were the best predictors of schizophrenia-like
psychosis.
Fujii et al.7 conducted a retrospective review of neu-
ropsychological testing results comparing three sam-
ples: 24 state hospital inpatients with psychotic disorder
following TBI (PDFTBI); 12 outpatients with a history of
TBI without psychosis (TBIWP); and 24 state hospital
inpatients with schizophrenia but no history of TBI.
Tests included the Wechsler Adult Intelligence Scale
(WAIS), verbal fluency, immediate recall of a narrative
story, and the Wisconsin Card Sorting Test (WCST). The
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PDFTBI group demonstrated significantly lower scores
than the TBIWP group in the WAIS IQ, semantic mem-
ory, verbal fluency, and WCST. The pattern of deficits
was similar to that of the schizophrenia group, though
the schizophrenia group demonstrated more severe and
global impairments than the PDFTBI group. The study
was limited by small sample size and the different func-
tion status of the study groups. The retrospective study
design is also a limitation.
A different approach to clarifying risk factors for post-
TBI psychosis involves retrospectively assessing prior
head injuries in patients currently diagnosed with
schizophrenia. Abdel Malik et al.8 compared 67 patients
with structured clinical interview-confirmed diagnoses
of schizophrenia or schizoaffective disorder with 102
unaffected siblings in families with multiple occurrences
of schizophrenia. Childhood head injuries (age of oc-
currence ⱕ10 years) occurred in 24% of schizophrenia
patients versus 12% of unaffected siblings. Moreover,
childhood head injuries were associated with a younger
age of onset of schizophrenia. The median time between
injury and first psychosis was 12 years. Malaspina et al.9
utilized the Diagnostic Interview for Genetic Studies to
determine the onset, nature, duration of loss of con-
sciousness, severity, and number of traumatic brain in-
juries in 565 subjects with at least two first-degree rela-
tives with schizophrenia. Schizophrenia patients had a
threefold increase in their risk for a prior TBI compared
with relatives without psychiatric illness. In contrast,
Silver et al.10 noted that among 5,034 participants inter-
viewed as part of a National Institute of Mental Health
(NIMH) Epidemiologic Catchment Area study in New
Haven, prior head injuries were not significantly asso-
ciated with a current diagnosis of schizophrenia. These
results suggest that in individuals with a genetic vul-
nerability for schizophrenia, TBI may be a contributing
factor to the expression of the disorder.
Summary and Recommendations The literature on post-
traumatic psychosis is limited by a lack of clear opera-
tional criteria to define it. The DSM diagnosis of psy-
chosis due to TBI has been inconsistently used across
studies and has limitations, prompting proposals for
modifications to the criteria. No firm conclusions can be
made regarding the incidence or prevalence of posttrau-
matic psychosis. A particular limitation of the literature
has been difficulty in distinguishing patients with post-
traumatic psychosis from patients with an “idiopathic”
psychosis who have a prior history of head injury. The
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

issue of a temporal versus causal relationship is not pos-
sible to resolve in the absence of a clearer understanding
of the pathophysiological mechanism underlying post-
traumatic psychosis, and a reliable means of distin-
guishing this process from that underlying idiopathic
psychosis. The use of case-control versus prospective
follow-up studies is problematic in that patients in pri-
mary mental health settings may have other etiological
factors for their psychotic illness. Future research is nec-
essary to accomplish several goals:
1. To clarify the diagnostic criteria for psychosis due
to traumatic brain injury. Specifically, this would
require:
a. Defining and validating core symptoms that distin-
guish “psychoticism” from cognitive or perceptual
disturbances. In particular, so-called negative
symptoms may prove nonspecific in their diagnos-
tic validity in the presence of amotivational frontal
symptoms.
b. Defining a minimum and maximum time frame be-
tween injury and onset of psychosis. Though this
would establish formal criteria for the temporal re-
lationship between TBI and psychosis, it would not
necessarily validate any causal relationship. Nev-
ertheless, a consistent definition of the temporal re-
lationship is a necessary prerequisite to research on
causality.
c. Defining exclusionary criteria that would differ-
entiate TBI-related psychoses from idiopathic psy-
chotic disorders.
2. To clarify the incidence, prevalence, and natural
time-course of posttraumatic psychosis in larger
population samples of patients in primary TBI set-
tings who are followed prospectively. This would
require large-scale prospective multicenter de-
scriptive studies. The TBI Model Systems (TBIMS)
network, funded by the National Institute on Dis-
ability and Rehabilitation Research (NIDRR), con-
sists of 16 sites that provide TBI services from acute
care through community reentry. A network of this
magnitude would likely be necessary to recruit suf-
ficient numbers of patients to establish valid epi-
demiological and time course data. However,
given the presumed low incidence and prevalence
of posttraumatic psychosis, such a study would be
justifiable only in the context of a larger study of
all major psychiatric syndromes following TBI.
3. To identify genetic, neuropsychological, and clini-
cal correlates that are predictive of the develop-
ment of post-TBI psychosis.
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KIM et al.
4. To clarify the pathophysiological mechanism of
posttraumatic psychosis compared with that of
schizophrenia. Functional neuroimaging and post-
mortem histological studies may help differentiate
the two syndromes and contribute to more reliable
diagnostic specificity. This is a prerequisite to dis-
tinguishing causal from temporal relationships be-
tween TBI and psychosis.
Post-TBI Depression
Nosology Because symptoms of depressed mood and
anxiety can represent appropriate situational reactions,
transient normative variations, or pathological states,
defining meaningful post-TBI depressive syndromes is
a crucial first step. The DSM-IV diagnosis of mood dis-
order due to a general medical condition includes two
subtypes that incorporate virtually the entire spectrum
of post-TBI depressive phenomena. The subtype “with
depressive features” refers to depressive symptoms that
fail to meet full criteria for major depressive disorder,
while the subtype “with major depressive features” in-
cludes those that meet full diagnostic criteria for major
depression.
One challenge to using these criteria is that the effect
of TBI on somatic and motivational symptoms may oc-
cur independently of effects on mood. For example, fa-
tigue, sleep disturbance, concentration difficulties, and
apathy are common signs and symptoms in TBI survi-
vors with and without mood disorders. The addition of
depressed mood to this constellation will result in meet-
ing criteria for major depressive disorder. As a result,
the prevalence of major depressive disorder in TBI sur-
vivors may be overestimated if unmodified DSM criteria
are used.11
Given this all-inclusive range, a review of the entire
literature in this area is unrealistic. Different authors,
depending upon the purpose of their study and the de-
cade of their work, used different approaches. Since the
mid-1990s, there has been a consistent move toward us-
ing criteria listed in DSM-IV and DSM-IV-TR rather than
rating scales alone which measure symptom severity ir-
respective of whether diagnostic criteria for the disorder
are met. Sliwinski et al.12 evaluated the relationship be-
tween the Beck Depression Inventory (BDI) and clinical
depression using an SCID in 100 survivors with TBI.
Twenty-five subjects were diagnosed as depressed. BDI
symptoms correlated with depression but were more
strongly related to other problems identified by The In-
stitute for Rehabilitation and Research (TIRR) symptom
checklist. The BDI had sensitivity of only 36% for dis-
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
criminating depressed from nondepressed individuals,
and a specificity of 80%.
Jorge et al.13 examined the stability and change of psy-
chological and somatic symptoms over the course of 1
year in 66 patients hospitalized for TBI, finding a 42%
incidence of major depressive disorder. The standard
DSM-III-R criteria for major depression had 100% sen-
sitivity and 94% specificity at initial evaluation and 80%
sensitivity and 100% specificity at 1 year. Four symp-
toms consistently differentiated depressed from non-
depressed patients: depressed mood, reduced energy,
feelings of worthlessness, and suicidal ideation. Though
the authors suggest that DSM criteria are valid for the
diagnosis of major depressive disorder in TBI survivors,
the lack of discriminatory validity of all criteria suggests
that some symptoms (e.g., sleep disturbance, dimin-
ished thinking ability, anhedonia) may be less useful in
this sample.
Kreutzer et al.14 evaluated 722 outpatients an average
of 30 months post-TBI in an outpatient TBI clinic using
the Neurobehavioral Functioning Inventory (NFI) to
identify and quantitate symptoms consistent with di-
agnostic criteria for major depressive disorder. The au-
thors categorized various items in the NFI to be consis-
tent with DSM-IV diagnostic criteria. In this sample,
42% of patients met criteria for major depressive disor-
der. This study did not employ a gold-standard psychi-
atric diagnostic interview to confirm major depressive
disorder diagnosis or validate the item clustering meth-
odology used. The most commonly reported symptoms
included fatigue, frustration, poor concentration, bore-
dom, and distractibility. Feeling sad or blue (NFI item)
was not endorsed frequently in this sample. This is at
variance with the findings of Jorge et al.13 that depressed
mood was a differentiating symptom.
Kennedy et al.15 evaluated 78 TBI patients in outpa-
tient follow-up an average of 76 months postinjury us-
ing the SCID-I and the patient version of the NFI to eval-
uate the usefulness of the NFI in identifying depression.
The SCID was used to identify patients meeting current
DSM criteria for major depressive disorder. NFI items
with the greatest importance in predicting a diagnosis
of major depressive disorder included: loss of interest in
sex, poor appetite, difficulty enjoying activities, lack of
confidence, being uncomfortable around others, forget-
ting to do chores, feeling lonely, feeling sad or blue, and
feeling frustrated. Items with the least importance in-
cluded: threatening to hurt oneself, cursing at others,
cursing at oneself, hitting others, sitting with nothing to
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do, screaming or yelling, restlessness, forgetting yester-
day’s events, and tiring easily during physical activity.
The authors cite the sample size as a limitation of the
study’s generalizability and also call into question the
validity of using DSM-IV criteria in diagnosing depres-
sion in TBI, given the overlap of neurovegetative symp-
toms in idiopathic depression and TBI without depres-
sion. Despite these limitations, this study represents a
strong validation of the use of nonvegetative signs in
assessing post-TBI depression.
Epidemiology Given the variability in nosology de-
scribed above, we adopted the most restrictive epide-
miological approach, examining studies of major de-
pressive disorder following TBI. Though this may
underrepresent the actual incidence and prevalence of
post-TBI depression, it was felt to be a more rigorous
approach.
Incidence of Major Depressive Disorder After TBI
Rapoport et al.16 assessed 170 consecutive survivors of
mild TBI using the SCID at their first follow-up appoint-
ment in a TBI clinic an average of 48 days postinjury.
Patients with preexisting major depression or bipolar
disorder were excluded from this sample. In this sam-
ple, 15.3% of the patients met DSM-IV criteria for major
depressive disorder. Subjects with major depressive dis-
order had higher rates of psychosocial dysfunction on
the Rivermead Head Injury Follow-up Questionnaire,
and psychosocial distress as measured on the General
Health Questionnaire. In a subsequent study, Rapoport
et al.17 evaluated 74 patients with the SCID in the same
setting an average of 200 days postinjury, finding a
28.4% incidence of major depression.
Jorge et al.18 assessed 91 consecutive TBI patients ad-
mitted to a general hospital at 3, 6, 9, and 12 months
postinjury. They were compared with 27 patients ad-
mitted for multiple trauma without TBI. In the TBI sam-
ple, 51.6% met DSM-IV criteria for mood disorder due
to TBI, 33% with major depressive features, 9.9% with
depressive features, and 8.8% with manic or mixed fea-
tures. In the comparison group, major depression was
identified in 7.4% of patients and 14.8% had depression
without major depressive features.
Chamelian and Feinstein19 evaluated 63 outpatients
at a TBI clinic 6 months following a mild to moderate
TBI using the SCID, Rivermead Post Concussion Symp-
toms Questionnaire, and a neuropsychological battery.
They noted an 18.5% incidence of post-TBI depression
in this sample. Levin et al.20 evaluated 129 patients with
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

mild TBI admitted to a trauma center at 1 week and 3
months postinjury using the SCID, noting an 11.6% in-
cidence of major depression at 3 months.
Prevalence of Major Depressive Disorder After
TBI Hibbard et al.21 evaluated 100 adults an average
of 8 years post-TBI using the SCID to identify Axis I
psychiatric disorders. This study yielded a prevalence
rate of 61% for major depressive disorder following TBI.
A separate analysis of major depressive disorder with
onset following TBI led to a lower but still substantial
rate of 48%. This second prevalence estimate may be a
more reliable indicator of depression with a higher like-
lihood of being caused by TBI. One limitation of this
study is that the sample was self-selected: participants
responded to active recruitment through TBI newslet-
ters and other means. This may have led to an “en-
riched” sample of TBI patients with an excess of psy-
chiatric symptomatology.
Seel et al.22 studied 666 outpatient survivors of TBI in
a prospective multicenter study. Data regarding major
depressive disorder were extracted from the NFI, which
was administered as part of a comprehensive outpatient
evaluation an average of 35.3 months following TBI. In
this sample, 27% of patients met DSM-IV criteria for ma-
jor depressive disorder. Symptoms with the highest dis-
criminatory power between depressed and nonde-
pressed patients included hopelessness and feelings of
worthlessness. Koponen et al.23 recruited 60 patients
who had sustained TBIs between 1950 and 1971 and as-
sessed them using the Schedules for Clinical Assessment
in Neuropsychiatry (SCAN). Major depression was
identified in 26.7% of the sample. Onset of depression
occurred either in the first year (32.5%) or more than 10
years postinjury (67.5%). The original population sam-
ple for this study was 210 patients. Of the original sam-
ple, 76 had died, and the rest either refused to partici-
pate or had nontraumatic neurological diseases that
resulted in exclusion from the study.
Fann et al.24 interviewed 50 consecutive survivors of
TBI in a brain injury clinic an average of 32.4 months
postinjury using the NIMH’s Diagnostic Interview
Schedule (NIMH-DIS) and the Medical Outcomes Study
Health Survey (MOSHS). In this sample, 26% met cri-
teria for current major depression and another 28% met
criteria for major depression that developed and re-
solved following injury. The mean time since injury was
32.5 months. Jorge et al.25 and Fedoroff et al.26 assessed
66 survivors of TBI during acute hospitalization and at
3-, 6-, and 12-month follow-ups for prevalence of pri-
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
mary mood disorder (DSM-III). Twenty-eight (42%) sub-
jects had major depression at some time during the
study period. Seventeen (26%) had acute-onset depres-
sion. Eleven (17%) had delayed-onset depression, which
appeared to be influenced by psychosocial factors as
well. Jorge et al.27 also examined those 66 survivors of
TBI for prevalence of major depression and generalized
anxiety disorder. Ten (15%) acute-onset subjects met cri-
teria for major depression without generalized anxiety
disorder and seven (11%) subjects had both major de-
pressive disorder and generalized anxiety disorder.
Holsinger et al.28 investigated the lifetime rates of de-
pression in World War II veterans who had a docu-
mented closed head injury using a modified version of
the NIMH-DIS. Men with dementia or penetrating head
injuries were excluded. Their sample included 520 vet-
erans with head injury and 1,198 veterans without head
injury. The lifetime prevalence of major depression in
the group with head injury was 18.5%. In the compari-
son group, the lifetime prevalence was 13.4%. This di-
agnosis was not attributable to cardiovascular diseases
or alcohol abuse. Lifetime risk of depression increased
with severity of head injury. Bowen et al.29 screened 99
survivors of TBI for emotional state about 6 months after
injury. Using the Wimbledon Self-Report Scale, the rate
of clinically significant mood disorder was 38%. Prein-
jury lack of occupation correlated with postinjury mood
disorder. Psychosocial disability was more strongly as-
sociated with mood disorder than physical disability.
Risk Factors Luis and Mittenberg30 assessed 96 children
consecutively admitted to a general hospital who were
subsequently followed for 6 months postinjury. The
sample consisted of 42 patients with mild TBI (GCS 13–
15), 19 with severe TBI (GCS⬍13), and 35 children who
had sustained skeletal fractures without head trauma or
neurological abnormalities. Assessment was measured
using the depression and anxiety modules of the Diag-
nostic Interview Schedule for Children-IV (DISC-IV). Se-
quential logistical regression was utilized to examine the
impact of brain injury, demographic variables, preinjury
psychiatric disturbance, developmental disorders, liti-
gation status, and postinjury environmental stress on
emotional outcomes. Postinjury level of stress and se-
verity of brain injury accounted for 23% of the variance
in the production of new onset depression and/or anxi-
ety disorder. Glenn et al.31 studied 41 outpatients in a
rehabilitation hospital an average of 41 months post-TBI
using the Beck Depression Inventory-II. Logistical re-
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
gression demonstrated a positive relationship between
depression and age, being female, having mild TBI, and
use of antidepressant medications.
Gomez-Hernandez et al.32 examined social factors
contributing to the development of major depression af-
ter TBI. They studied 65 individuals from in-hospital
care to 3-, 6-, 9-, and 12-month follow-ups. Fear of job
loss was significantly associated with depression early
in recovery. Fear of job loss and impaired close personal
relationships were associated with depression at 6–12
month follow-up. The semistructured psychiatric inter-
view, Hamilton Depression Rating Scale, and Social
Functioning Exam were the objective measures used.
Bay et al.33 interviewed 75 TBI survivors and their sig-
nificant others. All survivors were within 2 years of the
date of injury and were living in the community. Using
selective neuropsychological tests, the Perceived Stress
Scale, the Interpersonal Relatedness Inventory, the Sense
of Belonging Instrument, the Neurobehavioral Func-
tioning Inventory, and the Center for Epidemiological
Studies Depression Scale, the authors found a positive
correlation between perceived levels of stress and de-
pression. Sense of belonging was negatively related to
new onset of depression.
Paradiso et al.34 compared two small groups of TBI
survivors with focal lesions identified by magnetic res-
onance imaging (MRI) who were matched for age, race,
education, sex, socioeconomic status, and etiology of
lesion. Eight survivors had medial lesions and eight sur-
vivors had lateral lesions. At 3 months after injury, sur-
vivors with lateral damage had worse depressive symp-
toms and apathy, with greater impairment of activities
of daily living and social functioning. Satz et al.35 ex-
amined 100 survivors of TBI using self-rated depression
scales. Compared to 30 trauma survivors (nonbrain in-
juries), the severity of depressive symptoms correlated
with the functional level of the Patient Competency
Scale but did not correlate with neurocognitive perfor-
mance measures. Jorge et al.27 noted that patients with
major depression alone tended to have left anterior
hemisphere lesions, while depression with anxiety was
associated with right hemisphere lesions.
Piccinelli et al.36 elicited written responses from 158
survivors of TBI 60 months after injury. Thirty-eight
percent reported “definite” anxiety and/or depressive
disorders, although only 21% admitted to taking medi-
cations. Factors associated with development of depres-
sion or anxiety disorder were: sequelae of head injury
(cognitive problems, seizures, facial pain), writing im-
114 http://neuro.psychiatryonline.org
pairment, thorax problem, and new trauma. Initial
injury severity and overall disability rating by the in-
vestigator were not strong predictors of anxiety or
depression at follow-up. Bowen et al.’s study29 found
that preinjury lack of occupation correlated with post-
injury mood disorder. Psychosocial disability was more
strongly associated with mood disorder than physical
disability.
Levin et al.20 found that older age at occurrence of
injury, CT abnormalities, and higher scores on the Cen-
ter for Epidemiologic Studies Depression Scale at 1 week
postinjury predicted the development of depression at
3 months.
Summary and Recommendations There is substantial evi-
dence that depression is a common complication of TBI,
with a prevalence of 15.6% to 61% meeting criteria for
major depressive disorder. This high variability suggests
limitations in the diagnostic methods used, or perhaps
variability in sampling methods (randomized versus
self-selected based on referral/recruitment patterns). Be-
cause fatigue, poor concentration, and sleep distur-
bances are common post-TBI symptoms in the absence
of depression, these criteria may inflate the frequency
with which major depressive disorder is diagnosed in
this population. However, the threshold for identifying
“clinically significant” depressive syndromes is not
clearly defined. Depression is a common cause for func-
tional impairment in the general population, and there
is substantial evidence of a similar effect in TBI. Rapo-
port et al.16 and Fann et al.24 found that TBI patients with
depression had poorer functional and psychosocial out-
comes. Risk factors for post-TBI depression appear to be
related to stress, social isolation, and maladaptive cop-
ing styles, suggesting that reactions to injury-related def-
icits drive depressive symptomatology. Moreover, lat-
eral lesion locations are associated with an increased
risk of developing depression compared with medial le-
sions, with right lateral lesions increasing risk of anxious
depression and left anterior lesions increasing risk for
major depression. Future research is necessary to en-
hance knowledge in the following areas:
1. Diagnostic criteria: Develop standardized categor-
ical and dimensional criteria for post-TBI depres-
sion that have clinical and discriminative validity.
In particular, DSM criteria of reduced energy, im-
paired concentration, and sleep disturbance may
not reliably differentiate TBI-related depression
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

from nonspecific neuropsychiatric sequelae of TBI.
If this is the case, such symptoms should be elim-
inated from the diagnostic criteria in order to pre-
vent the inappropriate use of antidepressant med-
ications that may have little or no clinical value.
2. Post-TBI course of depression: Given the large di-
rect and indirect costs of depression identified in
the general population and other medical popula-
tions, it seems logical to prioritize the detailed
study of the incidence, prevalence, and post-TBI
course of depression in the TBI Model Systems net-
work using standardized, validated criteria and in-
struments.
3. Long-term effects of post-TBI depression: Describe
the long-term psychosocial, functional, and physi-
cal impact of post-TBI depression, particularly the
impact of early recognition and treatment on lon-
gitudinal outcome. Once standardized criteria for
diagnosis are developed, both prospective and ret-
rospective studies using case control methodolo-
gies could facilitate this objective.
4. Predictors of post-TBI depression: Identify biologi-
cal, psychosocial, and cognitive predictors for de-
veloping post-TBI depression. Such variables could
include family history of mood disorder, preinjury
psychological trauma, or post-TBI executive cog-
nitive impairment. The interactions between objec-
tive cognitive impairment and the processes by
which TBI survivors adjust to altered vocational
options as either knowledge workers or unskilled
laborers create additional variability that has yet to
be studied.
Posttraumatic Mania
Nosology A variety of diagnostic criteria have been ap-
plied to posttraumatic mania including those of Dalén,37
Feighner,38 the Research Diagnostic Criteria (RDC),39,40
DSM-III,39,41–44 DSM-III-R,44,45 and DSM-IV.46 Criteria
for secondary mania47,48 have been inconsistently ap-
plied. Dalén37 utilized clinical criteria and introduced
exclusion criteria consisting of other organic insults and
genetic diathesis. Assessment methodology has in-
volved the use of clinical diagnostic criteria and semi-
structured diagnostic clinical interviews. Gureje et al.40
utilized the Composite International Diagnostic Inter-
view (CIDI) to determine RDC diagnoses. Shukla et al.39
utilized the Schedule for Affective Disorders and
Schizophrenia–Lifetime version (SADS-L) to ascertain
RDC diagnoses, and both Shukla et al. and van Reekum
et al.44 used the SADS-L to determine DSM-III diagno-
ses. Jorge et al.45 used the Present State Exam (PSE) to
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
determine DSM-III-R diagnoses. Van Reekum et al.44
used the Structured Interview for Diagnosing Person-
ality–Revised (SIDP-R) for DSM-III-R Axis II disorders.
DelBello et al.46 used the SCID to ascertain DSM-IV bi-
polar disorder. Varney et al.49 interviewed at least one
first-degree relative to corroborate symptoms in sub-
jects. Shukla et al.39 examined specific symptom patterns
in posttraumatic mania, including psychosis and as-
saultiveness. They also considered longitudinal illness
course with respect to episodes of depression and hy-
pomania. Jorge et al.45 determined the duration of manic
episodes as well as mood and assaultiveness.
There are no identifiable studies that have evaluated
posttraumatic mania diagnostic validity or reliability.
There have been several approaches to diagnosing post-
traumatic mania. One straightforward approach ascer-
tains posttraumatic mania when mania is present in the
context of a previous history of TBI.39,41,43 This approach,
however, does not take into account the presence of ma-
nia prior to TBI, a genetic diathesis toward bipolar dis-
order, or other etiologies of mania. Thus, while in an
ideal setting the diagnosis of posttraumatic mania
would differentiate mania clearly attributable to TBI from
that simply observed following TBI, in the absence of a
validated pathophysiological model for the disorder, it
is difficult to do so. As a result, the use of a temporal
relationship in the absence of alternative explanatory
etiologies may be the most useful approach.
Feighner et al.38 have been credited with first extend-
ing nosological status to the concept of mania ascribable
to a medical condition. Krauthammer and Klerman47 in-
troduced the concept of secondary mania attributable to
specific primary medical etiologies; however, neither
their report nor an update by Stasiek and Zetin48 men-
tioned a posttraumatic etiology. Stipulating that mania
must be attributable to TBI is a refinement in posttrau-
matic mania nosology, but specificity can be improved
further. At some point, however, sensitivity will be sac-
rificed. To attain greater specificity, attempts have been
made to exclude other potential etiologies of mania,
such as family genetics. Dalén37 examined the hypoth-
esis that mania can be attributed to neurological disease.
He used the clinical criteria of distinct elevation in
mood, increased activity, tendency to act without proper
judgment during discrete time periods, and an episodic
course to define mania. Attribution of mania to trauma,
perinatal insult, infectiousness, or family histories was
assessed by review of medical records and interview of
relatives, introducing to the nosological concept of post-
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
traumatic mania the inclusion criterion of premorbid
TBI and the exclusion of infectious etiology and positive
family history of bipolar disorder. Other investigators,
including Wilcox and Nasrallah,50 Pope et al.,42 and Hoff
et al.,43 have similarly required posttraumatic mania on-
set to be temporally subsequent to TBI, suggesting at-
tribution to TBI.
The specific application of inclusion and exclusion cri-
teria to posttraumatic mania was suggested by Riess et
al.51 in a review of the literature. They concluded that
the diagnosis of posttraumatic mania should be consid-
ered in manic patients with an atypical age of onset,
absence of previous psychiatric illness, negative family
history for bipolar illness, and a close temporal relation-
ship to TBI.
Epidemiology
Incidence of Posttraumatic Mania Only one study
in the literature used a systematic approach sufficient to
yield information pertaining to incidence. Jorge et al.45
followed up 66 consecutive patients with closed head
injury at 3, 6, and 12 months. Inclusion criteria specified
patients over age 18 with acute closed head injury free
of multiple body injuries but with various levels of con-
sciousness. Severity of brain injury was determined us-
ing the 24-hour Glasgow Coma Scale score, but patients
with mild scores12–15 who underwent intracranial sur-
gical procedures or had focal lesions greater than 25cc
were considered to have moderate head injuries. Forty-
five of the 66 patients were classified as having moder-
ate head injuries. Patients were evaluated using a mod-
ified version of the PSE semistructured psychiatric
interview for DSM-III-R diagnoses, the Hamilton De-
pression Rating Scale, Mini-Mental State Examination,
Johns Hopkins Functioning Inventory for activities of
daily living, Social Functioning Exam, and Social Ties
Checklist. CT scans were obtained on admission and 1
to 2 weeks later, and lesion location analysis was un-
dertaken using logistic regression analysis. Patients with
delirium or affective disorder at the time of the TBI were
excluded. Though not specifically stated, it appears that
patients with a history of bipolar disorder prior to TBI
were also excluded. Six patients (9.1%) met criteria for
mania over the 12-month follow-up period. Irritability,
sometimes coupled with euphoria, was present in all
and half were aggressive. None had seizures. The in-
vestigators point out that the sample was primarily of
young white men from lower socioeconomic classes,
with alcohol or drug abuse and multifocal brain inju-
116 http://neuro.psychiatryonline.org
ries, and that 35% of patients were lost to 6- or 12-month
follow-up, with dropouts significantly correlating with
cortical and orbitofrontal lesions. The authors therefore
suggest that the rate of 9.1% with posttraumatic mania
may be a conservative figure because of the high drop-
out rate. If one considers the possibility that a majority
of posttraumatic mania cases develop after a period of
at least a 1-year delay, the figure may indeed constitute
an underestimate.
Any future determination of posttraumatic mania in-
cidence must be interpreted within the context of the
duration of surveillance post-TBI, because several stud-
ies have reported a substantial delay between the TBI
and the development of posttraumatic mania. For ex-
ample, Dalén37 observed two patients in whom post-
traumatic mania developed 4 to 5 years post-TBI. Shukla
et al.39 found that posttraumatic mania followed a la-
tency of 2.8 (SD⳱3.4) years. Consequently, studies of
incidence should look at different incidence surveillance
periods relative to the injury because incidence of new
cases of posttraumatic mania may depend upon time
elapsed since the lesion. On the other hand, the longer
the period of delay, the more the attribution to the index
TBI may be questioned.
Prevalence of Posttraumatic Mania Strictly de-
fined, only the study of Jorge et al.45 was adequately
designed to assess 12-month period prevalence of post-
traumatic mania. In this study, described in the section
on incidence, the authors followed up 66 consecutive
patients with closed head injury at 3, 6, and 12 months
and found a 12-month posttraumatic mania incidence of
9.1%, which might also be viewed as a 12-month period
prevalence figure. Mania was brief, with a duration of
about 2 months. Irritability, sometimes coupled with eu-
phoria, was present in all and half were aggressive.
None had seizures. Considerations regarding the valid-
ity of this 1-year figure were discussed under “Incidence
of Posttraumatic Mania.”
Varney et al.49 reviewed a sample of 120 patients with
closed head TBI referred for neuropsychological testing
at several hospitals, with a range of coma durations last-
ing a few minutes to 8 days. These subjects were com-
pared with 60 comparison subjects with back injuries
(without head injuries) referred for assessment with the
Minnesota Multi-Phasic Personality Inventory (MMPI)
and an interview at one of the hospitals. Subjects were
interviewed at least 2 years after the injury (range⳱2 to
8 years, mean⳱3.4 years) with regard to DSM-III symp-
toms of mania and family history. At least one first-
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

degree relative was interviewed to corroborate the fam-
ily history and the subjects’ symptoms. A structured
interview was not used and a family history of mania
was not specifically inquired about. Four patients (3.3%)
with closed head injury met DSM-III criteria for mania,
but three had a family history of bipolar affective dis-
order and were already being treated with lithium. It is
not clear how many of the patients were ill before the
onset of the head injury, so it is possible, yet inconclu-
sive, that one patient (0.83%) had secondary mania at-
tributable to the head injury.
Van Reekum et al.44 studied 18 subjects under age 40
from a regional TBI rehabilitation program at least 2
years postinjury. These subjects had no documented
preinjury psychiatric illness or cognitive deficits. All
subjects were interviewed by a psychiatric nurse using
the SADS-L for DSM-III-R Personality and the SIDP-R.
The subjects included 10 women and eight men with an
average duration from TBI to assessment of 4.9 years.
Three patients were diagnosed with bipolar affective
disorder and two were diagnosed with cyclothymia,
with one (5.6%) subject experiencing onset of the dis-
order prior to TBI. It was not clear whether this subject
was diagnosed with posttraumatic mania or cyclothy-
mia, and the follow-up period was not specified. Four
subjects had severe TBI while one had moderate severity
of TBI. The low participation rate and the highly se-
lected and retrospective nature of the study may inflate
the prevalence observed and call for caution in gener-
alizing the findings. However, the authors point out that
four of the five subjects with bipolar spectrum disorders
were men and that the actual prevalence of bipolar dis-
order in head injured patients may be higher than ob-
served in this sample, since men tend to predominate in
the TBI population, in contrast to the demographics of
the sample studied.
Shukla et al.39 examined the course of posttraumatic
mania in 20 TBI survivors referred from hospital clinics
with posttraumatic mania diagnosed by RDC and DSM-
III criteria and ascertained using the SADS-L. All sub-
jects lacked mania in first- and second-degree relatives
although six (30%) probands had one or more relatives
with depression. They found that manic episodes pre-
dominated over depressive episodes, 10 to 1, and that
hypomanic episodes predominated over depressive ep-
isodes, 5 to 1. The mean follow-up period of the study
appears to be 11 years after TBI, but a specified preva-
lence surveillance period was not uniformly applied to
each patient. Posttraumatic mania episodes were char-
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
acterized by sleeplessness in 100%, impaired judgment
in 100%, grandiosity in 90%, irritability in 85%, pres-
sured speech in 80%, flight of ideas in 75%, assaultive-
ness in 70%, hyperactivity in 65%, and hypersexuality
in 50%. Euphoria occurred in 15%, the same rate as for
psychotic features.
Risk Factors Shukla et al.39 found that posttraumatic
mania was associated with more severe TBI (long du-
rations of posttraumatic amnesia) among 20 outpatients
with relatively severe TBI. It should be noted that study
subjects had neurological sequelae and were referred by
neurologists, neurosurgeons, and consulting psychia-
trists at a large city hospital, leading to selection of more
severe TBI cases than usually encountered. Seizures oc-
curred in 50% of their sample of 20 outpatients with
posttraumatic mania, a rate 10 times that of the usual
seizure rate post-TBI. However, selection of patients
with more severe TBI and neurological sequelae might
also contribute to the high rate of posttraumatic seizures
in the sample. Hypomania and bipolar II disorder were
associated with milder trauma defined by briefer dura-
tions of posttraumatic amnesia among 20 outpatients
with relatively severe TBI. However, chronic hypoma-
nia, bipolar I, and schizoaffective disorder were associ-
ated with more severe trauma (longer posttraumatic
amnesia) in this study.
In the Jorge et al.45 study, posttraumatic mania was
associated with multifocal lesions, primarily in temporal
basal polar regions. Posttraumatic mania risk was not
associated with posttraumatic seizures, brain injury se-
verity, physical or cognitive impairment, social func-
tioning, or previous family or personal history of psy-
chiatric disorder. Dropouts from the study (35%)
significantly correlated with cortical and orbitofrontal
lesions. Wilcox and Nasrallah,50 in searching for preex-
isting head injury occurring before age 10 in patients
with seemingly primary mania, found lesions of the
right temporal (two patients), left temporal (one pa-
tient), and occipital (one patient) areas among their six
patients with posttraumatic mania. Starkstein et al.41
considered 11 consecutive patients with vascular, tu-
moral, or traumatic brain lesions and DSM-III major af-
fective disorder, manic episode, two of whom had ma-
nia in the wake of TBI. Lesions were present in the
frontal lobe in both patients, and one had a brain stem
injury as documented by CT. The laterality of the lesion
loci was not specified. Moreover, past personal and fam-
ily histories were not specified in these patients, so it is
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
not clear that these subjects had secondary mania by the
criteria of Krauthammer and Klerman.47
Starkstein et al.52 considered two patients with post-
traumatic mania in a series of 12 patients with mania
after brain injuries of various types. Presumably, both
patients lacked personal and family histories of perti-
nent psychiatric disorders. Although mania was sug-
gested to correlate with frontal disturbance in both and
cerebellar injury in one, CT was apparently obtained
only in the patient with the frontal injury and it actually
indicated multifocal lesions. Starkstein et al.53 also noted
neuroradiological and metabolic findings in eight pa-
tients with mania (all lacked personal histories but one
had a family history of mood disorder) after brain in-
juries of assorted types, but it appears that only two
subjects had posttraumatic mania, one with a small right
frontal white matter contusion and one with bilateral
orbitofrontal contusions. The rest of the subjects ap-
peared to have suffered mania as a sequel to a vascular
event. Starkstein et al.54 later reported bipolar and pure
manic states in 19 patients, but it appears that only two
suffered traumatic brain injuries, one involving the right
orbitofrontal white matter and left temporal tip, and one
with bilateral orbitofrontal lesions. Other patients had
vascular or tumor lesions, and personal and family his-
tories of mood disorders did not appear to represent
exclusion criteria.
On the other hand, in contrast to right hemisphere
injuries associated with secondary mania, Lim55 docu-
mented six cases from the literature wherein mania was
associated with left hemisphere pathology, including
one case following head injury. Lim suggested that the
unifying theme reconciling right and left hemisphere as-
sociations with posttraumatic mania was involvement
of the nondominant hemisphere, although handedness
was not established in three of the cases.
Sexual offenses may complicate the course of post-
traumatic mania. DelBello et al.46 assessed 25 convicted
sex offenders, six of whom also had a history of TBI and
SCID-diagnosed DSM-IV bipolar disorder. They found
that sex offenders with bipolar disorder had a higher
rate of head trauma than either sex offenders without
bipolar disorder or 15 bipolar patients lacking sexual
offenses. Head injury preceded commission of the sex-
ual offense in all six subjects. This study suggests that
sexual offense may complicate the outcome of bipolar
disorder following TBI in selected patients; however, fu-
ture studies should study the prevalence of sexual of-
118 http://neuro.psychiatryonline.org
fenses in patients with posttraumatic bipolar disorder to
establish this potential outcome.
Summary and Recommendations Diagnostic validity and
reliability studies in regard to posttraumatic mania are
greatly needed. These studies should consider diagnos-
tic sensitivity and specificity as a function of various
inclusion and exclusion criteria.
No firm conclusions can be drawn at this point about
incidence or prevalence rates of posttraumatic mania.
There is only one study designed to ascertain 12-month
posttraumatic mania incidence and prevalence (9.1% in
the study of Jorge et al.45) and no studies that assess
period prevalence over longer periods. Future studies
should follow each TBI patient through specified sur-
veillance periods and determine 1-year rates at varying
intervals from TBI onset to take into account posttrau-
matic mania development after a period of delay. Di-
agnostic criteria for posttraumatic mania should be
clearly specified, including exclusion criteria. Incidence
and prevalence rates may vary depending upon other
factors as well, such as duration of unconsciousness,
posttraumatic amnesia, presence of seizures, penetrat-
ing versus closed head injury, other TBI severity indices,
study setting, referral base, selection factors, posttrau-
matic mania diagnostic criteria, diagnostic ascertain-
ment method, and other factors.
Similarly, there is insufficient evidence to form defi-
nite conclusions regarding the prevalence of manic
symptoms or the characteristics of posttraumatic mania,
although two studies39,45 found irritability in 85% to
100% and aggression in 50% to 70% of subjects.
The point prevalence of posttraumatic mania in pa-
tients with mania would be better viewed as life prev-
alence of preexisting TBI in patients with seemingly
“primary” mania. These data are also problematic, with
limitations of recall bias and other methodological con-
cerns, including prevalence period ambiguities. Esti-
mates of 5% in 122 patients,50 14.3% in 56 patients,42 and
22.9% in 35 patients37 span a considerable range, and
selection factors are suspect, among other concerns.
There is the possibility of modifying population factors,
such as neurological patients43 with a posttraumatic ma-
nia point prevalence of 21.4% in 14 patients, and sex
offenders46 with a posttraumatic mania point prevalence
of 33.3% in nine subjects. Potential complicating factors
include observations of birth injuries in patients with
mania40 and a possible familial predisposition toward
head injury.9 An agenda for future research includes:
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

1. Development of a uniform operational definition
of posttraumatic mania using DSM-IV or RDC ma-
nia, evidence of TBI preceding mania onset, evi-
dence of attribution to TBI, and the absence of clear
alternative explanatory etiologies, such as sub-
stance use or other neurological illness. The stipu-
lation of additional inclusion (atypical age of onset,
specific temporal interval between TBI and mania
onset) and exclusion (previous psychiatric illness,
family history consistent with bipolar disorder) cri-
teria should be evaluated in future research.
2. Establishment of the incidence and prevalence of
posttraumatic mania using prospective observa-
tional studies and standardized diagnostic criteria
in TBI rehabilitation settings.
3. Clarification of clinical and neurophysiological risk
factors for posttraumatic mania, such as injury lo-
cation, cognitive impairment, genetic predisposi-
tion, and prior psychiatric illness. Additional fac-
tors to be studied would also include postinjury
psychotropic treatments (e.g., antidepressants, an-
ticonvulsants) that increase or reduce risk for de-
veloping posttraumatic mania.
4. Determination of the impact of posttraumatic ma-
nia on functional outcomes and quality of life post-
traumatic stress disorder (PTSD) after TBI.
Posttraumatic Stress Disorder
Nosology Bryant et al.56 evaluated 96 survivors of se-
vere TBI 6 months postinjury using a structured clinical
interview based on DSM-III-R criteria for PTSD. In this
study, the positive and negative predictive power of
PTSD symptoms was assessed. The symptoms with the
highest predictive power were intrusive memories,
nightmares, and emotional reactivity. Those with the
lowest power included concentration deficits, detach-
ment, diminished interest, and sense of a foreshortened
future. Predictive power defines the specificity of symp-
toms. Sensitivity was quite different; only 19.2% of pa-
tients meeting PTSD criteria experienced intrusive
memories, 23.1% had nightmares, and 96.2% experi-
enced emotional reactivity. Warden et al.57 evaluated 47
active-duty service members with moderate TBI and
posttraumatic amnesia lasting at least 24 hours using the
PSE and extracting questions consistent with DSM-III-R
criteria for PTSD. In this study, no patients met full cri-
teria for PTSD due to the absence of reexperiencing
symptoms, though 15% met avoidance and arousal cri-
teria.
These findings are contrasted by the study of Fein-
stein et al.58 who examined 282 TBI outpatients a mean
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
of 53 days post injury using the 15-item Impact of Event
Scale (IES) which measures symptoms of PTSD divided
into two subscales—reexperiencing phenomena and
avoidant behavior related to the traumatic event. Pa-
tients were divided into four groups based on duration
of posttraumatic amnesia ranging from 1 hour to 1
week. There were no group differences in the mean
scores on the intrusion subscale, though a subsequent
analysis dividing patients into less than or greater than
1 hour of posttraumatic amnesia found more intrusive
symptoms with the shorter duration.
Turnbull et al.59 solicited 371 patients who had been
discharged from a trauma center in the previous 6
months, yielding 53 consenting subjects. They were as-
sessed using the IES and the Clinician-Administered
PTSD scale for DSM-IV (CAPS-D). Patients were di-
vided into three groups: those with no memory of the
event, those with an “untraumatic” memory of the event
(i.e., the patient could recall the event but did not recall
feeling scared), and those with a traumatic memory of
the event. The majority of patients had been assaulted
and had posttraumatic amnesia for less than 1 hour. In
this sample, patients with no memory or traumatic
memories of their injury scored significantly higher on
the intrusive and avoidant subscales of the IES. The au-
thors used the IES score as a basis for validating or in-
validating a CAPS-D diagnosis of PTSD. Using the
CAPS-D alone, 27% of patients met criteria for PTSD.
When the authors eliminated patients with low IES
scores, that rate fell to 17%. The study is limited by the
low response rate, with a predominance of mild TBI due
to assault. However, it did employ a novel means of
refining the diagnosis of PTSD based on both categorical
(symptom presence) and dimensional (symptom sever-
ity) criteria that may provide better specificity. Creamer
et al.60 evaluated 301 consecutive patients admitted to a
trauma center following mild TBI prior to discharge and
12 months postinjury using the CAPS-D. Of the patients
with PTSD at 12 months, there were no differences in
reexperiencing, avoidance, or arousal symptom do-
mains in patients with full, partial, or no recall of the
injury.
In summary, the phenomenology of PTSD following
TBI is similar to that of PTSD without TBI, though there
are some inconsistent findings on the presence of reex-
periencing symptoms. PTSD with or without reexperi-
encing symptoms may occur even in the absence of spe-
cific memories of the event leading to TBI. It appears to
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
be a contradiction that one can have PTSD without recall
of the event. Gil et al.61 suggested that the traumatic
memories could be formed by circuits bypassing cortical
structures, leading to implicit (unconscious) memories,
or that formation of explicit memories within hippocam-
pal structures might be disrupted by stress-related glu-
cocorticoid surges. In any case, it appears that intrusive
memories are not always present in post-TBI PTSD, nor
do they rule out the presence of a TBI in patients with
PTSD.
Epidemiology
Incidence of Posttraumatic Stress Disorder Bryant
and Harvey62 assessed 79 patients with mild TBI within
1 month of their injury and at 6 months postinjury using
the PTSD module of the CIDI. Acute Stress Disorder was
diagnosed in 14% of patients at 1 month, and PTSD was
identified in 24% of patients at follow-up. Eighty-two
percent of the patients diagnosed with acute distress dis-
order developed PTSD during the follow-up period. The
study was limited by a relatively small sample size for
epidemiological purposes but used a standardized and
validated diagnostic measure. Gerring et al.63 evaluated
95 children admitted to a neurorehabilitation unit fol-
lowing severe TBI with a mean coma duration of 11
days. The patients were evaluated using the Diagnostic
Interview for Children and Adolescents (DICA), the
Child Behavior Checklist (CBCL), and the Psychosocial
Adversity Scale early postinjury upon enrollment and
then again at 1 year postinjury. In this sample, 13% of
patients developed PTSD at 1 year postinjury. In con-
trast to adult studies, 71% of the children with PTSD
experienced intrusive recollections of the event. As de-
scribed above, Turnbull et al.59 noted a 27% incidence of
PTSD within 6 months post-TBI using a structured in-
strument based on DSM-IV criteria, and a 17% incidence
using stricter criteria that required a minimal level of
symptom severity. Gil et al.61 assessed 120 patients ad-
mitted to a trauma center with mild TBI immediately
following admission, at 1 week and 3 and 6 months
postinjury using the CAPS-D, finding a 14% incidence
of PTSD over the 6 month follow-up period. Creamer et
al.’s60 study noted a 10% incidence of PTSD over 12
months postinjury.
Prevalence of Posttraumatic Stress Disorder Bry-
ant and Harvey64 compared 46 patients with mild TBI
to 59 multiple trauma survivors without TBI at 6 months
postinjury using the PTSD module of the CIDI. Post-
traumatic stress disorder was identified in 20% of TBI
120 http://neuro.psychiatryonline.org
patients and 25% of non-TBI patients. In a separate
study, Bryant65 interviewed 96 survivors of severe TBI 6
months postinjury for the prevalence and influence of
PTSD on the recovery process. Despite the fact that most
patients had no cohesive recall of the traumatic event,
27% met criteria for PTSD on the Posttraumatic Stress
Disorder Interview. A diagnosis of PTSD was also as-
sociated with higher scores on the Beck Depression In-
ventory and General Health Questionnaire.
Glaesser et al.66 evaluated 46 inpatients on admission
to a neurorehabilitation unit at 1 to 82 months post-
injury, dividing them into those with more than 12 hours
of unconsciousness (N⳱31) and those with less than 1
hour of unconsciousness (N⳱15). Diagnosis was ob-
tained using the PTSD module of the SCID. The preva-
lence of PTSD was 27% in patients with limited or no
unconsciousness, and 3% in patients with extended un-
consciousness. The low prevalence of PTSD in patients
with more severe brain injuries contrasts Bryant’s65 find-
ings. Limitations of this study include small sample size
and greater variability with respect to time postinjury.
Thus, strict comparison of the results is not possible.
Sumpter and McMillan67 assessed 34 severe TBI sur-
vivors at least 3 months postinjury using the CAPS-D
and the Posttraumatic Diagnostic Scale (PDS), a self-re-
port questionnaire. Though the self-report instrument
yielded a 59% prevalence of PTSD, the CAPS-D led to
only a 3% prevalence. The authors concluded that the
structured interview was a more reliable method of case
ascertainment for post-TBI PTSD. Because of the small
sample size, no statistical analysis was possible to de-
termine which items on the PDS were most likely to lead
to an overreporting of PTSD. Hibbard et al.’s21 study
(described in the section on depression) reported a 19%
prevalence of PTSD in patients following TBI.
Risk Factors Mayou et al.68 prospectively screened
1,148 individuals who survived road traffic accidents at
3 and 12 months after their visit to the emergency de-
partment. They found that the rate of PTSD and other
anxiety symptoms 3 months after injury were more
common in individuals who had been unconscious than
in those who had not been unconscious. At 1 year
follow-up, the rates were similar in both groups, by self-
report.
As mentioned previously, Bryant et al.62 noted that
82% of mild TBI survivors with acute distress disorder
at 1 month postinjury developed PTSD at 6 months
postinjury. This indicates that acute distress disorder is
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

a risk factor for the subsequent development of PTSD.
Harvey and Bryant69 searched for predictors of acute
stress disorder in 48 survivors of motor vehicle accident
with a TBI using the Acute Stress Disorder Interview
(ASDI). The Eysenck Personality Inventory (EPI) and
Coping Style Questionnaire (CSQ) were administered to
assess coping style. The rate of acute distress disorder
was 15%, with an additional 4% meeting subsyndromal
criteria. Avoidance coping and BDI scores were signifi-
cantly associated with a risk of developing acute distress
disorder.
Gerring et al.63 found that female sex and early post-
injury depressive and anxiety symptoms identified with
the CBCL and DICA were associated with an increased
risk of developing PTSD at 1 year in children with se-
vere TBIs and posttraumatic amnesia. Vasa et al.70 sub-
sequently reviewed brain MRI scans in 95 of the original
subjects in Gerring et al.’s63 study. PTSD was associated
with the presence of left temporal lesions, with in-
creased lesion volume increasing the risk of PTSD. Left
orbitofrontal cortex lesions decreased the risk of hyper-
arousal symptoms, while diffuse brain lesions increased
the risk of avoidant symptoms. The presence of post-
TBI anxiety symptoms was a risk factor for developing
PTSD.
Gil et al.61 assessed 120 patients admitted to a trauma
center with mild TBI immediately following admission,
at 1 week and 3 and 6 months postinjury using the
CAPS-D, dividing the sample into those with (45%) and
without (55%) memory of the event. Recall of the event
was a strong predictor of PTSD within 6 months post-
injury.
Summary and Recommendations There is substantial evi-
dence that survivors of TBI can develop subsequent
PTSD symptoms, even when the traumatic event is as-
sociated with altered consciousness and amnesia. Prev-
alence of the condition ranges from 3% in one subset of
patients with more severe TBI, to approximately 27%,
which has been reported in several studies. The clinical
presentation of PTSD in this population is less clear—
some studies indicate a relative absence of reexperienc-
ing symptoms, such as nightmares, intrusive memories,
and ruminations of the traumatic event. As a result, the
only conclusion the Committee can make is that reex-
periencing symptoms does not exclude the presence of
a TBI in patients with PTSD. No conclusions regarding
the diagnostic validity of reexperiencing symptoms in
the post-TBI PTSD syndrome can be made at this time.
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
The clinical course of PTSD following TBI appears to be
different from that experienced in non-TBI trauma sur-
vivors, particularly in the lower remission rates of acute
distress disorder that eventually evolve into PTSD. The
most consistent limitations in the literature are the ab-
sence of studies with larger sample sizes and the use of
the same sample in several reported studies. Recom-
mendations for future research include:
1. Clarifying the nosology of post-TBI PTSD to ad-
dress the validity and frequency of hyperarousal,
avoidance, and intrusive memories in the diagnos-
tic criteria. Approaches such as Turnbull’s meth-
odology that incorporate symptom severity and
symptom clusters may improve the specificity of
diagnostic criteria.
2. Identifying injury-related risk factors, such as se-
verity of injury, duration of posttraumatic amnesia,
recall of traumatic events, location of injury, per-
sistent cognitive impairment. In addition, clarify-
ing the neural mechanisms by which patients with-
out recall of the event can experience intrusive
memories will be an important step in the valida-
tion of diagnostic criteria and increasing under-
standing of traumatic memory formation.
Posttraumatic Aggression
Nosology The nosology of aggression and “agitation”
is particularly problematic, with a general lack of rig-
orous definition in the literature. For the purposes of this
review, we excluded the literature on posttraumatic ag-
gression that develops in patients emerging from coma.
This syndrome has been conceptualized as a form of
delirium.71 The DSM-IV classification system provides
the diagnosis of personality change secondary to a gen-
eral medical condition (APA) with several subtypes to
clarify the type of behavior changes manifested. The ag-
gressive type is characterized by predominantly aggres-
sive behavior, which may be directed towards self, oth-
ers, or inanimate objects. The disinhibited type is
characterized primarily by disinhibition and sexual in-
discretions, but patients may become aggressive when
redirected or frustrated. Patients with the labile type pri-
marily demonstrate affective lability, which may include
verbal outbursts with minimal provocation, but without
substantial threatening or violent behaviors. To further
complicate the diagnostic challenge, impulsive aggres-
sion may also occur in the context of a mixed bipolar
syndrome. Bipolar symptoms secondary to TBI are fre-
quently characterized by irritability and dysphoria.39,72
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
The appropriate diagnosis for this type of aggressive,
dysphoric syndrome is mood disorder secondary to a
general medical condition, mixed type (APA). The no-
sology of posttraumatic aggression may involve consid-
erable overlap between the personality and mood syn-
dromes associated with impulsive aggression. Certain
distinguishing symptoms of mania, such as increased
energy, reduced need for sleep, pressured speech and
racing thoughts, may assist in distinguishing personal-
ity from mood symptoms. Rao and Lyketsos73 propose
a nosology that incorporates syndromal intensity and
frequency. However, empirical data are lacking to vali-
date the classification of various parameters of post-TBI
aggression.
In summary, there is no consistent and validated no-
sology to characterize posttraumatic aggression in the
available literature. The DSM-IV classification system
has not been validated for this population and incor-
porates multiple behavioral domains not directly related
to aggression, per se. Since aggression may occur in the
context of multiple syndromes, there appears to be little
evidence supporting any systematic nosology to char-
acterize various domains of aggression, such as precip-
itants, impulsivity, and severity.
Epidemiology
Incidence of Posttraumatic Aggression Tateno et
al.74 evaluated 89 consecutive TBI patients admitted to
a hospital service. Using the Overt Aggression Scale
(OAS),75 30 (33.7%) patients were identified as having
clinically significant aggression during the first 6
months postinjury. Max et al.76 evaluated 46 children
who were admitted to an acute care hospital following
TBI and reevaluated them at 3-month intervals for 1
year. They also evaluated an additional 48 children ages
5 to 14 years who had previously been hospitalized for
TBI. A standardized psychiatric interview, the Neuro-
psychiatric Rating Scale, was used to identify psychiat-
ric symptoms. Thirty-eight percent of the sample devel-
oped aggressive behaviors, and nearly 49% developed
affective lability and irritability. Onset of these behaviors
usually occurred within the first 3 months. Nearly half
of these patients had persistent symptoms at 12 months
postinjury.
Prevalence of Posttraumatic Aggression Andrews
et al.77 compared 27 children with TBI with 27 nonin-
jured comparison subjects, all 6 to 17 years old, using
the DeBlois Aggressive and Antisocial Behavior Scales.
The head-injured children demonstrated greater aggres-
122 http://neuro.psychiatryonline.org
aggressive/antisocial behavior, though there was no
correlation between severity of injury and aggressive
behaviors among the patients with TBI. This correla-
tion between TBI and higher aggressive scores is not a
specific epidemiological finding but supports the con-
cept of TBI increasing the likelihood of aggressive be-
havior.
Rosenbaum et al.78 compared 53 men who physically
abused their spouses with 77 men who did not abuse
their spouses. A prior history of closed head injuries was
present in 53% of the violent men, compared with 19%
of the nonviolent men. In this point prevalence study,
the members of the aggressive sample were more likely
to have had a previous head injury. Though this does
not indicate causality, it does support the association be-
tween prior TBI and aggression.
Conditions related to agitation and aggression in-
clude disruptive behaviors observed in oppositional de-
fiant disorder and interpersonal hostility. Max et al.79
also followed 50 patients ages 6–14 years after a TBI,
using the Schedule for Affective Disorders and Schizo-
phrenia for School-Age Children, Epidemiologic Ver-
sion (K-SADS-E). This study specifically sought to iden-
tify the point prevalence of oppositional defiant
disorder at various points before and after an identified
TBI. In this sample, 6% of patients had a preinjury his-
tory of oppositional defiant disorder. By 12 months post-
injury, 18.2% of the sample met criteria for oppositional
defiant disorder. This decreased to 14% by 24 months.
Loosening the threshold from formal diagnosis to op-
positional defiant disorder symptoms, they found that
21.1% of patients developed at least one new opposi-
tional defiant disorder symptom within 3 months post-
injury, increasing to 40.9% by 12 months and then de-
creasing to 34.9% at 24 months. This finding indicates
that 20% to 40% of children develop some disruptive
behavioral symptoms shortly following TBI. In an at-
tempt to clarify long-term neurobehavioral outcome
following TBI, Marschark et al.80 compared 79 college
students with a history of mild TBI as children or ado-
lescents with 93 noninjured students using the SCL-90
and neuropsychological testing. There were no group
differences with respect to cognitive functioning, but the
students with a history of TBI had higher scores on the
symptoms of hostility and interpersonal sensitivity, as
well as higher total SCL-90.
Risk Factors Rapoport et al.81 followed a cohort of 282
patients with TBI of various severities at 3 months
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

postinjury using the Neurobehavioral Rating Scale–
Revised (NBR-R). Severity of injury was defined using
criteria from the Glasgow Coma Scale (GCS): a score of
less than 12 for mild, 9 to 12 for moderate, and greater
than 8 for severe. Subjects with severe injuries were
more likely to have higher scores on the hyperarousal
and cognitive factor scores on the NBR-R. The hyper-
arousal factor consisted of excitement, hyperactivity,
disinhibition, and unusual thought content. Irritability,
emotional lability, and hostility segregated to the emo-
tional factor, which was not correlated with severity of
injury.
The study by Tateno et al.74 examined clinical corre-
lates that predicted aggression following TBI. There
were no socioeconomic or demographic differences be-
tween the aggressive and nonaggressive groups. Ag-
gressive patients were more likely to have a preinjury
history of a mood disorder, alcohol or substance abuse,
and aggressive behaviors requiring legal intervention.
Frontal lobe lesions were more common in the aggres-
sive patients. There were no group differences in sever-
ity of injury, though nonaggressive patients were more
likely to have diffuse injuries on neuroimaging. Greve
et al.82 compared aggressive and nonaggressive patients
in a residential brain injury facility. A comparison group
of 19 residents with no reported behavioral problems
was compared with a group of 26 residents with “im-
pulsive aggression” as defined by “persistent uncon-
trolled loss of temper . . . manifested by verbal out-
bursts, striking, throwing, or damaging property, or
attacks on other persons within 3 months of evaluation.”
The Lifetime History of Aggression questionnaire83 was
used to determine preinjury and postinjury behavioral
disturbances, and a neuropsychological battery was ad-
ministered. There were no group differences in neuro-
psychological performance. Preinjury impulsive aggres-
sion was reported in 75% of the impulsive aggression
group versus 26% in the comparison group. In addition,
the impulsive aggression group demonstrated higher
levels of impulsivity on the Barratt Impulsiveness
Scale.84 These findings suggest that post-TBI impulsive
aggression may be an extension of premorbid impulsiv-
ity and aggression.
The 2-year follow-up study of Max et al.85 demon-
strated that patients with more severe injuries, lower
socioeconomic status, preinjury symptoms of opposi-
tional defiant disorder and preinjury family dysfunction
tended to develop more severe aggressive symptom-
atology. Moreover, these symptoms worsened to a
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007
KIM et al.
greater degree over time following injury compared
with patients without these characteristics.
Dunlop et al.86 conducted a retrospective chart review
study on 193 TBI subjects who had applied for federal
disability. Of these, 34 consecutive cases were studied
that had evidence of cognitive or emotional deteriora-
tion 6 months postinjury as demonstrated by an increase
of at least two points on the Neurobehavioral Rating
Scale (NBRS) relative to baseline. This sample was
matched with a comparison group of TBI patients
matched for severity of injury who improved as dem-
onstrated by a decline in two or more points from base-
line on the NBRS by 6 months postinjury. In the group
that improved, agitation and hostility were noted in 44%
of patients between 2 and 6 months, but only 6% of the
group developed worsening of agitation after 6 months.
By contrast, while 3% of the group that deteriorated had
moderate to severe agitation and hostility, 41% of the
group developed increasing agitation after 6 months.
The group that deteriorated was more likely to have
been injured in assaults and less likely to have been in-
jured in motor vehicle accidents. In addition, risk factors
for behavioral deterioration included a left parietal in-
jury, skull fracture, and a prior history of alcohol abuse.
This report is limited by its retrospective nature and the
selection of a sample applying for disability benefits.
Agitation and hostility emerged as major factors during
follow-up that were associated with the group that had
deteriorated.
Another risk factor for posttraumatic aggression ap-
pears to be prior episodes of head injuries. Carlsson et
al.87 compared 1,112 men ages 30, 50, and 60 years from
a general population. Though age at time of injury did
not affect the presence of irritability, the presence of two
or more injuries with loss of consciousness was signifi-
cantly associated with irritability. The symptom of irri-
tability was not clearly defined or associated with verbal
or physical aggression.
Summary and Recommendations The current literature is
severely limited by a lack of consistent methodology for
identifying aggression and agitation. Moreover, there is
a tremendous lack of clarity and consistency of termi-
nology, rendering comparisons of studies difficult.
There are a number of instruments, such as the Overt
Aggression Scale75 and Neurobehavioral Rating Scale,88
that may be used effectively to identify and monitor
change across time. However, these instruments are di-
mensional in nature, measuring the severity and fre-
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NEUROPSYCHIATRIC COMPLICATIONS OF TBI: A REVIEW
quency of aggressive behaviors. Establishing specific
thresholds for mild, moderate, and severe aggression
would further refine their utility. Other epidemiological
studies make use of symptom domains or DSM diag-
noses of personality disorders. However, there has been
little use of the diagnosis of personality change due to
a general medical condition, aggressive type, in studies
using DSM diagnoses. As a result, existing epidemio-
logical studies of DSM diagnoses offer little insight into
the prevalence and incidence of posttraumatic aggres-
sion. The challenge of assessing and monitoring post-
TBI aggression is complicated by the fact that this symp-
tom may present in a variety of clinical syndromes, such
as personality changes, delirium, and mania. Clearly,
more research is needed to establish a consistent oper-
ational definition of posttraumatic aggression for the
purposes of epidemiological and treatment research.
Of the three prospective studies reviewed, agitation
and aggression developed in 20% to 49% of child pa-
tients and approximately 33% of adult patients, with on-
set usually within the first year postinjury. Patients with
frontal lobe lesions, a preinjury history of substance
abuse, or impulsive aggression appear to be at higher
risk for developing post-TBI aggression. However, it is
difficult to differentiate posttraumatic aggression from
preinjury aggression, and no published studies defi-
nitely demonstrate that head trauma increases aggres-
sive behavior in premorbidly aggressive individuals.
There is inconclusive evidence regarding a relationship
between cognitive functioning and the development of
post-TBI aggression, though it is possible that the neu-
ropsychological batteries were unable to detect subtle
executive functions mediated by the frontal lobes.89 As
a result, the connection between dysexecutive symp-
toms and aggression may not be identified. Likewise,
there is inconsistent evidence defining the impact of so-
cioeconomic status and severity of injury on develop-
ment of posttraumatic aggression. Future research is
necessary to accomplish several goals:
1. To operationally define posttraumatic aggression
using both categorical and dimensional terms. The
Overt Aggression Scale provides a framework for
addressing frequency and severity variables within
the construct of aggression, as well as differentiat-
ing between aggression toward self, others, and
property. Other factors to be considered are precip-
itants and interepisode mood and affective states.
2. To clarify and validate a systematic nosology for
posttraumatic aggression using DSM-IV diagnosis
124 http://neuro.psychiatryonline.org
of personality change due to a general medical con-
dition as a reference point.
3. To clarify the incidence, prevalence, and natural
time course of posttraumatic aggression in large
prospective studies of TBI survivors.
4. To identify neuropsychological and clinical corre-
lates that are predictive of the development of post-
traumatic aggression.
5. To elucidate the neural substrates of posttraumatic
aggression through functional neuroimaging stud-
ies.
6. To clarify the relationship between posttraumatic
aggression and psychosocial functioning with re-
spect to family and social relationships, vocational
functioning, and costs of care (direct and indirect).
This would require the development of appropri-
ate quality of life and functional assessments re-
lated specifically to psychiatric symptomatology.
CONCLUSIONS
The literature on post-TBI psychiatric disorders is laden
with limitations related to sample size, diagnostic cri-
teria, and overall study design. As the field has evolved,
however, there appears to be a trend toward rigorously
designed studies that employ gold-standard assessment
tools in a prospective manner, though the validation of
these gold-standard tools in this special population is
ongoing and currently incomplete. Sample size and se-
lection, use of validated nosologies with appropriate in-
clusion and exclusion criteria, uniform ascertainment
methodologies, and defined surveillance periods remain
fairly consistent limitations, though studies are emerg-
ing in the literature that will address these concerns.
There remain significant opportunities to systematically
assess the nosology, epidemiology, and risk factors of
these disorders. The TBI Model Systems network, with
16 sites within the United States, is a favorable setting
in which to incorporate such systematic prospective
studies, which will lay the foundation for rigorous treat-
ment studies designed to reduce the impact of these dis-
orders on postinjury recovery and functioning. Because
of the capacity of each site to study the natural course
of TBI treatment and rehabilitation from acute interven-
tion through community reentry using standardized en-
rollment and outcome measurement procedures, the TBI
Model Systems is capable of providing adequate size
and scope to provide answers to many of the nosological
and epidemiological questions that have thus far eluded
single center studies. The incorporation of a prospective,
systematic effort to classify and characterize the clinical
J Neuropsychiatry Clin Neurosci 19:2, Spring 2007

course of neuropsychiatric sequelae of TBI within this
existing framework would greatly expedite progress to-
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