Depression in Frontotemporal Dementia

David M. Blass, M.D.

Peter V. Rabins, M.D., M.P.H.

Objective: The authors describe mood abnormalities seen in a case series of patients with fron-
totemporal dementia (FTD). Method: Authors provide a structured review of outpatient and in-
patient charts of FTD patients. Results: Three distinct depressive syndromes were identified: The
first corresponds to DSM–IV major depression. The second is a syndrome of mood lability with
prominent responsiveness to the environment. The third is a syndrome of profound apathy, with-
out other evidence of depression. Conclusion: A variety of mood disorders are seen in FTD,
requiring careful attention to differential diagnosis. FTD should be included in the differential
diagnosis during the evaluation of older patients with mood abnormalities.
(Psychosomatics 2009; 50:239 –247)

40%.5,14,16 Most studies of mood disturbances in FTD

F rontotemporal dementia (FTD), a progressive neuro-
degenerative disorder with personality changes, be-
havioral abnormalities, cognitive decline, and language
impairments, is characterized by pathologic and pheno-
typic heterogeneity.1,2 Symptom presentation is primarily
determined by anatomic region of disease involvement
rather than specific molecular pathology.3,4 Clinical and
neuropathological investigations have broadened the spec-
trum of which entities are considered part of FTD.5,6
Patients with FTD exhibit a broad range of psycho-
pathology.7 Most dramatic and characteristic are behavior
and personality changes.8 –11 Hyperorality, verbal and be-
havioral stereotypies, disinhibition, socially inappropriate
behavior, and neglect of personal hygiene are highly prev-
alent early in the FTD course and help distinguish it from
Alzheimer’s disease (AD).7,8,12 Personality changes in-
clude coldness, passivity, excessive jocularity, poor judg-
ment, decreased empathy, and loss of insight. Some of
these have been linked to the anatomic distribution of
disease involvement.11,13 Psychotic symptoms are uncom-
mon.5,7,8,14
Disturbances of mood and affective regulation have
been described in FTD; these include depression, apathy,
mood lability, anxiety, irritability, and euphoria.15 The
prevalence of depression in two studies was approximately
have used instruments such as the Neuropsychiatric Inven-
tory (NPI)17 or the BEHAVE–AD18 that do not generate a
clinical diagnosis of a mood disorder and are not depres-
sion-specific, such as the Cornell Scale for Depression in
Dementia (CSDD)19 or the Montgomery-Asberg Depres-
sion Rating Scale (MADRS).20 One case series, using a
descriptive phenomenological approach, noted that FTD
patients treated for major depression (MDD) before re-
ceiving the diagnosis of FTD primarily suffered from so-
cial withdrawal and psychomotor retardation, but not mel-
ancholia.21 Another descriptive series noted that depressed
mood states in FTD patients were short-lived, but, while
present, were intense, producing dysphoria and even sui-
cidal ideations.22 Overall, the mood disturbances of FTD
have not yet been fully characterized.
In clinical settings, early FTD can be confused with
depression.21 Many FTD patients are severely apathetic,
Received January 21, 2007; revised July 2, 2007; accepted July 25, 2007.
From Abarbanel Mental Health Center, affiliate of the Sackler School of
Medicine, Tel Aviv University; Johns Hopkins Medical Institutions,
Departments of Psychiatry and Behavioral Sciences, Medicine, and
Health Policy and Management. Send correspondence and reprint re-
quests to David M. Blass, M.D., Abarbanel Mental Health Center, 15
Keren Kayemet St., Bat Yam, Israel 59436. e-mail: dmblass@jhmi.edu
© 2009 The Academy of Psychosomatic Medicine

Psychosomatics 50:3, May-June 2009 http://psy.psychiatryonline.org 239

Depression in Frontotemporal Dementia

with profound executive disturbance, and may appear de-
pressed while having few symptoms of depression. Such
individuals are often diagnosed with and treated for MDD
before the definitive diagnosis of FTD.14,21
To date, investigations into the accuracy of the FTD
diagnosis, with some exceptions,23,24 have focused pri-
marily on differentiating FTD from other degenerative
dementias, and not from MDD. In this article, we present
a series of patients in whom depressive symptoms initially
complicated or delayed the diagnosis of FTD.
METHOD
This study utilizes a descriptive case-series methodology.
We present histories of selected FTD patients from the
Johns Hopkins Geriatric Psychiatry and Neuropsychiatry
inpatient and outpatient services. (Names have been al-
tered to protect patient identity.) The review was autho-
rized by the Johns Hopkins Hospital Institutional Review
Board. Although standardized diagnostic instruments were
not used, in all cases, MDD diagnosis was based on
DSM–IV criteria.25 Similarly, FTD diagnoses were, in all
cases, based on published diagnostic criteria.26 For the
sake of brevity, only some of the symptoms supporting the
diagnosis of FTD have been included in the case vignettes.
Many subjects had been evaluated by the neurology con-
sultation services in our center as well. All subjects un-
derwent a comprehensive dementia assessment that in-
cluded a detailed history, mental status and neurological
examination, relevant laboratory studies, and neuroimag-
ing, unless for practical reasons this could not be obtained.
Subject demographic and clinical information, including
medical and past psychiatric histories, and results of neu-
roimaging studies, are listed in Table 1, and results of
cognitive testing are shown in Table 2. A brief description
of the various psychometric tests applied is given in Ap-
pendix 1.
RESULTS
Case 1: “Mrs. A’s” depressive symptoms of 7 months’
duration included social withdrawal, reduced interest in
activities, poor grooming, tearfulness, anxiety, irritability,
diminished motivation, and somatic preoccupation. There
were no psychotic symptoms or suicidality. The family
reported mild memory impairment.
Mrs. A was admitted to the hospital for treatment.
Admission mental status exam (MSE) found her to be alert
and cooperative. She felt and appeared anxious but denied
sadness. She had little energy, motivation, or interest. She
was pessimistic and self-doubting, but not hopeless or
suicidal. There were no psychotic symptoms, obsessions,
compulsions, or phobias. Mini-Mental State Exam
(MMSE) was 26/30, and MADRS was 25/60. At this
point, Mrs. A met DSM–IV criteria for MDD. Neurolog-
ical examination was unremarkable.
On Hospital Day 2, Mrs. A denied sadness but re-
ported low energy, anhedonia, and diminished confidence.
Treatment with sertraline was started. On Hospital Day 3,
she appeared brighter, reported improved mood, and de-
nied anhedonia or self-doubt. Her MSE remained un-
changed for the next 5 days. She was discharged to the

TABLE 1. Demographics, History, and Neuroimaging

Past Past
Age, Marital Work Psychiatric Substance Medical
years Education Status Residence History History Abuse History CT/MRI SPECT
“Mrs. A” 77 9 years ⫹ Independent – – – CHF B/L F, LT 2RF, 2LT
“Mrs. B” 79 University ⫹ Independent – Recurrent MDDa – Elevated lipids General atrophy
“Mr. C” 68 University ⫹ Independent ⫹ Brief MDDb – Back pain B/L F, B/L T 2B/L F
“Mr. D” 89 High school ⫹ Independent ⫹ – – ALS, CHF
“Mr. E” 57 University – Independent ⫹ – – – Normal 2RF
“Mr. F” 62 High school – Independent ⫹ Brief MDDc – – B/L F, B/L T 2B/L F, 2B/L T
“Mrs. G” 68 High school ⫹ Independent ⫹ – – hypothyroid, PMR B/L F, B/L T 2B/L F, 2B/L T
“Mrs. H” 70 High school ⫹ Independent ⫹ – – –

Work History: stable work history before dementia onset; MDD: major depression; CHF: congestive heart failure; ALS: amyotrophic lateral
sclerosis; PMR: polymyalgia rheumatica; B/L F: bilateral frontal lobe; LT: left temporal lobe; B/L T: bilateral temporal lobes; CT/MRI: computed
tomography/magnetic resonance imaging scan; SPECT: single photon emission imaging; RF: right frontal lobe; 2: hypoperfusion.
a
Episodes at age 59 and 66; resolved with medication.
b
After losing job; mood improved after finding employment.
c
After being robbed 10 years earlier; resolved with hospitalization.

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 Blass and Rabins

Day Hospital and then to outpatient follow-up with a
behavior plan emphasizing increased structure and activ-
ity. Once depressive symptoms had resolved, Mrs. A un-
derwent a comprehensive dementia evaluation, and a di-
agnosis of FTD was made.
Case 2: “Mrs. B” was a 79-year-old woman referred for
evaluation of treatment-resistant recurrent depression and
mild cognitive impairment. She relapsed again at age 76
and had an unsuccessful high-lethality suicide attempt. All
three of her episodes met DSM–IV criteria for MDD.
Adequate trials of mirtazapine, bupropion, sertraline,
venlafaxine, fluoxetine, citalopram, and methylphenidate
were unsuccessful. A course of seven right-unilateral elec-
troconvulsive (ECT) treatments produced short-lived im-
provement. Symptoms during her post-ECT relapse were
crying, loneliness, insomnia, anorexia, guilt, poor concen-
tration, and lack of initiative. MMSE was 26/30. She was
readmitted to the hospital and treated with therapeutic
doses of nortriptyline and lithium without achieving full
remission. Neuropsychological testing performed during
this time revealed poor executive functioning (perfor-
mance in the 2nd percentile), without apraxia, agnosia,
aphasia, or impaired visual-spatial perception. She was
instructed to stop driving.
In the ensuing months, symptoms changed in character.
Her predominant mood state was not sadness, but apathy and
diminished interest. She slept well and did not feel guilty or
self-deprecating. She spent most days in bed, but could be
engaged in activities and enjoy them. She refused to change

TABLE 2. Neuropsychological Test Results

Mrs. A Mrs. B Mr. C Mr. D Mr. E Mr. F Mrs. G Mrs. H
BNT 20/30 (7) 21/30 25/30 (3) 30/30 42/60 (⬍1) 60/60
MMSE 26/30 21/30 25/30 27/30 28/30 21/30 24/30 28/30
Verbal Fluency-Literal 11 (7) 6 4 (⬍1) 13 (⬍10) 9 (1) 5 (⬍3) 5 (⬍3)
Verbal Fluency–Semantic 31 11 20 17 17
Clock–Command Deficient Deficient Normal Normal Borderline
Clock–Copy Normal Normal Borderline
HVLT–Delay 11 (84) 3 (2) 2 (1)
HVLT–Recognition 11 (25–50) 9 (21) 8 (8)
RAVLT–Total 29/75 (⬍3) 16/75 (⬍1) 42/75 (15)
RAVLT–Recall 6/15 (⬍20) 2/15 (⬍1) 9/15 (50)
Trails A 163 (⬍1) 54 (4) 82 (2)
Trails B D/C’ed 186 (⬍1) D/C’ed
Grooved Peg Board D: 227 (1) D: 70 (75) D: 243 (Abnormal) D: 70 (50) D: 59 (85)
ND: ND: 69 (77) ND: 220⫹ (Abnormal) ND: 73 (60) ND:
261 (1) 74 (57)
Rey-Osterrieth–Copy 9.5/36 (⬍1) 27/36 (5) 14/36 (⬍1) 26/36 (15) 30/36 (31)
Rey-Osterrieth–Recall 4/36 (4) 17/36 (69) 2.5/36 (⬍1) 13/36 (45) 4/36 (8)

A brief description of the neuropsychological tests can be found in Appendix 1. Values in parentheses are age-matched percentiles. BNT: Boston
Naming Test;52 MMSE: Mini-Mental State Exam;53 Fluency–Literal;54 Fluency–Semantic;54 Clock-Drawing;55 HVLT: Hopkins Verbal Learning
Test;56 RAVLT: Rey Auditory Verbal Learning Test;57 Trails A and B;58 Grooved Pegboard Test;59 Rey-Osterrieth;57 D/C’ed: discontinued; D:
dominant; ND: non-dominant.

TABLE 3. Depressive Syndromes Seen in Frontotemporal Dementia Patients

DSM–IV Major Depression
Mood reactivity and lability
Apathy syndrome
Clinical Description
ⱖ5 symptoms from the following: depressed mood, loss of interest or pleasure, change in appetite and sleep,
guilt feelings, psychomotor retardation or agitation, loss of energy, decreased concentration, thoughts of
death or suicide.
Symptoms are present daily for ⱖ2 weeks.
Highly reactive to immediate environment.
Rapidly modifiable by environmental changes.
Depressive symptoms (including suicidality) may only exist in certain environments or in the presence of
certain people.
Profound apathy
Absence of sadness, guilt, anxiety, pessimism, anorexia, insomnia

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Depression in Frontotemporal Dementia

clothes and had diminished attention to activities of daily
living (ADLs). She no longer initiated conversations and,
according to her husband, would “sit and stare at the walls.”
She had limited insight into her symptoms. She began smok-
ing cigarettes obsessively, exhausting her entire supply if
allowed to do so. She gained 10 –15 pounds. Behavior was
often silly. She was seen in the clinic 6 months after the most
recent hospital discharge.
MSE found the patient to be alert, cooperative, and
disheveled, with psychomotor slowing. Speech was of
normal volume and rate, but was inappropriate and disin-
hibited; she asked the examiner numerous personal ques-
tions. Expressed emotion was blunted, but she could
brighten. She denied feeling depressed, hopeless, anxious,
or guilty. There were no psychotic symptoms. Mrs. B’s
current mood syndrome was formulated as having an ap-
athy syndrome, rather than MDD. At this point, she did not
meet DSM–IV criteria for MDD.
Neurological examination was normal except for slowed
gait and agraphesthesia. Confrontation naming, praxis, plan-
ning, attention, and orientation were impaired. She often
perseverated in her answers. A smiley-face was drawn in the
clock after its completion. After a comprehensive dementia
evaluation, a diagnosis of FTD was made. This mood state
remained stable over the ensuing year.
Case 3: “Mr. C’s” current symptoms began at age 67,
when he became uninterested in hobbies or socializing. He
spent most days watching TV, only interrupting for meals.
He was otherwise apathetic about nearly all issues. His
personality turned cold and nasty, and he would yell and
curse at his family. He displayed contempt for driving
rules by speeding and not wearing a seatbelt. He often
repeated the same stereotyped phrases. He frequently
made inappropriate sexual remarks to women. He ap-
peared sad, but there was no crying, sadness, anxiety,
guilt, self-deprecation, suicidality, or change in sleep, ap-
petite, or energy. Mr. C developed difficulties with short-
term memory and word-finding. In the community, he had
been diagnosed with MDD and possible dementia and was
treated with escitalopram, without improvement. As cog-
nitive impairment and behavioral disturbance progressed,
he was referred for evaluation.
MSE revealed the patient to be alert, cooperative, and
disheveled. He had word-finding difficulties for common
words. He frequently repeated inappropriate stereotyped
phrases such as “It is all her fault” (when pointing to the
medical student). The patient was apathetic, with a re-
stricted range of emotion. He denied feeling depressed or
anxious. There was no guilt, self-deprecation, or suicidal-
ity, and he reported feeling optimistic. There were no
psychotic symptoms. MADRS was 5/60. Mr. C did not
meet DSM–IV criteria for MDD.
Neurological examination was normal except for a
prominent grasp reflex and bilateral agraphesthesia. Diag-
nostics are shown in Table 1 and Table 2. Language was
somewhat agrammatic, with phonemic paraphasias. There
was no apraxia, agnosia, visual-spatial impairment, ne-
glect, left-right confusion, or astereognosia. There was
significant perseveration in test answers. The patient’s to-
tal score on the Frontal Behavior Inventory (the FBI) was
greatly elevated, at 57.27 The patient was diagnosed with
FTD and admitted to the geriatric psychiatry service for
treatment of behavioral disturbances.
Case 4: “Mr. D” was referred for urgent admission be-
cause of depression and suicidality. Amyotrophic lateral
sclerosis (ALS) had begun at age 84. Psychiatric symp-

APPENDIX 1. Brief Description of Tests

Boston Naming Test (BNT):52 A test of ability to recognize and name objects.
Mini-Mental State Exam (MMSE):53 A brief cognitive screen that includes orientation, recall, attention, language, and constructional praxis.
Verbal Fluency:54 A timed test of word list-generation using one of two strategies, phonemic (literal), in which words beginning with a specific
letter are generated, or semantic, in which words from a category (e.g., animals) are generated.
Clock-Drawing:55 A test of constructional praxis in which patients draw a clock (placing numbers and hands) from memory and by copying from
a figure.
Hopkins Verbal Learning Test (HVLT),56 Rey Auditory Verbal Learning Test (RAVLT):57 Tests of verbal memory, assessing ability to learn a
word-list presented verbally, immediately after presentation and after a delay. In the recall task, patients reproduce words from memory. In the
recognition (HVLT) task, patients are presented a word-list containing some of the original words and have to identify the words from the
original list.
Trail-Making Test:58 A timed test of ability to connect circled letter and number icons on paper, following a pre-specified strategy of numbers in
ascending order (Trails A), or alternating letters and numbers in ascending order (Trails B).
Grooved Pegboard Test:59 A timed test of manual dexterity and fine motor movement.
Rey Osterrieth Complex Figure Test:55 A test of visual memory, assessing ability to reproduce from memory a previously-presented complex
figure.

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toms began at age 86, when personality changes, irritabil-
ity, impulsivity, and impaired judgment were noted. At
age 87, he developed low mood, anhedonia, and anorexia.
He frequently cried, feared he was burdening his family,
intermittently refused medications, and often expressed
the wish to die. He started doubting his wife’s fidelity.
Sertraline and quetiapine were prescribed without benefit.
He progressively developed insomnia, paranoia that his
children were stealing his money, and, ultimately, suicidal
ideation with a plan. He was admitted involuntarily with
the diagnosis of MDD with psychotic features.
By Hospital Day 2, depressive symptoms had re-
solved. He appeared cheerful, reported feeling happy, was
not anhedonic or pessimistic, had an intact self-attitude,
and a good appetite. He was not suicidal and had no
delusions. MADRS was 6/60. Paroxetine treatment was
started. Insight into previous symptoms was limited. Neu-
ropsychological testing was interrupted when he became
agitated. The patient was diagnosed with FTD-ALS syn-
drome.
Case 5: “Mr. E” developed symptoms of depression 14
months before the diagnosis of FTD. He reported sadness
and was noted to have low mood, decreased emotional
responsiveness, anergia, and decreased concentration. He
was unable to work. He was diagnosed with MDD. Trials
of fluoxetine, nefazodone, bupropion, and escitalopram
were ineffective. Over the next 8 months, Mr. E developed
perseverative speech and behavior, severe inattention, and
hyperorality, with craving for sweets. He was often anx-
ious and restless. Activity became limited to watching TV.
On MSE, Mr. E was alert, slow-moving, and restless.
He often looked down and blinked repetitively. He was
neatly dressed and appropriately groomed. Speech was
slow, quiet, and without spontaneity. He felt bored but not
sad. He appeared sad, with a restricted range of expressed
emotion. There was no guilt, self-deprecation, suicidality,
or psychosis. Orientation, recall, calculation, naming,
praxis, and visuospatial perception were normal. Tests of
executive functioning, including verbal fluency and di-
vided attention, showed impairment. Blood tests, lumbar
puncture, and EEG were negative. Neurological examina-
tion was unremarkable. Mr. E was diagnosed with FTD.
Over time, Mr. E became very withdrawn, limiting
interactions with family, and speaking little. His family
described him as apathetic about everything. He denied
feeling sad, hopeless, or guilty and was not observed to be
crying or anhedonic. Mr. E primarily described his mood
as “bored.” His syndrome at this time was felt to be
Psychosomatics 50:3, May-June 2009
Blass and Rabins
consistent with an apathy syndrome, rather than MDD.
This mood state persisted over the next year.
Case 6: “Mr. F” was admitted to the psychiatric unit
after being robbed. He became despondent, and was found
by the police wandering the streets in tears, stating that he
wished to kill himself. In the emergency room, Mr. F was
alert, disheveled, anxious, and mildly agitated. He re-
ported sadness and appeared depressed, but brightened
easily. He said that suicidal ideations began immediately
after the robbery. He acknowledged feeling like he wanted
to die and said that he would stab himself if he could.
There were no psychotic symptoms. MMSE was 25/30.
MADRS was 29/60. Initial differential diagnosis was ad-
justment disorder with depressed mood, rather than recur-
rent MDD.
Mr. F was treated with paroxetine. Symptoms of de-
pression improved slowly. During the hospital stay, he
was noted to be disheveled and unable to clean himself
properly. Fecal matter was found smeared on the patient,
his clothes, and throughout the bathroom after defecation.
His mood was extremely labile and very reactive to the
environment, shifting from cheerful to crying and suicidal
with the mere mention of the recent robbery. This was true
even after his mood had improved back to baseline. He
perseverated on specific themes, even when inappropriate
to the context. Insight into the impropriety of his behavior
was limited. After a comprehensive dementia evaluation,
the diagnosis of FTD was made. An occupational-therapy
assessment found Mr. F to be functionally impaired, un-
able to perform basic tasks because of disorganization,
impersistence, poor planning, and inattention to safety.
Mr. F was discharged to a dementia-specific assisted-liv-
ing facility.
Case 7: “Mrs. G’s” symptoms began at age 64 with
subtle changes in behavior and personality, with the pa-
tient becoming impatient, contrary, and argumentative. At
age 66, she developed difficulties with word-finding, keep-
ing track of time, and performing household tasks. She
then developed hyperorality with increased appetite (con-
sumption of large amounts of soda) and excessive food-
shopping. Neurological examination, EEG, lumbar punc-
ture, and laboratory evaluations were normal. She was
diagnosed with FTD after a comprehensive dementia as-
sessment.
At age 67, Mrs. G. developed a depression syndrome
characterized by sustained low mood, crying, anhedonia,
feeling as if she were dying, compulsive skin picking, and
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Depression in Frontotemporal Dementia
suicidality. She was diagnosed with MDD. Sertraline, ven-
lafaxine with quetiapine augmentation, and paroxetine
were ineffective. She became intermittently suspicious
that her husband was having an extramarital affair. When
present, this belief was absolutely fixed, but, at other
times, the belief was absent. Symptoms progressed to in-
clude agitation, with yelling, throwing objects at her hus-
band, and not letting him out of her sight.
MSE at age 68 revealed Mrs. G to be alert and coop-
erative. She became tearful as soon as her FTD illness was
discussed. She was overweight and disheveled. Posture
was inappropriately casual. Speech was halting, with
word-finding difficulties and frequent semantic and pho-
nemic paraphasic errors. She appeared sad and tearful,
although she laughed loudly and inappropriately at times.
She wished she were dead and thought about riding a
bicycle into traffic. Appetite, energy, and sleep were im-
paired. She perseverated on certain themes and phrases.
MMSE was 12/30, with impairments of orientation, new
learning, naming, repetition, writing, and praxis. Compre-
hension was impaired, and commands were followed in-
consistently. There were no cortico-sensory deficits.
Mrs. G was admitted to the psychiatry service with an
initial diagnosis of recurrent MDD. Initially, she remained
sad, self-deprecating, and hopeless, lacking energy, and
wishing for death. By Hospital Day 3, she was no longer
suicidal, and began sleeping and eating well. By Hospital
Day 4, her mood was good, and she consistently denied
concerns about her husband’s fidelity. MADRS was 4/60.
The patient was discharged home with her husband after a
10-day hospitalization.
Within an hour of leaving the hospital, Mrs. G again
became depressed. She cried, threatened her husband, and
became delusional about infidelity. However, when she
would visit with her children, these symptoms disappeared
almost immediately if her husband was not present. De-
spite trials of trazodone, quetiapine, olanzapine, and high
doses of SSRIs, Mrs. G could not remain living with her
husband because of agitation in his presence, and she
moved into an assisted-living facility. There, her mood
was stable, and delusions were not present. When her
husband visited, she would become irritable, sad, and
sometimes delusional. These symptoms would resolve
with his departure.
Case 8: Mrs. H’s language difficulties began at age 64,
with word-finding difficulties and intact comprehension.
Over the next 5 years, handwriting and spelling deterio-
rated, and she developed difficulty playing the piano.
244 http://psy.psychiatryonline.org
Other cognitive functions were initially intact. Neurolog-
ical examination was normal. After neurological evalua-
tion, she was diagnosed with primary progressive aphasia,
an FTD-spectrum condition. At age 70, in the setting of
more rapid speech deterioration, Mrs. H became sad, tear-
ful, easily frustrated, and pessimistic. She felt abandoned
by her friends, hopeless and anergic, and she had difficulty
falling asleep. Symptoms were present most of the time.
There was no guilt, suicidality, or psychosis.
MSE revealed Mrs. H to be alert, calm, and cooper-
ative. She was meticulously groomed and well-dressed.
There were no psychomotor abnormalities. Speech was
hesitant, but she formed complete, grammatically correct
sentences. She had frequent “Yes/No” substitutions, which
she would correct herself. Speech was monotonic, without
inflection, and with a metallic quality. She described her
mood as sad, and she appeared as such. She was frequently
tearful throughout the interview. She acknowledged feel-
ing guilty, unmotivated, and anhedonic. There were no
suicidal ideations, psychotic symptoms, obsessions, or
compulsions. The patient was diagnosed with DSM–IV
MDD.
Escitalopram was started. Within 1 month, her mood
improved, with a return of optimism, interest in activities,
initiative, and energy. She remained on escitalopram for
the next year. Depressive symptoms did not recur, al-
though she did develop symptoms of pseudobulbar palsy,
with instantaneous crying upon mention of the death
(many decades earlier) of a close relative, but with no
sustained sadness or tearfulness. Once depression re-
solved, her CSDD score was only 6, whereas her FBI
score remained elevated, at 30.27
DISCUSSION
FTD is a syndrome with protean neuropsychiatric mani-
festations. This case series illustrates three patterns of
depressed mood found among FTD patients.
The first pattern of depressive symptomatology is the
classic syndrome of MDD, meeting DSM–IV criteria.25
This pattern was seen at some point in time in the histories
of Patients 1, 2, 4, 5, 6, 7, and 8. Symptoms were generally
persistent over a significant period of time. Although the
mood symptoms resolved rapidly upon hospitalization in
Patients 1, 4, and 7, they had been present for weeks or
months in a pattern typical for MDD before the hospital-
ization. In these cases, the development of MDD may have
heralded the onset of FTD, which was not otherwise de-
tectable at that time. MDD is highly prevalent in the early
Psychosomatics 50:3, May-June 2009

stages of neurodegenerative disorders such as AD or Hun-
tington’s disease (HD), and may precede the development
of dementia in AD or movement disorder in HD.28,29
Some authors have suggested that depression seen in neu-
rodegenerative disorders is a consequence of damage to
subcortical structures,15,30,31 and there is evidence that, in
FTD, in particular, low mood may be associated with
involvement of the right temporal lobe.32 Thus, in some
patients, MDD may be the earliest manifestation of the
underlying FTD neuropathologic process.
The second mood syndrome is that of affective reac-
tivity and lability, seen in Patients 1, 4, 6, and 7. In these
patients, this syndrome followed the resolution of a full
MDD episode. Mood lability had the character of being
highly reactive to the immediate environment and was
rapidly modifiable by an environmental change. In Pa-
tients 1 and 4, longstanding depressive symptoms resolved
rapidly upon hospitalization, and, in Patient 7, the symp-
toms returned promptly after hospital discharge, despite
her having been consistently asymptomatic in the hospital.
In Patient 6, mood lability (including inducing passive
death wishes and suicidal ideations) was triggered by
changing the topic of discussion. In Patient 7, mood ab-
normalities were seen only in the presence of her husband
and disappeared promptly when he departed.
A number of forms of pathologic emotional reactivity
have been previously described. Pathologic crying or
laughing is defined as the sudden and insuppressible out-
burst of crying or laughing that may or may not occur in
socially appropriate settings. Many patients with this syn-
drome also are diagnosed with MDD or dysthymia. These
syndromes have been described in patients with AD,
stroke, multiple sclerosis, and traumatic brain injury,
among others.33–36 Such pathological displays of emotion
are thought to be mediated by interruptions of ascending
serotonergic projections from the raphe nuclei as they
project from the brainstem through the subcortical struc-
tures and to the frontal cortex.37 This mechanism may be
relevant in FTD, given the abnormalities of serotonergic
transmission believed to be present in FTD,38,39 as well as
the interruption in frontal–subcortical functional circuits
that occurs in FTD.40
A third affective syndrome, seen in Patients 2, 3, and
5, is profound apathy, easily misdiagnosed as MDD. FTD
patients with severe apathy may be so functionally im-
paired and uninterested in their environment that the initial
diagnosis is MDD. Arguing against the diagnosis of MDD
is the absence of sadness, anxiety, guilt, pessimism, an-
orexia, or insomnia. The apathy syndrome is distinguish-
Psychosomatics 50:3, May-June 2009
Blass and Rabins
able from MDD, but, clinically, this differentiation re-
mains a challenge, for a few reasons.41,42 First, MDD has
a much higher prevalence than FTD, possibly biasing cli-
nicians toward the diagnosis of MDD. Second, mild cog-
nitive abnormalities of early FTD can be obscured by the
more prominent psychopathology, particularly if cognition
is initially assessed with a screening instrument such as the
MMSE, which is relatively insensitive to the deficits of
early FTD. Moreover, cognitive abnormalities that are
identified may initially be attributed to presumed MDD.
Third, since the typical age at onset of FTD is relatively
young (in the 6th decade), dementia may not initially be
suspected.43 Finally, clinicians may naturally avoid mak-
ing a diagnosis of an irreversible neurodegenerative con-
dition when the possibility of a treatable and reversible
condition such as MDD exists.
In our experience in a geriatric psychiatry clinic special-
izing in mood disorders in elderly patients, many FTD pa-
tients were initially referred for evaluation of what was
thought to be treatment-resistant depression, without signifi-
cant consideration having been given to the possibility of
FTD. In contrast, the diagnosis of AD is often considered in
geriatric patients who are depressed and have mild memory
or language difficulties, although this differentiation can also
be challenging.44,45 The cases presented in this series illus-
trate the importance of considering the FTD diagnosis in
patients with atypical or treatment-resistant depressive symp-
toms. This differentiation can be especially challenging,
given that executive dysfunction, one of the central impair-
ments seen in FTD, is common in MDD.46,47
Precise characterization of the mood abnormalities of
FTD is important for several reasons. One reason is diagnos-
tic accuracy. As outlined above, the diagnosis of MDD may
stand in the way of an accurate diagnosis of FTD. Likewise,
it is important to identify MDD in FTD patients who develop
it, as MDD is associated with significant morbidity.
Second, accurate characterization of depressive symp-
toms may facilitate identification of neuroanatomic corre-
lations. Mood lability and reactivity may have a different
anatomic substrate than MDD with or without psychosis.
Current evidence suggests a link between mood lability
and dysfunction of the lateral orbitofrontal cortex, apathy
and dysfunction of the anterior cingulate circuit, and sad-
ness and anhedonia with dysfunction of the medial orbito-
frontal cortex.48 Indiscriminately grouping all of these
syndromes together in the category “depression” misses
the opportunity for better understanding.
Finally, there may be therapeutic implications of ac-
curate differentiation among different mood syndromes.
http://psy.psychiatryonline.org 245
Depression in Frontotemporal Dementia
Certain behavioral interventions or pharmacotherapy may
be effective for apathy, but ineffective for irritability or
mood lability. MDD may respond to medications or ECT
that are ineffective for apathy.
One important unanswered question about FTD epide-
miology is the discrepancy between prevalence estimates
derived from clinical versus pathological samples. Two epi-
demiological studies have found the population prevalence of
FTD to be low, approximately 10/100,000.49,50 In contrast,
autopsy series have found a prevalence (among dementia
patients) of 5%–10%. This discrepancy may be partially ac-
counted for by FTD that clinically resembles other neurode-
generative diseases, such as AD. However, the discrepancy
may also be explained by FTD patients who are diagnosed
with a primary psychiatric condition such as MDD instead of
FTD. With increased awareness of the true prevalence of
FTD and related disorders among adults in the presenium, a
broader differential diagnosis may be entertained in evaluat-
ing patients with atypical, treatment-resistant, or late-onset
depression or apathy.
This study has a number of limitations. A case-series is
neither controlled nor hypothesis-driven. Moreover, diag-
References
1. McKhann GM, Albert MS, Grossman M, et al: Clinical and
pathological diagnosis of frontotemporal dementia: Report of the
Work Group on Frontotemporal Dementia and Pick’s Disease.
Arch Neurol 2001; 58:1803–1809
2. Kertesz A: Pick complex: an integrative approach to frontotem-
poral dementia: primary progressive aphasia, corticobasal degen-
eration, and progressive supranuclear palsy. Neurologist 2003;
9:311–317
3. Constantinidis J, Richard J, Tissot R: Pick’s disease: histological
and clinical correlations. Eur Neurol 1974; 11:208 –217
4. Mychack P, Kramer JH, Boone KB, et al: The influence of right
frontotemporal dysfunction on social behavior in frontotemporal
dementia. Neurology 2001; 56(suppl 4):S11–15
5. Blass DM, Hatanpaa KJ, Brandt J, et al: Dementia in hippocam-
pal sclerosis resembles frontotemporal dementia more than Alz-
heimer disease. Neurology 2004; 63:492– 497
6. Hatanpaa KJ, Blass DM, Pletnikova O, et al: Most cases of
dementia with hippocampal sclerosis may represent frontotem-
poral dementia. Neurology 2004; 63:538 –542
7. Bozeat S, Gregory CA, Ralph MA, et al: Which neuropsychiatric
and behavioural features distinguish frontal and temporal vari-
ants of frontotemporal dementia from Alzheimer’s disease?
J Neurol Neurosurg Psychiatry 2000; 69:178 –186
8. Bathgate D, Snowden JS, Varma A, et al: Behaviour in fronto-
temporal dementia, Alzheimer’s disease, and vascular dementia.
Acta Neurol Scand 2001; 103:367–378
9. Nyatsanza S, Shetty T, Gregory C, et al: A study of stereotypic
behaviours in Alzheimer’s disease and frontal and temporal vari-
ant frontotemporal dementia. J Neurol Neurosurg Psychiatry
2003; 74:1398 –1402
246 http://psy.psychiatryonline.org
noses were clinical and did not rely on neuropathological
confirmation. Finally, dementia evaluations and neuropsy-
chological testing were not uniform in all cases. Nonetheless,
these limitations do not invalidate the study’s observations.
This case-series is a preliminary, hypothesis-generating de-
scriptive study and does not claim a broader scope. The
observations derived from this study can be used to refine
observation and measurement of mood in FTD patients and
may be used to help design future, larger studies. The lack of
neuropathological confirmation does reduce the certainty of
diagnosis; however most of the cases presented met diagnos-
tic criteria for FTD and were not felt to be borderline diag-
nostic cases. Finally, although the dementia work-up was not
uniform, it was similar in all cases in that it included detailed
history-taking and examination in all cases, structural neuro-
imaging in all cases, functional neuroimaging in most, and
cognitive testing that was similar in terms of the domains
tested, in most cases.
In conclusion, this case-series outlines three presenta-
tions of mood abnormalities in patients with FTD. Although
conclusions drawn from a small case-series are limited, this
study suggests directions for larger, prospective studies.
10. Ikeda M, Brown J, Holland AJ, et al: Changes in appetite, food
preference, and eating habits in frontotemporal dementia and
Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002; 73:
371–376
11. Rankin KP, Kramer JH, Mychack P, et al: Double dissociation of
social functioning in frontotemporal dementia. Neurology 2003;
60:266 –271
12. Lindau M, Almkvist O, Kushi J, et al: First symptoms: fronto-
temporal dementia versus Alzheimer’s disease. Dement Geriatr
Cogn Disord 2000; 11:286 –293
13. Gustafson L: Clinical picture of frontal lobe degeneration of
non-Alzheimer type. Dementia 1993; 4:143–148
14. Levy ML, Miller BL, Cummings JL, et al: Alzheimer disease and
frontotemporal dementias: behavioral distinctions. Arch Neurol
1996; 53:687– 690
15. Lopez OL, Gonzalez MP, Becker JT, et al: Symptoms of depres-
sion in Alzheimer’s disease, frontal lobe-type dementia, and
subcortical dementia. Ann N Y Acad Sci 1995; 769:389 –392
16. Porter VR, Buxton WG, Fairbanks LA, et al: Frequency and
characteristics of anxiety among patients with Alzheimer’s dis-
ease and related dementias. J Neuropsychiatry Clin Neurosci
2003; 15:180 –186
17. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric
Inventory: comprehensive assessment of psychopathology in de-
mentia. Neurology 1994; 44:2308 –2314
18. Reisberg B, Auer SR, Monteiro IM: Behavioral pathology in
Alzheimer’s disease (BEHAVE–AD) rating scale. Int Psychoge-
riatr 1996; 8(suppl 3):301–308; Discussion 351–354
19. Alexopoulos GS, Abrams RC, Young RC, et al: Cornell Scale for
Depression in Dementia. Biol Psychiatry 1988; 23:271–284
Psychosomatics 50:3, May-June 2009

20. Montgomery SA, Asberg M: A new depression scale designed to
be sensitive to change. Br J Psychiatry 1979; 134:382–389
21. Suzuki H, Kuroda S, Ishizu H, et al: Depression in the early
stages of Pick’s disease. Acta Med Okayama 1999; 53:253–257
22. Gustafson L: Frontal lobe degeneration of non-Alzheimer type,
II: clinical picture and differential diagnosis. Arch Gerontol Geri-
atr 1987; 6:209 –223
23. Swartz JR, Miller BL, Lesser IM, et al: Behavioral phenomenol-
ogy in Alzheimer’s disease, frontotemporal dementia, and late-
life depression: a retrospective analysis. J Geriatr Psychiatry
Neurol 1997; 10:67–74
24. Kertesz A, Nadkarni N, Davidson W, et al: The Frontal Behav-
ioral Inventory in the differential diagnosis of frontotemporal
dementia. J Int Neuropsychol Soc 2000; 6:460 – 468
25. American Psychiatric Association: American Psychiatric Asso-
ciation Task Force on DSM–IV. Diagnostic and Statistical Man-
ual of Mental Disorders: DSM–IV. Washington, DC, American
Psychiatric Association, 1994
26. Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar
degeneration: a consensus on clinical diagnostic criteria. Neurol-
ogy 1998; 51:1546 –1554
27. Kertesz A, Davidson W, Fox H: Frontal Behavioral Inventory:
diagnostic criteria for frontal lobe dementia. Can J Neurol Sci
1997; 24:29 –36
28. Zubenko GS, Zubenko WN, McPherson S, et al: A collaborative
study of the emergence and clinical features of the major depres-
sive syndrome of Alzheimer’s disease. Am J Psychiatry 2003;
160:857– 866
29. Nehl C, Ready RE, Hamilton J, et al: Effects of depression on
working memory in presymptomatic Huntington’s disease.
J Neuropsychiatry Clin Neurosci 2001; 13:342–346
30. Lind K, Edman A, Karlsson I, et al: Relationship between de-
pressive symptomatology and the subcortical brain syndrome in
dementia. Int J Geriatr Psychiatry 2002; 17:774 –778
31. Mayberg HS: Frontal lobe dysfunction in secondary depression,
in The Frontal Lobes and Neuropsychiatric Illness. Edited by
Salloway SP, Malloy PF, Duffy JD. Washington, DC, American
Psychiatric Publishing, Inc., 2001, pp 167–186
32. Mendez MF, McMurtray A, Chen AK, et al: Functional neuro-
imaging and presenting psychiatric features in frontotemporal
dementia. J Neurol Neurosurg Psychiatry 2006; 77:4 –7
33. Starkstein SE, Migliorelli R, Teson A, et al: Prevalence and
clinical correlates of pathological affective display in Alzhei-
mer’s disease. J Neurol Neurosurg Psychiatry 1995; 59:55– 60
34. Robinson RG, Parikh RM, Lipsey JR, et al: Pathological laugh-
ing and crying following stroke: validation of a measurement
scale and a double-blind treatment study. Am J Psychiatry 1993;
150:286 –293
35. Feinstein A: The neuropsychiatry of multiple sclerosis. Can
J Psychiatry 2004; 49:157–163
36. Tateno A, Jorge RE, Robinson RG: Pathological laughing and
crying following traumatic brain injury. J Neuropsychiatry Clin
Neurosci 2004; 16:426 – 434
37. Andersen G, Ingeman-Nielsen M, Vestergaard K, et al: Patho-
anatomic correlation between poststroke pathological crying and
damage to brain areas involved in serotonergic neurotransmis-
sion. Stroke 1994; 25:1050 –1052
38. Yang Y, Schmitt HP: Frontotemporal dementia: evidence for
impairment of ascending serotonergic but not noradrenergic in-
Psychosomatics 50:3, May-June 2009
Blass and Rabins
nervation: immunocytochemical and quantitative study using a
graph method. Acta Neuropathol (Berlin) 2001; 101:256 –270
39. Sparks DL, Markesbery WR: Altered serotonergic and cholin-
ergic synaptic markers in Pick’s disease. Arch Neurol 1991;
48:796 –799
40. Mega MS, Cummings JL: Frontal–subcortical circuits and neu-
ropsychiatric disorders. J Neuropsychiatry Clin Neurosci 1994;
6:358 –370
41. Marin RS: Differential diagnosis and classification of apathy.
Am J Psychiatry 1990; 147:22–30
42. Levy ML, Cummings JL, Fairbanks LA, et al: Apathy is not
depression. J Neuropsychiatry Clin Neurosci 1998; 10:314 –319
43. Dell DL, Halford JJ: Dementia presenting as postpartum depres-
sion. Obstet Gynecol 2002; 99:925–928
44. Lachner G, Engel RR: Differentiation of dementia and depres-
sion by memory tests: a meta-analysis. J Nerv Ment Disord 1994;
182:34 –39
45. des Rosiers G, Hodges JR, Berrios G: The neuropsychological
differentiation of patients with very mild Alzheimer’s disease
and/or major depression. J Am Geriatr Soc 1995; 43:1256 –1263
46. Kiosses DN, Klimstra S, Murphy C, et al: Executive dysfunction
and disability in elderly patients with major depression. Am J
Geriatr Psychiatry 2001; 9:269 –274
47. Kalayam B, Alexopoulos GS: Prefrontal dysfunction and treat-
ment response in geriatric depression. Arch Gen Psychiatry
1999; 56:713–718
48. Salloway S, Malloy P, Duffy JD: The Frontal Lobes and Neu-
ropsychiatric Illness, 1st Edition. Washington, DC, American
Psychiatric Publishing, 2001
49. Rosso SM, Donker Kaat L, Baks T, et al: Frontotemporal de-
mentia in The Netherlands: patient characteristics and prevalence
estimates from a population-based study. Brain 2003;
126:(201)620 – 622
50. Ratnavalli E, Brayne C, Dawson K, et al: The prevalence of
frontotemporal dementia. Neurology 2002; 58:1615–1621
51. Bird T, Knopman D, VanSwieten J, et al: Epidemiology and
genetics of frontotemporal dementia/Pick’s disease. Ann Neurol
2003; 54:(suppl 5):S29 –S31
52. Kaplan EF, Weintraub S: The Boston Naming Test. Philadelphia,
PA, Lea & Febiger, 1978
53. Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State:” a
practical method for grading the cognitive state of patients for the
clinician. J Psychiatr Res 1975; 12:189 –198
54. Benton AL: Multilingual Aphasia Examination. Iowa City, IA,
AJA Associates, 1989
55. Spreen O, Strauss, E: A Compendium of Neuropsychological
Tests. New York, Oxford University Press, 1991
56. Shapiro AM, Benedict RH, Schretlen D, et al: Construct and
concurrent validity of the Hopkins Verbal Learning Test, Re-
vised. Clin Neuropsychol 1999; 13:348 –358
57. Rey A: L’Examen Clinique en Psychologie. Paris, France, PUF,
1964
58. Reitan RM: The validity of the Trail-Making Test as an indicator
of organic brain disease. Percep Mot Skills 1958; 8:271–276
59. Ruff RM, Parker SB: Gender- and age-specific change in motor
speed and eye– hand coordination in adults: normative values for
the finger-tapping and grooved pegboard tests. Percep Mot Skills
1993; 76:1219 –1230
http://psy.psychiatryonline.org 247