The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

Dement Geriatr Cogn Disord 2015;39:257–271 DOI: 10.1159/000369882 Accepted: November 13, 2014 Published online: February 4, 2015

© 2015 S. Karger AG, Basel 1420–8008/15/0396–0257$39.50/0 www.karger.com/dem

Original Research Article

The Prevalence of Depressive Symptoms in Frontotemporal Dementia: A Meta-Analysis Trisha Chakrabarty a Amir A. Sepehry b, c Ging-Yuek Robin Hsiung b, c

Claudia Jacova b, c

a Department

of Psychiatry, and b Division of Neurology, Faculty of Medicine, and Hospital Clinic for Alzheimer Disease and Related Disorders, University of British Columbia, Vancouver, B.C., Canada

c

Key Words Frontotemporal dementia · Semantic dementia · Progressive nonfluent aphasia · Depressive disorder · Prevalence Abstract Background: Depression is common in Alzheimer’s and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. Methods: PubMed, EMBASE and PsychINFO were queried for ‘depression’ and/or ‘depressive mood’ in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. Results: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268–0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. Conclusions: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area. © 2015 S. Karger AG, Basel

Ging-Yuek Robin Hsiung Hospital Clinic for Alzheimer Disease and Related Disorders University of British Columbia, S152 – 2211 Wesbrook Mall Vancouver, BC V6T 2B5 (Canada) E-Mail hsiung @ mail.ubc.ca

Downloaded by: University of Alabama, Lister Hill Library 198.143.47.1 - 7/15/2015 4:47:48 AM

T.C. and A.A.S. should be considered as co-first authors. Part of the data of this study was presented at the 2013 Alzheimer’s Association International Conference.

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Dement Geriatr Cogn Disord 2015;39:257–271 DOI: 10.1159/000369882

© 2015 S. Karger AG, Basel www.karger.com/dem

Chakrabarty et al.: The Prevalence of Depressive Symptoms in Frontotemporal Dementia: A Meta-Analysis

Introduction

Depression is a common neuropsychiatric symptom in dementia. It is estimated that 15–40% of patients diagnosed with Alzheimer’s dementia (AD) and 20% with vascular dementia (VAD) will develop depressive symptoms in the course of their illness [1, 2]. These symptoms can impact cognitive performance, worsen functional outcomes and greatly add to caregiver and patient distress [1]. Recognition of the clinical significance of depression has led to the development of specific criteria to more accurately diagnose comorbid depression in AD [3], the symptomatology of which often differs from that of more classic depressive disorders. Frontotemporal dementia (FTD) is another subtype of dementia that usually develops in the presenile years, accounting for 20–50% of dementia cases in patients with an age at onset under 65 years [4]. Unlike AD, its most common form is characterized by early frontal lobe dysfunction with associated behavioral symptoms [5]. Some of the behavioral changes seen in FTD, such as apathy and diminished motivation, are difficult to distinguish from symptoms of major depressive disorder as defined in the DSM-IV-TR. Previous research has shown that emotional blunting and apathy are neuropathologically distinct from depressed mood [6, 7]. Thus, there is a considerable risk for neuropsychiatric symptoms of FTD to be misattributed to an affective disorder, and vice versa, which, in turn, may lead to a delay of diagnosis or inappropriate treatment [1, 6]. On the other hand, late-onset psychosis, in the context of bipolar disorder or schizophrenia, is a major differential diagnostic option to be considered in these patients. Depression is a core feature of the former and is commonly found in the latter. Understanding the prevalence and phenomenology of depressed mood in FTD would clarify whether the presence of such symptoms can distinguish between FTD and other primary psychiatric illnesses. The numerous pathologically related but clinically distinct FTD subtypes may further confuse the assessment of depression in FTD. The three most widely recognized subtypes are (1) behavioral-variant (bv)FTD (the most common form, as discussed above), (2) progressive nonfluent aphasia (PNFA) and (3) semantic dementia (SD) [5]. The predominant impairment in these subtypes is in behavior, expressive language or receptive language, respectively. Whether the prevalence of depression differs between these clinically distinct variants remains unclear. In this study, we used meta-analytic techniques to (1) assess the prevalence of depressive symptoms in FTD and its subtypes, (2) examine the methods used to diagnose depression in FTD and compare the prevalence reported by each and (3) compare the prevalence of depressive symptoms with that of other dementias in studies where data were available on FTD and at least one other non-FTD dementia. Our goal was to gain a better understanding of the burden of depression in FTD and its clinical assessment in this patient population. We predicted that depressive symptoms would be at least as prevalent in FTD as in AD and that a standardized method for diagnosing them in FTD would be lacking.

We searched the electronic literature using PubMed, PsychINFO and EMBASE with combinations of the following Medical Subject Headings (MeSH) terms (exploded): ‘frontotemporal lobar degeneration’, ‘frontotemporal dementia’, ‘pick disease’, ‘semantic dementia’, or ‘progressive non-fluent aphasia’ with ‘depression’, ‘depressive disorder’ or ‘mood disorder’. Searches were initiated at the end of January 2013, with subsequent updates to September 1, 2013. They were limited to peer-reviewed publications. Data from previously published reviews, meta-analyses or conference abstracts were excluded. Potentially relevant studies were identified by titles and abstracts, and the bibliographies of these studies were examined to identify additional


Methods

259




data sources. Two reviewers independently examined the abstracts yielded based on an a priori set of inclusion and exclusion criteria. In the presence of a discrepancy in study selection, discussions were carried out to reach a consensus. Observational studies (case-control, cohort and case series) and clinical trials were included if they (1) were English-language publications, (2) used a sample of patients with bvFTD or language-variant FTD diagnosed by established clinical criteria (i.e. pathological diagnosis or clinical diagnosis via the Lund and Manchester or Neary criteria) and (3) reported on the prevalence, incidence or frequency of depressive disorder or depressed mood in their sample. To minimize the heterogeneity of the sample, we excluded data on FTD variants with associated extrapyramidal or motor disorder (e.g. parkinsonism, progressive supranuclear palsy, corticobasal degeneration or motor neuron disease) from our review [5]. Studies investigating depression in primary progressive aphasia (PPA) were excluded if they did not specifically report on SD or PNFA, since another subtype of PPA, logopenic progressive aphasia, is more frequently associated with Alzheimer’s pathology [8]. We excluded studies that did not state the method used to assess depression in their sample. For longitudinal studies, we included only the depression prevalence rate reported from the baseline assessment of the subjects. We used Comprehensive Meta-Analysis Software version 2.0 to calculate the aggregate estimate of the event rate (ER) based on a random-effects model. The variables selected a priori included age, sex, MiniMental State Examination (MMSE) score, the method of FTD diagnosis, the FTD subtype, the method of depression diagnosis and the prevalence of depression. We first calculated an aggregate ER for depression prevalence based on all included studies regardless of the FTD variant and reported it as the ‘global’ rate. Separate ERs for global FTD were subsequently calculated based on the method of FTD diagnosis, the method of depression diagnosis and the source of information leading to the depression diagnosis (i.e. patient’s, caregiver’s or clinician’s observation). We then tabulated ERs for each of the FTD subtypes (bvFTD, SD and PNFA). Further analyses based on the method of FTD diagnosis, the depression diagnosis and the source of information were carried out for each subtype, as described above. All ERs are reported with 95% CIs. Age, sex, the duration of the disease and the MMSE score were used as covariates for metaregression. Where reported, we compared the depression prevalence rates between different types of dementia [i.e. AD, dementia with Lewy bodies (DLB) and VAD] by calculating an aggregate OR. Two independent reviewers (A.A.S. and T.C.) assessed the quality of the studies using STROBE statement guidelines [9]. Mixed-effects regression (method of moments) was used to examine the effect of study quality on the logit ERs. Cochrane’s Q test of heterogeneity (using p < 0.10 to define a significant result) was used to detect the presence of heterogeneity, and the I2 statistic to assess the magnitude of heterogeneity. Publication bias was assessed by visual inspection of the funnel plot as well as by quantitative assessment with the Begg and Mazumdar rank correlation test and Egger’s regression intercept.

Study Selection A total of 1,030 citations for bvFTD, 214 for SD and 41 for PNFA were generated from the electronic search engines (see online suppl. fig. 1; for all online suppl. material, see www.karger.com/doi/10.1159/000369882). After accounting for repeated citations, these numbers were reduced to 781, 181 and 32, respectively. For bvFTD, 134 of the 781 citations were identified as potentially relevant on the basis of their titles and abstracts. Twelve studies were excluded on the basis of the language of publication, and a further 11 were excluded as they were case reports. Six studies were excluded due to diagnostic issues: 3 did not use any published clinical criteria for the diagnosis of FTD, 2 included motor neuron variants in their sample, and 1 did not exclude patients with bipolar disorder. There were 87 studies that did not report an incidence or prevalence of depression in their sample, with many of these studies reporting only mean group scores for depressive symptomatology. Fifteen studies met our inclusion and exclusion criteria, with 5 more eligible studies subsequently identified from the bibliographies. This yielded a total


Results

260




of 20 studies reporting data on bvFTD. Studies using overlapping participants [6, 10–12] were excluded in favor of the most recent collected dataset or the most recent publication with the largest reported sample. For SD, the titles and abstracts of 43 of the 181 citations were examined. Four were excluded based on the language of publication, 6 were excluded as they were case reports, and 1 was excluded as it did not use consensus clinical diagnostic criteria. Two studies were excluded as they examined a population diagnosed with PPA without specification of the specific SD or PNFA subtypes [13, 14]. Twenty-four studies were excluded because they did not report the prevalence of depressive symptoms in their sample. This left a total of 7 eligible studies, with 2 of these identified from examination of the bibliographies. One of these studies reported on a mixed sample of SD plus PNFA. Thirty-two citations were found in search for studies of depression and PNFA. Ten of these were identified as potentially relevant on the basis of their titles and abstracts. Two were subsequently excluded based on the language of publication, and 1 was excluded as it was a case report. Five studies did not report on the prevalence of depressive symptoms, leaving only 2 studies that met our inclusion criteria.

Rates of Depression in Global FTD Based on the random-effects model, the omnibus ER for depression in global FTD was 0.334 (95% CI: 0.268–0.407) (table 2; fig. 1). The global ERs based on the method of FTD diagnosis were 0.311 (95% CI: 0.223–0.415) and 0.348 (95% CI: 0.268–0.438) for the Lund and Manchester and the Neary criteria, respectively. For the method of assessment of depression, the highest ER was based on the NPI-Q (0.505; 95% CI: 0.403–0.606), while the lowest ER was based on subjective caregiver reports


Description of Included Studies The above-mentioned search yielded 27 eligible individual citations. Five of these studies reported data separately for bvFTD and language-variant FTD patient groups, and 1 study reported separate data for SD and PNFA patients. Extracting data from these studies for each defined FTD variant yielded a total of 29 ERs, which were subsequently used in the analysis of depression rates in global FTD (i.e. all variants) (table 1). There were 20 individual ERs reported for bvFTD, 6 for SD, 2 for PNFA and 1 for mixed SD plus PNFA. The sample size ranged from 3 to 73 (total n = 870), the age at FTD onset ranged from 53.8 to 64 years, and the age at assessment ranged from 55 to 76 years. MMSE scores, where reported, ranged from 8.2 to 26.7. No clinical trials met our a priori inclusion criteria. FTD was diagnosed according to the criteria by Neary et al. [15] (n = 21), the Lund and Manchester criteria (n = 7) [16] or pathological diagnosis (n = 1). Methods used to assess depression included the depression items of the Neuropsychiatric Inventory Questionnaire (NPI-Q; n = 12) and the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVEAD; n = 2), subjective caregiver reports (n = 5), psychiatric interviews using the DSM-IV-TR criteria (n = 3), psychiatric interviews without specification of depression criteria (n = 3) and chart reviews without specification of depression criteria (n = 6). Two studies reported separately on prevalence by psychiatric interview without specific criteria and on prevalence by DSM-IV-TR criteria [17, 18]. The nonoverlapping values for these studies were included in their respective categories. Nineteen studies used information provided by caregivers to assess for depressed mood, which included studies using the NPI-Q, the BEHAVE-AD and subjective caregiver reports; 6 studies used information provided by medical charts, and 4 used data gained by physician assessment. Thirteen studies also reported on the prevalence of depression in AD, 3 on VAD and 3 on DLB. These were subsequently used for comparative analyses.

Sample

Study design

bvFTD vs. Cross-sectional AD vs. VAD comparison vs. DLB

bvFTD vs. SD + PNFA

Chiu et al. [36]

Chow et al. [37]

Cross-sectional interview

Diehl and Kurz [21]


Edwards-Lee Temporal et al. [39] variant vs. bvFTD

Cross-sectional survey

Cross-sectional comparison

De Vugt et al. bvFTD vs. [38] AD

Lund and Manchester

Lund and Manchester

Lund and Manchester

Caregiver NPI-Q

Caregiver + patient interview with no specific depression criteria

Caregiver NPI-Q

Caregiver NPI-Q

Caregiver BEHAVE-AD

Study-designed neuropsychiatric survey completed by caregiver

Caregiver NPI-Q

History of DSM-IV depression ascertained by patient and caregiver report, GP and medical notes

Depression diagnosis

5/50%

10/20% (rated as moderately severe)

50

10

bvFTD 7/25.9% AD 24/51.1%

bvFTD 27 AD 47

48

27/55.3%

Not reported

Not reported

bvFTD 13.2 (9.3) AD 19.3 (4.9)

Not reported

Not reported

57.8 at onset 61.4 at diagnosis

bvFTD 59.5 (8.4) at testing AD 71.5 (8.2) at testing

58 (9.1) at onset

Not reported

62%

bvFTD 56% AD 59.6%

49.4% (of total 62)

bvFTD 54% AD 36.5% VAD 43.8% DLB 71.4% bvFTD 61.8 (7.5) at onset AD 72.8 (9.1) VAD 75.1 (6.3) DLB 71.9 (5.9) bvFTD 8.2 (6.6) AD 16 (5.2) VAD 13.1 (6.3) DLB 8.0 (7.7)

bvFTD 1/7.7% AD 31/36.5% VAD 15/46.9% DLB 2/28.6%

bvFTD 13 AD 85 VAD 32 DLB 7

bvFTD 85% AD 51.4% bvFTD 60.2 (6.03) at testing AD 71.2 (6.95) at testing

bvFTD 24.3 AD 19.2 SD not reported

50%

bvFTD 46% AD 53%

Males

bvFTD 1/7% AD 9/24%

62.14 (10.59) at testing

bvFTD 55.7 (6.23) at onset AD 56.34 (5.92) at onset

Age, years

bvFTD 13 AD 37

18.04 (7.73) at time of testing from 24 reported

bvFTD 21 (7) AD 21 (7)

MMSE score

13/45%

bvFTD 14/22% AD 10/10.99%

Prevalence

28

bvFTD 63 AD 92

Patients

DOI: 10.1159/000369882

bvFTD

Neary

Neary

Neary

Neary

FTD diagnosis

Cross-sectional Neary and longitudinal comparison


bvFTD vs. AD vs. SD

Bozeat et al. [20]


bvFTD vs. PPA

Banks and Weintraub [35]

Behavioral variant Atkins et al. bvFTD vs. Longitudinal [34] early-onset prospective AD cohort analysis

Study

Table 1. Description of included studies

Dement Geriatr Cogn Disord 2015;39:257–271

261



bvFTD

bvFTD

bvFTD vs. AD vs. SD

bvFTD vs. Cross-sectional AD vs. SCD comparison

Gregory [17]

Hornberger et al. [42]

Liu et al. [43]

Lopez et al. [18]


Lund and Manchester

Neary

Cross-sectional Neary assessment and 3-year follow-up

Lund and Manchester

Lund and Manchester

Neary

FTD diagnosis

Semi-structured psychiatrist interview with patients and caregivers; additional assessment for DSM-IV-TR criteria

Caregiver NPI-Q

Review of clinical notes for clinician consensus criteria for depression

Semi-structured psychiatric interview + assessment of DSM-IV-TR criteria

Caregiver Spanish NPI-Q

Caregiver BEHAVE-AD


bvFTD 6/26% AD 6/27%

bvFTD 5/24% ‘major depression’ 9/43% ‘depressed mood’ AD 1/3% ‘major depression’ 7/33% ‘depressed mood’

bvFTD 24 AD 22

bvFTD 21 AD 21

71

30/42%

bvFTD 62.3 (9) at testing AD 67.4 (10.0) at testing bvFTD 65.1 (11.4) at testing AD 74.3 (5.4) at testing

bvFTD 20.5 (7.4) AD 19.6 (7.1)

56.3 (8.0) at onset 68.4 (8.0) at presentation bvFTD 20.8 (8.7) AD 20.9 (5.4)

25.2 (5.6)

26.7 (4.0) 3/20% reporting ‘sadness’ 1/0.07% meeting DSM-IV-TR criteria

15

62 (11.4) at testing

Not reported

Not reported

bvFTD 1/33% AD 25/30.9% VAD 6/42.9% DLB 3/30%

bvFTD 3 AD 81 VAD 14 DLB 10

bvFTD 52% AD 57%

bvFTD 50% AD 45%

73%

60%

Not reported

bvFTD 52% bvFTD 68.1 (10.2) AD 32.7% at inclusion, Mixed 46.2% 63.0 (9.7) at onset AD 75.8 (8.0) at onset, DLB 65% 79.5 (7.1) at inclusion Mixed 78.1 (5.5) at onset, 81.4 (5.3) at inclusion DLB 70.8 (6.8) at onset, 75.5 (6.1) at inclusion

bvFTD 15.0 (9.7) AD 12.8 (6.6) Mixed 14.0 (7.9) DLB 15.4 (7.0)

bvFTD 29 AD 205 Mixed 39 DLB 23

bvFTD 10/34.5% AD 90/43.9% Mixed 16/41% DLB 12/52.2%

Males

Age, years

MMSE score

Prevalence

Patients

DOI: 10.1159/000369882


bvFTD vs. Cross-sectional AD vs. DLB comparison vs. VAD

Fernandez Martinez et al. [41]

–

bvFTD vs. Cross-sectional AD vs. DLB survey vs. mixed VAD/AD

Engelborghs et al. [40]

Study design

Sample

Study

Table 1 (continued)


262



bvFTD vs. SD vs. AD

bvFTD vs. AD

bvFTD vs. Cross-sectional AD vs. VAD comparison

Shinigawa et al. [22]

Silveri et al. [24]

Srikanth et al. [25]


bvFTD vs. AD vs. SD vs. PNFA

bvFTD

Mendez et al. [45]

Neary

Lund and Manchester

Neary

Neary

Neary Retrospective, blinded chart review of patients with dementia diagnosis




Prior diagnosis of depression as per chart review

bvFTD 69 AD 65

bvFTD 23 AD 44 VAD 31

bvFTD 11 AD 29

Caregiver NPI-Q

NPI-Q completed by caregiver; reported as domain score >4

bvFTD 11 AD 29

bvFTD 36 AD 52

73

21

Patients

SPAS completed by patient

Subjective caregiver report with no specific depression criteria used

Clinician-administered self-designed psychiatric checklist

Pathological Chart review diagnosis

FTD diagnosis

bvFTD 21/30% AD 8/12.3%

bvFTD 16/69.6% with positive response, 56.5% with score ≥4 AD 41/93.2%, 75% with score ≥4 VAD 22/71%, 54.8% with score >4

bvFTD 5/45% meeting criteria for depression (score >10) AD 17/59% bvFTD 9/82% positive for ‘depression or anxiety’ AD 26/90%

bvFTD 1.6% ‘depression or anxiety’ as initial symptom AD 2.7%

20/27%

bvFTD 2/9.5% AD not reported

Prevalence

bvFTD 76.1 (8.9) at testing AD 75.6 (6.5)

bvFTD 19.7 (6.0) AD 17.8 (6.4)

bvFTD 22.2 (8.8) AD 18.7 (7.0)

bvFTD 53.8 at onset AD 56.9

bvFTD 55.2 (10.7) at testing AD 67.2 (9.3) VAD 59.6 (9.9)

bvFTD 68.8 (9.1) at testing AD 66.1 (7.3)

bvFTD 19.0 (9.0) AD 18.7 (6.1)

bvFTD 19.5 (5.2) AD 14.7 (5.6) VAD 17.6 (4.7)

57.7 (10.5) at onset 60.9 (10.9) at diagnosis

bvFTD 57.9 (8.7) at onset and testing

Age, years

22.7 (5.3)

Not reported

MMSE score

bvFTD 66.7% AD 58.5%

Not reported

Not reported

bvFTD 47% AD 28.8%

49%

61.9%

Males

DOI: 10.1159/000369882

Woolley et al. [28]


bvFTD vs. AD

Mendez et al. [44]

Cross-sectional assessment

Study design

Sample

Study

Table 1 (continued)


263



Sample

Neary

FTD diagnosis

bvFTD vs. AD vs. SD

bvFTD vs. AD vs. SD

SD vs. PNFA Cross-sectional comparison

SD

bvFTD vs. AD vs. SD vs. PNFA

Liu et al. [43]

Shinigawa et al. [22]

Rohrer and Warren [46]

Thompson et al. [47]

Woolley et al. [28]

SD 6/14.6% PNFA 2/11.7%

13/28%

47

SD 41 PNFA 17

SD 7/78% PNFA 8/57%

0/0% as initial symptom

12/44%

22/73%

9/45%

Prevalence

SD 9 PNFA 14

SD 17

27

30

20

Patients

SD 20.9 (10.9) PNFA 17.0 (0.0)

–

–

17.5 (10.0)

24.1 (4.2)

Not reported

16.4

MMSE score

–

63.4 (7.4)

SD 62.3 (9.0) PNFA 71.8 (6.8)

64.9 (7.8)

65.3 (9.2) at testing

64.7 (9.8)

63.0 (6.3) at testing

Age, years

SD 50% PNFA 50%

48.9%

SD 22.7% (5.2) PNFA 24.4% (5.6)

35%

59%

53%

35%

Males


DOI: 10.1159/000369882

MMSE score and age are expressed as means with standard deviations in parentheses. CG = Subjective caregiver report; CPRS = Comprehensive Psychiatric Rating Scale; Psych-Int = psychiatric interview without specification of depression criteria; SCD = subcortical dementia.

Prior diagnosis of depression as per chart review

Neary Retrospective, blinded chart review of patients with dementia diagnosis

Caregiver NPI-Q

Caregiver report

Caregiver NPI-Q

Review of case notes for presenting symptoms with no specific depression criteria

Neary

Neary

Neary

Caregiver NPI-Q

Study-designed neuropsychiatric survey completed by caregiver


Neary

Retrospective chart review



bvFTD vs. SD + PNFA

Cross-sectional Neary and longitudinal comparison


Study design

Chow et al. [37]

Language variant Bozeat et al. bvFTD vs. [20] AD vs. SD

Study

Table 1 (continued)


264



265

Dement Geriatr Cogn Disord 2015;39:257–271 © 2015 S. Karger AG, Basel www.karger.com/dem

DOI: 10.1159/000369882


Table 2. Depression ER by FTD subtype, method of FTD diagnosis, method of depression assessment and source of information leading to depression diagnosis

Domain of interest

Number ER

Lower limit Upper limit Q value

d.f. (Q) p value

I2

FTD diagnosis Global bvFTD SD PNFA SD + PNFA

29 20 6 2 1

0.3343 0.3174 0.3330 0.3092 0.7333

0.2684 0.2493 0.1838 0.0449 0.5504

0.4074 0.3944 0.5254 0.8099 0.8607

97.9361 56.4204 19.0689 6.1770 0.0000

28 19 5 1 0

0.0000 0.0000 0.0019 0.0129 1.0000

71.4 66.3 73.8 83.8 0.0

0.3108 0.3483 0.0952

0.2228 0.2680 0.0239

0.4149 0.4382 0.3113

7.8588 83.2472 0.0000

6 20 0

0.2486 0.0000 1.0000

23.7 76.0 0.0

0.2123 0.1353 0.2444 0.2119 0.5050 0.3009

0.0453 0.0446 0.1581 0.1407 0.4034 0.2053

0.6050 0.3442 0.3578 0.3062 0.6062 0.4175

2.7483 14.2525 15.3461 1.7662 24.5649 2.5399

1 4 5 2 11 2

0.0974 0.0065 0.0090 0.4135 0.0106 0.2809

63.6 71.9 67.4 0.0 55.2 21.3

0.3892 0.2444 0.2728

0.2893 0.1581 0.2022

0.4994 0.3578 0.3572

63.1311 15.3461 3.6689

18 5 3

0.0000 0.0090 0.2995

71.5 67.4 18.2

0.3108 0.3301 0.0952

0.2228 0.2410 0.0239

0.4149 0.4334 0.3113

7.8588 42.6968 0.0000

6 11 0

0.2486 0.0000 1.0000

23.7 74.2 0.0

0.2123 0.0941 0.2992 0.2119 0.4482 0.3009

0.0453 0.0227 0.1700 0.1407 0.3332 0.2053

0.6050 0.3167 0.4708 0.3062 0.5690 0.4175

2.7483 4.6546 7.0666 1.7662 14.6794 2.5399

1 2 2 2 7 2

0.0974 0.0976 0.0292 0.4135 0.0403 0.2809

63.6 57.0 71.7 0.0 52.3 21.3

0.3302 0.2992 0.2728

0.2249 0.1700 0.2022

0.4558 0.4708 0.3572

40.6442 7.0666 3.6689

12 2 3

0.0001 0.0292 0.2995

70.5 71.7 18.2

FTD Method of diagnosis Lund and Manchester 7 Neary 21 Pathology 1 Method of depression assessment BEHAVE-AD 2 CG 5 Chart 6 DSM-IV-TR 3 NPI-Q 12 Psych-Int 3 Source of information Caregiver 19 Chart 6 Corroborated 4 bvFTD Method of diagnosis Lund and Manchester 7 Neary 12 Pathology 1 Method of depression assessment BEHAVE-AD 2 CG 3 Chart 3 DSM-IV-TR 3 NPI-Q 8 Psych-Int 3 Source of information Caregiver 13 Chart 3 Corroborated 4

(0.135; 95% CI: 0.045–0.344). Only 3 included studies explicitly reported depression prevalence rates based on the DSM-IV-TR criteria, with an aggregate ER of 0.212 (95% CI: 0.141– 0.306). The ERs for diagnoses based on psychiatric interviews without specified criteria and chart reviews are reported in table 2. ERs calculated based on information sources leading to the depression diagnosis revealed that caregiver reports yielded the highest prevalence (0.389; 95% CI: 0.289–0.499), while clinical assessments yielded the lowest prevalence (0.273; 95% CI: 0.202–0.357).


CG = Subjective caregiver report; Psych-Int = psychiatric interview without specification of depression criteria.

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DOI: 10.1159/000369882


Model

Random

Group by Number ER FTD diagnostic categories

Lower limit

Upper limit

bvFTD

20

0.317

0.249

0.394

PNFA

2

0.309

0.045

0.810

SD

6

0.333

0.184

0.525

SD + PNFA

1

0.733

0.550

0.861

29

0.370

0.306

0.439

overall

ER and 95% CI

–1.00

–0.50

0

0.50

1.00

Fig. 1. Forest plot of depressive symptom event rates for global FTD, behavioral and language subtypes. The vertical lines with associated horizontal lines in the forest plot represent the event rate with 95% CI. The diamond represents the aggregate event rate. The numbers are the number of data points used in the analysis from all included studies. Calculated as Hedge’s G based on the random-effects model.

A mixed-effects metaregression was applied to the ERs for moderating variables (age, sex and MMSE score) where data were available. None reached the significance level of 0.05. This was also true for bvFTD and the language subtypes (see below). Rates of Depression in bvFTD The omnibus ER for bvFTD was 0.317 (95% CI: 0.249–0.394) (table 2). The prevalence was similar in magnitude for the Lund and Manchester criteria (0.311; 95% CI: 0.223– 0.420) and the Neary criteria (0.330; 95% CI: 0.241–0.433). Similar to global FTD, depression diagnoses based on the NPI-Q yielded the highest prevalence (0.448; 95% CI: 0.333–0.569), and subjective caregiver reports yielded the lowest prevalence (0.094; 95% CI: 0.0227– 0.317). Prevalence rates of depressive symptoms based on information provided by caregivers yielded the highest ER (0.330; 95% CI: 0.225–0.456), and clinical corroboration yielded the lowest prevalence (0.273; 95% CI: 0.202–0.357).

Assessment of Heterogeneity, Study Quality and Bias There was significant heterogeneity in estimated ERs for global FTD, bvFTD, SD and PNFA (table 1). With the exception of diagnoses by DSM-IV-TR criteria and by psychiatric


Rates of Depression in SD and PNFA The ER for SD was similar to that for global FTD and bvFTD (0.333; 95% CI: 0.183–0.525) (table 2). The Neary criteria were used for the diagnosis of SD across all studies. We did not calculate aggregate ERs for the method of depression diagnosis as there were only 2 studies each in the categories of subjective caregiver report, NPI and chart review. An ER based on the source of information leading to a depression diagnosis was calculated for caregiverprovided data (n = 3), yielding a prevalence of 0.354 (95% CI: 0.158–0.615). Given the limited data, no analysis was made for PNFA or on the combination of SD + PNFA.

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DOI: 10.1159/000369882


Group by Statistics for each study Depressed/total, n comparison OR lower upper Z value p value FTD dementia limit limit FTD vs. AD

1.328 0.734 2.403 0.938

0.348

95/362 274/809

FTD vs. DLB

2.085 0.794 5.472 1.492

0.136

12/45

17/40

FTD vs. VAD 2.176 0.529 8.943 1.078

0.281

18/39

43/77 0.1 0.2

OR and 95% CI

0.5 1

2

5 10

Fig. 2. Forest plot of aggregate OR of depressive symptoms in FTD versus AD, DLB and VAD. The vertical lines with associated horizontal lines represent the OR and 95% CI in depressive symptom prevalence in other dementia types compared to FTD. Values >1 indicate higher OR in AD/DLB/VAD compared to FTD.

interviews without specific criteria, there was significant heterogeneity within each method of depression diagnosis. The mixed-effects regression of study quality on logit ERs yielded a nonsignificant result (slope = –0.024; SE = 0.020; p = 0.227). Begg’s (p = 0.178) and Egger’s tests (p = 0.173) were nonsignificant for publication bias. Comparison with AD, VAD and FTD The analysis of the OR examining the magnitude of difference in depression prevalence rates between AD and FTD using a random-effects model yielded a nonsignificant (n = 13; OR = 1.159; 95% CI: 0.817–1.644; p = 0.408) and heterogeneous result (Q = 27.186; p = 0.004; I2 = 58.885) (fig. 2). There was a similar nonsignificant effect between FTD and VAD (n = 3; OR = 2.084; 95% CI: 0.794–5.471; p = 0.136); however, the aggregate was homogeneous (Q = 0.790; p = 0.674; I2 = 0.000). Further analysis comparing FTD with DLB yielded a nonsignificant, nonheterogeneous aggregate effect size (n = 3; OR = 1.768; 95% CI: 0.675– 4.628; p = 0.246; Q = 3.363; p value for Q test = 0.186; I2 = 40.540).

We examined the prevalence of depressive symptoms in bvFTD and language-variant FTD using meta-analytic techniques. Based on the data from 27 eligible studies reporting 29 ERs for all variants of FTD, we find that approximately one third (33%) of patients with FTD demonstrate depressive symptoms. A similar ER emerged from studies specifically examining patients with bvFTD, SD and PNFA, although there was little data (from 6 and 2 studies, respectively) on the language variants. There was no significant effect of age, gender or MMSE score on prevalence. We found only observational studies that met our a priori inclusion criteria, and the study quality did not significantly affect the reported ER. The quantitative analysis for publication bias also yielded nonsignificant results. There was no significant difference in prevalence between patients diagnosed with FTD based on the Neary criteria and those diagnosed according to the Lund and Manchester criteria, indicating homogeneity between these two diagnostic sets of criteria. None of the included studies used the newer criteria for bvFTD or language variants published in 2011


Discussion

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[19], which have been found to be more sensitive than the previously available criteria. Only 1 study used the gold standard of pathological diagnosis. There was a lack of uniformity in the assessment of depression in FTD patients. For bvFTD, a large number of studies (n = 14), including those using chart reviews (n = 6), psychiatric interviews (n = 3) and subjective caregiver assessments (n = 5), did not specify the exact criteria used to diagnose depression. Subjective caregiver reports, which provided the lowest ER (0.135; 95% CI: 0.0446–0.344), were the basis in 3 studies that used self-designed questionnaires [20–22]. In addition, the approach taken by Shinagawa et al. [22] further departed from the method of assessment used by other studies by requesting caregivers to recollect the initial symptom of the patients’ neurocognitive disorder. Thus, the low ER tabulated from this category was heavily weighted by their reported prevalence of depressive symptoms (1.6%) seen only at illness onset. It was similarly difficult to compare and assess the diagnostic methods of studies using retrospective chart reviews or psychiatric interviews without clearly specifying the diagnostic criteria. Many studies (n = 14), however, used standardized neuropsychiatric dementia scales, most notably the NPI-Q (n = 12). The NPI-Q yielded the highest ER (0.536; 95% CI: 0.415– 0.653) of all the methods of assessment. It uses a screening question to assess for the presence or absence of depression/dysphoria [23], with the frequency and severity of symptoms further delineated only in response to an affirmative screening. The studies using the NPI-Q to assess the prevalence of depression included all patients who had a positive screening result and thus did not reflect symptom severity or frequency. This may have inflated the reported prevalence in certain studies such as that of Silveri et al. [24], who compared mood as assessed by a patient-completed Survey Psychiatric Assessment Schedule (SPAS) to a caregiver-completed NPI-Q. The rate reported by the NPI-Q depression item was 82%, while that reported by the SPAS, which requires a cutoff score to meet depression criteria, was 45%. A similar discrepancy was seen in the data reported by Srikanth et al. [25], which showed a rate of 69.6% with any positive response to the NPI-Q screening question, but with only 56.5% of patients reaching a depression domain score of ≥4, calculated as the product of the frequency (maximum of 4) and severity scores (maximum of 3) [25]. Thus, studies that used the NPI-Q may have included patients with clinically insignificant transient or mild depressive symptoms. Two studies used the depression item of the BEHAVE-AD (n = 2) to assess depression. This scale has only been validated in AD, which presents a potential flaw in the assessment of depression in FTD. A scale for the assessment of neuropsychiatric and behavioral disturbances in patients with amyotrophic lateral sclerosis and bvFTD has recently been developed [26], and it would be of interest to assess the prevalence of depressive symptoms based on this tool. The majority of studies discussed above, including those using the NPI-Q, the BEHAVEAD and self-designed questionnaires, evaluated for signs of depressed mood only (e.g. tearfulness, expressed feelings of guilt or sadness, or suicidal gestures) [23, 27]. However, the presence of additional neurovegetative (e.g. changes in sleep, appetite and energy) and associated emotional/cognitive symptoms (e.g. guilt and decreased concentration) is necessary to diagnose major depression according to DSM-IV-TR criteria. Only 3 included studies explicitly reported the depression prevalence based on the DSM-IV-TR criteria, with an aggregate ER (0.212) that was lower than that calculated from studies using the NPI-Q or psychiatric interviews without specific criteria. Thus, the majority of the data for FTD related to the prevalence of depression are based on reports of depressed mood only, which does not satisfy the globally accepted definition of major depression. The discrepancy we find between ERs based on the DSM-IV-TR criteria and those based on the NPI-Q, although relying on limited data with respect to the former, may highlight the risks of overdiagnosing depression in FTD based on a single symptom. Conversely,



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applying the DSM-IV-TR to the FTD patient population is difficult, perhaps even fallacious, given the overlap in the neurovegetative symptoms of depression and neurobehavioral symptoms of FTD (i.e. changes in appetite, altered speech output and neglect of self-care) [28, 29]. Some of the included studies addressed the confusion between psychiatric and neurocognitive symptoms by excluding patients with a prior formal diagnosis of major depression, which further confounds our results [20, 22]. The risk of overdiagnosis based on an ‘isolated symptom approach’ (i.e. depressed mood only) versus the use of the full DSM-IV-TR criteria, which may not reliably distinguish symptoms of dementia from a true depressive syndrome, is a diagnostic issue that has been acknowledged for AD [30]. In AD, investigators have identified symptom clusters consistently occurring within a subgroup of patients with depressive symptoms and have subsequently proposed diagnostic criteria for depression in AD [3]. These alter the DSM-IV-TR criteria to better reflect the presentation of depression in AD. Although the validity of the criteria mentioned above remains a subject of debate [30, 31], similar attempts to define diagnostic criteria for depression in FTD are lacking. A latent cluster analysis approach using a validated depression scale such as the Hamilton Depression Rating Scale or the Cornell Scale for Depression in Dementia – which has been undertaken for AD [31, 32] – could help clarify these issues. Despite the limitations of basing prevalence estimates of depression on reports of depressed mood only, our results grounded on these data demonstrate that depressed mood is quite prevalent in FTD. This is notable, since it is commonly reported that apathy and emotional blunting predominate in FTD, while depressed mood is more commonly seen in AD [29, 33]. In contrast, we found that in studies where a comparison was conducted, the prevalence of depressed mood did not differ significantly between FTD and other forms of dementia such as AD, VAD and DLB. As discussed above, however, we cannot comment on the relative severity or frequency of depressive symptoms among these dementia subtypes. In summary, our findings suggest that depressed mood and its manifestations are commonly recognized in patients with FTD by their caregivers and clinicians. However, the validity of our results is limited by the lack of uniformity in methods of diagnosing depression as well as considerable variability in the literature regarding what symptoms constitute a depressive syndrome in FTD. Further examination of these issues, perhaps applying similar techniques that have been used to define depression criteria in AD, is warranted, given the apparent high prevalence of these symptoms in FTD patients. Developing validated methods of assessing depression in language-variant FTD, where there currently is a paucity of information, would be vital, given the challenges posed by impaired communication in this group. In addition, clarification of the prevalence of comorbid anxiety and apathy in patients exhibiting depressive symptoms would be of clinical use, since such symptoms often require different treatment approaches [6, 7]. Further exploration of the diagnosis and clinical manifestation of depression in patients with FTD will be needed in order to develop more effective management of these distressing symptoms. Acknowledgements

Disclosure Statement There are no financial or other conflicts of interest to disclose.


There was no external funding for this study.

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