Haller et al. BMC Psychiatry 2014, 14:128
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RESEARCH ARTICLE
Open Access
The prevalence and burden of subthreshold
generalized anxiety disorder: a systematic review
Heidemarie Haller, Holger Cramer, Romy Lauche, Florian Gass and Gustav J Dobos*
Abstract
Background: To review the prevalence and impact of generalized anxiety disorder (GAD) below the diagnostic
threshold and explore its treatment needs in times of scarce healthcare resources.
Methods: A systematic literature search was conducted until January 2013 using PUBMED/MEDLINE, PSYCINFO,
EMBASE and reference lists to identify epidemiological studies of subthreshold GAD, i.e. GAD symptoms that do not
reach the current thresholds of DSM-III-R, DSM-IV or ICD-10. Quality of all included studies was assessed and median
prevalences of subthreshold GAD were calculated for different subpopulations.
Results: Inclusion criteria led to 15 high-quality and 3 low-quality epidemiological studies with a total of 48,214
participants being reviewed. Whilst GAD proved to be a common mental health disorder, the prevalence for
subthreshold GAD was twice that for the full syndrome. Subthreshold GAD is typically persistent, causing considerably
more suffering and impairment in psychosocial and work functioning, benzodiazepine and primary health care use,
than in non-anxious individuals. Subthreshold GAD can also increase the risk of onset and worsen the course of a range
of comorbid mental health, pain and somatic disorders; further increasing costs. Results are robust against bias due to low
study quality.
Conclusions: Subthreshold GAD is a common, recurrent and impairing disease with verifiable morbidity that claims
significant healthcare resources. As such, it should receive additional research and clinical attention.
Keywords: Anxiety disorders, Epidemiology, Burden of illness, Systematic review
Background
Mental disorders and anxiety disorders in particular seem
to continually increase in incidence and prevalence [1-3],
raising questions about the early detection of potential risk
factors and the nature of ‘subthreshold’ states. Individuals
in such states experience psychopathological symptoms
that are mild, atypical, masked and/or brief but recurrent;
which however fail to reach the Diagnostic and Statistical
Manual of Mental Disorders (DSM) [4] or World Health
Organization’s International Classification of Diseases (ICD)
[5] standardized diagnostic thresholds by reason of their
number and/or duration. Whilst these states often cause
significant suffering and impairment [6-9], their doubtful
morbidities and lack of standardized definition lead to
* Correspondence: gustav.dobos@uni-essen.de
Department of Internal and Integrative Medicine, Kliniken Essen-Mitte,
Faculty of Medicine, University Duisburg-Essen, Am Deimelsberg 34a,
45276 Essen, Germany
ongoing marginalization [10]. Diagnostic thresholds current
disregard for subthreshold, subsyndromal and subclinical
symptoms may lead to considerable false negative cases.
For example, a 2007 American study of 5692 adult mental
health care users found that only 61.2% had a DSM-IV
diagnosis; a non-negligible percentage of mental health service, however, provided to patients suffering from subthreshold emotional problems [11].
Whilst previous systematic research has revealed consistent evidence of the impact of various subthreshold mental
disorders [12-18], past studies of generalized anxiety disorder (GAD) below the current diagnostic thresholds have
varied widely in their quality and results, with only nonsystematic reviews having been conducted to date [19]. To
determine the morbidity of subthreshold GAD, representative epidemiological data are required. The current review
therefore aimed to systematically assess prevalence, chronicity risk, human and economic burden as well as treatment need of subthreshold GAD.
© 2014 Haller et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.
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Methods
The review was planned and conducted in accordance with
the MOOSE (Meta-Analysis Of Observational Studies in
Epidemiology) [20] guidelines.
Literature search strategy
A systematic literature search was undertaken using
both electronic and manual methods. The former entailed
searching PUBMED/MEDLINE, PSYCHINFO and EM
BASE databases, from their inception until January 2013.
The search strategy focused on terms for ‘subthreshold’
and ‘anxiety’, with ‘epidemiology’, ‘human and economic
burden’ and ‘prevention and therapy’. The precise methods
used were tailored to each database in turn. The full search
strategy for the PUBMED was: (subthreshold [Title/Abstract] OR subsyndromal [Title/Abstract] OR subclinical
[Title/Abstract]) AND anxiety [Title/Abstract] AND (Anxiety Disorders/epidemiology [MeSH Terms] OR anxiety
disorders/economics [MeSH Terms] OR anxiety disorders/
complications [MeSH Terms] OR disability [Title/Abstract]
OR impairment [Title/Abstract] OR cost of illness [MeSH
Terms] OR health care costs [MeSH Terms] OR comorbidity [MeSH Terms] OR anxiety disorders/therapy [MeSH
Terms] OR anxiety disorders/control and prevention [MeSH
Terms]). No restrictions were placed on language, article
type or year of publication. Identified papers’ references
were screened manually to find additional related studies.
Eligibility criteria
Having read the located abstracts, researchers went on
to assess eligibility of selected full-text articles. Eligible
articles were required to meet the following criteria:
– Type of study: Only epidemiological trials with
original data, published in English or German as full
articles in peer-reviewed journals were included.
Reviews, study protocols, expert statements,
diagnostic or methodological pieces were all excluded.
– Diagnostic criteria: Only studies that defined
subthreshold GAD by relaxing one or more of the
diagnostic criteria from the standardized diagnostic
manuals (DSM-III-R, DSM-IV or ICD-10) were
included. Papers that used earlier versions of the
DSM or ICD were excluded, because of widely
deviating threshold definitions for GAD.
– Study samples: Only studies representative of the
general population (including sub-populations of
several age groups), or of specific patient populations
(e.g. primary care or psychiatry), were included.
Studies that treated subthreshold GAD as a comorbid
symptom of other physical or mental disorders were
excluded. Where two or more articles reported data
from the same study sample, only the most relevant
article was considered.
Page 2 of 13
Data extraction
Studies’ characteristics were extracted independently by
two reviewers. Inconsistencies were rechecked within the
research team and resolved by discussion. The following
data were extracted: setting (specific patient population,
general population, adolescents, older adults), country,
study period of data collection, study design (longitudinal,
cross-sectional, retrospective), sample size, age range,
assessment of GAD (type of interview, questionnaire),
definition of subthreshold GAD used and main findings
of the study.
Assessment of methodical quality
A scoring system previously used for observational trials
[21] was adapted to critically appraise the located epidemiological studies, awarding one point for each of the
following criteria:
1. Random population sample with unbiased sampling
strategy
2. Adequate sample size (>1000)
3. Adequate response rate (>70%)
4. Comparison between respondents/non-respondents
(those who refuse the initial query)
5. Reliable and valid assessment of GAD (standardized
instruments used).
Studies were rated as ‘low quality’, if they scored less
than three on five points, and as ‘high quality’ from three
to five points. The quality assessment was undertaken by
two reviewers independently, with comparison, discussion and agreement by consensus.
Data analysis
The median prevalence of subthreshold GAD was calculated for each homogeneous study population. Sensitivity
analyses of low versus high quality studies’ scores were
then performed, to test the robustness of studies’ outcome data. Additional study outcomes were summarized
qualitatively.
Results
Search results
Electronic database searching identified 1036 papers.
Another seven emerged from a manual search of studies’
reference lists. Of this total of 1043 papers, 407 proved
to be duplicates. The remaining 636 abstracts were then
screened, with 39 studies being read in full-text to assess
their eligibility for inclusion in the review. Of these, 21
studies [22-42] were excluded because they reported outcome data only for mixed subthreshold diagnoses, for subthreshold diagnoses other than GAD or because they
contained data analyzed in already included articles. Other
studies were excluded because they defined subthreshold
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GAD as an anxiety disorder not otherwise specified, also
comprising subjects with various anxiety and/or depressive symptoms that did not clearly match a single diagnostic category. Eighteen epidemiological studies were finally
included and reviewed [43-60] (Figure 1).
[43-46,48,50,51,53-56,60]. All but one study [60] used
standardized interviews to assess study diagnosis for subthreshold GAD.
Study characteristics
Median prevalence estimates were conducted for the different study populations (Table 3) and definitions of subthreshold GAD (Table 4). Two studies [43,51] found point
prevalence rates for subthreshold GAD amongst adults in
the general population (median 4.4%, range 2.1% - 7.7%).
Four others [46,51,56,57] reported 12-month prevalence
rates with a median of 3.9% (range 2.1% - 6.6%) and/or
lifetime prevalence rates with a median of 12% (range
8% - 13.7%) [45,51,56] for the general population.
The median prevalence of subthreshold GAD was generally found to rise in the general population, when the
GAD time criterion was relaxed from three to one month.
For subthreshold GAD lasting at least three months, the
median point prevalence, 12-month prevalence and lifetime prevalence was 4.2%, 3.6% and 8% respectively.
Where the condition lasted for at least one month, these
figures were 5.2%, 6.1% and 12.4%. These data are all
based on high-quality studies.
For specific age groups, the median of prevalences
could not be determined because of N = 1 studies. A single
high-quality study of young women [49] found a pointprevalence rate of 2.4% for subthreshold GAD; lower than
that in the general population. By contrast, two other
high-quality studies of adults/primary care patients [45,53]
The reviewed studies were conducted between 1979 and
2006 (Table 1). Most were cross-sectional in nature, with
the exception of two studies [43,52], and were based on
European [43,44,46,48,49,55,57,58,60] or North American
[45,47,50,51,53,54,56,59] data. One cross-cultural study
was included [52]. A total of 62,501 participants between
15 and 96 years was enrolled in these studies, but
data on only 48,241 of this number remained when
different studies of the same sample were subtracted
[44,46,47,51,52,54,56,58]). Participants came from the
general population [43-46,51,56], were older adults
[47,48,54,59], adolescents [49] or primary care patients
[50,52,53,55,57,58,60].
Study quality
Fifteen of the reviewed studies were assessed as being of
high quality [43-47,49,51-58,60] and three of low quality
[48,50,59] (Table 2). All but one of the former [55] used
unbiased random population samples greater than 1000,
with eight studies reporting response rates greater than
70% [44,46,51,52,54,56,57,60]. The low quality studies
did not fulfill any of these criteria. Twelve of the
reviewed studies performed analyses of non-respondents
Figure 1 Flowchart of study exclusions.
Study results
Prevalence estimates
Source
Setting
Study period Study design
Sample Age
Assessment
size (n) range of GAD
Definition of subthreshold GAD
Main findings
Angst,
2006 [43]
General population
(Switzerland | ZCS)
1979-1999
591
DSM-III-R diagnosis of GAD with
relaxed duration criterion (1 versus
3 months of duration)
- Point prevalence of SUB GAD = 6.2% for
3-month
GAD/7.7% for 1-month GAD
Longitudinal
19–41 Interview (SPIKE)
- High levels of distress, social and work
impairment & comparable comorbidity rates
and suicide attempts in all SUB GAD groups
(sign. differences compared to controls, but
no sign. differences compared to 6-month GAD)
- Same age of onset, course, and treatment
rates in SUB GAD and GAD cases
- 57.5% of treated patients had SUB
DSM-III-R GAD & 50% had SUB DSM-IV GAD
Beesdo,
2009 [44]
General population
(Germany | GHS)
1998-1999
Cross-sectional 4181
18–65 Interview (CIDI)
Anxious worrying for at least
3 months with at least 2 of the
other DSM-IV criteria for GAD
- Higher associations between GAD, also on
the SUB level, and medically unexplained pain
compared to other anxiety disorders
(independent from comorbid depression)
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Table 1 Description of included studies
- Lowest quality of life, greatest disability and
health care utilization in the group with both
unexplained pain and (SUB) GAD
Bienvenu,
1998 [45]
General population
(United States | ECA)
1993
Cross-sectional 1920
≥27
Carter,
2001 [46]
General population
(Germany | GHS)
1998-1999
Cross-sectional 4181
18–65 Interview (CIDI)
Interview (DIS)
Group 1: DSM-III-R GAD with duration - Lifetime prevalence of SUB GAD = 8% for
of 1–6 month / Group 2: DSM-III-R
group 1/12% for group 2
GAD of 1–6 month + fewer than
- Higher SUB GAD prevalence in women
6 associated symptoms
and younger adults
Persistent worrying for at least
3 months with at least 2 of the
other DSM-IV criteria for GAD
- 12-month prevalence of SUB GAD = 2.1%
- Higher prevalence in women and in older adults
- High levels of distress and impairment in
younger and older SUB GAD cases
- Same comorbidity rates in SUB GAD and
threshold GAD (commonly occurring: other
anxiety disorders, depression, and
somatoform disorders)
Grenier,
2011 [47]
Community-dwelling
2005-2006
older adults (Canada|ESA)
Cross-sectional 2784
≥65
Interview (ESA-Q)
Symptoms of anxiety, not meeting all
symptom criteria of DSM-IV GAD
- 12-month prevalence of SUB GAD = 3.0%
- Chronic physical health problems, social
disability, use of benzodiazepines and comorbid
depression not sign. different between SUB
GAD and threshold GAD, but sign. higher in
SUB GAD than in controls
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Heun,
2000 [48]
Older adults (Germany)
1993-1994
Cross-sectional 287
≥60
Interview (CIDI)
Hoyer,
2002 [49]
Young women,
(Germany|DPS)
1996-1997
Cross-sectional 2064
18–25 Interview (ADIS)
DSM-II-R GAD of 6 months, but
fewer than 6 associated symptoms
- Lifetime prevalence of SUB GAD = 5.2%
Fulfilling 3 out of 4 DSM-IV
criteria for GAD
- Point prevalence of SUB GAD = 2.4%
- Higher SUB GAD prevalence in women
- 42% of the SUB GAD cases have other
comorbid mental disorders
- Sign. reduced psychosocial functioning in SUB
GAD cases compared to controls
Kertz,
2011 [50]
Primary care patients
(United States)
NR
Cross-sectional 329
22–88 Interview (PRIME-MD)
GAD symptoms fulfilling DSM-IV
criterion A in addition to 1 or 2 of
the other GAD criteria
- Point prevalence of SUB GAD = 6%
- Point prevalence of GAD symptoms = 24%
- SUB GAD as risk factor for threshold GAD
- Sign. poorer physical health, greater stress
and sleep difficulty in SUB GAD than in the no
worry group; but no sign. differences between
GAD, SUB GAD and no worry group on health
care utilization and work productivity
Kessler,
2005 [51]
General population
(United States|NCS-R)
2001-2003
Cross-sectional 9282
≥18
Interview (CIDI, SCID)
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Table 1 Description of included studies (Continued)
DSM-IV diagnosis of GAD with relaxed - Point prevalence of SUB GAD = 2.1% for
duration criterion (1 versus 3 months 3-month GAD / 2.6% for 1-month GAD
of duration)
- 12-month prevalence of SUB GAD = 3.9%
for 3-month GAD / 5.5% for 1-month GAD
- Lifetime prevalence of SUB GAD = 8% for
3-month GAD / 12.7% for 1-month GAD
- Onset, persistence, comorbidity, social and
work impairment not greatly different between
1–5 months GAD and over 6 months GAD
- Short SUB GAD episodes typically recur over years
Maier,
2000 [52]
Primary care patients
(Cross-cultural|PPGHC)
1991-1992
Longitudinal
5604
15–65 Interview (CIDI)
All ICD-10 GAD symptom criteria, but
relaxed time criterion (<1 versus
1–6 months of duration)
- Not sign. smaller psychosocial disability for
SUB GAD with 1–6 months (24.3%) and with
GAD over 6 month (24.9%), a little smaller
in <1 month SUB GAD (17.3%), higher than in
those with chronic somatic diseases (19.5%)
- Higher disability in (SUB) GAD with other
comorbid psychiatric syndromes
Olfson,
1996 [53]
Primary care patients
1994
(United States|SDDS-PC)
Cross-sectional 1001
35–65 Interview (SCID)
Excessive anxiety for the past
6 months, not meeting full DSM-III-R
criteria for GAD
- Point prevalence of SUB GAD = 6.6%
- Higher prevalence in younger adults
- 48.5% met criteria for another mental disorder
Page 5 of 13
- After adjustment for covariates, no more
differences on work, family, social function,
and health care utilization in SUB GAD
compared to controls
Potvin,
2011 [54]
Community-dwelling
2005-2006
older adults (Canada|ESA)
Cross-sectional 2414
65–96 Interview (ESA-Q)
At least 1 essential symptom of a
DSM-IV GAD without fulfilling
all criteria
- In men, global cognitive impairment is sign.
linked to SUB GAD whether depression was
comorbid or not
Rucci,
2003 [55]
Primary care patients
(Italy|PPGHC + BS)
Cross-sectional 554
15–65 Interview (CIDI)
3+ ICD-10 GAD criteria of 1-month
duration including apprehension,
motor tension, and automatic
overactivity
- Point prevalence of SUB GAD = 8.3%
1991-1992
- Higher SUB GAD prevalence in women
- (SUB) GAD and depression were the
most frequent disorders
- SUB GAD as a precursor of threshold GAD
- Poorer health perception and higher psychological
distress in SUB GAD than in controls, but no sign.
differences in physical disability
Ruscio,
2007 [56]
General population
(United States|NCS-R)
2001-2003
Cross-sectional 5692
≥18
Interview (CIDI, SCID)
DSM-IV symptom criteria for GAD,
- 12-month prevalence of SUB GAD = 6.6%
relaxed duration of 1+ months, also
- Lifetime prevalence of SUB GAD = 13.7%
non-excessive worry, and only 2+
criterion C symptoms
- Risk of comorbid psychiatric disorders equal for
GAD (92.1%) and SUB GAD (86.3%)
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Table 1 Description of included studies (Continued)
- Sign. risk of onset of various comorbid anxiety
& mood disorders caused by SUB GAD
Szadoczky, Primary care
2004 [57] patients (Hungary)
1998-1999
Cross-sectional 1815
18–65 Interview (DIS)
1 to 5 symptoms of DSM-III-R GAD
and duration of less than 6 months
- Point prevalence of SUB GAD = 5.7%
- 12-month prevalence of SUB GAD = 10.9%
- Higher SUB GAD prevalence in women
Weiller,
1998 [58]
Primary care patients
(Europe|PPGHC)
1991-1992
Cross-sectional 1973
≤65
Interview (CIDI)
4+ symptoms of ICD-10 GAD with
1 automatic arousal symptom,
3–6 months or all ICD-10 criteria, but
no automatic arousal symptom or
all ICD-10 criteria, but <4 symptoms
- Point prevalence of SUB GAD = 4.1%
- Sign. poorer overall health status and higher
psychosocial disability in SUB GAD patients than
in controls, and no differences between GAD
and SUB GAD
- Sign. more general practitioner visits for
psychological problems in SUB GAD than controls
(but no more anxiolytics or antidepressants in
adjusted statistics)
- 39% of SUB GAD an 33% of GAD cases were
identified as clinical relevant
Wetherell,
2003 [59]
Older adults
(United States)
NR
Cross-sectional 90
55–88 Interview (ADIS)
Anxiety symptoms, not meeting
criteria for
DSM-IV GAD
- Sign. more sleep disturbance, fatigue, distress/
impairment, higher history of psychotherapy, history
and current medication use (antidepressants +
benzodiazepines) in GAD and SUB GAD
than in controls
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- Current psychotropic medication use in 54.5%
of SUB GAD (vs. 6.3% in controls)
Wittchen,
2002 [60]
Primary care patients
(Germany)
2000
Cross-sectional 17739
≥16
Questionnaire (GAS-Q) Full DSM-IV GAD, but of 1–6 months
of duration
- Point prevalence of SUB GAD = 1.3%
- Point prevalence of GAD symptoms = 21.7%
- Higher point prevalence in women
- No sign. differences between SUB GAD and
GAD on onset, course, and disability
Abbreviations: ADIS Anxiety Disorder Interview Schedule, BS Bologna Study, CI Confidence Interval, CIDI Composite International Diagnostic Interview, DIS Diagnostic Interview Schedule for DSM, DPS Dresden Predictor
Study, DSM Diagnostic and Statistical Manual of Mental Disorders, ECA Epidemiologic Catchment Area Program, ESA Enquête sur la Santé des Aînés Study, GAD Generalized Anxiety Disorder, GAS-Q Generalized anxiety
screening questionnaire, GHS German National Health Interview and Examination Survey, ICD International Statistical Classification of Diseases and Related Health Problems, n Number of Study Participants,
NCS-R National Comorbidity Survey Replication, NR Not Reported, PPGHC WHO International Study on Psychological Problems in General Health Care, PRIME-MD Primary Care Evaluation of Mental Disorders Structured
Psychiatric Interview, SCAN Schedules for Clinical Assessment in Neuropsychiatry, SCID Structured Clinical Interview for DSM Diagnoses, SDDS-PC Symptom-Driven Diagnostic System for Primary Care, sign significant,
SPIKE Structured Psychopathological Interview and Rating of Social Consequences of Psychic Disturbances for Epidemiology, SUB Subthreshold, Subclinical, or Subsyndromal, ZCS Zurich Cohort Study.
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Table 1 Description of included studies (Continued)
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Table 2 Quality assessment of epidemiological studies included
Criterion
Unbiased
random
population sample
Adequate
sample size
(>1000)
Adequate
response rate
(>70%)
Analysis of
non-respondents
Reliable and
valid assessment
of GAD
Total quality
score (max. 5)
Angst, 2006 [43]
1
1a
0b
1b
1
4
Beesdo, 2009 [44]
1
1
1
1e
1
5
c
Bienvenu, 1998 [45]
1
1
0
1
1
4
Carter, 2001 [46]
1
1
1
1
1
5
Grenier, 2011 [47]
1
1
0
0
1
3
Heun, 2000 [48]
0
0
0
1d
1
2
Hoyer, 2002 [49]
1
1
0
0
1
3
Kertz, 2011 [50]
0
0
0
1
1
2
f
Kessler, 2005 [51]
1
1
1
1
1
5
Maier, 2000 [52]
1g
1g
1g
0g
1
4
Olfson, 1996 [53]
1
1
0
1
1
4
Potvin, 2011 [54]
1
1
1
1
1
5
Rucci, 2003 [55]
1
0
0
1
1
3
Ruscio, 2007 [56]
1
1
1
1f
1
5
Szadoczky, 2004 [57]
1
1
1
0
1
4
Weiller, 1998 [58]
1
1
0
0
1
3
Wetherell, 2003 [59]
0
0
0
0
1
1
Wittchen, 2002 [60]
1
1
1
1
0
4
a
the stratified sample represents 2600 persons; bfrom [61]; cfrom [62]; dfrom [63]; efrom [64]; ffrom [65]; gfrom [66].
found higher point and lifetime prevalence rates in younger than in older people. In older adults, a single highquality study [47] found a 12-month prevalence of 3% for
subthreshold GAD and a low-quality study [48] a lifetime
prevalence of 5.2%. Within the general population, older
adults also seemed to have a higher 12-month prevalence
rate for subthreshold GAD than other age groups [46].
For primary care patients, point prevalence rates were
reported in five high-quality studies [53,55,57,58,60] and
one low-quality one [50]. Although subthreshold GAD
was defined variously in these studies, they suggest a median point prevalence of 5.9% (range 1.3% - 8.3%). Further
discrimination, based on the duration of participants’ conditions, was not possible. In addition, one high-quality
study in primary care patients [57] found a 12-month
prevalence rate of 10.9% for subthreshold GAD. Beside
Table 3 Median prevalence rates of mixed subthreshold
GAD diagnoses
Point
prevalence
12-month
prevalence
Lifetime
prevalence
General population
4.4% (N = 2)
3.9% (N = 4)
12% (N = 3)
Adolescents
2.4% (N = 1)
n/a
n/a
Older adults
n/a
3% (N = 1)
5.2% (N = 1)
Primary care patients
5.9% (N = 6)
10.9% (N = 1)
n/a
Abbreviations: N Number of Studies, n/a not available.
depression, (sub)threshold GAD was cited as the most frequent mental health disorder in primary care [55]. When
all cases with at least one of the core symptoms of GAD
were included in this review, the median point prevalence
of subthreshold GAD rose to 22.9% [50,60].
Women had higher prevalence rates for subthreshold
GAD than men, independent of studies’ populations
[45,46,48,55,57,60]. No systematic differences were linked
to studies’ country of origin. Prevalence rates for subthreshold GAD were generally twice as high as those for
threshold GAD throughout [43,46,48,51,53,56]; a picture
that did not change when the single low-quality study [48]
was excluded from this aspect of the analysis.
Risk, onset and course
Subthreshold GAD was reported as a risk factor or precursor for the onset of threshold GAD [50,55]. It also
Table 4 Median prevalence rates of 1-month and
3-month subthreshold GAD for the general population
Point
prevalence
12-month
prevalence
Lifetime
prevalence
SUB GAD of >1-month
duration
5.2% (N = 2)
6.1% (N = 2)
12.4% (N = 3)
SUB GAD of >3-month
duration
4.2% (N = 2)
3.6% (N = 3)
8% (N = 1)
Abbreviations: N Number of Studies.
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raised the risk of experiencing other anxiety, mood and
substance disorders. This risk was cited as substantively
lower than that of threshold GAD in only one of fourteen
comparisons made [56]. Subthreshold GAD was also seen
to worsen the course of concurrent somatic diseases [50].
In terms of onset, course and persistence, subthreshold
GAD and threshold GAD were reported as not significantly
different [43,51,60]. Most subthreshold GAD cases recurred
over time [51]. Whilst all but one [50] of these findings
come from high-quality studies, most are of cross-sectional
nature, except one [43], necessarily restricting a longitudinal view.
Comorbidity
The rates of comorbid mental disorders were generally
high in people with subthreshold GAD; similar to those
occurring in threshold GAD [46,47,51,56]. More than
two fifths (42%) of young women with subthreshold GAD
also cited symptoms of other (sub)threshold mental health
disorders [49]. Adults and primary care patients with
subthreshold GAD had comorbidity rates of 86.3% and
48.5% respectively [53,56]. Various forms of anxiety disorder were most often comorbid with subthreshold GAD,
followed by minor or major depression and somatoform
disorders [46,47,56]. Having other comorbid mental health
disorders also led to higher levels of functional impairment
than having subthreshold GAD alone [52,58]. All of the
above data come from high quality studies. Another highquality study found strong links between participants’ pain
disorders and subthreshold GAD, while associations between chronic pain and other subthreshold anxiety disorders were weaker [44]. In this study, participants with
chronic pain and subthreshold GAD reported significantly
lower levels of mental quality of life, more disability days,
and greater healthcare utilization than groups without
additional subthreshold GAD [44]. The results were independent of participants’ levels of comorbid depression.
Human burden
Impairment in people with subthreshold GAD is not explained exclusively by comorbidity. Where participants
had subthreshold GAD alone, or study statistics were
adjusted for comorbidity, significantly higher levels of
distress [43,50,55,59] and lower levels of psychosocial
functioning in daily activities [43,47,49,51,58,59] occurred
in all study populations – compared to groups without any
symptoms of GAD. Distress or functional impairment
(a key criterion of a DSM-IV GAD diagnosis) was also
reported by at least 83.7% of younger (18–34 years) and
75% of older (35–65 years) participants with subthreshold
GAD [46]. Subthreshold GAD cases also noted significantly greater sleep disturbance and fatigue [50,59], suicide
attempts [43] and poorer perceived physical health, along
with more somatic diagnoses, than controls [47,50,55,58].
Page 9 of 13
In older men, subthreshold GAD was significantly linked
to global cognitive impairment [54]. All of these studies,
except two [50,59], contained high-quality data.
Moreover, high-quality studies showed no significant
difference in the levels of distress [43,50,55] or psychosocial impairment experienced by individuals with subthreshold and threshold GAD, in any study population.
Similar rates of marked social disability were found in
primary care patients with chronic somatic diseases, people
with threshold GAD and those with subthreshold GAD
of 1–6 months duration and also less than 1 month duration [52].
However, other high quality data comparing primary
care patients with subthreshold GAD to others without
anxiety symptoms found no difference in psychosocial
functioning, once appropriate adjustments had been made
for covariates [53,55].
Economic burden
Study results about subthreshold GAD’s economic impact
were inconsistent. Two studies on the general population
found no significant difference in the work performance of
participants with subthreshold or threshold GAD [43,51];
impairments in both groups were significantly higher than
in controls [43]. But in studies on primary care patients,
the differences found between cases with subthreshold
GAD and controls did not reach the level of statistical
significance [50,53].
With regard to healthcare utilization and costs, primary
care patients with subthreshold GAD and controls did not
differ significantly on mental health visits within the previous month [53] or primary care visits within the previous
three months [50]. When asked about the previous six
months, patients with subthreshold GAD reported significantly more primary care visits for psychological problems
than controls, independently of comorbid depression [58].
Within the last 12 months, 57.5% of participants of a general population sample with a subthreshold DSM-III-R
GAD diagnosis and 50% of those with a subthreshold
DSM-IV GAD diagnosis were treated by doctors or psychologists for GAD [43]. A significantly higher percentage
of older adults with subthreshold GAD had a history of
psychotherapy (72.7% vs. 43.8%), psychotropic medication
use (81.8% vs. 28.1%) or current antidepressant or benzodiazepine use than controls (54.5% vs. 6.3%) [59]. Another
study of older adults found that benzodiazepine use did
not differ significantly between those with subthreshold or
threshold GAD, but was significantly higher than in controls [47]. By contrast, adjusted statistics showed no more
significance in the prescription of anxiolytics and antidepressants to primary care patients with or without subthreshold GAD [58]. The data from two of these studies
[50,59] should, however, be interpreted with care as being
of low quality.
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Prevention and therapy
The reviewed studies generally stated the importance of
early detection, intervention and prevention for averting
subthreshold GAD’s progression [47,50,51,55]. Whilst individuals with subthreshold GAD sought care for psychological problems significantly more often than controls
[58], issues of prevention, therapy or primary care physicians’ ability to identify clinically-relevant (sub)threshold
GAD were not considered. In the reviewed studies physicians identified only 39% of those with subthreshold GAD
and 33% of those with threshold GAD as having clinicallyrelevant symptoms [58]. The reviewed studies did not
recommend using current treatments for people with
threshold GAD for those with GAD symptoms under the
threshold for standardized diagnosis, until clinical validation in subthreshold samples [55].
Discussion
This review found consistent evidence for high prevalence rates of subthreshold GAD; mostly twice as high
as those for DSM-IV GAD. If the duration criterion for
diagnosing threshold GAD is relaxed, the prevalence of
subthreshold GAD increases. Subthreshold GAD is more
prevalent in primary care patients than in the general
population, suggesting that those affected are frequent
primary healthcare resource users. In general, women
are more affected by subthreshold GAD than men, as
with threshold GAD [24,25]. Other populations presenting higher prevalence rates of subthreshold GAD include
adolescents and older adults in contrast to middle aged
individuals. Having subthreshold GAD was identified as
a significant risk factor for developing threshold GAD
and also elevates the risk of developing other anxiety,
mood and substance use disorders. Although results show
that both threshold and subthreshold GAD are generally
recurrent, the latter may fail to meet the DSM-IV or ICD10 thresholds, due to periods of symptom-free recovery.
High levels of comorbidity between subthreshold GAD
and other subthreshold mental health disorders, which
were found throughout all study populations, may also
cause this diagnostic threshold to be missed. Study results
show that boundaries between different GAD symptoms
are essentially arbitrary; that symptoms actually merge
into one another, with significant distress and disability
even in the absence of a threshold diagnosis.
Subthreshold GAD is related closely to other mental
health conditions and impacts negatively on pain-related
disorders. Its burden, however, cannot be explained by
comorbidity alone. Results of this review show that subthreshold and threshold GAD cases of all study populations essentially experience the same degree of distress
and psychosocial impairment; levels that significantly exceed those in non-anxious individuals. Only in primary
care patients, study results are contradictory, also finding
Page 10 of 13
cases with subthreshold GAD that were no more functionally impaired than controls. In terms of work productivity,
healthcare utilization and economic costs, the evidence is
inconsistent. Whilst the economic burden of subthreshold
GAD appears to be relatively slight, compared to the
human burden, a number of high-quality studies show
marked differences between those affected and controls.
This is especially true for primary health care and benzodiazepine use. Comorbid subthreshold GAD can also worsen
the course of other mental health and somatic disorders,
further raising healthcare utilization and costs.
These results are in line with other systematic reviews
of subthreshold anxiety and affective disorders. A review
of the literature on panic disorders concluded that people
with subthreshold panic experienced high comorbidity
with other mental health disorders, as well as substantial
distress and functional impairment [14]. Two more recent
studies substantiated these results, finding subthreshold
panic to be more prevalent than threshold panic. Subthreshold panic also raised the odds for a range of comorbid disorders and functional impairments, and increased
the likelihood of healthcare utilization beyond controls
[12,18]. Subthreshold social and specific phobias showed
increased prevalence rates, with those affected having a
higher use of benzodiazepine medications than nonanxious individuals [15,16]. The impact of subthreshold
depression was also largely comparable to that of the subthreshold anxiety disorders described [13,17].
The benefit of early intervention and prevention was
highly valued for individuals with subthreshold GAD and
other subthreshold psychiatric syndromes [16,67,68]. Clinical trials examining people with various types of subthreshold anxiety confirm this benefit. They found preliminary
evidence for the benefits of herbal medicine (lavender)
compared to placebo on self-report measures for anxiety
[69] and for a self-help intervention program compared
to usual care, which reduced the incidence of new fullsyndrome anxiety diagnoses by 50% and therefore saved
health-care costs each disorder-free year [70,71].
Evidence is needed to show whether the pharmacological and counseling strategies used to treat threshold
mental health conditions also benefit subthreshold ones,
if they are to be prescribed [72-74]. To save healthcare
resources, studies propose stepwise treatment algorithms
of increasingly intensive interventions for subthreshold
conditions; starting with ‘watchful waiting’ and self-help
strategies (life-style changes, appropriate self-medication);
working through to primary care and specialist care when
symptoms persist or increase [73].
The results of this review should be interpreted in the
light of certain limitations. Firstly, the literature search
included only studies indexed by the stated databases,
excluding non-electronic information sources. The completeness of the extracted information is therefore arguable.
Haller et al. BMC Psychiatry 2014, 14:128
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The absence of a unified definition of subthreshold GAD,
below the standardized diagnosis, complicated the search.
A myriad of possible search terms, including subthreshold,
subclinical, subsyndromal, minor, partial, brief, intermittent,
short-term reflects the complexity of the concept. This may
have led to further relevant studies being missed. Secondly,
the median prevalence estimates presented are based on an
insufficient number of studies found for some subpopulations, heterogenic definitions of subthreshold GAD and inadequate response rates in more than half of the identified
studies. The system used to score the reviewed papers introduces a third limitation. No consensus currently exists
about the most appropriate criteria for assessing the quality
of epidemiological trials. In the current review, different
evidence selection criteria may have led to other quality assessments and possibly to different conclusions. Under the
chosen scoring system, quality issues did not appear to influence the identified study outcomes systematically. When
low-quality studies were excluded from the analysis, the
evidence for subthreshold GAD’s influence did not change.
Although the impact of subthreshold GAD cannot be
denied, such anxiety symptoms should not seek to be
discussed in a way to lower diagnostic thresholds – for
the reason that thresholds for GAD did not change
essentially from DSM-IV [4] to DSM-V [75]. Further
research, however, should try to clarify the thresholds
between subthreshold GAD and non-pathological anxiety
states. As the absence of mental health signs is not enough
to ensure differentiation, with the attendant risk of overdiagnosis, the main diagnostic criterion should be significant impairment [22]. Such impairment should meet the
clinical criteria for morbidity [73], including episodes of
suprathreshold anxiety and effects on individuals’ work
performance, social relationships and/or quality of life. It
should also meet the Global Assessment of Functioning
Scale’s criteria for treatment [76]. Finally, research should
examine cost-effective treatment options to avert overmedicalization below the threshold of full-syndrome anxiety disorders, and to prevent progression to states of
severe illness or secondary complications such as alcohol
or drug misuse.
Conclusion
Subthreshold GAD is a common, recurrent mental health
disorder that causes distress and impairs psychosocial and
work functioning as often as several chronic somatic diseases. In those affected, subthreshold GAD increases primary health care and benzodiazepine use. Subthreshold
GAD has high comorbidity rates with other anxiety and
mood disorders, somatoform and chronic pain disorders;
further increasing costs.
Competing interests
The authors declare that they have no competing interests.
Page 11 of 13
Authors’ contributions
HH has been responsible for conception, design, analysis and interpretation
of data and for drafting the manuscript. HC has been involved in
conception, design, analysis and interpretation of data; and in revising the
manuscript critically. RL has been involved in conception, design, analysis
and interpretation of data; and in revising the manuscript critically. FG has
been involved in analysis and interpretation of data. GJD has been
responsible for conception and design; and has been involved in revising
the manuscript critically. All authors approved the final manuscript.
Acknowlegements
The authors want to thank Dr. Petra Klose for her assistance in acquiring the
literature reviewed.
Received: 4 July 2013 Accepted: 23 April 2014
Published: 1 May 2014
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subthreshold generalized anxiety disorder: a systematic review. BMC
Psychiatry 2014 14:128.
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