European Neuropsychopharmacology (2006) 16, S109–S118

w w w. e l s e v i e r. c o m / l o c a t e / e u r o n e u r o

Generalized anxiety disorder: A comorbid disease

David Nutt *, Spilos Argyropoulos, Sean Hood, John Potokar

Psychopharmacology Unit, University of Bristol, Bristol, United Kingdom

KEYWORDS: Abstract Generalized anxiety disorder (GAD) frequently occurs comorbidly with other
Generalized anxiety conditions, including depression and somatic complaints. Comorbid GAD sufferers have increased
disorder; psychologic and social impairment, request additional treatment, and have an extended course and
Comorbidity; poorer outcome than those with GAD alone; therapy should alleviate both the psychic and somatic
Prevalence; symptoms of GAD without negatively affecting the comorbid condition. The ideal treatment would
Burden; provide relief from both GAD and the comorbid condition, reducing the need for polypharmacy.
Diagnosis; Physicians need suitable tools to assist them in the detection and monitoring of GAD patients—the
Neurobiologic GADI, a new, self-rating scale, may meet this requirement. Clinical data have shown that various
mechanisms neurobiologic irregularities (e.g., in the GABA and serotonin systems) are associated with the
development of anxiety. Prescribing physicians must take into account these abnormalities when
choosing a drug. Effective diagnosis and treatment should improve patients' quality of life and their
prognosis for recovery.
© 2006 Elsevier B.V. and ECNP. All rights reserved.

1. Introduction hindrance to the progression of research into this important,

although somewhat neglected, psychiatric condition.
GAD is frequently comorbid with major depressive
Generalized anxiety disorder (GAD) is one of the most
disorder (MDD), panic disorder (PD), social anxiety
common conditions that occurs comorbidly with other
disorder (SAD), specific phobia (SP), and post-traumatic
disorders, particularly other anxiety and depressive disor-
stress disorder (PTSD), and is additionally associated with
ders. Indeed, comorbidity of mood and anxiety disorders is a
chronic pain conditions, medically unexplained somatic
hallmark feature of GAD (Judd et al., 1998; Ninan, 2001).
symptoms, and sleep disorders—in fact many physicians
Research into GAD is far behind that of many other psychiatric
believe that much of the insomnia reported by their
disorders, the main reason being that until fairly recently
patients is actually a variant of GAD. These patterns of
many eminent physicians still believed that GAD was not a
comorbidity increase the individual and economic burden
separate disorder, but rather a variant of depression. This
of GAD and add to the challenge of treatment. Indeed,
misapprehension arose because GAD often occurs comorbidly
comorbidity should be thought of as a challenge rather
with depression, which can mask the symptoms of GAD.
than a nuisance—it is very important clinically, both when
Consequently it has taken some time to establish that GAD
considering neurobiologic disorders and the individual
does occur as a discreet condition, and that it definitely is not
comorbidities. This article will discuss the issues surround-
a form of depression. This was, and still can be, a big
ing GAD and its various comorbidities. In addition, we will
* Corresponding author. Psychopharmacology Unit, Dorothy Hodg- also address the need for appropriate tools to aid the
kin Building, Whitson Street, Bristol, BS1 3NY, United Kingdom. Tel./ diagnosis of this condition, and appraise the potential role
fax: +44 117 331 3143. of various neurobiologic mechanisms in the development
E-mail address: david.j.nutt@bristol.ac.uk (D. Nutt). and treatment of GAD.

0924-977X/$ - see front matter © 2006 Elsevier B.V. and ECNP. All rights reserved.
doi:10.1016/j.euroneuro.2006.04.003
S110
2. Prevalence of psychiatric comorbidity
Many studies have reported a high prevalence of comorbidity
with psychiatric disorders as well as with general medical
conditions, both of which lead to a complex clinical
presentation. Data from a large general population survey
in the USA (the National Comorbidity Survey, NCS) suggest the
vast majority (90%) of people with lifetime GAD have a
lifetime history of at least one other psychiatric diagnosis
(Table 1) (Wittchen et al., 1994). Among individuals with
current GAD (defined as the most recent 6-month period of
anxiety still ongoing in the 30 days prior to interview), 66%
had at least one other concurrent psychiatric disorder: 39%
had MDD, 27% agoraphobia, 25% simple phobia, 23% SAD, and
23% PD (Table 1) (Wittchen et al., 1994). Of those diagnosed
as having met criteria for GAD within the preceding
12 months, 58% had also experienced an episode of MDD in
the previous 12 months; in another US survey (the Midlife
Development in the United States Survey, MDUSS), this figure
was 70% (Kessler et al., 1999). A representative sample of
adults in Germany (the German National Health Interview and
Examination Survey-Mental Health Supplement, GHS) showed
similar patterns of comorbidity; this survey focused on the 12-
month prevalence rates with a requirement that all diagnos-
tic criteria were fully present in the 12 months prior to
interview (Wittchen et al., 2000; Carter et al., 2001). In the
GHS, 40% of all 12-month GAD cases had current (within the
preceding 30 days) depression, 59% had experienced an
episode of MDD within the preceding 12 months, and 56% met
criteria for any other anxiety disorder within the preceding
12 months (Carter et al., 2001). These incidence rates
reinforce how prevalent comorbid GAD is within the
population as a whole.
Comparable rates of comorbidity with those observed in
general population surveys have been reported in clinical
samples, overall rates of comorbidity are high with 45–98% of
patients with GAD having lifetime comorbid anxiety, depres-
Table 1 Lifetime prevalence of disorders comorbid with
GAD in the National Comorbidity Survey (NCS)
Comorbid disorder Current GAD a Lifetime GAD b
(%) (%)
Any of the following 66.3 90.4
Major depression 38.6 62.4
Agoraphobia 26.7 25.7
Simple phobia 24.5 35.1
Social anxiety disorder 23.2 34.4
Panic disorder 22.6 23.5
Dysthymia 22.1 39.5
Mania 12.1 10.5
Alcohol abuse 11.2 37.6
Drug abuse 5.1 27.6
Adapted from Wittchen et al. (1994), with the kind permission of
JAMA.
a
30-day prevalence of other disorders among respondents with
30-day GAD, defined as the most recent 6-month period of
anxiety still ongoing in the 30 days prior to interview.
b
Lifetime prevalence of other disorders among respondents
with lifetime GAD.
D. Nutt et al.
Figure 1 Increase in comorbidity of GAD and MDD over time in
a prospective study (Bruce et al., 2001).
sive, or substance use disorders (Noyes, 2001). As in the
general population, MDD is the most common disorder
occurring comorbidly with GAD in these samples (Noyes,
2001). One study of patients with GAD, which excluded those
with concurrent MDD, found that 42% had experienced at
least one major depressive episode during their lifetime
(Brawman-Mintzer et al., 1993). A prospective study indi-
cated that 39% of patients with GAD had a comorbid diagnosis
of MDD at intake, with the rate increasing as the study
progressed (Fig. 1) (Bruce et al., 2001). Comorbid anxiety
disorders occur with GAD in a substantial proportion of
patients with up to 59% of GAD patients having a lifetime
history of SAD, and up to 56% a history of SP (Noyes, 2001). PD
is also a prevalent comorbidity with GAD. However, many
studies of patients with GAD specifically exclude those with
PD, so rates of lifetime comorbidity found in such studies are
likely to underestimate the true prevalence of comorbid PD
(Noyes, 2001). In a study of patients with current GAD, 48% of
those also had current PD with or without agoraphobia
(Massion et al., 1993); in another study of patients with PD,
63% had GAD (Cassano et al., 1990). In the Harvard/Brown
Anxiety Disorders Research Program (HARP), a longitudinal
study of over 700 treatment-seeking patients, 62% of those
with a diagnosis of lifetime GAD had lifetime PD (14% without
and 48% with agoraphobia) (Goisman et al., 1995). Preva-
lence of comorbidity with PTSD is less well established than
other conditions; 39% of a sample of patients with PTSD in
primary care had comorbid GAD (Stein et al., 2000).
Although in general the prevalence of GAD in children and
adolescents is relatively low in relation to other anxiety
disorders, when GAD is present in these groups, high rates of
comorbidity similar to those seen in adults, are observed
(Masi et al., 2001; Wagner, 2001; Masi et al., 2004). A recent
study of 157 children and adolescents (7–18 years, mean age
13.4 years) with GAD, who attended an outpatient clinic
between 1997 and 2002, found comorbid anxiety disorders in
75% and depressive disorder in 56% (Masi et al., 2004).
Although the prevalence of other anxiety disorders appears
to diminish with age that of GAD is maintained or even
increased in elderly populations (Krasucki et al., 1998).
Again, there is considerable comorbidity, with depression in
particular, but GAD may be more likely to be secondary to
depression in elderly patients (Flint, 1994; Noyes, 2001). A
community-based sample of over 4000 elderly patients found
Generalized anxiety disorder: A comorbid disease
prevalence rates of 12% for depression, 3% for GAD, and 2%
for mixed depression-anxiety; comorbidity of GAD and
depression was twice as frequent in elderly women as in
men (Schoevers et al., 2003).
The high rates of psychiatric comorbidity in individuals
with GAD had led some to suggest that GAD should not be
regarded as a distinct disorder but rather a prodromal stage
of depression, but there are several lines of evidence
against this proposition (Kessler et al., 2001; Wittchen et
al., 2002). For example, the exceedingly high rates of GAD
and MDD comorbidity are confined to certain clinical studies
with potential for self-selection bias, while the rates of
comorbidity in the general population are not higher than
for most other mood or anxiety disorders. Furthermore,
symptom profiles of GAD and MDD are different (Kessler et
al., 2001). Although frequently comorbid, GAD occurs
sufficiently often independently of MDD for it to be
regarded as a separate diagnostic entity (Brawman-Mintzer
et al., 1993; Kessler et al., 1999). In general, GAD is
temporally the primary disorder in cases of comorbidity
with MDD (Kessler, 2000); in a study of depressed patients
with comorbid GAD (11% of the total depressed sample),
GAD preceded the first episode of MDD in 63% of cases (Fava
et al., 2000). Primary GAD is a significant predictor of
subsequent depression (Kessler, 2000; Bruce et al., 2001).
In addition to comorbidity with mood and anxiety
disorders, personality disorders are common in patients
with GAD, with up to 50% of patients with GAD having been
reported to meet criteria for a personality disorder
(Sanderson et al., 1994; Garyfallos et al., 1999), a rate
comparable with that associated with other anxiety
disorders (Sanderson et al., 1994; Noyes, 2001). Cluster C
personality disorders are the most frequently occurring
type in patients with GAD, as they are in other anxiety
disorders such as PD and obsessive-compulsive disorder
(OCD), but avoidant personality and interpersonal sensitiv-
ity may be particular features of, or associations with, GAD
(Garyfallos et al., 1999; Noyes, 2001).
3. Prevalence of non-psychiatric medical
comorbidity
Patients suffering from chronic conditions such as arthritis,
headache, or chronic obstructive pulmonary disease fre-
quently have mood or anxiety disorders. Similarly GAD, in
common with depression and other anxiety disorders, is
often accompanied by chronic pain symptoms such as
backache, headache, gastrointestinal pain, joint pain, or
migraine (Puca et al., 1999; Juang et al., 2000; Sheftell and
Atlas, 2002; Brenes, 2003; Bensenor et al., 2003; McWilliams
et al., 2003; Zwart et al., 2003; Grothe et al., 2004). Some
studies have found that GAD is the most frequently diagnosed
anxiety disorder among patients presenting with both
headache and an anxiety disorder, occurring in 14% of
patients with episodic cluster headache (60% of all those
with a concomitant anxiety disorder) (Jorge et al., 1999) and
in 45% of patients with tension-type headache (84% of those
with a concomitant anxiety disorder) (Puca et al., 1999). A
significant proportion of patients with GAD also manifest
concurrent irritable bowel syndrome (IBS) (Tollefson et al.,
1991).
S111
Sleep complaints are also frequent among patients with
GAD (Belanger et al., 2004), and GAD is the most prevalent
diagnosis in patients suffering from insomnia with an
associated mood or anxiety disorder (Monti and Monti,
2000). Some 60–70% of patients with GAD have an insomnia
complaint, the severity of which parallels that of the anxiety
disorder (Monti and Monti, 2000). Sleep disturbance in GAD
seems to be more a problem of sleep maintenance than onset
(Monti and Monti, 2000). A sample of patients with GAD
reported difficulties in initiating sleep (48%), maintaining
sleep (64%), and early waking (57%); the vast majority (87%)
reported never having experienced insomnia without having
excessive worries, although insomnia severity and GAD
severity were not correlated (Belanger et al., 2004).
Depending on the type and severity of a sleep complaint,
physicians may consider certain aspects to be symptomatic
of the GAD, but true insomnia should be considered a
comorbidity.
4. Burden of comorbidity
In general, comorbidity in GAD patients is associated with
greater severity, more impairment, increased help-seeking,
and worse outcome of the primary disorder, than in the
patients without comorbidity (Bakish, 1999; Wittchen et al.,
2000; Noyes, 2001). Undeniably these patients are more of a
burden, or challenge, for their physician. As a consequence
the economics surrounding comorbidity are all negative-
including increased healthcare and hospitalization rates, and
a greater number of sick days. In fact comorbid GAD,
especially with depression, leads to a considerable increase
in loss of productivity through days off work.
Data from the NCS and the MDUSS surveys show that while
individuals with (12-month) GAD or MDD showed more
impairment than individuals with neither disorder, and
similar levels of impairment to each other, those with GAD
and comorbid MDD showed more impairment than those with
only one of the two disorders (Fig. 2) (Kessler et al., 1999).
For example, according to the MDUSS over 50% of patients
with comorbid GAD and MDD considered their mental health
to be poor/fair, compared with 25% and 29% of those with
either respective condition in isolation (Kessler et al., 1999).
In the GHS survey, measures of impairment taken as a whole
suggested that respondents with (12-month) comorbid GAD
and MDD suffered highest impairment as measured either by
a reduction of at least 50% in overall activity, or by the
number of days of impairment, within the preceding month
(Wittchen et al., 2000). In the NCS, more respondents with
lifetime GAD and any other comorbid disorder reported
interference of their symptoms with their life and activities
than those with pure GAD (Table 2) (Wittchen et al., 1994;
Judd et al., 1998). Individuals with 12-month GAD and MDD
have lower quality of life, as assessed by general health,
mental health, social functioning, and vitality scales, than
those with pure MDD (Wittchen et al., 2000).
Similar indications of a greater burden of comorbid GAD
include functional impairment and duration of illness.
Comorbidity of GAD and depression is associated with a
lower chance of remission from depression (Sherbourne and
Wells, 1997), and an episode of MDD or PD comorbid with GAD
decreases the probability of a patient achieving remission
S112 D. Nutt et al.

Figure 2 Effect of comorbidity on measures of impairment in the NCS and MDUSS surveys among patients with or without 12-month
GAD and/or MDD (Kessler et al., 1999). (A) Perceived mental health, NCS (B) Perceived mental health, MDUSS (C) Days of work
impairment in past month, NCS (D) Days of work impairment in past month, MDUSS.

from GAD (Bruce et al., 2001). Yonkers et al. found that the
likelihood of a patient achieving remission from both GAD
and a comorbid condition after 1 year was half that of a
patient with pure GAD achieving remission from the disorder
(Yonkers et al., 1996). Comorbidity with GAD in patients with
SAD increases severity of social anxiety and avoidance,
general anxiety, depressed mood, functional impairment,
and overall psychopathology in comparison with those
without comorbid GAD (Mennin et al., 2000). In another
study, full or partial remissions were less likely to occur in
patients with personality disorders and poor relationships
(Yonkers et al., 2000). The World Health Organization study
on psychologic problems in primary care, a cross-cultural
study covering 14 countries, also found that marked social
disability was more frequent among patients with GAD with a
comorbid psychiatric disorder (46%) than those with pure
GAD (25%) (Maier et al., 2000), and that patients with
comorbid GAD suffered more days of disability than those

Table 2 Effect of comorbidity with any other disorder on interference with daily activities, help seeking, and medication use in
lifetime GAD in the NCS
Interference Help seeking Medication Any of these
% SE % SE % SE % SE
Pure GAD 28.1 0.08 48.2 0.10 24.1 0.08 59.2 0.10
Comorbid GAD 51.2 0.04 67.9 0.04 46.2 0.04 84.4 0.03
Total for combined pure and 49.0 0.04 66.0 0.03 44.0 0.04 82.0 0.02
comorbid GAD populations
Reproduced from Wittchen et al. (1994), with the kind permission of JAMA.
Generalized anxiety disorder: A comorbid disease
with pure GAD (Ormel et al., 1994). Comorbidity of GAD and
other anxiety or depressive disorders also increases risk of
suicide (Rudd et al., 1993; Allgulander and Lavori, 1993; Masi
et al., 2001; Wittchen et al., 2002). In patients with chronic
medical conditions, comorbid anxiety reduces levels of
functioning and well-being (Sherbourne et al., 1996).
Comorbidity has a significant impact on medical utilization
(Wittchen et al., 2002). GAD is the most prevalent anxiety
disorder in primary care (Maier et al., 2000) as well as in
patients with chronic medical conditions (Sherbourne et al.,
1996), and is one of the most common diagnoses in patients
presenting with medically unexplained somatic symptoms
(Roy-Byrne, 1996). Individuals with comorbid GAD are more
likely to seek professional help, seek psychiatric outpatient
treatment, and take medications for GAD symptoms than
those with pure GAD (Table 2) (Wittchen et al., 1994; Bland et
al., 1997; Judd et al., 1998). A study of over 1000 patients
with GAD found that comorbidity resulted in increased costs
for hospitalization, laboratory tests, medications, and absen-
teeism from work (Souetre et al., 1994).
5. The therapeutic challenge of comorbidity
Comorbidity adds to the therapeutic challenge of GAD and
has several implications for its management (Noyes, 2001).
Comorbidity, with depression in particular, significantly
lowers the probability of GAD being successfully diagnosed
and treated (Wittchen et al., 2002). Commonly, patients
may present with multiple unexplained physical rather than
psychiatric symptoms, the cause of which the primary care
physician (PCP) is unable to determine using the standard
laboratory tests such as blood tests, or an electrocardio-
gram. Patients become dissatisfied and frequently become
labeled as “difficult patients”, further hampering recogni-
tion and diagnosis. Moreover, because a diagnosis is not
forthcoming these patients will often continue to complain
about their symptoms, generating irritability in the treating
physician, which in turn results in the patient becoming
more stressed. The prevalence of comorbidity associated
with GAD makes it imperative that patients fulfilling
diagnostic criteria for GAD are carefully evaluated for
depressive and other anxiety symptomatology (Kaufman
and Charney, 2000). Depressed patients with GAD in whom
the comorbidity has not been recognized, would commonly
be treated with a selective serotonin reuptake inhibitor
(SSRI), with variable success from patient to patient; they
also need to be assessed and monitored for suicidal
ideation.
It is possible that effective, early treatment of GAD might
prevent comorbid conditions that tend to develop later
(Noyes, 2001). This is an important consideration not least
because, as discussed earlier, primary GAD is a significant
predictor of subsequent depression (Kessler, 2000; Bruce et
al., 2001). Any treatment must relieve the patient's anxiety
without aggravating their comorbid condition; ideally, the
anxiolytic treatment would additionally have efficacy
against the comorbid condition, reducing the need for
polypharmacy. Unfortunately, as patients with comorbidity
are often specifically excluded from clinical trials of
antidepressant and anxiolytic agents, there is an insufficient
evidence base on treatment responses in patients with GAD
S113
and comorbidities, and treatment decisions have to be made
largely on the basis of related clinical trials and personal
experience.
The benefits of psychologic therapy for GAD may extend
to comorbid conditions, perhaps as a result of overlapping
symptoms or of generalization of therapeutic skills. Psycho-
therapy for GAD in a sample of patients with comorbid
disorders such as social and simple phobia (but not MDD) was
found to be associated with a reduction in the number of
additional diagnoses and coexisting conditions, with the
reduction being significantly greater among patients for
whom therapy for GAD was successful than among those for
whom psychotherapy for GAD was not successful (Borkovec
et al., 1995). Cognitive-behavioral therapy for PD was found
to be effective in reducing the frequency and severity of
comorbid conditions, which included GAD, though comorbid-
ity tended to reduce the likelihood of marked improvement
of PD (Tsao et al., 1998).
6. Clinical data for GAD drug treatments
There are several classes of pharmacologic agent with
proven efficacy in the treatment of anxiety disorders
(Ballenger, 1999). However few studies have looked at
treatment response in patients with comorbid GAD and
depression—physicians need a drug that effectively treats
both conditions without the need for polypharmacy and
which does not aggravate the comorbidity. Currently there is
no single therapeutic agent that can combine the speed of
onset of a benzodiazepine (BZD) with the efficacy of an SSRI.
There is substantial evidence that SSRIs and serotonin and
norepinephrine reuptake inhibitor (SNRIs) can be effective
against depression with associated anxiety. There are,
however, disadvantages to SSRI/SNRI use including a rela-
tively slow onset of action, which often necessitates their
combination with a short course of BZDs to achieve initial
symptom control. There can also be unpleasant side effects
of SSRIs/SNRIs, such as nausea and sexual dysfunction, in
addition to the recent concerns regarding suicide risk. There
have been few studies of SSRIs/SNRIs specifically in patients
with a diagnosis of GAD and comorbid depression. Those that
have been completed have involved fairly small numbers of
patients or have been open label. Subanalysis of a subgroup
of 92 patients with comorbid MDD and GAD from a double-
blind, placebo-controlled trial found that after 12 weeks of
treatment, venlafaxine, but not fluoxetine, had effected a
reduction in both HAM-D (Hamilton Rating Scale for
Depression) and HAM-A (Hamilton Rating Scale for Anxiety)
scores that was significantly greater than placebo (Silver-
stone and Salinas, 2001). Comparison with 276 non-comorbid
patients from the trial suggested meaningful symptom relief
took more time in the patients with comorbidity, and that
these patients may require a longer period of treatment
(Silverstone and Salinas, 2001). In a small study of 32
outpatients with GAD and either MDD (n = 21) or dysthymia
(n = 11), although venlafaxine reduced depressive symptoms
in patients with comorbid MDD after 8 weeks, significant
reduction of anxiety scores required more time and did not
occur in some patients (Perugi et al., 2002). Open-label trials
have reported that non-SSRI/SNRI antidepressants mirtaza-
pine and moclobemide may also be of some value in treating
S114 D. Nutt et al.

patients with comorbid GAD and MDD (Goodnick et al., 1999;
Pini et al., 2003).
Pharmacotherapeutic trials of GAD with comorbid condi-
tions other than depression are even more limited. BZDs may
have efficacy in patients with GAD and comorbid IBS. In an
open-label trial of alprazolam a significant anxiolytic
response was seen in 94% of the 32 patients treated within
6 weeks, and a concomitant reduction in IBS severity in 89%
and a small post-treatment rebound effect was observed
(Tollefson et al., 1991). Merging of data from 3 double-blind,
placebo-controlled studies of comorbid GAD and post-stroke
depression (combined total of 27 patients) suggested that
nortriptyline (a tricyclic antidepressant) was more effective
than placebo in relieving anxiety and depressive symptoms,
although the anxiety symptoms improved more rapidly than
the depressive symptoms (Kimura et al., 2003).
Insomnia associated with mild-to-moderate GAD can be
treated with anxiolytic BZDs, which shorten latency to
sleep, prolong sleep, reduce the number of night-time
awakenings, and improve sleep quality; patients with more
severe GAD may require higher doses of BZDs for weeks or
months (Monti and Monti, 2000). As a result of the potential
for dependence and withdrawal symptoms observed with
BZDs (Lader, 1999), SSRIs may be a preferable pharmaco-
therapy, though onset of efficacy is slower; trials of such
agents in patients with GAD and sleep problems are needed.
Also, sedative properties can result in daytime sedation,
which is undesirable, and can lead to decreased perfor-
mance and accidental injury.
as worry or apprehension, and 2 somatic factors; the first of
these comprising symptoms such as trembling, dizziness, or
paresthesias (9 items relate to this factor), and the second,
which was quite independent, comprising sleep problems (2
items relate to this factor) (Argyropoulos et al., 2001).
These 3 independent factors comprise the full spectrum of
GAD.
The data showed significant differences between the GAD
patients versus students (control population), and the other
anxiety and depression patient cohort (Fig. 3). It should,
however, be noted that this scale is intended for use in
monitoring the status of patients, not as a diagnostic tool. In
addition, its psychometric properties are still under
evaluation.
8. Neurobiologic mechanisms in GAD
The scientific basis for the pharmacologic treatment of
anxiety disorders, including GAD, is mainly derived from
empirical data supporting the efficacy of drug therapies.
Furthermore, clinical data suggest that there are neurobio-
logic anomalies associated with these anxiety conditions,
which may be reversed or corrected through pharmacologic
intervention. Such abnormalities have been recognized for
several neurotransmitter-receptor systems, including dopa-
mine, norepinephrine, the gamma-amino butyric acid
(GABA)-BZD receptor complex, and serotonin (5-HT) (John-
son and Lydiard, 1995).

8.1. Benzodiazepine receptor binding

7. The Generalized Anxiety Disorder-Inventory
(GADI) The recognized effectiveness of BZDs in reducing anxiety has
meant that GAD research has focused on the GABA-BZD
Recently our research has focused on trying to understand system. Indeed, the theory that patients with GAD may have
how GAD can be rated and diagnosed appropriately in a deficiency in the GABA-BZD system, in the form of either
relation to other psychiatric disorders. This has been carried reduced receptor sensitivity or a deficit of endogenous
out through the development of a new scale that assists in inhibitory transmitters, has been postulated.
rating GAD severity. Data obtained from human brain imaging studies indicate
The GADI was modeled on the types of scales that have that the frontal cortex and medial temporal lobe are
previously been designed for patient-rated assessment of involved in experiencing and controlling fear and anxiety
anxiety disorders, such as the Social Phobia Inventory (SPIN), (Nordahl et al., 1990; Wu et al., 1991; De Cristofaro et al.,
developed by Jonathan Davidson (Connor et al., 2000). The 1993; Rauch et al., 1996). Tiihonen et al. tested the
symptoms of GAD, as published in the Diagnostic and hypothesis that BZD receptor binding is decreased in the
Statistical Manual of Mental Disorders, third edition-revised
(DSM-IIIR), the DSM-IV, and the World Health Organization's
(WHO's) Tenth International Classification of Diseases (ICD-
10), were used to develop a 19-item self-rating scale (GADI)
that fulfilled the required criteria: easy to administer and
score. Patient's self-assessment of the severity of each of the
19 items is rated on a scale from 0 to 4 (not at all, a little bit,
somewhat, very much, and extremely). The full-scale score,
therefore, gives a maximum score of 76, with higher scores
corresponding to a greater level of anxiety. The patient is
asked to rate how they have felt over the previous 2 weeks in
relation to each of the questions posed.
Data were collected for GAD patients, patients with
another anxiety disorder or depression, and a control
population (university students). A factor analysis was
then carried out on the initial data, which showed that 3
factors explained 60% of the patient variance. These factors Figure 3 Preliminary self-rater data from the Generalized
were a cognitive factor (8 items relate to this factor), such Anxiety Disorder-Inventory (GADI).
Generalized anxiety disorder: A comorbid disease
left temporal pole and increased in the right prefrontal area
among patients with GAD. The cerebral BZD receptor binding
and distribution were investigated using single photon
emission computed tomography (SPECT) analysis with a
new 123I-labeled specific BZD receptor radioligand, NNC 13-
8241. The findings showed that binding of the radioligand
was significantly decreased in the left temporal pole in
patients with GAD compared with controls, but no significant
difference was seen in the right prefrontal cortex (Tiihonen
et al., 1997). These results are not unlike those observed in
the positron emission tomography (PET) binding study of 11C-
flumazenil in PD patients for whom a universal reduction in
BZD binding has been reported versus healthy controls
(Malizia et al., 1998). Together these data confirm that in
both GAD and in PD, patients have reduced central BZD
receptor function.
8.2. Tryptophan depletion
5-HT is known to play an important role in a wide variety of
functions including anxiety, appetite, and sleep, although
the precise details of these processes have yet to be clearly
defined. Further illumination of this scenario has been
hindered by the fact that until quite recently it has not
been possible to directly measure the concentration of 5-
HT in the brain. In the last decade neurotransmitter
depletion protocols have offered another method to study
the neurobiologic systems involved in psychiatric condi-
tions, including anxiety and depression disorders, demen-
tia, and bulimia nervosa (Smith et al., 1997; Barr et al.,
1997; Kaye et al., 2000; Bell et al., 2002; Porter et al.,
2003; Argyropoulos et al., 2004). In particular, tryptophan
depletion has emerged as an essential tool in the
investigation of 5-HT functionality.
The aim of tryptophan depletion is to reduce the
concentration of 5-HT in the brain. This is achieved by
using up the body's reserves of the 5-HT amino acid
precursor tryptophan. The level of tryptophan in the plasma
is dependent on the balance between dietary intake of
protein and on its removal from the plasma due to protein
synthesis. Free tryptophan (~5%), in the plasma, is actively
transported across the blood-brain barrier by a protein
pump. Five other large neutral amino acids (LNAAs),
including valine and isoleucine, also compete for the use
of this protein pump. Once transported into the brain,
tryptophan can take part in the synthesis of 5-HT. The
tryptophan molecule is first converted to 5-hydroxytrypto-
phan (5-HTP) by the enzyme tryptophan hydroxylase; 5-HTP
is then decarboxylated by the enzyme aromatic acid
decarboxylase to produce 5-hydroxytryptamine (5-HT).
The rate-limiting factor in this process is the availability
of tryptophan in the plasma. Fig. 4 illustrates the processes
involved in the transport of tryptophan into the brain and its
synthesis into 5-HT.
As previously discussed, free plasma tryptophan levels
may vary with the amount of dietary tryptophan and the rate
of protein synthesis. Completely removing tryptophan from
the diet will only reduce the plasma concentration by 15–
20%. A much greater reduction in plasma tryptophan can be
achieved by giving subjects a large bolus of LNAAs via a
tryptophan-free drink. This has two effects: the liver is
stimulated to synthesize protein, thus removing even more
S115
Figure 4 Processes involved in the transport of tryptophan
into the brain, and its synthesis into 5-HT (reproduced from Bell
et al., 2001, with the kind permission of the Royal College of
Psychiatrists).
tryptophan from the plasma; the LNAAs compete with what
little tryptophan is left in the circulation to cross the blood–
brain barrier, thus further restricting the entry of tryptophan
into the brain (Reilly et al., 1997).
In depression, tryptophan depletion studies have shown a
marked, rapid adverse decrease in mood in patients treated
with SSRIs (Delgado et al., 1999). Patients previously
euthymic on an SSRI will experience a severe reoccurrence
of the mood disorder ~5 h after the tryptophan depletion. The
mood disorder disappears quite rapidly when the tryptophan
is replaced. This study has been used to uncover the fact that
SSRIs do not free the patient from their depression, but rather
stop them from experiencing it. In effect, if 5-HT is removed,
then the patient's depression will return; that is to say
tryptophan depletion causes a relapse (Smith et al., 1997;
Barr et al., 1997). Our own studies in PD and SAD also show
that patients, who have recovered with SSRI treatment will
relapse if 5-HT is taken away (Bell et al., 2002; Argyropoulos
et al., 2004). Interestingly, in OCD, tryptophan depletion
studies do not appear to cause a relapse in the patient's
condition (Barr et al., 1994).
What happens in the case of GAD? The key to the PD and
SAD studies has been the use of challenge tests: the patients
are tryptophan depleted and then given a provoking agent,
which is something similar to a panicogenic challenge. To
secure a similar effect in GAD patients we use an inhalation
of CO2 at 7.5% for 20 min, which leads to a significant level of
anxiety (20–30 on the Visual Analog Scale). In addition,
patients suffer many of the symptoms of GAD: heavy headed,
headaches, tension, and worry making it a very interesting
GAD model. In this model, taking away the 5-HT has very
little effect until patients are challenged—that is to say when
they put on the mask to breath CO2. Those observing can see
an increase in anticipatory anxiety, which is not evident if
patients are not tryptophan depleted. The CO2 then
subsequently increases the patient's anxiety. We believe
that this is evidence that in panic, in SAD, and likewise in
GAD, SSRIs are suppressing the anxiety because they are
increasing the serotonin—if you take the tryptophan source
of 5-HT away, the anxiety condition returns.
S116
9. Conclusions
Comorbidity in GAD is common, and is associated with
reduced probability of successful diagnosis, greater impair-
ment, more severe symptoms, less favorable treatment
outcome, and increased utilization of healthcare services.
It is now accepted, after much heated debate, that GAD is
a specific, distinct disorder in its own right, and not merely
a variant of depression. GAD is not always associated with
comorbidity, but because of the patterns of comorbidity
frequently associated with GAD, it may be helpful, in terms
of recognition and diagnosis, to view the disorder as
involving a specific set of psychologic dysfunctions that
manifest as a complex matrix of anxious-somatic or
anxious-somatic-depressive symptoms (Stein, 2001). Thus,
physicians should aim to recognize symptom dimensions
such as anxiety or panic in their presenting patient. In
addition, primary care physicians should also assess for any
additional symptoms of anxiety, depression, or somatiza-
tion in patients presenting with any one of these sets of
complaints. It is also important for physicians to be aware
that patients who present without psychiatric symptoms,
but with multiple unexplained physical problems may well
also be suffering from GAD. In both instances an
appropriate treatment choice may hasten the relief of
symptoms.
There is a need for an appropriate tool to assist in the
recognition of GAD patients and to monitor their progress.
The GADI is a new self-rating scale that is currently in
development, which is specifically targeted at GAD. Initial
data suggest that the scale is easy to self-administer and that
it can differentiate between GAD and other anxiety and
depression disorders. It should, however, be noted that the
GADI needs further validation in the clinical trial environ-
ment, especially versus some of the older, more established,
but less sensitive scales, such as the HAM-A. It is anticipated
that the GADI will perform well in this setting.
The GABA system may be important in the development
and treatment of certain anxiety conditions, such as GAD
and PD. SPECT and PET data have confirmed that in both
these anxiety disorders patients have reduced central BZD
receptor number, which should be accounted for in the
treatment choices made by the physician. In addition, the
symptoms of the various anxiety conditions and depression
potentially overlap—at least by the way that SSRIs work in
the different disorders. The tryptophan depletion data at
least for some of these disorders, including depression, PD,
SAD, and GAD, seems to indicate that making more
serotonin available at the synapse is important in keeping
a person well.
In conclusion it is apparent that GAD patients often suffer
from comorbid mood and anxiety disorders such as MDD or PD,
or from somatic conditions, such as chronic pain or sleep
conditions. Regrettably few studies have examined the
response to treatment in patients with comorbid GAD and
these other conditions—physicians require a drug that will
effectively treat both the GAD and the other comorbid
conditions, without employing polypharmacy. At present
there is no single therapy that can provide the speed of onset
of a BZD with the efficacy of an SSRI. Unfortunately
comorbidity also increases the individual and economic
burden of GAD and adds to the therapeutic challenge of
D. Nutt et al.
treatment. Regardless of all of these negatives, physicians
and researchers must learn to perceive comorbidity as a
challenge rather than a problem, to ensure a more stable
future for this patient group.
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