Stuart A. Montgomery-Handbook of Generalized Anxiety Disorder - CMG (2009)

Handbook of
Generalised Anxiety Disorder

Handbook of
Generalised Anxiety Disorder
Stuart A Montgomery
Imperial College School of Medicine
London, UK
Published by Springer Healthcare, 236 Grays Inn Road, London, WC1X 8HB, UK
www.currentmedicinegroup.com
Copyright 2009 Current Medicine Group, a part of Springer Science+Business Media
Reprinted 2010
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ISBN 978 1 85873 441 5
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Contents
Author biography vii
1 The changing concept of generalised anxiety disorder 1
2 How common is generalised anxiety disorder? 5

GAD in children and adolescents 7
Course of GAD in adults 7
3 Presenting features of generalised anxiety disorder 9

Somatic symptoms 10
Pain 10
Sleep disturbance 11
4 Cormobidity of generalised anxiety disorder with

other conditions 13
Comorbidity with depression 14
Comorbidity with anxiety disorders 14
Somatic disorders 15
Identifying GAD and comorbid conditions 15
5 Burden of generalised anxiety disorder 17

Suicide risk and the burden of GAD 18
Costs of GAD 19
6 Measuring the severity of generalised anxiety disorder 21
7 Pharmacological treatments 25
Serotonin reuptake inhibitors 25
Serotonin noradrenaline reuptake inhibitors 31
Calcium channel GABA receptor modulators 34
Benzodiazepines 39
Busiprone 41
Forthcoming and other treatments for GAD 42
vi t $0/5&/54
8 Psychological treatments 45
Psychological and psychopharmacological treatments 46
9 Which treatments, when and for how long? 49

How long should treatment be continued? 49
Choice of treatment based on predominant complaints
or comorbidity 50
GAD and bipolar depression 51
GAD in elderly people 52
References 53
Index 59
Author biography
Dr Stuart A Montgomery is Emeritus Professor of Psychiatry at the Imperial
College of Medicine in the University of London. He completed his undergradu-
ate and postgraduate training in medicine at University College, University of
London, UK. He carried out further postgraduate research at the Karolinska
Institute, Stockholm, Sweden, where he was awarded his research md.
Dr Montgomery is one of the foremost researchers in the treatment of
depression and anxiety disorders. He has a great breadth of experience in
the field of psychotropic medicine with seminal work in depression, anxiety
disorders, suicide prevention and schizophrenia. His reputation was estab-
lished with his early work on improving the methodology of clinical trials.
His numerous placebo-controlled studies in the long-term treatment of
depression and anxiety have set the standard for investigations in the field.
The Montgomery and Asberg Depression Rating Scale is now recognised as
the most sensitive instrument for measuring efficacy. He has published more
than 400 research reports and reviews and has authored 26 books.
Dr Montgomery has served on the executive committee and councils
of numerous national and international scientific societies. He has been
President of the British Association of Psychopharmacology and President
of the European College of Neuropsychopharmacology. He has considerable
experience in the licensing of treatments and has served for many years on
the Committee on Safety of Medicines in the UK in the past.
Dr Montgomery is editor of International Clinical Psychopharmacology
and European Neuropsychopharmacology as well as serving on the editorial
board of numerous other scientific journals.
Chapter 1
The changing concept of generalised

anxiety disorder
Generalised anxiety disorder (GAD) is commonly regarded to be the key anxiety

disorder. How it acquired this position can be traced, to some extent, to the changes
that have occurred over time in the development of the Diagnostic and Statistical
Manual (DSM) of the American Psychiatric Association which is the main tool
used for diagnosis.15 This system, which continues to be developed by committee,
has been through major changes in the course of successive versions.
The vague notion of anxiety neurosis, put forward by Freud in 1884 to make
a separation from neurasthenia but without criteria, was adopted uncritically in
the early version of DSM5 and DSM-II.6 The concept of neurosis was abandoned
as unhelpful in DSM-III2 where operational criteria for individual anxiety dis-
orders were introduced.
There is a well-recognised tension between those who prefer wider cate-
gories of disorders and those who prefer to refine the wider category into smaller
contributing components, known familiarly as the difference between lumpers
and splitters. When the DSM-III was developed the splitters predominated on
the committees and it was decided to recognise panic disorder as a separate
category. This left a larger category of a more general sort of anxiety, later named
generalised anxiety disorder. Some recognition that GAD was the true inheritor
of the anxiety label came when buspirone, which had been investigated for
efficacy in placebo-controlled studies in anxiety neurosis,7,8 was approved in the
US by the Food and Drug Administration (FDA) for the treatment of GAD on
the grounds that this was the closest equivalent diagnosis.
The evolution of GAD in the DSM system was helped by its recognition in
1980 in DSM-III2 as a separate disorder defined by a relatively large number
of anxiety symptoms, both somatic and psychic, which were required to have
persisted for a period of at least 30 days. The definition of GAD in DSM-III
S. A. Montgomery, Handbook of Generalised Anxiety Disorder
Current Medicine Group 2009
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appears to match quite closely the concept of GAD as measured on the Hamilton
Anxiety Scale9 in which both psychic and somatic symptoms are well represented.
The relatively short duration of the disorder required would allow the inclusion
of a number of individuals with short-lived anxiety states as well as a larger
group with the more chronic condition. In a radical change of position in the
DSM-IIIR1 categorisation, episodes of anxiety having a duration of less than 6
months were excluded and the diagnosis of GAD reserved exclusively for the
persistent, chronic form of the disorder. This development helped identify a
group associated with a high degree of suffering and fewer short episodes. GAD
in this formulation might still have a waxing and waning character but now
on a background of clearly demonstrable chronic persistent anxiety. There is,
however, a fairly large group of sufferers of GAD who have discrete episodes of
anxiety separated by periods of remission and these are neglected in the current
definition. These short-lived, more discrete episodes of anxiety are also associ-
ated with considerable disability.10
In 1994, the DSM system was again revised (DSM-IV)4 to redefine GAD
focusing on the core psychic symptoms of anxiety (Figure 1.1). This stated that
Current DSM-IV diagnostic criteria for generalised anxiety disorder

A Excessive anxiety and worry (apprehensive expectation) occurring more days than not for
at least 6 months, about a number of events or activities
B The person finds it difficult to control worry
C The anxiety and worry are associated with three (or more) of the following six symptoms
(with at least some symptoms present for more days than not for the past 6 months)
Note: only one item is required in children
(1) restlessness or feeling keyed up or on edge
(2) being easily fatigued
(3) difficulty concentrating or mind going blank
(4) irritability
(5) muscle tension
(6) sleep disturbance (difficulty falling or staying asleep or restless unsatisfying sleep)
D The focus of the anxiety and worry is not confined to features of another axis 1 disorder
E The anxiety, worry or physical symptoms cause clinically significant distress of
impairment in social, occupational or other important areas of functioning
F The disturbance is not due to the direct physiological effects of a substance (eg, a drug
of abuse, a medication) or a general medical condition (eg, hyperthyroidism), and
does not occur exclusively during a mood disorder, a psychotic disorder or a pervasive
developmental disorder
Figure 1.1 Current DSM-IV diagnostic criteria for generalised anxiety disorder.
DSM, Diagnostic and Statistical Manual. Adapted from the American Psychiatric Association.3
5)& $)"/(*/( $0/$&15 0' (&/&3"-*4&% "/9*&5: %*403%&3 t
there had to be excessive anxiety or worry about a number of events or activities

accompanied by at least half of a list of symptoms encompassing restlessness or
mental tension, fatigue, poor concentration, irritability, muscle tension, sleep
disturbance, all occurring for most days over a 6-month period. There is an
additional requirement that the worry is difficult to control and causes significant
distress or impairment in function.
These frequent changes in diagnostic definitions reflect the pleomorphic
nature of anxiety and the question arises as to whether the committee have
correctly defined GAD. The rapid changes in what is required to fulfil the diagnosis
of GAD have left many doctors and their patients behind; many doctors are
still in the habit of using a broader number of anxiety symptoms to define the
condition. Questions also remain concerning the almost complete exclusion of
somatic symptoms to help define GAD since autonomic symptoms and pain are
frequent in GAD. The diagnosis of GAD as currently defined in the DSM may
not adequately define this serious disorder. There have been some suggestions
that major depressive disorder (MDD) and GAD might be merged because of
the number of overlapping symptoms. However, the data from follow-up studies
carried out in Zurich10 show that the more serious overlap of symptoms occurs
not with MDD but with bipolar depression.
The studies investigating the efficacy of treatments for GAD were all carried
out using the DSM criteria. Health statistics are gathered using the International
Classification of Diseases (ICD). This is potentially confusing as the descriptions
in the current ICD version, ICD-10,11 do not exactly match those of DSM and
tend to be more loosely defined. Strictly speaking there is no direct evidence
of efficacy of treatment of GAD defined by ICD-10 but the categorisation is
sufficiently close to assume that efficacy of treatment established using DSM-IV
probably also applies to ICD-10.
Chapter 2
How common is generalised anxiety

disorder?
Generalised anxiety disorder (GAD) as currently defined is a very common

disorder with an estimated lifetime prevalence reported in European and US
epidemiological studies of 46% and a 12-month prevalence of 1.52% (Figure
2.1). Prevalence estimates inevitably vary depending on the strictness of the
diagnostic definition used to define a case. Higher estimates can be expected
12-month prevalence of clinically significant DSM-IV anxiety disorders in 16

EU countries
In millions EU estimate*
GAD 1.7 5.9 (5.36.2)
PTSD 1.1 3.6 (3.24.0)
0$% 0.7 2.7 (2.53.1)
Any specific 6.4 18.5 (12.721.2)

phobia
Social 2.3 6.7 (5.49.3)
phobia
Agoraphobia 1.3 4.0 (3.34.7)
Panic 1.8 5.3 (4.35.3)

disorder
0 1 2 3 4 5 6 7
Figure 2.1 12-month prevalence of clinically significant DSM-IV anxiety disorders in 16 EU

countries&6 &VSPQFBO6OJPO("% HFOFSBMJTFEBOYJFUZEJTPSEFS0$% PCTFTTJWFoDPNQVMTJWF
disorder; PTSD, post-traumatic stress disorder. *Total EU population (aged 1865) = 301.7 million;
estimates were based on n = 156 000. Adapted from Wittchen et al.12

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if the less demanding one-month minimum duration criterion is applied.2 The

later, more restrictive criteria of DSM-IV appear to identify a smaller, more stable,
possibly more homogeneous group, albeit one where the presentation is
somewhat skewed in the direction of psychic symptomatology. As with other
depressive and anxiety disorders, there is an over-representation of women, in
whom the disorder is observed twice as frequently as in men.
Prevalence estimates of GAD are particularly high if they are based on
a primary care population rather than the general population (Figure 2.2).
It has been estimated that there is a lifetime prevalence of 68% in primary
care compared with 2% in the community samples. Those with GAD appear to
recognise their need for care and are frequent attenders in primary care clinics.
In this regard they differ from those with depression both major depressive
disorder (MDD) and bipolar depression who very frequently do not recognise
their need for treatment.
GAD differs from depression and other anxiety disorders in having a late age
of onset (Figure 2.3). In other anxiety disorders the average age of onset occurs
in the late teens or early twenties. In contrast, GAD has a late average onset of
around age 35. This is reflected in the increasing prevalence reported with age.
The maximum 12-month prevalence, for example, was not reached in men until
GAD is the most frequent anxiety disorder in primary care
50
Generalised anxiety symptoms only
40 GAD (DSM-IV)
Patients (%)
30
20
10 23.3 23.2
20.3 21.1 23.3
19.6
0 5.6 6.6 6.8 7.0 6.6 2.9
1619 2029 3039 4049 5059 60+
Age groups (years)
Figure 2.2 GAD is the most frequent anxiety disorder in primary care. DSM, Diagnosic and Statistical
.BOVBM("% HFOFSBMJTFEBOYJFUZEJTPSEFS3FTVMUTGSPNUIFHFOFSBMJTFEBOYJFUZEJTPSEFSJOQSJNBSZ
care (GAD-P) study showed that a third of patients had some GAD symptoms. Point prevalence
among consecutive attenders; n = 20 451 patients total assessment. Based on DSM-IV criteria.
Adapted from Wittchen et al.13
)08 $0..0/ *4 (&/&3"-*4&% "/9*&5: %*403%&3 t
Cumulative age of onset for GAD
10 USA
Cumulative probability of lifetime disorder (%)
9 The Netherlands
8 Canada
7 Brazil
6
5
4
3
2
1
0
0 10 20 30 40 50
Age (years)
Figure 2.3 Cumulative age of onset for GAD. GAD, generalised anxiety disorder. Age of onset
distributions for lifetime generalised anxiety disorder. Data from Kessler et al.14
age 65 and in women until age 49.12 In a small study in a German population the
prevalence in those aged over 55 (2.2%) was more than double the prevalence
in those under 35 (<1%).15 This helps explain why GAD is the most frequent
psychiatric disorder in those over the age of 55 attending for treatment.16
GAD in children and adolescents

Anxiety occurs in both children and adolescents but the diagnosis of GAD is
complicated by the difficulty in identifying defined core symptoms. The DSM-IV
system acknowledges this problem and has tried to make it easier to fulfil the
diagnostic criteria by lowering the number of core supporting symptoms required
from three of six to only one of six. Even with these much more flexible criteria the
prevalence of GAD in children and adolescents appears to be very low. Because
of the variation in the diagnostic requirements it is problematic to regard GAD
in children or adolescents as the same disorder as in adults. The course of illness
is more variable and less predictable in younger people than in adults where it is
mostly a long-term disorder. This suggests that it is not quite the same disorder.
Course of GAD in adults

GAD is defined as a long-term and largely persistent disorder. By defini-
tion, it is a disorder the diagnosis of which, in addition to certain symptoms,
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depends on a minimum 6-month duration of illness that is chronic; however,

GAD mostly achieves a degree of chronicity far beyond this minimum level.
The long duration of prior illness can be seen in the description of patients
entering placebo-controlled efficacy studies of various treatments. The mean
prior duration of the GAD in these studies is long (617 years).17,18 Follow-up
studies such as the Harvard Brown Anxiety Research Programme (HARP) study
reported that 25% of a community sample fulfilled criteria for GAD at enrol-
ment and had persistent symptoms for a median of 16 years, with low rates of
recovery and remission.19 A study over 3 years carried out in the Netherlands
found that only 12% of GAD sufferers had remission of their disorder.20 Lower
levels of the persistence of GAD have been reported in some epidemiological
studies and it is possible that persistence is influenced by the severity of GAD
on entry to a study. Only patients with moderate or severe GAD are generally
included in clinical efficacy studies where a long duration of symptoms is
consistently reported. It is possible that individuals who meet criteria for GAD
but who have low severity may have less persistent symptoms and higher
remission rates. This would contribute to the perception that the course of GAD
is long term but that it may run an episodic course.
The long-term outcome of GAD depends partly on whether the individual
receives appropriate and adequate treatment. The data in this respect are some-
what mixed. The general picture has been one of undertreatment, for example
it has been reported that only 40% of those recruited to clinical efficacy studies
in GAD had received prior treatment despite the very long prior duration of
illness.17 Similar figures are reported from a recent survey of 136 primary care
practices in Norway, which found that the rate of identification of GAD was
low and of those who were recognised only 36% were treated.21
Even when patients receive treatment, the quality of care provided is uneven.
Much of the treatment offered has not been established as effective. As few as
11% of individuals with GAD appear to be offered medication while 22% are
provided with information only, 35% counselling and 13% counselling or help
with practical issues.22
Chapter 3
Presenting features of generalised anxiety

disorder
The key symptoms of GAD defined in the current version of the DSM are: exces-
sive anxiety and worry that are difficult to control and present for most days
for a period of 6 months or more. However, the primary complaints that bring
patients to seek medical attention are frequently at variance with this picture.
Anxiety symptoms, while present, are frequently not the primary complaint in
patients with GAD presenting in primary care (Figure 3.1), which is unfortunate
as those presenting with anxiety symptoms stand a better chance of their GAD being
detected. Since those with GAD complain mostly about somatic symptoms and pain
it is unfortunate that these are not included as important diagnostic features.
Primary reasons for the presentation of GAD
Somatic
complaints 47.8
Pain 34.7
Depression 15.5
Sleep disturbance 32.5
Anxiety 13.3
Frequency of patients reporting reason for contact
Figure 3.1 Primary reasons for presentation of GAD. GAD, generalised anxiety disorder. Data
from Wittchen et al.13

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Somatic symptoms
It is clear that in primary care the majority of those with GAD present with
various somatic complaints (Figure 3.2). In a study carried out in primary care
in Germany,13 anxiety was the primary complaint in only 13.3% of patients
with GAD. Approximately 48% presented with various somatic symptoms, and
approximately 35% with pain symptoms. These somatic symptoms (Figure 3.3)
are often not recognised as being part of GAD and contribute to the poor rec-
ognition rate of pure GAD in primary care. This failure to detect GAD leads to
a large number of investigations aimed at exploring possible physical conditions
while the GAD is overlooked. Approximately half of the direct costs of manag-
ing GAD can be attributed to the cost of these investigations.
GAD is associated with an increased risk of a variety of physical disorders.
These include irritable bowel syndrome, coronary heart disease, diabetes and
arthritis.23 Careful investigation is needed when these disorders present for
treatment in order to identify the possible presence of GAD. For example,
in a series of patients investigated for atypical chest pain 23% had GAD. 24
In another study of chest pain half the patients with a normal angiogram were
found to have GAD.25 GAD is conceptualised as an anxiety disorder not as a
somatic disorder and a presentation with predominantly physical symptoms is
a significant negative predictor of recognition of GAD.
Pain
Pain is a presenting symptom of GAD in 35% of cases. The painful symptoms
may manifest as headache, chest pain, gut pain, or muscle and joint pain. It is not
surprising that the GAD, of which these symptoms form a part, may frequently
be overlooked. There is substantial overlap between pain syndromes and GAD
and it is estimated that the risk of somatoform pain disorder or somatisation
disorder in GAD is more than doubled. The reverse is also true in that those with
a pain disorder have an eight-fold increase in GAD. It is therefore important to
Presenting features of GAD in primary care

Complaint Percentage Odds ratio 95% confidence
Somatic illness and complaints 47.8 1.5 1.31.8
Pain 34.7 1.3 1.11.6
Depression 15.5 8.6 6.811.0
Sleep disturbance 32.5 8.4 6.411.0
Anxiety 13.3 8.0 6.210.2
Figure 3.2 Presenting features of GAD in primary care. GAD, generalised anxiety disorder.
Data from Wittchen et al.13
13&4&/5*/( '&"563&4 0' (&/&3"-*4&% "/9*&5: %*403%&3 t
Somatic symptoms associated with GAD

Psychic Somatic
Nervousness, irritability, worrying Muscle tightness or stiffness
3FTUMFTTOFTT UFOTJPO JOBCJMJUZUPSFMBY Headache, back pain
Difficulty concentrating, memory problems Gastrointestinal symptoms
Anxiety Cardiovascular
3FTQJSBUPSZ
Insomnia
Fatigue
Figure 3.3 Somatic symptoms associated with GAD. GAD, generalised anxiety disorder.
bear both aspects of the disorder in mind when considering choice of treatment.
Clearly, a treatment that has a good therapeutic effect on both the anxiety and
the pain symptoms should be preferred where both disorders coexist. This is
not the case with all the medications that have been shown to be effective in
GAD, for example, selective serotonin reuptake inhibitors (SSRIs), buspirone
and benzodiazepines are not effective in pain disorders.
Sleep disturbance
It is not always fully appreciated that sleep disturbance is a core feature of GAD
and is the presenting complaint in over 30% of patients with GAD. Unfortunately
most of the treatments licensed for GAD (eg, SSRIs, serotonin noradrenaline
reuptake inhibitors [SNRIs], buspirone) do not target sleep disturbance and may
even make the sleep worsen initially. Only one treatment licensed for GAD,
pregabalin, has a direct, early and beneficial effect on sleep. Benzodiazepines or
other hypnotics are also useful for relieving sleep disturbance but, in practice,
are most likely to be given in low doses that are unlikely to have any therapeutic
effect on the other symptoms of GAD.
Chapter 4
Comorbidity of generalised anxiety disorder

with other conditions
Comorbidity is common with GAD and the majority of patients presenting with
GAD also have at least one other diagnosis. Analysis of data from Germany
found that comorbidity for any depressive or anxiety disorder was 91.3%
(Figure 4.1).15 This high level of comorbidity is similar to the estimate from
the prospective naturalistic follow-up study of patients with anxiety disorders
from the Harvard Brown Anxiety Disorders Research Program (HARP) where
83% of patients with GAD had another anxiety disorder.19
Comorbidity with GAD over 12 months in Germany

Comorbidity Percentage
Major depressive disorder 59
Somatoform disorder 48.1
Dysthymia 36.2
Specific phobia 29.3
Social anxiety disorder 28.9
Panic disorder 21.5
Nicotine dependence 14
Agoraphobia without panic disorder 11.3
0CTTFTTJWFoDPNQVMTJWFEJTPSEFS 10
Alcohol abuse/dependence 6.4
Eating disorder 2.5
Drug abuse/dependence 1.4
Any 1 91.3
Any 2 40.6
Any 3 or more 32.7
Figure 4.1 Comorbidity with GAD over 12 months in Germany. GAD, generalised anxiety
disorder. Data taken from Carter et al.15

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Comorbidity with depression

The most commonly observed comorbidity is with major depressive episodes
(both bipolar and unipolar). In the National Comorbidity Study (NCS) those with
the lifetime prevalence of GAD comorbid with depression was 62%, and 39%
reported having depression in the previous 30 days.26 A high level of comorbidity
with depression (59%) was reported in the German study15 as discussed earlier
and was similar to that reported in the ESEMeD study (European Study of
Epidemiology of Mental Disorders) where 70% of those with GAD had comorbid
MDD in the preceding year.27
Those with depression who also have GAD are more likely to suffer a
relapse of their disorder and this also applies if the GAD symptoms are sub-
syndromal. It should be noted that subsyndromal GAD impairs functioning.19
Comorbidity of GAD and depression may also impair the response to treatment
of the depression. Where GAD is comorbid with depression a poor outcome
of the GAD is more likely and there is a lower chance of remission.28,29 Recent
data from the Treatment Resistant Depression Group shows that comorbidity
with any anxiety disorder including GAD is a predictor of treatment resistance
in depression.30
Comorbidity with anxiety disorders

There is considerable comorbidity of GAD with other anxiety disorders: social
anxiety disorder, specific phobia and panic disorder are found in 2030% of
individuals with GAD.15 Panic disorder, social and specific phobias, and post-
traumatic stress disorder were the most common comorbid anxiety disorders
reported in the NCS.31 There is, of course, a considerable overlap in symptoms
among the anxiety disorders. This makes it difficult to separate the different
disorders and, unless close attention is paid to whether the two disorders have
a different time course, the estimates of comorbidity may in some cases be
exaggerated. However, since GAD has a late age of onset and the other anxiety
disorders have an early age of onset, it is easier to separate the long-term clinical
course of GAD and that of the comorbid disorder.
When GAD is comorbid with other anxiety disorders impairment increases,
as does health-seeking behaviour when compared with GAD or the other
anxiety disorders alone.14 The presence of comorbid panic disorder or other
anxiety disorders with GAD worsens the outcome despite the increase in
health-seeking behaviour.19 Poor levels of recognition and the failure to
provide the appropriate treatment for GAD are also likely to contribute to
a poor outcome.
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Somatic disorders
GAD is associated with somatic symptoms and it is no surprise that there
is substantial comorbidity of GAD with a variety of physical disorders.
People with GAD have an increased risk of coronary heart disease,
hypertension and irritable bowel disease. The risk of having any chronic somatic
disease comorbid with GAD is doubled when compared with the healthy
population.23,32 Comorbidity of GAD with a physical disorder raises the level of
dysfunction but at the same time appears to lower the level of the recognition
of GAD. This is not surprising since the focus of attention of the patient with
GAD and the presenting complaints are largely somatic.
GAD is frequently comorbid with both pain and pain disorders. The pre-
senting complaint in patients with GAD is frequently pain, and the odds ratio
of having a pain syndrome is high. As with other somatic complaints, the focus
on pain by the patient tends to divert the doctor away from considering the
presence of GAD. The presence of pain or other somatic complaints should
lead the clinician to consider the possible presence of GAD in the differential
diagnosis rather than neglect this possibility.
Identifying GAD and comorbid conditions

Although primary care doctors recognise a clear impairment due to the
presence of a mental disorder they appear to recognise pure GAD less readily
than, for example, pure major depressive disorder (MDD).13 The frequent
comorbidity of GAD can complicate the diagnosis and this may partly explain
the relatively low recognition rate for GAD in primary care.
Most anxiety disorders have an early age of onset and any comorbid
depression tends to develop later. The opposite is true with GAD. The depression
tends to develop first and then later comorbid GAD may arise. This is not
unlike the development of bipolar disorder where MDD develops first and then
some time later the bipolar disorder becomes evident with the development of
hypomania or mania. Since there is evidence that there is a close overlap of GAD
with bipolar disorder, this raises the question of whether the late development
of GAD is related to bipolar disorder.
Anxiety symptoms are common in MDD and many patients with GAD may
fulfil diagnostic criteria for MDD so that it is sometimes difficult to separate
the two disorders. The time course of each of the disorders (MDD or GAD)
can provide guidance; if both disorders have exactly the same time course it is
likely that only one disorder (probably depression) is present. If, however, the
time courses of the anxiety or depressive symptoms differ and they are not con-
temporary at all times then it is more likely that two separate disorders of MDD
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and GAD are present. In these cases there may well be an advantage in prescribing
a treatment that is effective in both conditions. Since some selective serotonin
reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors
(SNRIs) have been found to be effective in both MDD and GAD, these treatments
should be used preferentially in the presence of an obvious comorbidity.
The same principle applies in separating GAD from other comorbid
disorders (eg, irritable bowel syndrome, respiratory disorders, cardiac disorders,
pain disorders). Here, too, separation of the time course of each disorder is
helpful. Clearly where an effective therapy for GAD exists that is also effective
in treating the comorbid disorder, that treatment will be preferred.
Chapter 5
Burden of generalised anxiety disorder
GAD is associated with major functional impairment in work (Figure 5.1) or

social activity and impairs the quality of life. The requirements to meet the
diagnosis of GAD according to the DSM-IV take account of this reduction in
function: it is necessary to establish that the individual suffers either clinically
significant distress or impairment in social, occupational or other areas of
functioning. The effects of the disorder are detrimental to individual sufferers
but the disorder also affects their families and the cost to society is high. Yet
the rates of recognition and treatment are unusually low for a disorder with
such far-reaching consequences.
GAD is a long-term disorder that is associated with increased disability and
a reduced quality of life. The disability, identified in terms of work impairment
and distress, appears to be similar in young adults regardless of the defining
duration of the disorder (eg, 2 weeks, 1 month, 3 months, 6 months). 33 Social
impairment increased with the longer duration of GAD but the data from the
Zurich study10,33 suggest that the overall burden of illness is similar in short and
longer durations of GAD.
Studies to assess disability in GAD carried out in the US, Europe and Australia
come to very similar conclusions. In the US, one study found that scores on all
domains measured by the Short-Form (SF-36) Health Survey (eg, mental health,
social function, role function, general health, bodily pain) were significantly
lower in GAD compared with controls without GAD.34 These impairments in
quality of life persisted despite treatment of varying kinds received by some 60%
of those followed up in the study. Similar results are reported in other studies
in the US, with higher levels of disability recorded in patients with GAD when
compared with those without the disorder.35 Moreover, in the US, some low-
income groups with GAD also have higher levels of disability when compared
with those with other psychiatric disorders.36

t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
The disability associated with major depressive disorder (MDD) is now

recognised as being greater than with many other chronic physical disorders.
The disability associated with GAD has been recognised more recently. Social
and work impairment in GAD was found to be in line with that reported in
MDD in both the US37 and Germany.38 Where there was comorbidity of GAD
with MDD there was even greater disability compared to the pure disorders.
However, GAD does occur on its own, independently of MDD.
GAD itself is associated with high levels of disability and impairment in
daily functioning. The impairment increases with increased severity of the
GAD.39 The level of impairment of pure GAD is in line with that observed in
depression. However, this high level of impairment in GAD is increased further
when comorbidity with depression supervenes.38 This increased impairment
in GAD, together with the extra comorbidity with depression, also raised the
suicide rate above that observed for either GAD or depression alone. A study
in the US reported similar results; in patients with pure GAD the disability
and impairment were the same as in patients with pure depressive disorders
although the disability in the comorbid group was still higher.40 As might be
expected, the severity of the disorder plays its part and the burden of GAD has
been shown to be related to the severity of the psychic and somatic symptoms
as measured on the Hamilton Anxiety Scale.
The pattern of symptoms of GAD are similar in elderly patients to those
seen in younger patients as was reported in the only placebo-controlled study
of GAD in those aged over 65 years.41 However, the anxiety symptoms seem
to be more severe in older patients, compared with younger patients, and the
impairment and disability consequently greater.42
Suicide risk and the burden of GAD

The burden of GAD should include the dangers inherent in the disorder. GAD
is a risk factor for suicide as well as for suicidal thoughts and attempted suicide.
In the Harvard Brown Anxiety Research Programme (HARP) study on GAD
Keller et al19 reported that in 7% of the sample who entered the study suicide
attempts had occurred. The suicide attempt rate was higher (15%) when GAD
was comorbid with depression, but both disorders are independent risk factors.
The rate of completed suicide in depression is high, estimated to be a lifetime risk
of at least 15%. This rate is reported to be even higher in those with increased
anxiety symptoms or in those with comorbid GAD or panic disorder. For
example, in primary care around 25% of patients with pure GAD and 64% of
those with comorbid GAD and MDD had suicidality (thoughts, plans or actual
suicide attempts) in the preceding month.13
#63%&/ 0' (&/&3"-*4&% "/9*&5: %*403%&3 t
Costs of GAD
Most of the estimates of the cost burden of anxiety disorders have not separated
GAD from the other anxiety disorders. However in those studies that focused
on GAD the costs are reported to be high. In a primary care sample in the US,
for example, the median medical care costs per year for patients with GAD were
$US 2375 compared with $US 1448 in those without GAD. The combination of
pain and GAD appears to be particularly costly and the medical care costs were
highest for those who had GAD in combination with pain that caused interference
in function.43 Similar increases in the direct costs of GAD have been reported in
France where the costs were higher in the presence of any comorbidity.44 These
costs were due to clinic visits, hospitalisations, accident and emergency costs,
internal medicine consultations, and diagnostic and laboratory tests. The costs
of medication represented only 5% of the total costs.
Attendance rates in primary care are three to four times higher than expected
from the prevalence data and this frequent attendance contributes to the costs
of the disorder. An increase in emergency department visits compared with
other axis I disorders is also reported.45 The high direct cost of managing GAD,
particularly when levels of pain are high, relates in large part to the costs of
investigating the physical symptoms with which patients present.
Days lost from work due to GAD
10
8
Days lost in the past month
0
No mental GAD without GAD and current
disorder depression depression
Figure 5.1 Days lost from work due to GAD. ("% HFOFSBMJTFEBOYJFUZEJTPSEFST3FQSPEVDFE
with permission from Wittchen et al.46
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
The failure to recognise and properly treat GAD has the effect of greatly increas-
ing the number of investigations, many of them potentially unnecessary. One
study over a 12-month period found that, although over half the sample with
GAD had received some form of intervention including psychotherapy, social
support and counselling, evidence-based medical interventions (ie, medicine
or cognitivebehavioural therapy) were used in only 6.9% of the sample.22 The
failure to provide appropriate treatment prolongs the disorder, the accompany-
ing pain and somatic suffering and repeat clinic visits, and therefore further
increases the direct costs.
The indirect costs of GAD include the loss of work days and also inefficient
work days (Figure 5.1). A 50% reduction of work productivity and an increase
in days not working are reported.38 Further costs are incurred in providing
the necessary appropriate financial and social support for sufferers and their
dependants. Nor should the cost burden of early retirement be overlooked.
Both direct and indirect costs of GAD are high which emphasises the need for
better recognition and effective treatment.
Chapter 6
Measuring the severity of generalised

anxiety disorder
The most widely used instrument for measuring the severity of GAD is the
Hamilton Anxiety (HAM-A) scale (Figure 6.1).9
The HAM-A comprises a mixture of psychic anxiety symptoms, somatic
anxiety symptoms and depressive symptoms. The major subscales used are the
psychic anxiety and the somatic anxiety subscales to measure possible differential
effects of treatments. The psychic anxiety symptoms on the scale, which measure
worries, irritability, fears, fatigability, poor concentration, as well as the somatic
symptom of insomnia, are currently used to define GAD; the somatic symptoms
which include pain, cardiovascular, respiratory, gastrointestinal, genitourinary,
autonomic and other somatic symptoms have been somewhat overlooked. This
neglect stems to some extent from the rush to use selective serotonin reuptake
inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) that
have been shown to be effective in GAD but which may not work well on these
somatic symptoms. A reappraisal of this strategy is long overdue.
Other assessment scales that have been used both in GAD and in other
anxiety disorders include the anxiety subscale of the Hospital Anxiety and
Depression Scale47 which has proved the most useful in identifying effective
treatments compared with placebo. For example, this self-rating scale proved
capable of demonstrating the efficacy of venlafaxine in all five placebo-controlled
studies in GAD, whereas the HAM-A showed its efficacy in only three of the five
studies. This was possibly because venlafaxine had a differential benefit on the
psychic symptoms of anxiety rather than on the somatic ones. The Covi Anxiety
(Figure 6.2) and Raskin Depression scales are sometimes applied particularly
at the beginning of a treatment study in order to establish whether anxiety or
depressive symptoms are the more predominant.48,49 Efficacy on the three-item
Covi scale has been reported but it appears less sensitive than other scales.
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Hamilton Anxiety rating scale

All items scored 04
0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe
1 Anxious mood
Worries, anticipation of the worst, apprehension (fearful anticipation), irritability
2 Tension
Feelings of tension, fatigability, inability to relax, startle response, moved to tears easily,
trembling, feelings of restlessness
3 Fears
Dark, strangers, being left alone, large animals, traffic, crowds
4 Insomnia
Difficulty in falling asleep, broken sleep and fatigue on waking, dreams, nightmares,
night terrors
5 Intellectual (cognitive)
Difficulty in concentration, poor memory
6 Depressed mood
Loss of interest, lack of pleasure in hobbies, depression, early waking, diurnal swing
7 General somatic (muscular)
Muscular pains, aches, stiffness, twitching, clonic jerks, grinding of teeth, unsteady
voice
8 General somatic (sensory)
Tinnitus, blurring of vision, hot and cold flushes, feelings of weakness, pricking
sensations
9 Cardiovascular symptoms
Tachycardia, palpitations, pain in chest, throbbing of vessels, fainting feelings, missing
beat
10 3FTQJSBUPSZTZNQUPNT
Pressure or constriction in chest, choking feelings, sighing, dyspnoea
11 Gastrointestinal symptoms
Difficulty in swallowing, wind, dyspepsia, pain before and after meal, burning
sensations, fullness, water brash, nausea, vomiting, sinking feelings, working in
abdomen, borborygmi, looseness of bowels, loss of weight, constipation
12 Genitourinary symptoms
Frequency and/or urgency of micturition: amenorrhoea, menorrhagia, development of
frigidity, premature ejaculation, loss of libido, impotence
13 Autonomic symptoms
Dry mouth, flushing, pallor, tendency to sweat, giddiness, tension, headache, raising
of hair
14 Behaviour at interview (general)
Tense, not relaxed, fidgiting hands, picking fingers, clenching, tics, restlessness,
pacing, tremor of hands, furrowed brow, strained face, increased muscular tone, sighing
respirations, facial pallor
Figure 6.1 Hamilton Anxiety rating scale. Adapted from Hamilton.9

.&"463*/(5)&4&7&3*5: 0' (&/&3"-*4&% "/9*&5: %*403%&3 t
Covi-Anxiety Scale
All items scored 15
1 = not at all, 2 = somewhat, 3 = moderately, 4 = considerably, 5 = very much
1 Verbal report
Feels nervous shaky, jittery, jumpy, suddenly, scared for no reason, fearful, apprehensive,
tense or keyed up, has to avoid certain things, places, activities because of getting
frightened, finds it hard to keep mind on a task
2 Behaviour
Appears frightened, shaking, restless apprehensive, jumpy, jittery
3 Somatic complaints
Unjustified sweating, trembling, heart pounding or racing, trouble getting breath, hot or
cold spells, restless sleep, going unjustifiably more frequently to bathroom, discomfort at
pit of stomach, lump in throat
Figure 6.2 Covi-Anxiety Scale. Adapted from Lipman et al.48
In addition to the scales measuring specific aspects and symptoms of GAD it is

customary to make a global assessment of severity of the disorder. The Clinicians
Global Scale for Severity (CGI-S) and the Clinicians Global Impressions Scale
for Change (CGI-C) (Figure 6.3)50 are used routinely and successfully in studies
investigating efficacy. Several measures of impairment or disability have also been
developed, of which the most sensitive and the most widely used is the Sheehan
Disability Scale (SDS) (Figure 6.4), recently reviewed.51
Clinical Global Impression Scale

1 Severity
1 = normal, not at all ill, 2 = borderline ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill,
6 = severely ill, 7 = among the most extremely ill patients
2 Improvement/Change
1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change,
5 = minimally worse, 6 = much worse, 7 = very much worse
Figure 6.3 Clinical Global Impression Scale. Adapted from Guy.50

t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Sheehan Disability Scale
A brief, patient-rated measurement of disability and impairment.

1MFBTFNBSL0/&DJSDMFGPSFBDITDBMF
Work*/School
The symptoms have disrupted your work/school work
Not at all Mildly Moderately Markedly Extremely
0 1 2 3 4 5 6 7 8 9 10
I have not worked/studied at all during the past week for reasons unrelated to the disorder.
*
Work includes paid, unpaid volunteer work or training
Social life
The symptoms have disrupted your social life/leisure activities
0 1 2 3 4 5 6 7 8 9 10
Family life/Home responsibilities

The symptoms have disrupted your family life/home responsibilities
0 1 2 3 4 5 6 7 8 9 10
Days lost
0OIPXNBOZEBZTJOUIFMBTUXFFLEJEZPVSTZNQUPNTDBVTFZPVUPNJTTTDIPPMPSXPSLPS
leave you unable to carry out your normal daily responsibilities?
Days unproductive
OIPXNBOZEBZTJOUIFMBTUXFFLEJEZPVGFFMTPJNQBJSFECZZPVSTZNQUPNTUIBU FWFO
0
though you went to school or work, your productivity was reduced?
Figure 6.4 Sheehan Disability Scale.%BWJE74IFFIBO"MMSJHIUTSFTFSWFE3FQSPEVDFE

with permission of the author.
Chapter 7
Pharmacological treatments
The changes over time in the criteria used to diagnose GAD make it difficult to
generalise the findings on efficacy from early studies where the selected patient
samples fulfilled earlier criteria focusing on short prior duration of the condition.
These studies would include an undetermined but substantial proportion of
patients in whom the GAD was of short duration. Relating the results to GAD
as currently defined by a prolonged prior duration is complicated. Caution is
therefore needed in assessing the efficacy of some of the earlier treatments where
studies were carried out in patient samples with short duration GAD.
Serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are thought to exert their
therapeutic effect via their action in blocking the reuptake of serotonin
(5-hydroxytryptamine or 5-HT) at the synapse. While this applies broadly to all
the SSRIs there are considerable pharmacological differences between members
of this group of drugs. Most have minor effects on other transmitters such as
noradrenaline or dopamine, as well as serotonin, with the most selective being
citalopram and escitalopram. Some of these different actions may influence
the choice of medication as preferred treatment for particular conditions. For
example, fluoxetine in addition to its serotonin reuptake inhibition activity acts
as an agonist of 5-HT2C. It is this activity that may be the source of the increase
in anxiety early in treatment that is often seen with fluoxetine. This may account
for the failure of fluoxetine to separate from placebo in many of the studies of
GAD. Fluoxetine inhibits cytochrome P450 (CYP) isoenzymes 2D6 and 3A4
which alter the metabolism of some medications used concomitantly. The
active metabolite of fluoxetine, norfluoxetine, has a long elimination half-life
so that the drug persists for some 35 weeks after termination of treatment.
Paroxetine has some anticholinergic properties which may produce a seda-
tive effect and can impair cognitive function. It inhibits CYP2D6 isoenzymes
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
which can increase the plasma levels of some treatments used concomitantly.
Sertraline has some activity in inhibiting reuptake of dopamine, an action that
has been suggested could increase anxiety at the start of treatment and it also
binds to sigma receptors. Its effects on adrenoceptors may lead to mydriasis and
dry mouth. It shares the disadvantage of some of the other SSRIs in producing
inhibition of CYP2D6. Citalopram, which has not been properly investigated
in GAD, is a selective inhibitor of the reuptake of serotonin which lacks
important effects on noradrenaline, dopamine or muscarinic receptors, giving
it a relatively low side-effect burden. Like other SSRIs, escitalopram, which is
the active S-enantiomer of citalopram, binds to the serotonin transporter to
produce serotonin reuptake inhibition but in addition to binding to the primary
site it also binds to the allosteric binding site of the serotonin transporter. It is
thought that this additional augmenting effect is behind the superior efficacy
reported with escitalopram as an antidepressant.52,53
The SSRIs are effective antidepressants and some, but not all, have been
shown to be effective in treating anxiety disorders such as panic disorder or
social anxiety disorder. For the treatment of GAD, however, only escitalopram,
paroxetine and sertraline have been shown to be effective at a level recognised
by licensing authorities. All three medications are established antidepressants
and since depressive symptoms are frequently a part of GAD the possibility
of their exerting a therapeutic effect via an antidepressant action has to be
addressed. To demonstrate a direct effect on the GAD independent of the
efficacy in depression, patients with comorbid major depression have had to
be excluded from the efficacy studies.
Paroxetine
Paroxetine was the first SSRI to be investigated and licensed for the treatment
of GAD. The studies supporting the regulatory submission were comparisons
with placebo but paroxetine has since been included as an active comparator in
subsequent studies of other potential treatments for GAD so that some estimate
of its relative place in treatment is possible.
Two studies in short-term treatment of GAD patients without significant
comorbidity, one having a flexible dose (2050 mg)54 and the other compar-
ing fixed doses of 20 mg and 40 mg with placebo,55 showed that paroxetine
was effective in treating GAD. In the flexible dose study the efficacy appeared
late at 6 weeks. The rate of response on placebo in the study was high (56%)
compared with paroxetine (72%). There is a risk in flexible dose studies that
the dose rises carry an extra placebo effect which may contribute to the high
placebo response that is frequently observed in this type of study. In the fixed
1)"3."$0-0(*$"-53&"5.&/54 t
dose study both paroxetine 20 mg and paroxetine 40 mg were associated with

higher levels of responders (62% and 68%) than placebo (46%) measured on
the Hamilton Anxiety A (HAM-A) rating scale. The response was mainly seen
on the psychic symptoms of anxiety and paroxetine did not seem to be effective
on the somatic symptom subscale of the HAM-A. The efficacy of paroxetine
was also seen in the advantage compared with placebo on the measures of dis-
ability applied in this study. The efficacy demonstrated in these two positive,
short-term, placebo-controlled studies was further strengthened by the positive
result from with paroxetine in preventing relapse over 24 weeks, shown in the
long-term relapse-prevention study (Figure 7.1).56
Some indication of the relative place of paroxetine compared with other SSRIs
is provided by later studies where it was included as a reference medication. For
example, it was included as a reference in a study of escitalopram, which investi-
gated doses of 5 mg, 10 mg and 20 mg compared with placebo (Figure 7.2).17 Both
doses of escitalopram that were shown to be effective were reported as superior
to paroxetine though the evidence, coming from different analyses, is not strong.
The failure of paroxetine to separate from placebo in this study suggests that the
study may have been underpowered but nevertheless provides some indication
that paroxetine may not be the most effective treatment for GAD.
Time to relapse during the double-blind treatment phase (KaplanMeier curve)
0.6
Placebo (n = 286)
0.5 Paroxetine (n = 274)
Proportion of patients relapsed
0.4
0.3
0.2
0.1
0
0 50 100 150 200
Days on treatment
Figure 7.1 Time to relapse during the double-blind phase (KaplanMeier curve). 3FQSPEVDFE
with permission from Stocchi et al.56
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Mean total scores on the Hamilton Anxiety rating scale
25
24 Placebo (n = 162)
23 Paroxetine (n = 181)
22
21
Mean total score
20
19
18
17
16
15
14
13
12
11
0 1 2 3 4 5 6 7 8
Week
Figure 7.2 Mean total scores on the Hamilton Anxiety rating scale. Adapted from Pollack et al.54
Paroxetine has other disadvantages. In the treatment of depression it is

associated with marked discontinuation effects in the week after treatment is
terminated which reduce after 2 or 3 weeks.57 This phenomenon is also observed
in GAD.58 Paroxetine, like fluoxetine and to a lesser extent sertraline, is a strong
inhibitor of the CYP 2D6 isoenzyme which raises the plasma levels of those
medications that are largely metabolised by this system. These include drugs
such as antiarrhythmics, tricyclic antidepressants (TCAs) and unfortunately
paroxetine itself. The interaction with the metabolism of antiarrhythmics in
particular may lead to high and potentially dangerous plasma levels and there-
fore caution is needed.
Escitalopram
The efficacy of escitalopram in GAD is soundly based on the evidence from
four placebo-controlled studies of short-term treatment and also one study
that investigated efficacy in relapse prevention. Three of the short-term treat-
ment studies carried out in non-depressed outpatients meeting GAD criteria
of DSM-IV followed the same protocol with randomisation to treatment
with escitalopram 10 mg or placebo following a single-blind placebo run-in
period. After 4 weeks the dose of escitalopram or placebo could be raised to
20 mg/day day for a further 4 weeks. The efficacy of escitalopram compared
1)"3."$0-0(*$"-53&"5.&/54 t
with placebo at endpoint was shown in all three studies on the HAM-A, the
primary efficacy scale. Significant efficacy was also shown on the psychic
anxiety symptoms subscale of the HAM-A and the Clinical Global Impression
(CGI) severity rating which are secondary scales. There was some evidence
of an early effect with escitalopram in the first of the three studies59 but not in
the other two (Figure 7.3).
The use of the same protocol in the three studies made it possible to carry
out a pooled analysis of the data that supported the efficacy of escitalopram
shown in the individual studies, registered on the primary HAM-A scale and
all the secondary scales at endpoint.60 Analysis of subgroups of the patient
population established the efficacy of escitalopram in both the moderate and
the severe GAD groups, in men and women, and in the older patients aged
between 60 and 65. The analysis showed significantly higher remission rates,
defined as HAM-A 9 or 7 on escitalopram than placebo.
Escitalopram was shown in a fixed-dose, placebo- and paroxetine-controlled
study to be effective when given in doses of 10 mg or 20 mg but the 5 mg dose
did not separate from placebo. It is unusual to detect a difference between
Mean change from baseline in HAM-A total scores by visit (intention to treat,
observed cases) and at last observation carried forward
0 Placebo
Escitalopram 5 mg
Escitalopram 10 mg
Mean change in HAM-A total score
4
Escitalopram 20 mg
Paroxetine 20 mg
8
12 *
*
-0$'
*
*

16
* *
* *

20
0 2 4 6 8 10 12
Treatment week
Figure 7.3 Mean change from baseline in HAM-A total scores by visit (intention to treat, observed
cases) and at last observation carried forward. )"." )BNJMUPO"OYJFUZSBUJOHTDBMF-0$' MBTU
observation carried forward. Difference vs placebo, *P <0.05; P <0.01; P<0.001; difference vs
Paroxetine P < BOBMZTJTPGDPWBSJBODF
3FQSPEVDFEXJUIQFSNJTTJPOGSPN#BMEXJOFUBM17
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
active medications in a single study and it is therefore interesting that at 12

weeks in the last observation carried forward analysis, which takes account of
discontinuations from treatment, escitalopram 10 mg was more effective than
paroxetine 20 mg and in the observed case analysis escitalopram 20 mg was
better than paroxetine.17 The efficacy of escitalopram in short-term treatment
is supported by efficacy shown in a study of relapse prevention.61
Escitalopram appears to be a well-tolerated treatment in GAD in both the
short and the long term. There was a low level of unwanted side effects and
few patients discontinued treatment for this reason. In the short-term studies
nausea, insomnia, fatigue and sexual side effects had an incidence greater than
5% and were twice as frequent as placebo.
Sertraline
The efficacy of sertraline in the treatment of GAD has been shown in two large
placebo-controlled studies. In the first of these studies18 flexible doses from 50 mg
to 150 mg of sertraline were compared over 12 weeks with placebo in patients
with GAD who did not have current MDD and had only low scores of depressive
symptoms. Efficacy was seen at the 12-week endpoint on the primary scale, the
HAM-A, and on a variety of secondary measures including assessments of quality
of life and daily function. Sertraline did not show a particularly fast effect and a
significant advantage compared with placebo was seen only after 4 weeks treatment.
Sertraline was effective on both the psychic symptoms and the somatic symptoms
although the treatment effect on the somatic symptoms was less substantial. The
mean dose in the study was approximately 95 mg/day but, because of the flexible
dosage regimen and the slow conservative upward titration of the dose, it is not
possible to determine the contribution of the higher and lower doses. The second
study also investigated flexible doses of sertraline but the range was from 50 mg to
200 mg over 10 weeks.62 This study also found that sertraline was effective compared
with placebo at the endpoint measured by the HAM-A. The stronger effect of
sertraline on psychic symptoms over somatic symptoms was more apparent in this
study and the difference from placebo on somatic symptoms was not significant.
Although the effect size on the significant measures was not particularly large, it
appears that sertraline has a place in the treatment of GAD.
Few studies have been carried out in children of any treatment for GAD
so evidence of efficacy is sparse. Sertraline was investigated in a placebo-
controlled study in a very small sample of 22 children with GAD over 9 weeks
and appeared to be effective.63
Sertraline was well tolerated in the studies in GAD, with side effects similar
to those expected for SSRIs.
1)"3."$0-0(*$"-53&"5.&/54 t
Serotonin noradrenaline reuptake inhibitors

The serotonin noradrenaline reuptake inhibitors (SNRIs) inhibit the reuptake of
both serotonin and noradrenaline though the potency of their action on noradrena-
line reuptake varies between members of this group and may depend on dose.
Venlafaxine
The description of venlafaxine as an SNRI is complicated by the dose issue.
Only the higher doses of venlafaxine are thought to have a significant effect
on noradrenaline reuptake inhibition. Venlafaxine in a dose of 75 mg/day is
thought to have only negligible effects on noradrenaline reuptake and to work
almost exclusively as an SSRI.
Venlafaxine was introduced in an immediate-release formulation and
later an extended-release (ER) formulation. In GAD venlafaxine ER has been
found to be effective in a series of short-term and long-term studies in doses
of 75, 150 and 225 mg/day compared with placebo (Figure 7.4).6467 All three
doses of venlafaxine were significantly better than placebo on some or all the
measures used in the studies. There appears to be a greater effect on the psychic
symptoms of GAD than on the somatic symptoms. The therapeutic benefit of
venlafaxine is also seen in its effect in improving social function.39 The studies
Venlafaxine ER compared with placebo in the treatment of GAD
Baseline Week 1 Week 2 Week 3 Week 4 Week 6 Week 8

0
Mean change from baseline in HAM-A total scores
Placebo (n = 96)
2 7FOMBGBYJOF&3NHEBZ n = 86)
7FOMBGBYJOF&3NHEBZ n = 81)
4
7FOMBGBYJOF&3NHEBZ n = 86)
10
12
*
14
Figure 7.4 Venlafaxine ER compared with placebo in the treatment of GAD. &3 FYUFOEFE
release; GAD, generalised anxiety disorder; HAM-A, Hamilton Anxiety rating scale. *P<0.05.
3FQSPEVDFEXJUIQFSNJTTJPOGSPN3JDLFMTFUBM64
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
on venlafaxine included several different primary measures of efficacy and a

statistical adjustment usually applied to multiple comparisons appears to be
lacking. Combined with doubts about possible selective reporting this com-
plicates the interpretation of the results.
The studies did not suggest a significant doseresponse relationship and
there was an increase in adverse events with higher doses, so that the optimum
and target dose should be 75 mg. It seems that in GAD the contribution of
noradrenaline reuptake to efficacy is minimal in the short term. The picture is
less clear in long-term treatment. A post-hoc meta-analysis68 of the data from
the two 6-month studies66,67 showed there was a significantly better outcome
with increasing doses of venlafaxine. In the short term the adverse events that
accompany high doses appear to compromise efficacy but over the long term,
when individuals are to some extent habituated to treatment, there may be an
advantage in raising the dose.
As with other antidepressants, venlafaxine is not associated with a fast
separation from placebo. Of the five placebo-controlled studies submitted to
obtain a licence, efficacy on the HAM-A does not suggest a fast response. In
a recent study, in which venlafaxine was included as a reference medication, a
significant effect for venlafaxine compared with placebo was seen at 2 weeks
compared with efficacy seen at 1 week with pregabalin.69 Similarly in a more
recent study that compared placebo and flexible doses of venlafaxine ER up to
225 mg or pregabalin up to 600 mg response was more rapid with pregabalin and
appeared at 4 days. Venlafaxine showed a significant difference from placebo
in the middle of the study but failed to separate from placebo at the endpoint.70
However, in the two studies of duloxetine where venlafaxine was used as an active
comparator venlafaxine in a flexible dose separated significantly from placebo
in both studies. Venlafaxine in a flexible dose was also effective compared with
placebo in primary care.71
Two small placebo-controlled studies investigated the efficacy of venla-
faxine ER in children aged between 6 and 11 years and adolescents ranging
in age from 12 to 17 years. Efficacy in these studies was assessed on the basis
of a score derived from nine items from the generalised anxiety section of a
version of the Schedule for Affective Disorders and Schizophrenia for School-
Age Children. Although venlafaxine was shown to be effective in one study
the difference from placebo in the second fell just short of significance.72
Venlafaxine is less well-tolerated than the SSRIs particularly when given in
higher doses. Venlafaxine raises blood pressure and it is recommended that all
patients (including adolescents) should be monitored. Venlafaxine also raises
total cholesterol at a modest level.
1)"3."$0-0(*$"-53&"5.&/54 t
Duloxetine
Duloxetine is the most recent SNRI to be licensed for the treatment of GAD
both in the US and in the EU. Its efficacy was established on the basis of three
placebo-controlled studies of 9 or 10 weeks duration. In one study, which
investigated duloxetine in fixed doses of 60 mg or 120 mg, both doses showed
a significant separation from placebo at 2 weeks.73 There was no evidence of
one dose having a therapeutic advantage over the other, which suggests that the
lower dose should be preferred. This could also be interpreted as showing that
any additional noradrenaline reuptake inhibition associated with higher doses
did not make an obvious contribution to efficacy. The higher doses were less
well tolerated with more frequent reports of dizziness, dry mouth and hyper-
hidrosis, which might be taken as indirect evidence of greater noradrenaline
reuptake inhibition activity at higher doses.
Duloxetine was investigated in a flexible dose of 60120 mg/day in a second
study which showed a significantly greater improvement compared with placebo
measured on the HAM-A, a higher response rate and greater global improve-
ment.74 The significantly better response in the duloxetine-treated patients was
also seen in the improvement in the functional measures included in the study.
There appeared to be no difference in efficacy between venlafaxine, included as
a comparator in a further study, and duloxetine, both being significantly better
than placebo. Duloxetine was given in a flexible dose of 60120 mg/day (mean
approximately 108 mg/day) and venlafaxine, in a flexible dose of 75225 mg/day
(mean approximately 184 mg/day).75 Evidence of early response with duloxetine
is not convincing. Early separation from placebo at 1 week was seen in only
one study.75 The most frequent adverse events with duloxetine included nausea,
decreased appetite, constipation and decreased libido.
Duloxetine is poorly tolerated by some patients even at the lower dose of
60 mg/day and as many as 20% of patients may need their dosage lowered in the
first week. The mixed effects repeated measures (MMRM) analysis applied in
the studies tends to underestimate the influence of early discontinuations from
treatment by assuming that these patients would have continued to improve
with the rest of the patients who did not discontinue treatment. Many doctors
have adopted the procedure where treatment is started on a low, subtherapeutic
dose of duloxetine 30 mg, the dose being later raised to the therapeutic dose of
60 mg (Figure 7.5). This may reduce early dropouts but would also be expected
to prolong the time before a significant difference from placebo is observed.
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Calcium channel GABA receptor modulators

Pregabalin
Pregabalin modulates the calcium channel in the 2 subunit of the GABA
(-aminobutyrate) receptor complex which has the effect of dampening the
neurotransmission in excited neurons. The benefits of this action can be seen
in the reduction of pain in peripheral and central neuropathy treated with
pregabalin in monotherapy, and also in the reduction of partial seizures with
pregabalin given as adjunctive treatment.76,77 Pregabalin has been extensively
investigated in eight placebo-controlled studies in GAD and significant efficacy
was reported in all but one of these. Pregabalin has currently the largest evidence
base of efficacy in the treatment GAD (Figures 7.67.9).
Three early 4-week studies investigated the efficacy of pregabalin compared
with placebo and with lorazepam in a dose of 6 mg acting as a reference drug.
In two of these studies pregabalin in a dose of 600 mg separated significantly
from placebo in contrast to lorazepam where only one study showed efficacy.
The lower dose of 150mg of pregabalin failed to separate from placebo at the
Mean change from baseline to endpoint in HAM-A total score by treatment

week (MMRM) and at endpoint (week 9, LOCF)
0
Placebo
2
Least squares: mean change from baseline
Duloxetine 60 mg
4 Duloxetine 120 mg
6
Improvement
*
8
*
10
*
12 * *
*
*
*
14 *
*
16
18
-0$'
Treatment week
Figure 7.5 Mean change from baseline to endpoint in HAM-A total score by treatment week (MMRM)
and at endpoint (week 9, LOCF). *P )"." )BNJMUPO"OYJFUZSBUJOHTDBMF-0$' MBTU
PCTFSWBUJPODBSSJFEGPSXBSE..3. NJYFEFGGFDUTSFQFBUFENFBTVSFT3FQSPEVDFEXJUIQFSNJTTJPO
from Koponen et al.73
1)"3."$0-0(*$"-53&"5.&/54 t
Pregabalin efficacy across phase 3 GAD studies: mean (95% CI) HAM-A score
difference vs placebo at endpoint
4UVEZ 3JDLFMTFUBM 1PIMFUBM .POUHPNFSZFUBM
1
Mean difference from placebo (95% CI)
2 * *
*
*
*
* *
3 * *
*
4
7
300 450 600 ALP 1.5 200 400 450 400 600 VEN 75
(n = 89)(n = 87)(n = 85) (n = 88) (n = 75) (n = 85) (n = 85)(n = 94)(n = 104)(n = 110)
Dose (mg/day)
Figure 7.6 Pregabalin efficacy across phase 3 GAD studies: mean (95% CI) HAM-A score
difference vs placebo at endpoint. ALP, alprazolam; CI, confidence interval; GAD, generalised
anxiety disorder; HAM-A, Hamilton Anxiety rating scale; VEN, venlafaxine. *P<0.05 vs placebo.
%BUBUBLFOGSPN3JDLFMTFUBM78 Pohl et al.79 Montgomery et al.69
4-week endpoint in any of these three studies. A pooled analysis of the two
positive studies found that pregabalin 150 mg was associated with a signifi-
cant treatment effect but the effect was obviously less than that of the 600 mg
dose.80,81 Pregabalin 150 mg is therefore considered the subtherapeutic dose.
Pregabalin has been found to be effective compared with placebo in a series
of studies at daily doses between 200 mg and 600 mg with little difference in
efficacy between them so that the target dose of pregabalin for treatment of
GAD is usually 300 mg.
A three times daily dosage regimen was used in the early studies but in a
later placebo-controlled comparison study a twice daily regimen of pregabalin
was as effective.79 The simpler twice-daily dosage regimen, which is preferred
by patients, is therefore recommended.
Two of the later studies included a comparator drug as well as placebo.
Alprazolam in a daily dose of 1.5 mg was the reference comparator in one 4-week
study investigating three doses of pregabalin (300, 450, and 600 mg/day).78 All
three doses of pregabalin separated early from placebo at 1 week through to
the endpoint on the HAM-A scale. The significant treatment effect (difference
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Efficacy of pregabalin seen by week: least square mean change in HAM-A total score
Placebo (n = 101)
0
Pregabalin 400 mg/day (n = 97)
2
Mean change in HAM-A total score
Venlafaxine 75 mg/day (n = 113)

4

6
10 *

12

*
14 * *

16
*
18
#BTFMJOF -0$'
Treatment week
Figure 7.7 Efficacy of pregabalin seen by week 1:least square mean change in HAM-A total score.
)"." )BNJMUPO"OYJFUZSBUJOHTDBMF-0$' MBTUPCTFSWBUJPODBSSJFEGPSXBSE*P<0.05; P<0.01.
Adapted from Montgomery et al.69
between active medication and placebo) early in the study with pregabalin at
1 week was nearly twice that seen with alprazolam, which helps to confirm that
pregabalin has a fast action in GAD. Efficacy was observed on both the psychic
and somatic subscales.
A further placebo-controlled study examined the efficacy of pregabalin
in fixed doses of 400 and 600 mg/day with venlafaxine 75 mg/day included as
an active comparator. All the treatments separated significantly from placebo
at treatment endpoint but the efficacy of pregabalin was seen already after
1 weeks treatment whereas venlafaxine had a slower response.69 The advantage for
pregabalin is unlikely to be attributable to the dose of venlafaxine being too low
since there is no clear doseresponse relationship for venlafaxine.
Further information on the dose issue comes from a placebo-controlled study
investigating escalating doses of pregabalin up to 600mg/day and increasing doses
of venlafaxine up to 225mg in the XR formulation. Pregabalin showed very early
significant separation from both placebo and venlafaxine at 4 days. The efficacy of
pregabalin was maintained until the treatment endpoint. The high dose of venla-
faxine failed to separate from placebo at treatment endpoint although efficacy was
observed midway through the study. This study confirms the very early response
seen with pregabalin in the treatment of GAD.70
1)"3."$0-0(*$"-53&"5.&/54 t
Pregabalin reduces both psychic and somatic symptoms of GAD: pooled

analysis from six GAD studies
Treatment week
0 1 2 3 4 Endpoint
0
1 Placebo (n = 484)
Psychic mean change from baseline (%)

2 Pregabalin 200450 mg/day (n = 534)

4

*

5 *
*

*
6

#BTFMJOFNFBOT1#0 1(#NHEBZ oNHEBZ NHEBZ
Treatment week
0 1 2 3 4 Endpoint
0
1 Placebo (n = 484)
Somatic mean change from baseline (%)

*

#BTFMJOFNFBOT1#0 1(#NHEBZ oNHEBZ NHEBZ
Figure 7.8 Pregabalin reduces both psychic and somatic symptoms of GAD: pooled analysis from
six GAD studies. ("% HFOFSBMJTFEBOYJFUZEJTPSEFS-0$' MBTUPCTFSWBUJPODBSSJFEGPSXBSE1#0
placebo; PGB, pregabalin; VEN, venalafaxine. *P<0.05; P<0.001 vs placebo; Endpoint: 4 weeks
-0$'
4JYTUVEJFTDPNCJOFE
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Pregabalin versus placebo in the treatment of elderly patients with GAD
Week Endpoint
0 1 2 3 4 6 8 9
0
2 Placebo (n = 95)
Mean change from baseline (%)
8

10
*
12

14
*
16
Figure 7.9 Pregabalin versus placebo in the treatment of elderly patients with GAD. GAD,
generalised anxiety disorder. *P<0.05, P<0.01 vs placebo. Mean HAM-A baseline score was
26.5. An 8-week, double-blind, randomised placebo-controlled trial of pregabalin in the
treatment of patients over the age of 65 years with GAD. Adapted from Montgomery et al.41
Pregabalin is the first treatment for GAD to be investigated in a specific

study in elderly patients over the age of 65.41 The treatment effect in this placebo-
controlled study was significant and similar to that observed in non-elderly
patients. GAD is the most common anxiety disorder presenting for treatment
in elderly people and the result, which shows that age is no bar for treatment,
is important for the field.
Both the psychic symptoms and the somatic symptoms responded well to
pregabalin, an effect that was seen in the individual studies as well as in the
pooled analysis of several studies.69,78,81 In this respect pregabalin differs from
the SSRIs and SNRIs where efficacy is concentrated on psychic symptoms.
The therapeutic effect on both psychic and somatic symptoms is particularly
relevant since those with GAD present for treatment most commonly with
somatic rather than psychic symptoms. Good efficacy in treating both these
sets of symptoms of GAD is important. A separate analysis of the effect of
pregabalin on GI symptoms in the pooled analysis of six studies of GAD
confirms this advantage.82
Sleep disturbance is a common presentation of GAD and is recognised as
a core diagnostic symptom in DSM-IV. Pregabalin is effective and has a fast
1)"3."$0-0(*$"-53&"5.&/54 t
action in improving sleep disturbance compared with placebo in GAD, in con-

trast to SSRIs and SNRIs which tend to disrupt sleep.81 An analysis of the effect
of pregabalin on the depressive symptoms associated with GAD in one study69
shows that both pregabalin and venlafaxine are effective compared with placebo
and this benefit with pregabalin was also reported in the meta-analysis of six
studies.83 The frequently observed mild depressive symptoms appear to be part
of GAD rather than representing a comorbid disorder. However, where MDD
is present and the depressive symptoms reach a moderate or greater severity
level then treatment with an antidepressant is indicated.
In summary, pregabalin is effective in GAD and has advantages not
enjoyed by alternative treatments: it is fast in its action with differences from
placebo significant by the fourth day.70 It is effective in improving sleep and
improving equally the psychic and somatic symptoms of GAD in contrast
to SSRIs or SNRIs. It is effective in the treatment of pain and, as GAD is
frequently comorbid with pain disorders and pain is a presenting symptom
in as many as a third of GAD patients, this is a clear advantage, particularly
when compared with SSRIs or benzodiazepines which are not thought to be
effective in pain disorders. Pregabalin is clearly effective in short-term treat-
ment but it is also effective compared with placebo in relapse prevention over
a period of 6 months.84
Pregabalin is well tolerated with a level of adverse events comparable to
that seen on placebo. The number of patients who discontinued treatment with
pregabalin in the studies due to adverse events was small (11%), close to the
number on placebo (9%), and compares very favourably with the 20% of patients
who discontinued venlafaxine at the lowest dose, or 35% who discontinued
lorazepam in the comparator studies. The most common adverse events are
somnolence and dizziness which tend to improve with prolonged treatment.
Unlike benzodiazepines pregabalin shows no signals of dependence either in
animal models or in the extensive clinical trial programme. Discontinuation
symptoms following abrupt termination of treatment do not appear to be a
problem; the rate is low after both short-term and long-term treatment.
Benzodiazepines
Despite the acknowledged side effects and risks of dependence associated with
benzodiazepines these drugs are still widely used in primary care in the treatment
of GAD. To some extent this continued use is due to their long availability and
hence familiarity. Their use also perhaps reflects a less than adequate assess-
ment of the efficacy of benzodiazepines and the ratio of risk to benefit. The
problem is compounded by the relatively weak evidence of efficacy accepted in
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
the less demanding climate for testing efficacy in anxiety or anxiety neurosis,
prevailing at the time that benzodiazepines were introduced, and by the failure
to take into account the safety issues which, to be fair, became more evident
over subsequent years. Studies that did not specify the nature of the anxiety
disorder studied cannot provide evidence of efficacy in GAD; evidence can be
obtained only from placebo-controlled studies that specifically studied GAD
defined by accepted criteria.
There are suggestions that benzodiazepines may lose efficacy with time
and this tolerance has been reported to lead to dose escalation and an
increased risk of dependence. Benzodiazepines have profound effects on
short-term memory, a property that has been found particularly useful in
dental and surgical procedures where they are widely used for this purpose.
The disturbances in cognition are also seen in the daytime even when taken
at night, particularly with benzodiazepines that have a long half-life or when
those with a short half-life are prescribed in the multiple daily dose regimens
considered necessary in the treatment of daytime anxiety. Benzodiazepines
are associated with daytime drowsiness which impairs the ability of the
individual to work or function adequately and users should not drive or
operate heavy machinery.
Concerns relating to tolerance, dose escalation and addiction85,86 have led
regulatory authorities in Europe to restrict the use of all benzodiazepines to
short-term use for no longer than 3 months. This limits the suitability of benzo-
diazepines for the treatment of GAD which is a chronic disorder requiring
treatment over long periods.
The evidence of the efficacy of benzodiazepines in GAD is modest and the
number of placebo-controlled studies surprisingly small. In an early study in
GAD defined using a short duration criterion, diazepam in a dose of 15 mg was
shown to be significantly better than placebo over 8 weeks measured on the
HAM-A.87 Efficacy was greatest in the early weeks and then appeared to tail off.
The question mark over the efficacy of the benzodiazepine in this study is also
underlined by the greater treatment effect observed with imipramine in the same
study. However, efficacy is reported for diazepam in several placebo-controlled
studies.8792 A range of studies investigating 5-HT3-receptor antagonists in GAD,
which included diazepam as a reference anxiolytic drug and failed to separate
from placebo, has regrettably never been properly published.93 This leads to a
very real concern that negative results often remain unpublished and that the
efficacy of diazepam may not be strong.
The best evidence that benzodiazepines are effective in treating GAD defined
by a longer duration comes from the placebo-controlled studies investigating
1)"3."$0-0(*$"-53&"5.&/54 t
the efficacy of pregabalin, in which benzodiazepines were included as refer-

ence agents. Lorazepam in a dose of 6 mg was effective at 4 weeks in two of the
three studies.80,81 At this high dose of lorazepam there were numerous dropouts
(35%), higher than seen with pregabalin (11%) which was close to the placebo
rate (9%). The therapeutic effect of lorazepam appeared early with a significant
difference from placebo at 1 week observed with lorazepam, but only in one of
the three studies, in contrast to pregabalin where a significant difference from
placebo at 1 week was observed in all three lorazepam controlled studies and
at all doses in the six pivotal placebo-controlled studies.81
The efficacy of alprazolam in GAD has been shown in a number of short-
term placebo-controlled studies.78,94,95 Alprazolam in a dose of 1.5 mg was the
reference agent in a placebo-controlled study of the efficacy of three differ-
ent doses of pregabalin.78 Alprazolam and pregabalin showed a significantly
greater reduction in HAM-A score compared with placebo at the endpoint
of the 4-week study. Alprazolam separated significantly from placebo at one
week measured on the HAM-A, as did the three doses of pregabalin. In this
study therefore alprazolam was associated with early onset efficacy, though the
treatment effect versus placebo at 1 week was about half that observed on all
three doses of pregabalin.
In summary there is evidence that high doses of lorazepam 6 mg, diazepam
15 mg, and lower doses of high-potency benzodiazepines, eg alprazolam 1.5 mg, are
effective in treating GAD, but the number of dropouts is high and the problem of
impairment of cognition and concerns about the possible development of depend-
ence, particularly over the medium and long term, limits their usefulness.
Buspirone
Buspirone, an azapirone drug that has partial agonist activity at the 5-HT1A
receptor, is one of the earlier medications that has shown efficacy in GAD
although not all studies were positive. An early study in patients who would
have fulfilled criteria for anxiety neurosis in the DSM version current at the time
found similar efficacy between buspirone and diazepam.96 Its efficacy in GAD
as later defined is not well established and in one study it failed to show efficacy
whereas venlafaxine was reported to be effective.65 A meta-analysis of the studies
carried out with buspirone concluded that the efficacy was comparable with that
of benzodiazepines97 but it is not generally a first choice treatment. Uncertainty
about the therapeutic dose range and the appearance of unwanted effects such
as dizziness attributable to the -agonist actions of buspirones active metabolite
also detract from its value in treatment. There have been reports of a reduction
in efficacy where buspirone follows treatment with benzodiazepines.
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Forthcoming and other treatments for GAD

A number of treatments have been found to be effective in treating GAD
judged by the criterion of at least one positive placebo-controlled study. These
treatments would be expected sooner or later to join the small list of options
approved for the treatment of GAD. To this could be added some treatments
that have shown efficacy but may have been considered by the authorities to
be lacking some component in the efficacy deemed necessary for licensing.
Some are unlikely to be pursued because the treatments are now generic and
the impetus to finance and conduct these studies is not forthcoming.
Quetiapine XR
This atypical antipsychotic has begun a comprehensive programme to investi-
gate efficacy in both MDD and GAD. The MDD programme is complete and is
currently under review by the various licensing agencies. Suffice to say there is
clear efficacy in four out of five placebo-controlled studies in the acute treatment
of MDD, including in elderly people, as well as in a long-term efficacy study.98
Efficacy is seen in fixed doses of 50, 150 and 300 mg/day with an optimum ratio
of efficacy to side effects at 150 mg/day. There is good evidence of fast onset of
efficacy in MDD with separation from placebo consistently observed at 1 week
and sustained to the end of the 6-week studies.
Some caution is needed in interpreting the results of the studies of quetiapine
XR in GAD since these have not yet been published in peer-reviewed journals,
although they have been presented at international conferences and can be
checked on the AstraZeneca website (www.astrazenecaclinicaltrials.com). Two
studies reported early and persistent efficacy of quetiapine XR in the short-term,
8-week treatment of GAD. In one study quetiapine in doses of 50 or 150 mg/
day were significantly better than placebo at both 4 days and endpoint. In the
other study quetiapine in doses of 150 or 300 mg were again effective at 4 days
and endpoint. In both studies the 150 mg dose was significantly better than both
placebo and the comparators in the two separate studies, paroxetine 20 mg and
escitalopram 10 mg. The 150 mg dose of quetiapine was therefore the most effec-
tive dose with the most consistent efficacy on the secondary study measures.
Quetiapine XR appeared well tolerated with somnolence dizziness, and dry
mouth being the most common adverse events. At the lower doses weight gain
was minimal and the rate of extrapyramidal symptoms observed was less than
that seen with duloxetine, the comparator used in the MDD study. Concerns
about the metabolic syndrome have led the FDA not to approve the licence for
monotherapy in GAD.
1)"3."$0-0(*$"-53&"5.&/54 t
Agomelatine
Agomelatine is now licensed as an antidepressant in the EU and some other
countries at doses of 2550 mg/day. There is evidence of superior efficacy
compared with venlafaxine and sertraline, driven to some degree by the much
better tolerability and compliance observed with agomelatine. Because of its
5-HT2C-antagonist properties agomelatine does not increase serotonin or
noradrenaline levels. Discontinuation symptoms are therefore not observed
following abrupt cessation of treatment.57 There are also low levels of sexual
dysfunction or other well-known serotoninergic side effects. There are some
concerns about possible liver toxicity, particularly at the higher dose, which
requires monitoring.
In GAD there is one positive placebo-controlled study99 in which agomelatine
showed efficacy with a typical treatment effect and separation from placebo in
the 12-week study (Figure 7.10). We await further studies.
Agomelatine in acute treatment of GAD randomised: double-blind, flexible-

dose, placebo-controlled, 12-week study
80 *
P =0.026
Placebo (n = 58)
70 Agomelatine 2550 mg/day (n = 63)
60
50
Percentage
P =0.027
*
40
30
20
10
0
3FTQPOTF 3FNJTTJPO
(reduction in HAM-A >50%) (HAM-A score <7)
Figure 7.10 Agomelatine in acute treatment of GAD: randomised, double-blind, flexible-dose,

placebo-controlled, 12-week study. GAD, generalised anxiety disorder; HAM-A, Hamilton
Anxiety rating scale. Mean baseline HAM-A scores: placebo 28.6, agomelatine 29.0. Adapted
from Stein et al.99
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
Imipramine
The efficacy in GAD of the tricyclic antidepressant (TCA), imipramine, was shown
in an 8-week study compared with placebo in patients whose GAD symptoms
had persisted for at least 4 months.87 The study included the benzodiazepine
diazepam as a comparator given at a high dose of 15 mg/day. The effect was largely
confined to the psychic symptoms of anxiety in contrast to diazepam. Although
diazepam was associated with efficacy early in the study at 2 weeks, by the end
of the study imipramine showed a significant advantage over diazepam. Similar
results are seen in the comparison with alprazolam.100 The absence of long-term
efficacy, regarded as mandatory in the EU, and the reported cardiotoxicity and
poor tolerability of the TCAs have compromised the use of imipramine in GAD
and it is unlikely that it will ever be licensed for GAD.
Hydroxazine
The antihistamine hydroxazine has been found to be effective in placebo-con-
trolled studies in the acute treatment of GAD101 in a study where the comparator
buspirone did not separate from placebo. This study has not been followed by
studies examining efficacy in long-term treatment so that it is unlikely that
hydroxazine can ever be recommended for the treatment of GAD.
Other treatments
-blockers, which are useful in managing tremor associated with performance
anxiety, have been tested in GAD and failed to separate from placebo. CCK
antagonists, which were thought at one stage to be useful in anxiety disorders in
the light of the provocation of anxiety by CCK, was found not to separate from
placebo in GAD.102 The 5-HT1A-antagonist ipsapirone was found to be effective
in GAD91 but since it failed to separate from placebo in MDD its development
was abandoned. The result suggests that other 5-HT1A-antagonist may also have
efficacy but the high levels of dizziness and poor compliance reported might
well, as with buspirone, limit their potential.
Chapter 8
Psychological treatment
Despite the body of evidence showing the disability associated with GAD there
are still many who do not recognise that GAD is a serious, dangerous and
impairing disorder and who prefer to believe that right living, right thinking
and exercise are the answer. Formal investigation of the possible efficacy of these
types of intervention has not been undertaken in adequately controlled trials
that take account of confounding variables such as the halo effects of enthusi-
asts. In a climate of cost cutting there is a risk that alternative approaches such
as self-help manuals, counselling and exercise are promoted in order to save
money on drug budgets without appropriate critical reference to the quality
of the evidence base.
The evidence supporting the efficacy of psychological treatments in GAD
is derived from a small number of studies relative to the large body of evidence
for the efficacy of pharmacological treatments. Nevertheless there is a growing
literature on the use of behavioural therapies and several treatment packages
have been proposed. These have included anxiety management through relaxa-
tion therapy, components of cognitive therapy aimed at addressing worrying
and behavioural challenges to confront worry behaviours.103,104
The problem of identifying an adequate control treatment group in studies
of psychological treatments makes for a major difficulty in obtaining a valid and
reliable estimate of efficacy. Various designs have been applied, for example,
taking a no treatment group as a control, or a group remaining on the waiting
list for treatment, but these are flawed by the potential bias of untreated patients
exaggerating their symptoms and those receiving treatment reporting responses
that may be due to non-specific factors unrelated to the treatment. Giving or
receiving a treatment perceived by both therapist and patient as effective carries
an additional therapeutic effect over and above that which may be due to the
treatment itself. It is not possible to control for this except by comparing treat-
ments given under open conditions by doctors who believe in the efficacy of
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
the comparator treatments. It is essential in these studies to use raters blinded

to treatment to try to counter the bias of the therapist.
Some studies indicate that cognitivebehavioural therapy (CBT) and relaxa-
tion therapy produced a similar improvement in symptoms.104,105 In a study
where CBT was compared with anxiety management, despite the CBT group
having greater contact, both treatments were similar in effect and superior to
psychotherapy at 6 months. Direct comparisons of CBT with analytical psy-
chotherapy have favoured CBT106 which supports the generally held view that
analytical psychotherapy is not helpful in GAD. Comparisons of CBT with
behaviour therapy or a waiting list control have reported that most significant
improvement is seen with CBT compared with the wait list control and that the
therapeutic gains are maintained over the longer term.104,105,107
The comparisons of different psychological treatments suggest that CBT is
an effective treatment for GAD. For a reliable assessment, however, one would
wish that efficacy was supported with evidence from studies that had used more
stringent methodology.
Psychological and psychopharmacological treatments

Assessing the efficacy of psychological treatment relative to pharmacotherapy is
not easy on the basis of the studies that have been carried out in this area. For a
fair comparison recognised pharmacological treatments for GAD, in doses with
established efficacy, must be used. For example, a study that compared CBT,
anxiety management and lorazepam given in a dose of 3 mg/day, then 2 mg/day
followed by 1 mg/day, each for a period of 10 days, does not meet this standard.
The drug produced an early response that tailed off during the study whereas
the effect of psychological treatment appeared later but was sustained. Clearly
no conclusions can be drawn from such a poor design.108
CBT is sometimes compared in an open treatment arm of a study where
drug or placebo is given under double-blind conditions. In this type of design
the CBT, which has the added effect of the reassurance of open treatment,
cannot be fairly compared with the drug or placebo arms which lack this reas-
suring effect. The claim that CBT and CBT plus diazepam had greater efficacy
than diazepam or placebo is thus overstated.109 For a fair comparison between
a pharmacological treatment and a psychological treatment, which is given
openly with both the therapist and patient knowing that they are receiving
what they consider an effective treatment, the pharmacological treatment also
needs to be given openly. In this way the therapist and patient are reassured
by knowing the treatment is active. Therapist contact time needs to be equal-
ised between groups and improvement assessed by raters blind to the study.
14:$)0-0(*$"-53&"5.&/5 t
Independent raters will, to some extent, reduce the bias of open studies though
the patient is inevitably aware of the nature of the treatment. The bias of this
knowledge and beliefs about the treatment, in addition to dependence on the
therapist, may exaggerate response. Such a design, which might cope with the
extra non-specific benefits that accompany open treatment, does not appear
to have been attempted.
In studies investigating the efficacy of pharmacotherapy, recording of the
discontinuations from treatment is mandatory and the analysis of efficacy is
carried out in the randomised population on a last observation carried forward
analysis to address the influence of early withdrawals. These data are rarely
provided in studies of CBT. Ignoring the substantial number of patients who
refuse treatment or discontinue early produces a biased sample that will distort
the results in the direction of those who benefit from treatment.
Chapter 9
Which treatments, when and for how long?
The evidence base for the pharmacological treatment of GAD is now substantial.
However, there are few studies comparing treatments to inform rational choices
either for GAD as a whole or for selective treatments for particular subgroups
of GAD. The best guidance therefore comes from a careful analysis of the data
from placebo-controlled studies that indicate the strengths and weaknesses of
particular treatments.
How long should treatment be continued?

A number of relapse prevention studies have demonstrated the benefits of long-
term treatment. These studies are designed to investigate whether persistence of
treatment in those who respond to short-term therapy will lead to fewer patients
having exacerbations of symptoms or relapse than placebo. These studies usually
run for some 6 months to a year after the acute treatment period is complete.
The consistent results from these studies show that the risk of relapse is about
three times higher in those treated with placebo than in those receiving active
treatment for GAD, even over this relatively short period. This continued
therapeutic and protective effect supports the recommendation that short-term
prophylaxis is insufficient and that treatment should be continued to keep the
individual well. The studies vary slightly in their design features and the dif-
ferences observed between treatments in the significant benefit in long-term
outcome compared with placebo probably arises from these variations in design
rather than any inherent disparity in the efficacy of treatments. The relapse
prevention studies have been carried out in patients with moderate-to-severe
GAD and therefore in these patients treatment in the long term is indicated.
In patients with severe or dysfunctional GAD there are reasonable grounds for
continuing the treatment indefinitely.
There is no evidence of loss of efficacy in relapse prevention whether the
randomisation to the continued drug or placebo occurs early or later in the
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
course of treatment. Efficacy is not dependent on the total length of exposure

to a treatment, whether 9 or 18 months. There is no evidence of loss of efficacy
for any of the licensed treatments for GAD.
The recommendation of the British Association of Psychopharmacology110
is that treatment should be continued for 6 months after a response to 12 weeks
treatment. In my view, this does not take adequate account of the probability
that patients with GAD will remain well if treatment with medication is con-
tinued for longer periods.
The long-term efficacy of cognitivebehavioural therapy (CBT) is supported
by a lower level of scientific evidence, being based on uncontrolled open studies.
It is claimed that there are fewer relapses on CBT than with medication but the
comparison is misleading, not least because the studies on CBT generally recruit
less severe patients who do not have the same high relapse rates.
In those with moderate or severe GAD, if the treatment is discontin-
ued, for whatever reason, there is likely to be a relapse over the subsequent
months. The frequency of monitoring needs to be increased so that treatment,
preferably having a fast onset of effect, can be initiated at the first signs of
relapse. There are, as yet, too few data from long-term comparator studies to
suggest that one effective licensed treatment for GAD is better than another.
The doctor is free to choose the treatment that is best tolerated and which
best suits the pattern of predominant complaints and comorbidity in the
individual sufferer.
Choice of treatment based on predominant complaints or

comorbidity
Somatic symptoms
Somatic symptoms are the most common complaint of those with GAD and there
is a clear difference between the various treatments in their ability to improve
these symptoms. In general the selective serotonin reuptake inhibitors (SSRIs)
and serotonin noradrenaline reuptake inhibitors (SNRIs) are less effective in
managing these symptoms. While they have some benefit this is often not evident
in short-term studies where clear evidence of benefit on psychic symptoms is
consistently observed. On the other hand somatic symptoms respond rapidly to
pregabalin in doses of 200600 mg/day which show a separation from placebo
as early as day 4, with the benefit persisting to the end of the study. Pregabalin
therefore should be considered early in these patients. The recommendation to
use benzodiazepines to treat the somatic symptoms of GAD is not supported
by the same strength of evidence and the riskbenefit assessment of using a
potentially dependence-inducing treatment is negative.
8)*$)53&"5.&/54 8)&/ "/% '03 )08 -0/( t
Sleep disturbance
Sleep disturbance is a core diagnostic symptom of GAD and is reported as the
main presenting complaint in some 35% of those with GAD attending primary
care. SSRIs and SNRIs are often disruptive on sleep particularly in the early
stages of treatment. Duloxetine and sertraline are particularly troublesome.
For this reason SSRIs and SNRIs are not the preferred choice for those with
predominant sleep problems. Pregabalin by contrast has a beneficial effect on
sleep disturbance which is seen early and persists and pregabalin should be
considered a priority in those with prominent sleep difficulties.
Depression
Major depressive disorder (MDD) is one of the most frequent comorbid condi-
tions in GAD and for patients with both GAD and MDD it makes sense to select a
treatment that is effective in both. Since both the SSRIs and the SNRIs have shown
efficacy in both MDD and GAD they are obvous first-line treatments where there is
overlap. Anxiety symptoms subside when the MDD is treated with SSRIs or SNRIs
and depressive symptoms when the GAD is treated. Prospective trials of efficacy
in GAD comorbid with MDD would be helpful. In GAD with mild depression that
does not meet the diagnostic criteria for MDD there appears to be no advantage
for antidepressants compared with other treatments. Pregabalin and venlafaxine
were equally effective in GAD compared with placebo in improving mild depres-
sive symptoms as measured on the Hamilton Depression Scale (HAMD)111 and it
seems likely that these mild symptoms are part of GAD rather than representing
a comorbid depressive disorder. Benzodiazepines are thought to be ineffective or
even to make depression worse and, since they are not licensed for either GAD
or depression and have other well-known risks, they should be avoided.
GAD and bipolar depression

There is a high level of comorbidity between GAD and bipolar disorder and treat-
ing GAD under these circumstances is particularly difficult. It is recommended
that antidepressants in general should be avoided in bipolar depression as they
may cause switches to mania and are not particularly effective. Lithium, which
is widely used, has been shown to be effective in mania but is less effective for
depression and in recent studies in bipolar depression lithium did not separate
from placebo in the short or long term.112 The only treatment licensed in bipolar
depression in the EU is quetiapine and some very recent data show placebo-
controlled efficacy of this drug at relatively low doses in both GAD and MDD.
The use of a licensed treatment for GAD concomitantly with a licensed treatment
for bipolar depression would appear to be the only evidence-based option.
t )"/%#00, 0' (&/&3"-*4&% "/9*&5: %*403%&3
GAD in elderly people

The treatment of GAD in elderly people has not, until recently, been well investigated.
This is regrettable since GAD is the most frequent anxiety diagnosis in elderly
patients attending for treatment and is therefore a large public health issue. It
is reported that about half of the elderly population with GAD have a recent
onset.113 Post-hoc meta-analyses of placebo-controlled datasets suggest that some
treatments for GAD appear to be effective in older patients aged 6065 as well
as younger patients.114,115 A small placebo-controlled study looking at anxiety
disorders, including GAD, in elderly people showed benefit with citalopram;
however, given that there were no other placebo-controlled data on the efficacy
of citalopram in GAD this finding is of limited value.116 Pregabalin in a flexible
dose has been shown to be effective compared with placebo and well tolerated
in a specific study of GAD in patients over the age of 65.41 The treatment effect
was similar to that observed in non-elderly GAD suffers and there appeared
to be no diminution of treatment effect in the smaller subgroups over the age
of 70 or 75.41 Until further studies become available pregabalin has the most
secure evidence base for the treatment of GAD in elderly people.
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91. Boyer WF, Feighner JP. A placebo-controlled double-blind multicenter trial of two doses
of ipsapirone versus diazepam in generalized anxiety disorder. Int Clin Psychopharmacol
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'POUBJOF 3 "OOBCMF - $IPVJOBSE ( FU BM #SPNB[FQBN BOE EJB[FQBN JO HFOFSBMJ[FE
anxiety : a placebo-controlled study with measurement of drug plasma concentrations.
J Clin Psychopharmacol 1983; 3: 807.
'SFFNBO".*** 8FTUQIBM+3 /PSSJT(5 FUBM&GGJDBDZPGPOEBOTFUSPOJOUIFUSFBUNFOUPG
generalized anxiety disorder. Depress Anxiety 1997; 5:1401.
-ZEJBSE3# #BMMFOHFS+$ 3JDLFMT,"EPVCMFCMJOEFWBMVBUJPOPGUIFTBGFUZBOEFGGJDBDZ
of abecarnil, alprazolam, and placebo in outpatients with generalized axiety disorder.
Abecarnil Work Group. J Clin Psychiatry 1997; 58:118.
.PMMFS)+ 7PM[)1 3FJNBOO*8 FUBM0QJQSBNPMGPSUIFUSFBUNFOUPGHFOFSBMJ[FEBOYJFUZ
disorder: a placebo-controlled trial including an alprazolam-treated group. J Clin
(PMECFSH )- 'JOOFSUZ 3+ 5IF DPNQBSBUJWF FGGJDBDZ PG CVTQJSPOF BOE EJB[FQBN JO UIF
treatment of anxiety. Am J Psychiatry 1979; 136:11847.
(BNNBOT 3& 4USJOHGFMMPX +$ )WJ[EPT "+ FU BM 6TF PG CVTQJSPOF JO QBUJFOUT XJUI
generalized anxiety disorder and coexisting depressive symptoms. A meta-analysis of
eight randomised controlled studies. Neuropsychobiology 1992; 25:193201.
98. Montgomery SA. Clinically relevant outcome measures in MDD: focus on the latest
RVFUJBQJOF93EBUB1SFTFOUFEBUUI*OUFSOBUJPOBM'PSVNPO.PPEBOE"OYJFUZ%JTPSEFST
7JFOOB "VTUSJB/PWFNCFSo 40
t 3&'&3&/$&4
99. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder:
a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2008;
28:5616.
)PFIO4BSJD3 .D-FPE%3 ;JNNFSMJ8%%JGGFSFOUJBMFGGFDUTPGBMQSB[PMBNBOEJNJQSBNJOF
in generalized anxiety disorder: somatic versus psychic symptoms. J Clin Psychiatry. 1988;
49:293301.
101. Lader M, Scotto JC. A multicentre double-blind comparison of hydroxysine, buspirone
and placebo in patients with generalized anxiety disorder. Psychopharmacology (Berlin).
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"EBNT +# 1ZLF 3& $PTUB + FU BM " EPVCMFCMJOE QMBDFCPDPOUSPMMFE TUVEZ PG B $$,#
receptor antagonist, CI-988, in patients with generalized anxiety disorder. J Clin
#SPXO5" 0-FBSZ5" #BSMPX%)(FOFSBMJ[FEBOYJFUZE%JTPSEFS*O#BSMPX%) FE$MJOJDBM
)BOECPPLPG1TZDIPMPHJDBM%JTPSEFST/FX:PSL(VJMGPSE1SFTT o
104. Borkovec TD, Costello E. Efficacy of applied relaxation and cognitive-behavioral therapy in
the treatment of generalized anxiety disorder. J Consult Clin Psychol 1993; 61:6119.
#BSMPX %) 3BQFF 3. #SPXO5" #FIBWJPSBM USFBUNFOU PG HFOFSBMJ[FE BOYJFUZ EJTPSEFS
Behav Ther 1992; 23:55170.
%VSIBN3$ .VSQIZ5 "MMBO5 FUBM$PHOJUJWFUIFSBQZ BOBMZUJDQTZDIPUIFSBQZBOEBOYJFUZ
management training for generalised anxiety disorder. Br J Psychiatry. 1994; 165:315
23.
%VSIBN3$ 5VSWFZ""$PHOJUJWFUIFSBQZWTCFIBWJPVSUIFSBQZJOUIFUSFBUNFOUPGDISPOJD
HFOFSBMBOYJFUZ#FIBW3FT5IFSo
-JOETBZ83 (BNTV$7 .D-BVHIMJO& FUBM"DPOUSPMMFEUSJBMPGUSFBUNFOUTGPSHFOFSBMJ[FE
anxiety. Br J Clin Psychol 1987; 26:315.
1PXFS,( 4JNQTPO3+ 4XBOTPO7 FUBM"DPOUSPMMFEDPNQBSJTPOPGDPHOJUJWFCFIBWJPS
therapy, diazepam, and placebo in the management of generalized anxiety. J Anxiety
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Psychol 1967; 6:27896.
#PXEFO$- $BMBCSFTF+3 4BDIT( FUBM"QMBDFCPDPOUSPMMFENPOUIUSJBMPGMBNPUSJHJOF
and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I
disorder. Arch Gen Psychiatry 2003; 60:392400.
#MB[FS%( )VHIFT% (FPSHF-, FUBM(FOFSBMJ[FEBOYJFUZEJTPSEFS*O3PCJOT-/ 3FHJFS
DA (eds.) Psychiatric Disorders in America: the Epidemiologic Catchment Area Study.
/FX:PSL5IF'SFF1SFTTo
,BU[*3 3FZOPMET$' "MFYPQPVMPT(4 FUBM7FOMBGBYJOF&3BTBUSFBUNFOUGPSHFOFSBMJ[FE
anxiety disorder in older adults: pooled analysis of five randomized placebo-controlled
clinical trials. J Am Geriatr Soc 2002; 50:1825.
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Am J Psychiatry 2005; 162:14650.
Index
adolescents 7, 32 chronic anxiety 8

age of onset 67, 14 citalopram 26, 52
agomelatine 434 clinical efficacy studies 8
alprazolam 356, 41 Clinical Global Impression Scale 23, 29
antiarrhythmics 28 cognition 25, 40, 41
antidepressants 2531, 39, 434, 51 cognitive-behavioural therapy
antihistamines 44 (CBT) 20, 46, 50
antipsychotics 423 comorbidity 1316
anxiety disorders 15 coronary heart disease 10, 15
duration 23 costs 1920
in European Union 5 Covi Anxiety Scale 21, 23
GAD comorbidity 14
anxiety management 46 depression 512
anxiety neurosis 1, 40, 41 GAD comorbidity 14, 15, 18
arthritis 10 treatment 28
assessment of severity 214 diabetes 10
atypical chest pain 10 diagnosis 13, 78, 15
autonomic symptoms 3 Diagnostic and Statistical Manual
(DSM) system 13
benzodiazepines 11, 3941, 42, 44, 50, 51 diazepam 401, 44, 46
beta-blockers 44 disability 1718
bipolar depression 3, 6, 15, 512 discontinuation symptoms 39, 43
-blockers 44 dose escalation 40
Brazil 7 dropout rate (treatment) 41
British Association drug dependency 39, 40, 41
of Psychopharmacology 50 drug treatment 2544
burden of illness 1720 DSM-III criteria 12
buspirone 1, 11, 412 DSM-IV criteria 23, 7, 17, 28
duloxetine 324, 43, 51
calcium channel receptor modulators 349 duration of illness 8, 1516
Canada 7
cardiac disorders 10, 15, 16 economic costs 1920
CBT see cognitive-behavioural therapy efficacy studies 8
CCK antagonists 44 elderly people 18, 29, 38, 52
channel receptor modulators 349 escitalopram 26, 27, 2830
chest pain 10 ESEMeD (European Study of Epidemiology
children 7, 30, 32 of Mental Disorders) 14
cholesterol 33 EU (European Union) 5
t */%&9
European Study of Epidemiology of Mental

Disorders (ESEMeD) 14 National Comorbidity Study (NCS) 14
European Union (EU) 5 Netherlands 7, 8
neurosis concept 1
flexible doses 26, 32, 33 Norway 8
fluoxetine 25
France 19 PCTFTTJWFDPNQVMTJWFEJTPSEFS 0$%

functional impairment 1718 older people 18, 29, 38, 52
onset age 67, 14
GABA receptor modulators 349 open treatment 46
GAD definition 13 outcomes 14
Germany 67, 10, 13
pain 3, 1011, 15, 16, 19
Hamilton Anxiety (HAM-A) treatment 34, 39
scale 1, 21, 22, 27, 28, 29, 34, 41 panic disorder 1, 14, 26
Hamilton Depression Scale (HAMD) 51 paroxetine 258, 30
)BSWBSE#SPXO"OYJFUZ3FTFBSDI1SPHSBNNF pharmacology 2544
)"31
pharmacotherapy 467
Holland 7, 8 post-traumatic stress disorder (PTSD) 5, 14
Hospital Anxiety and Depression Scale 21 pregabalin 11, 349, 41, 50, 51, 52
hydroxazine 44 presenting features see symptoms
hypertension 15 prevalence 58
primary care
ICD attendance rates 19
(International Classification of Diseases) 3 GAD presentation 910
imipramine 40, 44 psychic symptoms 1, 11, 21, 29
insomnia 21 treatment 30, 32, 37, 38, 39, 44
International Classification of psychotherapy 46
Diseases (ICD) 3 PTSD see post-traumatic stress disorder
ipsapirone 44 pyschological treatment 457
irritable bowel syndrome 10, 15, 16
quality of life impairment 1718
lithium 51 quetiapine 51
liver toxicity 43 RVFUJBQJOF93o
lorazepam 34, 35, 41
lost work days 19, 20 3BTLJO%FQSFTTJPO4DBMF
lumpers 1 recognition level 14, 15, 17
relapse prevention 27, 30, 4950
major depressive disorder relaxation therapy 46
(MDD) 3, 6, 14, 15, 18, 42 remission rates 29
treatment 51 respiratory disorders 16
mania 51
MDD see major depressive disorder SDS see Sheehan Disablility Scale
measurement of severity 214 selective serotonin reuptake inhibitors
medical care costs 1920 443*T
o
medication 2544 self-rating scales 21, 23, 24
memory impairment 40 serotonin noradrenaline reuptake inhibitors
meta-analyses 32, 412, 52 4/3*T
o
mild depression 51 sertraline 26, 301, 43, 51
NJYFEFGGFDUTSFQFBUFENFBTVSFT ..3.
severity measurement 214
analysis 33, 34, 36 Sheehan Disablility Scale (SDS) 23, 24
*/%&9 t
Short-Form (SF-36) Health Survey 17

side effects 25, 26, 30, 31, 33, 39, 42, 43, 44
sleep disturbance 11, 21, 39, 51
4/3*TTFFTFSPUPOJOOPSBESFOBMJOF
reuptake inhibitors
social anxiety disorder 14, 26
social impairment 17, 18
somatic disorders 15
somatic symptoms 1, 3, 10, 11, 21
treatment 30, 32, 37, 38, 39, 50
somatisation disorder 10
somatoform pain disorder 10
specific phobia 14
splitters 1
443*TTFFTFMFDUJWFTFSPUPOJO
reuptake inhibitors
suicide 18
symptoms 911
severity measurement 214
TCAs see tricyclic antidepressants

time courses of symptoms 1516
treatment 8, 16, 20, 4952
duration 4950
pharmacological 2544
pyschological 457
5SFBUNFOU3FTJTUBOU%FQSFTTJPO(SPVQ
tricyclic antidepressants (TCAs) 28, 44
undertreatment 8
USA 7, 19
venlafaxine 21, 313, 35, 36, 38, 39,

41, 43, 51
women 6
work impairment 17, 18, 19, 20
Zurich study 17
Index compiled by Indexing Specialists (UK) Ltd

www.indexing.co.uk

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Handbook of

Generalised Anxiety Disorder

Copyright 2009 Current Medicine Group, a part of Springer Science+Business Media

ISBN 978 1 85873 441 5

British Library Cataloguing-in-Publication Data.

Commissioning editor: Ian Stoneham

Author biography vii

1 The changing concept of generalised anxiety disorder 1

2 How common is generalised anxiety disorder? 5

3 Presenting features of generalised anxiety disorder 9

4 Cormobidity of generalised anxiety disorder with

5 Burden of generalised anxiety disorder 17

6 Measuring the severity of generalised anxiety disorder 21

9 Which treatments, when and for how long? 49

The changing concept of generalised

Generalised anxiety disorder (GAD) is commonly regarded to be the key anxiety

Current DSM-IV diagnostic criteria for generalised anxiety disorder

there had to be excessive anxiety or worry about a number of events or activities

How common is generalised anxiety

Generalised anxiety disorder (GAD) as currently defined is a very common

12-month prevalence of clinically significant DSM-IV anxiety disorders in 16

PTSD 1.1 3.6 (3.24.0)

0$% 0.7 2.7 (2.53.1)

Any specific 6.4 18.5 (12.721.2)

Panic 1.8 5.3 (4.35.3)

Figure 2.1 12-month prevalence of clinically significant DSM-IV anxiety disorders in 16 EU

S. A. Montgomery, Handbook of Generalised Anxiety Disorder

if the less demanding one-month minimum duration criterion is applied.2 The

GAD is the most frequent anxiety disorder in primary care

Age groups (years)

Cumulative age of onset for GAD

GAD in children and adolescents

Course of GAD in adults

depends on a minimum 6-month duration of illness that is chronic; however,

Presenting features of generalised anxiety

Primary reasons for the presentation of GAD

Sleep disturbance 32.5

Frequency of patients reporting reason for contact

S. A. Montgomery, Handbook of Generalised Anxiety Disorder

Presenting features of GAD in primary care

Somatic symptoms associated with GAD

Comorbidity of generalised anxiety disorder

Comorbidity with GAD over 12 months in Germany

S. A. Montgomery, Handbook of Generalised Anxiety Disorder

Comorbidity with depression

Comorbidity with anxiety disorders

Identifying GAD and comorbid conditions

Burden of generalised anxiety disorder

GAD is associated with major functional impairment in work (Figure 5.1) or

S. A. Montgomery, Handbook of Generalised Anxiety Disorder

The disability associated with major depressive disorder (MDD) is now

Suicide risk and the burden of GAD

Days lost from work due to GAD

Measuring the severity of generalised

Hamilton Anxiety rating scale

Figure 6.1 Hamilton Anxiety rating scale. Adapted from Hamilton.9

Figure 6.2 Covi-Anxiety Scale. Adapted from Lipman et al.48

In addition to the scales measuring specific aspects and symptoms of GAD it is

Clinical Global Impression Scale

Figure 6.4 Sheehan Disability Scale.%BWJE74IFFIBO"MMSJHIUTSFTFSWFE3FQSPEVDFE

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