Mb managing anxiety_in_practice_april_26

MIND & BRAIN, THE JOURNAL OF PSYCHIATRY MEETING REPORT

Managing Anxiety in Practice: Focus on Generalized
Anxiety Disorder
Dr. Henk Parmentier, MD, DFFP
General Practitioner, Croydon, South London, United Kingdom

A B S T R A C T

Generalized Anxiety Disorder (GAD) is the second most common anxiety disorder (after phobias) with a lifetime prevalence of
approximately 5–10% and a point prevalence in the general population of approximately 2%, depending on gender. Despite its prevalence,
only one-third of patients with GAD are diagnosed by their primary care physician even though they are frequent attenders of primary care
clinics. Patients with GAD constitute a diagnostic challenge because they often present with disturbed sleep or medically unexplained
symptoms such as pain rather than with anxiety per se. GAD is usually comorbid with other disorders, particularly other psychiatric disorders,
and with medical disorders, which presents further diagnostic challenges. GAD itself is a risk factor for the development of subsequent Major
Depressive Disorder and may also contribute to an increased risk of or poorer outcomes from medical disorders such as diabetes and
cardiovascular disease. GAD exacts a substantial personal, societal and economic burden. Based on a thorough review of the evidence, the
World Federation of Societies of Biological Psychiatry has recommended pregabalin, SSRIs and SNRIs as first-line treatments for GAD.
Benzodiazepines are reserved as a second-line treatment for short-term use due to concerns about the potential for abuse and dependence.
Experts in the management of GAD regard it as an important psychiatric and public health problem that has been somewhat neglected and
for which better physician education is needed.

Correspondence: Henk Parmentier, MD, 53 Smitham Bottom Lane Purley, Surrey, CR8 3DF, United Kingdom, Email:
henk.parmentier@gmail.com

INTRODUCTION genuine desire amongst delegates to engage, to learn, and to
exchange practical clinical experiences. It was also stimulat-
Generalized Anxiety Disorder (GAD) is the second most
ing to see the collaboration and the exchange of ideas
common anxiety disorder (after specific phobias).[1]. It
between primary care practitioners and secondary care
affects approximately 2% of the general adult population in
psychiatric colleagues.
a given year, which equates to approximately 6 million people
in Europe[2], and it is associated with a substantial personal, If all of the clinicians who came to the meeting went back to
societal and economic burden. However, despite its high their own practices with expanded knowledge and the passion
prevalence and significant impact on the sufferer, GAD can be to share that knowledge with colleagues and patients, we may
challenging to diagnose as patients often present with vague be one step closer to moving GAD out of the shadows as one of
medically unexplained symptoms, and many have concurrent the most under-recognized mental disorders and improving
psychiatric or physical disorders that can mask the underlying the recognition, diagnosis, and treatment of this condition.
anxiety disorder. This report presents highlights from the plenary presenta-
Many experts in the management of GAD believe the tions given at the MAP meeting as well as some practice
condition has been somewhat neglected as a public health points that might be useful to practicing clinicians in all
concern and that better and broader physician education is spheres of medicine and their patients.
needed. To help address this educational need, the Managing
Anxiety in Practice (MAP2) program convened a pan-European REFERENCES
meeting that was attended by around 1000 physicians with a 1. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe – a
special interest in anxiety disorders. The program was critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005;
developed by a steering committee of European experts in 15(4):357–76.
GAD, with additional experts contributing to the content of 2. Lieb R, Becker E, Altamura C. The epidemiology of generalized anxiety
disorder in Europe. Eur Neuropsychopharmacol. 2005;15(4):445–52.
the plenary sessions and interactive workshops.
As a General Practitioner myself, I found the meeting both
stimulating and thought-provoking. I was surprised at the GAD: THE MAGNITUDE OF THE PROBLEM
different levels of understanding and the different ways of Professor Hans-Ulrich Wittchen from the Technical
working represented in the room, reflecting clinical practices University of Dresden, Germany, gave an overview of the
from all over Europe. I was also reassured that there was a burden of GAD in terms of its prevalence and cost to the

M&B 2010; 000:(000). Month 2010 1 www.slm-psychiatry.com

Mind & Brain, the Journal of Psychiatry jop222386.3d 26/4/10 15:56:20
The Charlesworth Group, Wakefield +44(0)1924 369598 - Rev 9.0.225/W (Oct 13 2006)

Mind & Brain, the Journal of Psychiatry

Age of subject when examined: 45

Mean: 1.4% (Range: 0.2_3.1)* Current (point) prevalence Age of subject

Median: 1.7% (IQR: 0.8_2.2)*† Age of subject
12-month prevalence

5.1%(SE=0.3)‡ Age of subject
Lifetime prevalence

8.3%(SE= 0.4)§ Age 75
Projected lifetime risk up to age 75

Figure 1. Examples of different approaches to the evaluation of GAD epidemiology.
* Reference 2; {Reference 3; {Reference 4; 1Reference 5

individual and to the healthcare system, its association with and depression are highly inter-related and that clinicians
other conditions, and its likelihood of being recognized and should seek to establish the presence of GAD in any
appropriately treated in clinical practice. According to individual presenting with chronic pain, insomnia, or Major
Professor Wittchen, studies assessing the epidemiology of Depressive Disorder (MDD).
GAD have been hampered by a number of issues, including Professor Wittchen also showed evidence that patients with
multiple changes in the diagnostic criteria over the past two GAD visit doctors at least as often as patients with MDD
decades, a lack of recognition and diagnostic assignment of (Figure 3). In addition, patients with GAD are more impaired
patients, and the fact that the DSM-IV criteria currently require
in daily life than those with other anxiety disorders,[9] and
patients to have a strictly defined number of very specific
they use more healthcare resources than those with MDD
symptoms on most days for at least six months.[1] He also
(J1557 vs. J1035 per year).[10, 11] He also presented
suggested that GAD was quite a difficult diagnostic concept,
unfortunate evidence that primary care teams correctly
with the condition frequently being misunderstood and
diagnose GAD in only around one-third of cases despite
misinterpreted as either a personality variant/trait or a variant
high rates of recognition that the patient has a ‘‘mental
of depression. Professor Wittchen gave an elegant overview of
disorder’’.[10] One of the main reasons that most patients are
the different epidemiological approaches to reporting the
not identified or correctly diagnosed is because most do not
prevalence and risk of GAD (Figure 1). Well conducted
actually present with anxiety as their primary complaint;
epidemiological studies using strict DSM-III or IV criteria
instead, they often present with sleep disorders and somatic
suggest that in any given year, approximately 6 million adults
complaints. Patients most likely to be overlooked in primary
in the European Union will suffer from the condition.[2]
care include those with vague presenting problems and
Community-based studies have also confirmed that GAD multiple concurrent disorders, concurrent threshold and
affects adults across the lifespan, with prevalence rates subthreshold depression, medically unexplained somatoform
tending to increase with age (Figure 2).[4] Overall, the syndromes and pain disorders, and sleep disorders. Perhaps
estimated prevalence is 2.6% in men and 6.6% in women. even more worryingly, studies also suggest that GAD patients
Unlike other anxiety disorders, DSM-IV GAD is rare in who are not recognized and diagnosed appropriately either
children and adolescents[6, 7] but quite prevalent among
older patients.[4] In a recent study, the overall prevalence of 10
GAD among elderly people was estimated to be 8.9%, which Primary care setting General population
was higher than previously thought.
8
Studies have found that GAD is 3–6 times more prevalent in
Point prevalence (%)

the primary care setting than in the general population
(Figure 2)[8], suggesting that patients with GAD are frequent 6
attenders of their primary care clinics. Indeed, GAD has been
found to be the most common anxiety disorder in the primary 4
care setting.[8]
GAD frequently co-exists with other medical and psychiatric 2
conditions. According to one study in Germany conducted in
a nationally representative sample of adults aged 18–65 years
(N54181), 59% of patients with 12-month GAD also fulfilled 0
15_24 25_34 35_44 45_65 65+
the DSM-IV criteria for major depression, 36% of patients
also had dysthymia, and around one-third had phobia (Table Age range (years)
1).[6] Interestingly, almost half (48.1%) of the GAD patients
Figure 2. Current (point) prevalence of GAD in the primary care setting
also had a somatoform disorder and 38% had a pain compared with the general population according to age group
disorder.[6] Professor Wittchen noted that that anxiety, pain Reference 8



Managing Anxiety in Practice

Table 1. Percentage of adults with 12-month DSM-IV GAD and concurrent 80
conditions compared with those without GAD or MDD. No GAD or MDE (n=16,023)
70 Pure GAD (n=666)
GAD No GAD Odds

% of respondents
60 Pure MDE (n=772)
Comorbid disorder (n573) (n54108) Ratio P Value* GAD + MDE (n=278)
50
Alcohol abuse/dependence 6.4 3.9 2.8 NS
40
Nicotine dependence 14 10.2 1.7 NS
30
Drug abuse/dependence 1.4 0.7 4.2 NS 20
Any depressive disorder 70.6 9.9 20.3 ,0.05 10

Major depression 59 7.5 16.7 ,0.05 0
4 to PCP 2 to other 1 to psychiatrist
Dysthymia 36.2 4 12 ,0.05 specialist
Any anxiety disorder 55.9 12.9 8.1 ,0.05 Doctors visited in the past year

Panic disorder 21.5 2 12.3 ,0.05 Figure 3. Doctor visits on the past year* with and without GAD and/or MDE.
*Generalized Anxiety and Depression in Primary Care (GAD-P) study involving
Agoraphobia without panic 11.3 1.9 5.4 ,0.05 558 primary care physician practices in Germany that screened 17,739
consecutive primary care patients. MDE: major depressive episode.
Social phobia 28.9 1.6 25.9 ,0.05 Reference 8
Specific phobia 29.3 7.3 4.9 ,0.05
Phobia NOS 10.6 3.3 3 ,0.05 10. Wittchen HU, Kessler RC, Beesdo K, et al. Generalized anxiety and
depression in primary care: prevalence, recognition, and management. J
Obsessive–compulsive disorder 10 0.6 19.6 ,0.05
Clin Psychiatry. 2002b;63 (suppl 8):24–34.
Any somatoform disorder 48.1 10.4 7.2 ,0.05 11. Andlin-Sobocki P, Wittchen HU. Cost of anxiety disorders in Europe. Eur
J Neurol. 2005;12 (suppl 1):39–44.
Any eating disorder 2.5 0.3 9.2 ,0.05
Any of the above disorders 93.1 33.5 26.6 ,0.05
One of the above disorders 19.7 23.2 0.8 NS
Two of the above disorders 40.6 7.4 8.3 ,0.05 PRACTICE POINTERS
Three of the above disorders 32.7 2.9 16.6 ,0.05 The finding that the majority of patients with GAD are
overlooked in primary care is not surprising. Primary
*P value based on Odds Ratio for GAD vs. no GAD, controlled for age and gender. care physicians see many patients with concurrent
NS: Not statistically significant (P$0.05). anxiety, depression and mixed somatic symptomatol-
Reference 6
ogy, and it is often difficult to distinguish the clinical
receive no treatment for their anxiety or receive inadequate entities and treat them adequately. Professor Wittchen
treatments such as sedatives and herbal medications.[10] did well to remind us that patients with GAD are often
more disabled than those with depression because we
can usually see the despair in our depressed patients,
REFERENCES while our patients with GAD frequently present with
1. American Psychiatric Association. Diagnostic and Statistical Manual of other dominant complaints.
Mental Disorders (4th Edition, Text Revision). Washington DC, 2000.
2. Lieb R, Becker E, Altamura C. The epidemiology of generalized anxiety The key ‘‘take home’’ messages from this presenta-
disorder in Europe. Eur Neuropsychopharmacol. 2005;15(4):445–52. tion are:
3. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe – a N Dig beneath the surface for symptoms of anxiety in
critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005;
patients who present with vague problems like aches
15(4):357–76.
4. Wittchen HU, Zhao S, Kessler RC, et al. DSM-III-R generalized anxiety
and pains or insomnia for which there is no medical
disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1994; explanation. Ask the question: ‘‘Why aren’t you
51(5):355–64. sleeping?’’
5. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and N Recognize that many patients with GAD are frequent
comorbidity of 12-month DSM-IV disorders in the National attenders in primary care. Some of our most
Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–27.
challenging patients who are chronically unwell with
6. Carter RM, Wittchen HU, Pfister H, et al. One-year prevalence of
subthreshold and threshold DSM-IV generalized anxiety disorder in a
a variety of unexplained complaints could well be
nationally representative sample. Depress Anxiety. 2001;13(2):78–88. suffering from an underlying and treatable disorder
7. Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost such as GAD.
to society. Depress Anxiety. 2002a;16(4):162–71. N If you suspect a mental health problem, explore the
8. Wittchen HU, Krause P, Hoyer J, et al. Prevalence and correlates of possibility that it is GAD rather than just excluding
generalized anxiety disorders in primary care. Fortschr Med Orig. 2001;119
depression.
(suppl 1):17–25.
9. Wittchen HU, Carter RM, Pfister H, et al. Disabilities and quality of life in
N Strive to recognize GAD early, diagnose accurately,
pure and comorbid generalized anxiety disorder and major depression in and treat appropriately.
a national survey. Int Clin Psychopharmacol. 2000;15(6):319–28.

www.slm-psychiatry.com 3 M&B 2010; 000:(000). Month 2010



NEUROBIOLOGY AND a3 receptor subtypes held some promise as anxiolytics
without these unwanted effects. He also highlighted the
PSYCHOPHARMACOLOGY OF GAD
limitations of the azapirones, which target 5-HT1A receptors,
Professor Johan A. den Boer from the University Medical as potential treatments for GAD, referring to a recent
Centre in Groningen, The Netherlands, presented a compre- Cochrane Review that was broadly negative for azapirones
hensive review of recent genetic and neuro-imaging studies in this indication.[10]
that have contributed to our current understanding of the
genetics and neurobiology of GAD. He emphasized at the Professor den Boer described the utility of SNRIs (e.g.,
start of his presentation that ‘‘worrying’’ has major biological venlafaxine, duloxetine) and a2d ligands (e.g., pregabalin) as
relevance, with studies suggesting that intense worrying is pharmacological treatments for GAD. He presented the
correlated with reduced immune function, increased levels of results from a range of studies with these agents and
pro-inflammatory cytokines, increased risk of heart disease, demonstrated the efficacy of both classes of drug as
and an increased risk of mortality.[1, 2] treatments for GAD.[11–13]

Reviewing recent genetic studies in GAD, Professor den Finally, Professor den Boer reviewed ongoing work that
Boer showed evidence that there is no single gene for GAD; could yield novel therapies for GAD in the future, including
rather, there is a complex interaction between a combination studies with peptides, 5-HT2C receptor antagonists, melato-
of genetic polymorphisms and environmental and psycholo- nergic receptor agonists, and mGlu receptor ligands.
gical factors that determines an individual’s response to
stress. In one study of patients with GAD he presented[3], the REFERENCES
frequencies of the serotonin transporter (5-HTT) gene-linked 1. Sternberg EM and Gold PW. The Mind-Body Interaction in Disease.
functional polymorphism region (5-HTTLPRS) short/short Scientific American, Special Edition: The Hidden Mind.2002;2(1):82–29
genotype was found to be significantly higher in GAD 2. Culpepper L. Generalized Anxiety Disorder and Medical Illness. J Clin
patients than control subjects (68% vs. 49%; p50.002), Psychiatry. 2009;70(suppl 2):20–24
3. You JS, Hu SY, Chen B, et al. Serotonin transporter and tryptophan
suggesting that this polymorphism may increase the risk for
hydroxylase gene polymorphisms in Chinese patients with generalized
GAD. In another study assessing the genetic association anxiety disorder. Psychiatr Genet. 2005;15(1):7–11.
between six single nucleotide polymorphisms from the 4. Wray NR, James MR, Mah SP, et al. Anxiety and comorbid measures
PLXNA2 gene and anxiety[4], a significant association was associated with PLXNA2. Arch Gen Psychiatry. 2007;64(3):318–26.
found between the rs2478813 polymorphism (and other 5. Jabbi M, Korf J, Kema IP, et al. Convergent genetic modulation of the
polymorphisms associated with it) and anxiety. However, as endocrine stress response involves polymorphic variations of 5-HTT,
COMT and MAOA. Mol Psychiatry. 2007;12(5):483–90.
Professor den Boer pointed out, neither of these results are 6. Whalen PJ, Johnstone T, Somerville LH, et al. A functional magnetic
specific to GAD, as similar results have been found in resonance imaging predictor of treatment response to venlafaxine in
depression and other anxiety disorders. generalized anxiety disorder. Biol Psychiatry. 2008;63(9):858–63.
7. Mathew SJ, Price RB, Mao X, et al. Hippocampal N-acetylaspartate
In an attempt to try and explain why some individuals have a concentration and response to riluzole in generalized anxiety disorder.
propensity to react in a distressed way to environmental Biol Psychiatry. 2008;63(9):891–8.
stimuli, Professor den Boer presented a study showing a clear 8. Blair K, Geraci M, Devido J, et al. Neural response to self- and other
correlation between the response to stress and the presence of referential praise and criticism in generalized social phobia. Arch Gen
polymorphic variations in genes coding for monoamine Psychiatry. 2008;65(10):1176–84.
9. Nitschke JB, Sarinopoulos I, Oathes DJ, et al. Anticipatory activation in
oxidase A (MAOA) and catechol-O-methyl transferase the amygdala and anterior cingulate in generalized anxiety disorder and
(COMT).[5] He said it seemed likely that people who carry prediction of treatment response. Am J Psychiatry. 2009;166(3):302–10.
these and other polymorphisms are especially prone to 10. Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized
psychological distress under challenging conditions. anxiety disorder. Cochrane Database Syst Rev. 2006 ;3:CD006115.
11. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) in
Neuro-imaging studies also support the theory that GAD the treatment of generalized anxiety disorder: twenty-four-week placebo-
has a biological foundation, with several studies demonstrat- controlled dose-ranging study. Br J Psychiatry. 2001;179:15–22.
ing that individuals with GAD have intensified responses to 12. Koponen H, Allgulander C, Erickson J, et al. Efficacy of Duloxetine for the
potentially adverse cues.[6–9] In one recent functional MRI Treatment of Generalized Anxiety Disorder: Implications for Primary
Care Physicians. Prim Care Companion J Clin Psychiatry. 2007;9(2):100–107.
study[9], Professor den Boer demonstrated that individuals
13. Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety of
with GAD had heightened and indiscriminate responses in pregabalin in the treatment of generalized anxiety disorder: a 6-week,
the amygdala to anticipatory signals of an aversive visual multicenter, randomized, double-blind, placebo-controlled comparison
stimulus, which he said suggested an over-emotional of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):771–82.
response based on fearful anticipation.
Turning to a discussion of the psychopharmacology of KEY DIAGNOSTIC ISSUES IN GAD
GAD, Professor den Boer urged delegates to look beyond The key diagnostic challenges associated with GAD were
benzodiazepines as treatments for GAD. He said current outlined by Professor Carlo Altamura from the Department of
therapeutic strategies that target the a1 subunit of the c- Psychiatry at the University of Milan in Italy. He explained that
aminobutyric acid (GABA)A receptor, such as benzodiaze- significant progress had been made over the years in defining
pines, caused unacceptable CNS depression, amnesia and GAD as a distinct clinical entity and in separating it from the
withdrawal effects, but that newer agents targeting the a2 or other anxiety disorders.[1] Today, both DSM-IV and ICD-10




untreated illness had a poorer response to pharmacological
PRACTICE POINTERS treatment and a worse clinical outcome.[4] The mean
I’m sure many clinicians, like me, find neurobiologi- duration of untreated illness before patients received
cal research somewhat daunting. As we consult with antidepressants was found to be 84.1 months in this study
our patients and try to reduce their anxiety symptoms – far longer than reported for other major psychiatric
and treat concurrent disorders and symptoms, few of us conditions (e.g., schizophrenia, depression).
will be wondering whether a polymorphism of the One of the main challenges for accurate identification of
PLXNA2 gene might be the underlying cause. GAD is that patients with GAD do not typically present with
Thankfully, however, as we focus on doing our best anxiety as their primary complaint.[5] Indeed, a very large
for our patients, scientists like Professor den Boer are study of primary care physicians conducted in Germany found
striving to find hidden keys to unlock new targets for that only 13% of patients with GAD presented with anxiety as
novel treatments that may one day end up on our their primary complaint (Figure 4). Patients frequently
prescription pads as more effective treatments with complain of gastrointestinal, cardiovascular or pain symp-
fewer side effects and better cost-effectiveness. toms, often leading to wasted resources spent pursuing
Although this presentation was highly technical, several medical lines of investigation that leave symptoms unex-
practice pointers emerged for me: plained and often untreated. In formal studies, GAD has been
N Many patients appear to be genetically or biologically strongly associated with chronic pain such as cluster head-
predisposed to suffer from anxiety. Some patients aches[6] and tension-type headaches[7], and a significant
will draw comfort from this, and we should use this proportion of patients with GAD manifest with painful
knowledge to reassure them that GAD is a serious irritable bowel syndrome (IBS).[8] In one study published in
disorder that, much like other medical conditions, 2009, 26% of patients with IBS were found to have GAD.[9]
has a solid biological foundation. An additional complication in the diagnosis of GAD is that the
N The use of benzodiazepines in a chronic condition such condition may present differently in older and younger
as GAD cannot be justified as a first-line treatment. individuals. The assessment of GAD in the elderly, in particular,
Thankfully, we now have several agents that are effective is often confounded by the presence of other chronic
in reducing anxiety, have different side effect profiles conditions, the frequent use of ‘‘irrational’’ polypharmacy, the
and are not associated with the problematic cognitive presence of cognitive impairment and a reluctance to report
impairment, dependence and withdrawal syndrome we psychiatric symptoms. Differentiating between depression and
see with chronic benzodiazepine treatment. anxiety is especially challenging in the elderly.
N The SSRIs, SNRIs and pregabalin appear to be
today’s drug treatments of choice in GAD. According to Professor Altamura, one of main problems in
Psychological therapies such as cognitive behavioral establishing a diagnosis of GAD in clinical practice is
therapy (CBT) also have an important role if patients disentangling the symptoms of anxiety disorders from those
are able to gain access to such treatments. of depressive disorders, particularly as GAD so often occurs
N Effective treatments for GAD are now available. concurrently with depression.[10] He noted that both GAD
Therefore, our priorities in clinical practice must be and major depressive disorder (MDD) were associated with
to identify our unidentified patients with GAD and sleep disturbances, concentration problems, fatigue, and
ensure that they are appropriately managed. psychomotor/arousal symptoms. However, these disorders
also have very specific symptoms that can help to distinguish
between them. Specific symptoms of MDD include suicidality,
diagnostic criteria focus on the quality and duration of the loss of appetite/weight, feelings of guilt/worthlessness, and
anxiety, on its clinical manifestations, and on the importance loss of interest/pleasure. In contrast, specific symptoms of
of differentiating it from other disorders in the clinic (Table anxiety disorders include muscle tension, compulsions,
2). The two criteria are similar in that they both require the worry, phobic avoidance and panic attacks. Often, a doctor
persistence of excessive anxiety and the presence of physical can ‘‘see’’ when a patient is depressed by their manner and
symptoms. However, as Professor Altamura explained, the posture – they may seem flat, sad, and sluggish. In contrast,
criteria differ in terms of the duration of symptoms ($6 chronic anxiety is not so easy to ‘‘see’’ – patients may seem
months in DSM-IV vs. several months in ICD-10), the need for alert, eager and vigilant, and this presentation may not strike
autonomic hyperactivity and physical manifestations, and the physician as being a signal of underlying psychopathology.
whether functional impairment is a requirement (Table 3). It may be less problematic to distinguish between the
Professor Altamura went on to present the results of a study different anxiety disorders. The British Association for
illustrating the importance of early diagnosis and effective Psychopharmacology (BAP) has provided guidance for physi-
treatment of GAD.[4] In this study, 100 patients with GAD cians to help them explore a suspected anxiety disorder and to
(DSM-IV criteria) were treated with SSRIs or venlafaxine for differentiate between the different variants (Figure 5).[11] The
eight weeks in open-label conditions, and treatment response cardinal sign of GAD is uncontrollable worry in multiple
and other clinical variables were assessed according to the areas of life, much of which is unfounded and has no rational
duration of untreated illness (#12 months or .12 months). basis. Pejoratively, others may consider such people ‘‘neuro-
The study found that patients with a longer duration of tic’’, and this label too can impact the physician’s assessment




Table 2. Summary of core DSM-IV and ICD-10 diagnostic criteria for GAD*.

DSM-IV ICD-10

A. At least 6 months of excessive anxiety and worry about a variety N Anxiety is generalized and persistent and not associated with a particular
of events and situations environmental circumstance (i.e., it is ‘‘free-floating’’)
B. Significant difficulty in controlling anxiety and worry N Anxiety present most days for at least several weeks at a time and usually for several
months
C. The presence for most days over the previous 6 months of three N Symptoms should involve elements of:
or more (only one for children) of the following symptoms:
1. Feeling wound-up, tense, or restless – Apprehension (worry about future, feeling ‘on edge’, difficulty concentrating)
2. Easily becoming fatigued or worn-out – Motor tension (restlessness, fidgeting, tension headaches, trembling, inability
to relax)
3. Concentration problems – Autonomic overactivity (lightheadedness, sweating, tachycardia or tachypnea,
epigastric discomfort, dizziness, dry mouth, etc.)
4. Irritability
5. Significant tension in muscles
6. Difficulty with sleep

D. Symptoms are not part of another mental disorder N Must not meet full criteria for depressive episode, phobic anxiety disorder, panic
disorder or obsessive-compulsive disorder
E. Symptoms cause clinically significant distress or functional impairment
F. Not due to medication, illness or substance abuse

*Both the DSM-IV and ICD-10 diagnostic criteria are being updated, with revised versions due to be published in 2013.
References 2,3

of the patient. One confounding factor in using such a more complete investigation of the possibility of GAD or
simplistic approach is often that GAD presents concurrently another anxiety disorder may be warranted.
with other anxiety disorders,[10] and the apparent predomi-
nance of one disorder does not preclude the existence of REFERENCES
another. 1. Rickels K, Rynn MA. What is generalized anxiety disorder? J Clin
Psychiatry. 2001;62 (suppl 11):4–12.
The use of screening tools (e.g., GAD-7, ASQ-15) to alert 2. American Psychiatric Association. Diagnostic and Statistical Manual of
the physician to the possibility that GAD may be present, Mental Disorders (4th Edition, Text Revision). Washington DC, 2000.
particularly among challenging patients, could help to
improve recognition of the disorder in psychiatric and
primary care settings. The GAD-7 screening tool (Figure 6)
may be especially helpful in primary care for identifying
Anxiety
probable cases of GAD and alerting the physician that further
diagnostic assessments may be required.[12] A score of 10 or
higher on the GAD-7 screening tool would indicate that a Depression

Sleep
disturbance
Table 3. DSM-IV and ICD-10 GAD diagnostic criteria: some key differences*.

DSM-IV ICD-10 Pain
Diagnostic classification Independent category Residual category
Worry/anxiety symptoms Excessive anxiety and Persistent free-floating Somatic
worry anxiety illness/
complaints
Duration $6 months Several months
0 20 40 60
Autonomic hyperactivity Not essential Must be present % of patients with GAD (n=666)
and physical symptoms
Figure 4. Primary complaint at presentation among patients with GAD in
Functional impairment Must be present Not specified the primary care setting*.
*Generalized Anxiety and Depression in Primary Care (GAD-P) study
*Both the DSM-IV and ICD-10 diagnostic criteria are being updated, with involving 558 primary care physician practices in Germany that screened
revised versions due to be published in 2013. 17,739 consecutive primary care patients.
Reference 1 Reference 5




Specific anxiety-related symptoms
& impaired function

Yes
Also moderate/severe Treat
depression? depression?
No Persistent anxiety symptoms despite
adequate trial of antidepressant treatment
Predominant symptom focus
Trauma history & Obsessions ± Uncontrollable worry in Intermittent panic/anxiety attacks and avoidance
flashbacks compulsion several areas

Fear of social Discrete/ Some uncued/
scrutiny object situation spontaneous

Check for Social Check for specific Check for Panic
Check for PTSD Check for OCD Check for GAD
Anxiety Disorder phobia Disorder

Figure 5. Guidance to exploring a suspected anxiety disorder and identifying the prevailing anxiety disorder(s)*.
*Adapted from the British Association for Psychopharmacology guidelines.
Reference 11

3. World Health Organization (WHO). The ICD-10 Classification of Mental 8. Tollefson GD, Luxenberg M, Valentine R, et al. An open label trial of
and Behavioural Disorders. Geneva, 1992. alprazolam in comorbid irritable bowel syndrome and generalized anxiety
4. Altamura AC, Dell’osso B, D’Urso N, et al. Duration of untreated illness disorder. J Clin Psychiatry. 1991;52(12):502–8.
as a predictor of treatment response and clinical course in generalized 9. Gros DF, Antony MM, McCabe RE, Swinson RP. Frequency and severity
anxiety disorder. CNS Spectr. 2008;13(5):415–22. of the symptoms of irritable bowel syndrome across the anxiety disorders
¨
5. Wittchen HU, Kessler RC, Beesdo K, Krause P, Hofler M, Hoyer J. and depression. J Anxiety Disord. 2009;23(2):290–6.
Generalized anxiety and depression in primary care: prevalence, 10. Carter RM, Wittchen HU, Pfister H, et al. One-year prevalence of
recognition, and management. J Clin Psychiatry. 2002;63(Suppl 8): subthreshold and threshold DSM-IV generalized anxiety disorder in a
24–34. nationally representative sample. Depress Anxiety. 2001;13(2):78–88.
6. Jorge RE, Leston JE, Arndt S, Robinson RG. Cluster headaches: 11. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for
association with anxiety disorders and memory deficits. Neurology. the pharmacological treatment of anxiety disorders: recommendations
1999;53(3):543–7. from the British Association for Psychopharmacology. J Psychopharmacol.
7. Puca F, Genco S, Prudenzano MP, et al. Psychiatric comorbidity and psychosocial 2005;19(6):567–96.
stress in patients with tension-type headache from headache centres in Italy. ¨
12. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for
The Italian Collaborative Group for the Study of Psychopathological assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;
Factors in Primary Headaches. Cephalalgia. 1999;19(3):159–64. 166(10):1092–7.

More Nearly
Over the last 2 weeks, how often have you Not Several than half every
been bothered by the following problems? at all days the days day
1. Feeling nervous, anxious or on edge 0 1 2 3
2. Not being able to stop or control worrying 0 1 2 3
3. Worrying too much about different things 0 1 2 3
4. Trouble relaxing 0 1 2 3
5. Being so restless that it is hard to sit still 0 1 2 3
6. Becoming easily annoyed or irritable 0 1 2 3
7. Feeling afraid as if something awful might happen 0 1 2 3
Total Add
= + +
Score Columns
If you checked off any problems, how difficult have these problems made it for you
to do your work, take care of things at home, or get along with other people?
Not difficult Somewhat Very Extremely
at all difficult difficult difficult

Figure 6. The generalized anxiety disorder 7-item (GAD-7) screening questionnaire{.
{
Score $10 indicates a possibility of GAD.
Reference 12




MANAGEMENT AND TREATMENT OF GAD:
PRACTICE POINTERS REVIEW OF TREATMENT GUIDELINES
This presentation was most informative and I was Professor Borwin Bandelow from the Department of
reassured to hear that research programs support what ¨
Psychiatry and Psychotherapy at the University of Gottingen
we often see in clinical practice – anxious patients in Germany, and lead author of the updated treatment
presenting with physical symptoms such as palpita- guidelines issued by the World Federation of Societies of Biological
tions, shortness of breath, or ‘‘mysterious’’ stomach Psychiatry (WFSBP) in 2008[1], outlined how the guidelines
pains and other medically unexplained symptoms. were developed and discussed key recommendations for the
Based on this presentation, a number of take home treatment of GAD. Professor Bandelow stressed that the
messages stand out: development of the guidelines was not supported by
N Don’t let patients go undiagnosed and untreated. pharmaceutical companies, but were developed independently
Leaving patients without treatment could mean storing by a panel of 30 international experts who reviewed over 500
up problems for patients and ourselves in the future, randomized and 130 open-label clinical trials. The evidence
and may lead to a poorer response to treatment. was carefully graded according to strict criteria that took
N GAD is almost always concurrent with another into account not only the quality and number of positive/
disorder(s), including psychiatric disorders (e.g., negative studies but also the risk:benefit ratio of each
depression, another anxiety disorder) and/or medical treatment, which significantly enhances the clinical relevance
disorders (e.g., diabetes, pain syndromes, headaches of the guidelines.
or arthritis).
According to the WFSBP treatment guidelines, the drugs
N DSM-IV and ICD-10 diagnostic criteria are helpful in
with the best quality evidence for benefits in GAD patients
showing clinicians what types of symptoms might be
and therefore recommended for first-line use are the SSRIs
present in GAD and reinforcing the chronic nature of
(escitalopram, paroxetine and sertraline), the SNRIs (venla-
those symptoms. However, few of us apply these
faxine and duloxetine) and the calcium channel modulator
criteria rigorously in day to day clinical practice.
pregabalin (Table 4, Figure 7). Although the quality of
Identification in the primary care setting could be
evidence was considered to be good for TCAs and benzodia-
improved by an awareness of the fact that patients
zepines, the guidelines have downgraded these treatments to
might have GAD if they have chronic medically-
second-line use in light of tolerability and other concerns
unexplained physical symptoms or residual symp-
(Table 4, Figure 7). Quetiapine was considered to have a good
toms and impairment when treated for depression.
evidence base, but is not currently a recommended treatment
N Because headache, stomach pains, IBS, cardiovascu-
in practice as it does not have a license for GAD in Europe.[1]
lar, and respiratory symptoms are clearly linked with
GAD, we should probe for anxiety symptoms in From a practical perspective, Professor Bandelow high-
patients presenting with these complaints. lighted the WSFBP recommendation that all first-line agents
N To disentangle anxiety from depression, we should should be used for at least 4–6 weeks before evaluating
look for the cardinal symptoms that help us to efficacy and safety and deciding, in the case of insufficient
differentiate between the two conditions. However, efficacy, to either change the dose, switch to another first-line
both often co-exist, and identifying GAD in patients agent, combine first-line agents, or use a second-line option
with depression is challenging. (Figure 7).[1] He said one of the disadvantages of the SSRIs/
N Stress symptoms secondary to environmental stres- SNRIs was the latency of effect (2–6 weeks) that necessitates
sors, like with the adjustment disorders, are different this 4–6-week initial trial period. In contrast, he said
from GAD symptoms but may overlap. pregabalin had a rapid onset of effect, with clinical trials
N Chronic benzodiazepine use may actually fuel anxiety demonstrating relief of anxiety symptoms within a matter of
due to withdrawal symptoms, and the anxiolytic days.[2]
benefits of benzodiazepines can often diminish with Professor Bandelow presented some of the studies that led
long term use. the WFSBP guidelines task force to make its recommenda-
N Elderly patients with GAD need special attention; tions and showed evidence that venlafaxine in doses of 75–
they do not always present in the same way as 225 mg/day significantly improved HAM-A total scores vs.
younger patients with GAD. We need to learn how to placebo over eight weeks of treatment and produced a $50%
recognize GAD in the elderly population. improvement from baseline in HAM-A total scores at eight
N Although the diagnosis of GAD is based on clinical weeks in most published placebo-controlled trials (Figure
history (i.e. there are no markers, blood tests, EEG 8).[3–5]
etc.), practices should consider using GAD screening
tools (such as GAD-7 and ASQ-15) in patients who In reviewing the duloxetine studies in GAD[6–9], Professor
are suspected of having GAD; this may prompt the Bandelow shared data showing that not only was duloxetine
physician to further evaluate the patient using a more superior to placebo in reducing anxiety symptoms (HAM-A
comprehensive and objective diagnostic process. total scores) in most short-term studies (Figure 9), it was also
superior to placebo for relapse prevention in patients with
GAD who had initially responded to duloxetine.[10]




Table 4. Category of evidence and recommended grades from WFSBP evidence-based review of GAD treatments,

Treatment Examples Category of evidence* Recommendation grade{ Recommended daily dose for adults
SSRIs .Escitalopram A 1 10–20 mg
.Paroxetine A 1 20–50 mg

.Sertraline A 1 50–150 mg
SNRIs .Venlafaxine A 1 75–225 mg
.Duloxetine A 1 60–120 mg
Calcium channel modulator .Pregabalin A 1 150–600 mg
Atypical antipsychotic .Quetiapine A 1 50–300 mg
TCA .Imipramine A 2 75–200 mg

Benzodiazepines .Diazepam A 2 5–15 mg
.Lorazepam A 2 2–8 mg
Antihistamine .Hydroxyzine A 2 37.5–75 mg
Tricyclic anxiolytic .Opipramol B 3 50–150 mg
Azapirone .Buspirone D 5 15–60 mg

*A5full evidence from controlled studies; B5limited positive evidence from controlled studies; C5evidence from uncontrolled studies or case reports/expert
opinion; D5inconsistent results; E5negative evidence; F5lack of evidence.
{15category A evidence and good risk:benefit ratio; 25category A evidence and moderate risk:benefit ratio; 35category B evidence; 45category C evidence;
55category D evidence.
Not all agents listed have a licensed indication for GAD in Europe.
Reference 1

According to Professor Bandelow, pregabalin has the most studies that have been conducted to assess the efficacy and
comprehensive database supporting the efficacy and toler- safety of pregabalin in the treatment of GAD[2, 11–17]. In
ability of any drug in GAD. He reviewed some of the many these studies, pregabalin has been shown to be significantly
more effective than placebo in reducing the HAM-A total
FIRST-LINE score (Figure 10) and was shown to reduce the risk of
Pregabalin relapse.[18] In one recently published study including
SSRIs
SNRIs pregabalin (300–600 mg/day; n5121), venlafaxine XR (75–
225 mg/day; n5122) and placebo (n5127) over an eight week
4–6 period, statistically significant improvements in HAM-A total
Weeks scores were seen as early as day 4 in the pregabalin group
(p#0.001 vs. placebo; p,0.05 vs. venlafaxine).[2]
Response?
When discussing the treatment of GAD in the elderly, he
Partial presented one of the only well controlled studies specifically
No Yes
conducted in this vulnerable group of patients, which
Change dose demonstrated that pregabalin at a mean dose of 270 mg/day
or Continue was effective and generally well tolerated in this popula-
switch Further
4–6 weeks tion.[16] Professor Bandelow also presented data from a
recent placebo-controlled study in patients with refractory
GAD who were suboptimal responders to SSRIs/SNRIs and
had a significant improvement in their HAM-A total score
SECOND LINE
Benzodiazepines (2 nd line because of abuse potential)
when pregabalin was added as an adjunctive treatment.[17]
– Treatment-resistant patients with no history of dependence This study is the first well controlled study to demonstrate the
– Add-on to SSRIs/SNRIs in first few weeks until onset of efficacy of
efficacy of an agent as an adjunctive treatment in patients with
antidepressant
TCAs refractory GAD.
– Imipramine effective, but potentially lethal in overdose and
tolerability less than first-line
Finally, he reviewed a range of mostly unpublished studies
conducted with the atypical antipsychotic quetiapine, and
Figure 7. World Federation of Societies of Biological Psychiatry GAD he suggested that although the treatment is not licensed for
treatment guidelines
use in GAD, there was evidence from one published study[19]
SSRIs recommended as first-line: escitalopram, paroxetine, sertraline.
SNRIs recommended as first-line: venlafaxine, duloxetine. and from congress poster presentations that quetiapine
Reference 1 monotherapy is an effective anxiolytic in GAD with a rapid




Davidson et al. 1999 Gelenberg‡ et al. 2000 Allgulander et al. 2001
8 weeks 12 weeks 8 weeks

80 * *P<0.05 vs. placebo
*
70

60
% of patients

50

40

30

20

10
N=98 N=87 N=87 N=93 N=127 N=124 N=130 N=134 N=137
0
Pbo Ven 75 Ven 150 Busp 30 Pbo
Ven Pbo Ven 75 Ven 150
75–225
Treatment (mg/day)

Figure 8. HAM-A responder rates{ across clinical trials of venlafaxine in GAD.
{$50% improvement from baseline at 8 weeks except Gelenberg showed $40% improvement at 12 weeks.
Pbo: placebo, Ven: venlafaxine, Busp: buspirone, Dlulox: duloxetine.
References 3–5

onset of action. He added that in a recently completed REFERENCES
study[20], quetiapine was not significantly more effective 1. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of
than placebo as an adjunctive treatment in refractory GAD. Biological Psychiatry (WFSBP) guidelines for the pharmacological
treatment of anxiety, obsessive-compulsive and post-traumatic stress
In terms of the disadvantages and side effects of the various
disorders - first revision. World J Biol Psychiatry. 2008;9(4):248–312.
recommended GAD treatments, Professor Bandelow noted 2. Kasper S, Barry H, Nivoli G, et al. Efficacy of pregabalin and venlafaxine-
the latency of effect and the risk of discontinuation XR in generalized anxiety disorder: results of a double-blind, placebo-
syndromes with both SSRIs and SNRIs; the initial ‘‘jitteriness’’, controlled, 8-week trial. Int Clin Psychopharmacol. 2009;24(2):87–96.
nausea, restlessness, and sexual dysfunction with SSRIs; 3. Davidson JR, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, and
the risk of hypertension and other side effects with SNRIs; tolerability of venlafaxine extended release and buspirone in outpatients
with generalized anxiety disorder. J Clin Psychiatry. 1999;60(8):528–35.
and the risk of dizziness and somnolence with pregabalin 4. Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxine
(Table 5).[21] extended-release capsules in nondepressed outpatients with generalized

Koponen et al. 2007 Rynn et al. 2008 Hartford et al. 2007 Nicolini et al. 2009
9 weeks 10 weeks 10 weeks 10 weeks
80
*P<0.05, **P 0.01, ***P 0.001 vs. placebo
70
***
** ***
60 ***
*** ***
% of patients

50

40

30

20

10
N=175 N=168 N=170 N=159 N=168 N=161 N=162 N=164 N=170 N=84 N=158 N=169
0
Pbo Dulox Dulox Pbo Dulox Pbo Dulox Ven XR Pbo Dulox Dulox Ven XR
60 120 60_120 60_120 75_225 20 60_120 75_225
Treatment (mg/day)

Figure 9. HAM-A responder rates{ across clinical trials of duloxetine in GAD.
{$50% improvement from baseline.
Pbo: placebo, Ven: venlafaxine, Dulox: duloxetine.
References 6–9




Pohl et al. 2005 Montgomery et al. 2006 Kasper et al. 2009
6 weeks 6 weeks 8 weeks
80 *P<0.05, **P 0.01, ***P 0.001 vs. placebo
70 †P<0.05 vs. venlafaxine
* ** *†
60 **
** **
% of patients
50
40
30
20
10
N=83 N=75 N=85 N=85 N=100 N=94 N=104 N=110 N=28 N=121 N=125
0
Pbo PGB PGB PGB Pbo PGB PGB Ven IR Pbo PGB Ven XR
(n=83) 200 400 450 400 600 75 300_600 75_225
(BID) (BID) (TID)

Treatment (mg/day)

Figure 10. HAM-A responder rates{ across clinical trials of pregabalin in GAD.
{$50% improvement from baseline.
Pbo: placebo, Ven: venlafaxine, PGB: pregabalin.
Pregabalin dosing BID except in the Pohl study, which had a 450 mg/day group.
References 11, 15, 2

anxiety disorder: A 6-month randomized controlled trial. JAMA. 2000; controlled comparison of BID versus TID dosing. J Clin Psychopharmacol.
283(23):3082–8. 2005;25(2):151–8.
5. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) in 12. Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized
the treatment of generalised anxiety disorder: twenty-four-week placebo- anxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003;160(3):
controlled dose-ranging study. Br J Psychiatry. 2001;179:15–22. 533–40.
6. Koponen H, Allgulander C, Erickson J, et al. Efficacy of duloxetine for the 13. Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind,
treatment of generalized anxiety disorder: implications for primary care placebo-controlled, fixed-dose, multicenter study of pregabalin in
physicians. Prim Care Companion J Clin Psychiatry. 2007;9(2):100–107. patients with generalized anxiety disorder. J Clin Psychopharmacol. 2003;
7. Rynn M, Russell J, Erickson J, et al. Efficacy and safety of duloxetine in the 23(3):240–9.
treatment of generalized anxiety disorder: a flexible-dose, progressive- 14. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of
titration, placebo-controlled trial. Depress Anxiety. 2008;25(3):182–9. generalized anxiety disorder: a 4-week, multicenter, double-blind,
8. Hartford J, Kornstein S, Liebowitz M, et al. Duloxetine as an SNRI placebo-controlled trial of pregabalin and alprazolam. Arch Gen
treatment for generalized anxiety disorder: results from a placebo and Psychiatry. 2005;62(9):1022–30.
active-controlled trial. Int Clin Psychopharmacol. 2007;22(3):167–74. 15. Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety
9. Nicolini H, Bakish D, Duenas H, et al. Improvement of psychic and of pregabalin in the treatment of generalized anxiety disorder: a 6-
somatic symptoms in adult patients with generalized anxiety disorder: week, multicenter, randomized, double-blind, placebo-controlled com-
examination from a duloxetine, venlafaxine extended-release and parison of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):
placebo-controlled trial. Psychol Med. 2009;39(2):267–76. 771–82.
10. Davidson JR, Wittchen HU, Llorca PM, et al. Duloxetine treatment for 16. Montgomery S, Chatamra K, Pauer L, et al. Efficacy and safety of
relapse prevention in adults with generalized anxiety disorder: a pregabalin in elderly people with generalised anxiety disorder. Br J
double-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2008; Psychiatry. 2008;193(5):389–94.
18(9):673–81. 17. Miceli J, Ramey T, Weaver J, et al. Adjunctive pregabalin treatment after
11. Pohl RB, Feltner DE, Fieve RR, Pande AC. Efficacy of pregabalin in the partial response in generalized anxiety disorder (GAD): results of a
treatment of generalized anxiety disorder: double-blind, placebo- double-blind, placebo-controlled trial. 162nd Annual Meeting of the

Table 5. Qualitative assessment of the tolerability and safety of classes of drugs used to treat generalized anxiety disorder*.

Sedation/Psychomotor Weight Sexual GI side Abuse Discontinuation/Withdrawal Risk of drug
Drug class impairment gain dysfunction effects potential syndrome interaction{
Benzodiazepines +++ + 0/+ 0 ++ +++ ++
SSRIs and SNRIs{ +/++ + ++ + 0 0/+/++ 0/+/++
a2 -d ligands ++ ++ 0/+ 0 + + 0/+

TCAs ++ ++ + + 0 ++ ++
Azapirones + + + + 0 + +

0: Minimal-to-none; +: Some; ++: Moderate; +++: Marked
*Not all agents in all classes are approved for the treatment of GAD. {Pharmacokinetic and pharmacodynamic interactions. {SSRIs and SNRIs exhibit a range
of adverse events, risk of drug–drug interactions and risk of discontinuation symptoms. GI: Gastrointestinal.
Reference 21




PRACTICE POINTERS
Evidence-based guidelines for the treatment of GAD, such as those described by Professor Bandelow, are invaluable for
front-line clinicians such as those of us in primary care. From my point of view, the most obvious practice pointers from
this talk are:
N All of the drugs recommended as first-line therapies in the WFSBP guidelines can be readily and safely initiated in the
primary care setting, bringing the effective management of GAD within our grasp. The recommended 4–6 week
treatment duration prior to reviewing patient response may be an especially helpful point, as I suspect that 4–6 weeks is
longer than many of us have waited before considering changing treatment.
N While approximately 50% of patients will have a good response to any single agent, there are some patients who will
not respond; doctors need to be prepared to try several treatments in some patients. There is no way of predicting who
will have a good response to any of the medications we use for GAD.
N The first-line choice of treatment should consider potential side effects, like the risk of sexual dysfunction with SSRIs
and hypertension with SNRIs, and their tolerability to the individual patient.
N Pregabalin has been the most extensively studied of all of the treatments used for GAD and is an important addition to
the treatment options for GAD. It is also clinically important that it has been demonstrated to be effective as an adjunct
to SSRIs/SNRIs in refractory patients.
N SSRIs and SNRIs may relieve the depressive symptoms in patients with concurrent Major Depression and GAD, but in
some patients GAD symptoms might persist. We need to be prepared to consider contingencies to manage such patients.
N To minimize side effects in clinical practice, it is often preferable to start a new treatment at a relatively low dose and
escalate the dose based on the balance between tolerability and efficacy in the individual patient. This type of treatment
plan might mean starting at doses far below the recommended doses.
N Anxiety disorders have a waxing and waning course. After remission, treatment should continue for at least several
months. Expert consensus recommends a duration of drug therapy of at least 12–24 months, although evidence for this
recommendation is currently lacking.
N Psychosocial interventions such as cognitive behavioral therapy (CBT) have an important role to play in the treatment of
GAD. Patients should ideally be offered CBT either as an initial approach to treatment or in combination with
pharmacotherapy.

American Psychiatric Association; 16–21 May 2009, San Francisco, USA. with GAD remain unrecognized,[1–3] and that those who are
Abstract NR4-015.
diagnosed are frequently untreated, under-treated, or inap-
18. Feltner D, Wittchen HU, Kavoussi R, et al. Long-term efficacy of
pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol. propriately treated with benzodiazepines or other hypnotics
2008;23(1):18–28. (Figure 11).[4–6] There is a pressing need to educate
19. Bandelow B, Chouinard G, Bobes J, et al. Extended-release quetiapine physicians about how to diagnose and treat GAD to ensure
fumarate (quetiapine XR): a once-daily monotherapy effective in that patients do not suffer in silence and to make the
generalized anxiety disorder. Data from a randomized, double-blind,
management of patients with GAD a more rewarding
placebo- and active-controlled study. Int J Neuropsychopharmacol. 2009 Aug
20:1–16. [Epub ahead of print] experience for clinicians.
20. Astrazenecaclincialtrials.com accessed 26 November 2009, Study 16:
Palladium. NCT00534599 The Swedish Experience
21. Montgomery SA. Pregabalin for the treatment of generalised anxiety
disorder. Expert Opin Pharmacother. 2006;7(15):2139–54. Professor Allgulander has worked extensively with
primary care teams in Sweden and believes there are a
number of barriers to the recognition and treatment of
ANXIETY DISORDER/GAD EDUCATION:
psychiatric disorders in this setting. Patient-related
EXPERIENCES FROM EUROPE AND THE factors include presentation with predominantly somatic
DEVELOPING WORLD rather than psychological symptoms, the co-occurrence of
The final plenary presentations at the meeting were given by medical and psychiatric problems, and the stigma associated
Professor Christer Allgulander from the Department of with mental health issues.[7] Physician-related factors
Clinical Neuroscience at Karolinska Institute in Stockholm, include insufficient consultation time, inadequate interview
Sweden and Professor Dan Stein from the Department of and diagnostic skills, insufficient undergraduate and post-
Psychiatry and Mental Health at the University of Cape Town graduate training, and a lack of knowledge about new
in South Africa. Both experts came to the meeting to share treatments.[7]
their experience of extensive programs to educate primary In a major effort to improve the outcomes for GAD patients
care and allied health professionals about the importance of in primary care in Sweden, a nationwide educational program
recognizing and treating GAD and other anxiety disorders. has been developed and implemented. The ‘‘GAD 60
Studies in primary care have consistently revealed that Minutes’’ program was developed by GAD experts and
despite its high prevalence, around one-third of all individuals enables a network of psychiatrists working at a local level



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