Mb managing anxiety_in_practice_april_26

Managing Anxiety in Practice: Focus on GeneralizedAnxiety DisorderDr. 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:[email protected]

INTRODUCTION

Generalized Anxiety Disorder (GAD) is the second mostcommon anxiety disorder (after specific phobias).[1]. Itaffects approximately 2% of the general adult population ina given year, which equates to approximately 6 million peoplein Europe[2], and it is associated with a substantial personal,societal and economic burden. However, despite its highprevalence and significant impact on the sufferer, GAD can bechallenging to diagnose as patients often present with vaguemedically unexplained symptoms, and many have concurrentpsychiatric or physical disorders that can mask the underlyinganxiety disorder.

Many experts in the management of GAD believe thecondition has been somewhat neglected as a public healthconcern and that better and broader physician education isneeded. To help address this educational need, the ManagingAnxiety in Practice (MAP2) program convened a pan-Europeanmeeting that was attended by around 1000 physicians with aspecial interest in anxiety disorders. The program wasdeveloped by a steering committee of European experts inGAD, with additional experts contributing to the content ofthe plenary sessions and interactive workshops.

As a General Practitioner myself, I found the meeting bothstimulating and thought-provoking. I was surprised at thedifferent levels of understanding and the different ways ofworking represented in the room, reflecting clinical practicesfrom all over Europe. I was also reassured that there was a

genuine desire amongst delegates to engage, to learn, and toexchange practical clinical experiences. It was also stimulat-ing to see the collaboration and the exchange of ideasbetween primary care practitioners and secondary carepsychiatric colleagues.

If all of the clinicians who came to the meeting went back totheir own practices with expanded knowledge and the passionto share that knowledge with colleagues and patients, we maybe one step closer to moving GAD out of the shadows as one ofthe most under-recognized mental disorders and improvingthe recognition, diagnosis, and treatment of this condition.

This report presents highlights from the plenary presenta-tions given at the MAP meeting as well as some practicepoints that might be useful to practicing clinicians in allspheres of medicine and their patients.

REFERENCES1. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe – a

critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005;15(4):357–76.

2. Lieb R, Becker E, Altamura C. The epidemiology of generalized anxietydisorder in Europe. Eur Neuropsychopharmacol. 2005;15(4):445–52.

GAD: THE MAGNITUDE OF THE PROBLEM

Professor Hans-Ulrich Wittchen from the TechnicalUniversity of Dresden, Germany, gave an overview of theburden of GAD in terms of its prevalence and cost to the

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MIND & BRAIN, THE JOURNAL OF PSYCHIATRY MEETING REPORT

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individual and to the healthcare system, its association withother conditions, and its likelihood of being recognized andappropriately treated in clinical practice. According toProfessor Wittchen, studies assessing the epidemiology ofGAD have been hampered by a number of issues, includingmultiple changes in the diagnostic criteria over the past twodecades, a lack of recognition and diagnostic assignment ofpatients, and the fact that the DSM-IV criteria currently requirepatients to have a strictly defined number of very specificsymptoms on most days for at least six months.[1] He alsosuggested that GAD was quite a difficult diagnostic concept,with the condition frequently being misunderstood andmisinterpreted as either a personality variant/trait or a variantof depression. Professor Wittchen gave an elegant overview ofthe different epidemiological approaches to reporting theprevalence and risk of GAD (Figure 1). Well conductedepidemiological studies using strict DSM-III or IV criteriasuggest that in any given year, approximately 6 million adultsin the European Union will suffer from the condition.[2]

Community-based studies have also confirmed that GADaffects adults across the lifespan, with prevalence ratestending to increase with age (Figure 2).[4] Overall, theestimated prevalence is 2.6% in men and 6.6% in women.Unlike other anxiety disorders, DSM-IV GAD is rare inchildren and adolescents[6, 7] but quite prevalent amongolder patients.[4] In a recent study, the overall prevalence ofGAD among elderly people was estimated to be 8.9%, whichwas higher than previously thought.

Studies have found that GAD is 3–6 times more prevalent inthe primary care setting than in the general population(Figure 2)[8], suggesting that patients with GAD are frequentattenders of their primary care clinics. Indeed, GAD has beenfound to be the most common anxiety disorder in the primarycare setting.[8]

GAD frequently co-exists with other medical and psychiatricconditions. According to one study in Germany conducted ina nationally representative sample of adults aged 18–65 years(N54181), 59% of patients with 12-month GAD also fulfilledthe DSM-IV criteria for major depression, 36% of patientsalso had dysthymia, and around one-third had phobia (Table1).[6] Interestingly, almost half (48.1%) of the GAD patientsalso had a somatoform disorder and 38% had a paindisorder.[6] Professor Wittchen noted that that anxiety, pain

and depression are highly inter-related and that cliniciansshould seek to establish the presence of GAD in anyindividual presenting with chronic pain, insomnia, or MajorDepressive Disorder (MDD).

Professor Wittchen also showed evidence that patients withGAD visit doctors at least as often as patients with MDD(Figure 3). In addition, patients with GAD are more impairedin daily life than those with other anxiety disorders,[9] andthey use more healthcare resources than those with MDD(J1557 vs. J1035 per year).[10, 11] He also presentedunfortunate evidence that primary care teams correctlydiagnose GAD in only around one-third of cases despitehigh rates of recognition that the patient has a ‘‘mentaldisorder’’.[10] One of the main reasons that most patients arenot identified or correctly diagnosed is because most do notactually present with anxiety as their primary complaint;instead, they often present with sleep disorders and somaticcomplaints. Patients most likely to be overlooked in primarycare include those with vague presenting problems andmultiple concurrent disorders, concurrent threshold andsubthreshold depression, medically unexplained somatoformsyndromes and pain disorders, and sleep disorders. Perhapseven more worryingly, studies also suggest that GAD patientswho are not recognized and diagnosed appropriately either


Mean: 1.4% (Range: 0.2_3.1)*

Median: 1.7% (IQR: 0.8_2.2)*†

5.1%(SE=0.3)‡

8.3%(SE= 0.4)§

Current (point) prevalence Age of subject

Age of subject

Age of subject

Age 75

12-month prevalence

Lifetime prevalence

Projected lifetime risk up to age 75

Age of subject when examined: 45

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

0

2

4

6

8

10

15_24 25_34 35_44 45_65 65+

Poi

nt

prev

alen

ce (

%)

Age range (years)

Primary care setting General population

Figure 2. Current (point) prevalence of GAD in the primary care settingcompared with the general population according to age groupReference 8

Mind & Brain, the Journal of Psychiatry


receive no treatment for their anxiety or receive inadequatetreatments such as sedatives and herbal medications.[10]

REFERENCES1. American Psychiatric Association. Diagnostic and Statistical Manual of

Mental Disorders (4th Edition, Text Revision). Washington DC, 2000.2. Lieb R, Becker E, Altamura C. The epidemiology of generalized anxiety

disorder in Europe. Eur Neuropsychopharmacol. 2005;15(4):445–52.3. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe – a

critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005;15(4):357–76.

4. Wittchen HU, Zhao S, Kessler RC, et al. DSM-III-R generalized anxietydisorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(5):355–64.

5. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, andcomorbidity of 12-month DSM-IV disorders in the NationalComorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–27.

6. Carter RM, Wittchen HU, Pfister H, et al. One-year prevalence ofsubthreshold and threshold DSM-IV generalized anxiety disorder in anationally representative sample. Depress Anxiety. 2001;13(2):78–88.

7. Wittchen HU. Generalized anxiety disorder: prevalence, burden, and costto society. Depress Anxiety. 2002a;16(4):162–71.

8. Wittchen HU, Krause P, Hoyer J, et al. Prevalence and correlates ofgeneralized anxiety disorders in primary care. Fortschr Med Orig. 2001;119(suppl 1):17–25.

9. Wittchen HU, Carter RM, Pfister H, et al. Disabilities and quality of life inpure and comorbid generalized anxiety disorder and major depression ina national survey. Int Clin Psychopharmacol. 2000;15(6):319–28.

10. Wittchen HU, Kessler RC, Beesdo K, et al. Generalized anxiety anddepression in primary care: prevalence, recognition, and management. JClin Psychiatry. 2002b;63 (suppl 8):24–34.

11. Andlin-Sobocki P, Wittchen HU. Cost of anxiety disorders in Europe. EurJ Neurol. 2005;12 (suppl 1):39–44.


Table 1. Percentage of adults with 12-month DSM-IV GAD and concurrentconditions compared with those without GAD or MDD.

Comorbid disorderGAD

(n573)No GAD(n54108)

OddsRatio P Value*

Alcohol abuse/dependence 6.4 3.9 2.8 NS

Nicotine dependence 14 10.2 1.7 NS

Drug abuse/dependence 1.4 0.7 4.2 NS

Any depressive disorder 70.6 9.9 20.3 ,0.05

Major depression 59 7.5 16.7 ,0.05

Dysthymia 36.2 4 12 ,0.05

Any anxiety disorder 55.9 12.9 8.1 ,0.05

Panic disorder 21.5 2 12.3 ,0.05

Agoraphobia without panic 11.3 1.9 5.4 ,0.05

Social phobia 28.9 1.6 25.9 ,0.05

Specific phobia 29.3 7.3 4.9 ,0.05

Phobia NOS 10.6 3.3 3 ,0.05

Obsessive–compulsive disorder 10 0.6 19.6 ,0.05

Any somatoform disorder 48.1 10.4 7.2 ,0.05

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

Three of the above disorders 32.7 2.9 16.6 ,0.05

*P value based on Odds Ratio for GAD vs. no GAD, controlled for age and gender.NS: Not statistically significant (P$0.05).Reference 6

�4 to PCP �1 to psychiatrist�2 to otherspecialist

No GAD or MDE (n=16,023)

Pure GAD (n=666)

Pure MDE (n=772)

GAD + MDE (n=278)

Doctors visited in the past year

80

60

70

50

40

30

20

10

0

% o

f re

spon

den

ts

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 involving558 primary care physician practices in Germany that screened 17,739consecutive primary care patients. MDE: major depressive episode.Reference 8

PRACTICE POINTERS

The finding that the majority of patients with GAD areoverlooked in primary care is not surprising. Primarycare physicians see many patients with concurrentanxiety, depression and mixed somatic symptomatol-ogy, and it is often difficult to distinguish the clinicalentities and treat them adequately. Professor Wittchendid well to remind us that patients with GAD are oftenmore disabled than those with depression because wecan usually see the despair in our depressed patients,while our patients with GAD frequently present withother dominant complaints.

The key ‘‘take home’’ messages from this presenta-tion are:N Dig beneath the surface for symptoms of anxiety in

patients who present with vague problems like achesand pains or insomnia for which there is no medicalexplanation. Ask the question: ‘‘Why aren’t yousleeping?’’

N Recognize that many patients with GAD are frequentattenders in primary care. Some of our mostchallenging patients who are chronically unwell witha variety of unexplained complaints could well besuffering from an underlying and treatable disordersuch as GAD.

N If you suspect a mental health problem, explore thepossibility that it is GAD rather than just excludingdepression.

N Strive to recognize GAD early, diagnose accurately,and treat appropriately.

Managing Anxiety in Practice

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

NEUROBIOLOGY ANDPSYCHOPHARMACOLOGY OF GAD

Professor Johan A. den Boer from the University MedicalCentre in Groningen, The Netherlands, presented a compre-hensive review of recent genetic and neuro-imaging studiesthat have contributed to our current understanding of thegenetics and neurobiology of GAD. He emphasized at thestart of his presentation that ‘‘worrying’’ has major biologicalrelevance, with studies suggesting that intense worrying iscorrelated with reduced immune function, increased levels ofpro-inflammatory cytokines, increased risk of heart disease,and an increased risk of mortality.[1, 2]

Reviewing recent genetic studies in GAD, Professor denBoer showed evidence that there is no single gene for GAD;rather, there is a complex interaction between a combinationof genetic polymorphisms and environmental and psycholo-gical factors that determines an individual’s response tostress. In one study of patients with GAD he presented[3], thefrequencies of the serotonin transporter (5-HTT) gene-linkedfunctional polymorphism region (5-HTTLPRS) short/shortgenotype was found to be significantly higher in GADpatients than control subjects (68% vs. 49%; p50.002),suggesting that this polymorphism may increase the risk forGAD. In another study assessing the genetic associationbetween six single nucleotide polymorphisms from thePLXNA2 gene and anxiety[4], a significant association wasfound between the rs2478813 polymorphism (and otherpolymorphisms associated with it) and anxiety. However, asProfessor den Boer pointed out, neither of these results arespecific to GAD, as similar results have been found indepression and other anxiety disorders.

In an attempt to try and explain why some individuals have apropensity to react in a distressed way to environmentalstimuli, Professor den Boer presented a study showing a clearcorrelation between the response to stress and the presence ofpolymorphic variations in genes coding for monoamineoxidase A (MAOA) and catechol-O-methyl transferase(COMT).[5] He said it seemed likely that people who carrythese and other polymorphisms are especially prone topsychological distress under challenging conditions.

Neuro-imaging studies also support the theory that GADhas a biological foundation, with several studies demonstrat-ing that individuals with GAD have intensified responses topotentially adverse cues.[6–9] In one recent functional MRIstudy[9], Professor den Boer demonstrated that individualswith GAD had heightened and indiscriminate responses inthe amygdala to anticipatory signals of an aversive visualstimulus, which he said suggested an over-emotionalresponse based on fearful anticipation.

Turning to a discussion of the psychopharmacology ofGAD, Professor den Boer urged delegates to look beyondbenzodiazepines as treatments for GAD. He said currenttherapeutic strategies that target the a1 subunit of the c-aminobutyric acid (GABA)A receptor, such as benzodiaze-pines, caused unacceptable CNS depression, amnesia andwithdrawal effects, but that newer agents targeting the a2 or

a3 receptor subtypes held some promise as anxiolyticswithout these unwanted effects. He also highlighted thelimitations of the azapirones, which target 5-HT1A receptors,as potential treatments for GAD, referring to a recentCochrane Review that was broadly negative for azapironesin this indication.[10]

Professor den Boer described the utility of SNRIs (e.g.,venlafaxine, duloxetine) and a2d ligands (e.g., pregabalin) aspharmacological treatments for GAD. He presented theresults from a range of studies with these agents anddemonstrated the efficacy of both classes of drug astreatments for GAD.[11–13]

Finally, Professor den Boer reviewed ongoing work thatcould yield novel therapies for GAD in the future, includingstudies with peptides, 5-HT2C receptor antagonists, melato-nergic receptor agonists, and mGlu receptor ligands.

REFERENCES1. Sternberg EM and Gold PW. The Mind-Body Interaction in Disease.

Scientific American, Special Edition: The Hidden Mind.2002;2(1):82–292. Culpepper L. Generalized Anxiety Disorder and Medical Illness. J Clin

Psychiatry. 2009;70(suppl 2):20–243. You JS, Hu SY, Chen B, et al. Serotonin transporter and tryptophan

hydroxylase gene polymorphisms in Chinese patients with generalizedanxiety disorder. Psychiatr Genet. 2005;15(1):7–11.

4. Wray NR, James MR, Mah SP, et al. Anxiety and comorbid measuresassociated with PLXNA2. Arch Gen Psychiatry. 2007;64(3):318–26.

5. Jabbi M, Korf J, Kema IP, et al. Convergent genetic modulation of theendocrine stress response involves polymorphic variations of 5-HTT,COMT and MAOA. Mol Psychiatry. 2007;12(5):483–90.

6. Whalen PJ, Johnstone T, Somerville LH, et al. A functional magneticresonance imaging predictor of treatment response to venlafaxine ingeneralized anxiety disorder. Biol Psychiatry. 2008;63(9):858–63.

7. Mathew SJ, Price RB, Mao X, et al. Hippocampal N-acetylaspartateconcentration and response to riluzole in generalized anxiety disorder.Biol Psychiatry. 2008;63(9):891–8.

8. Blair K, Geraci M, Devido J, et al. Neural response to self- and otherreferential praise and criticism in generalized social phobia. Arch GenPsychiatry. 2008;65(10):1176–84.

9. Nitschke JB, Sarinopoulos I, Oathes DJ, et al. Anticipatory activation inthe amygdala and anterior cingulate in generalized anxiety disorder andprediction of treatment response. Am J Psychiatry. 2009;166(3):302–10.

10. Chessick CA, Allen MH, Thase M, et al. Azapirones for generalizedanxiety disorder. Cochrane Database Syst Rev. 2006 ;3:CD006115.

11. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) inthe treatment of generalized anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Br J Psychiatry. 2001;179:15–22.

12. Koponen H, Allgulander C, Erickson J, et al. Efficacy of Duloxetine for theTreatment of Generalized Anxiety Disorder: Implications for PrimaryCare Physicians. Prim Care Companion J Clin Psychiatry. 2007;9(2):100–107.

13. Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety ofpregabalin in the treatment of generalized anxiety disorder: a 6-week,multicenter, randomized, double-blind, placebo-controlled comparisonof pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):771–82.

KEY DIAGNOSTIC ISSUES IN GAD

The key diagnostic challenges associated with GAD wereoutlined by Professor Carlo Altamura from the Department ofPsychiatry at the University of Milan in Italy. He explained thatsignificant progress had been made over the years in definingGAD as a distinct clinical entity and in separating it from theother anxiety disorders.[1] Today, both DSM-IV and ICD-10




diagnostic criteria focus on the quality and duration of theanxiety, on its clinical manifestations, and on the importanceof differentiating it from other disorders in the clinic (Table2). The two criteria are similar in that they both require thepersistence of excessive anxiety and the presence of physicalsymptoms. However, as Professor Altamura explained, thecriteria differ in terms of the duration of symptoms ($6months in DSM-IV vs. several months in ICD-10), the need forautonomic hyperactivity and physical manifestations, andwhether functional impairment is a requirement (Table 3).

Professor Altamura went on to present the results of a studyillustrating the importance of early diagnosis and effectivetreatment of GAD.[4] In this study, 100 patients with GAD(DSM-IV criteria) were treated with SSRIs or venlafaxine foreight weeks in open-label conditions, and treatment responseand other clinical variables were assessed according to theduration of untreated illness (#12 months or .12 months).The study found that patients with a longer duration of

untreated illness had a poorer response to pharmacologicaltreatment and a worse clinical outcome.[4] The meanduration of untreated illness before patients receivedantidepressants was found to be 84.1 months in this study– far longer than reported for other major psychiatricconditions (e.g., schizophrenia, depression).

One of the main challenges for accurate identification ofGAD is that patients with GAD do not typically present withanxiety as their primary complaint.[5] Indeed, a very largestudy of primary care physicians conducted in Germany foundthat only 13% of patients with GAD presented with anxiety astheir primary complaint (Figure 4). Patients frequentlycomplain of gastrointestinal, cardiovascular or pain symp-toms, often leading to wasted resources spent pursuingmedical lines of investigation that leave symptoms unex-plained and often untreated. In formal studies, GAD has beenstrongly associated with chronic pain such as cluster head-aches[6] and tension-type headaches[7], and a significantproportion of patients with GAD manifest with painfulirritable bowel syndrome (IBS).[8] In one study published in2009, 26% of patients with IBS were found to have GAD.[9]

An additional complication in the diagnosis of GAD is that thecondition may present differently in older and youngerindividuals. The assessment of GAD in the elderly, in particular,is often confounded by the presence of other chronicconditions, the frequent use of ‘‘irrational’’ polypharmacy, thepresence of cognitive impairment and a reluctance to reportpsychiatric symptoms. Differentiating between depression andanxiety is especially challenging in the elderly.

According to Professor Altamura, one of main problems inestablishing a diagnosis of GAD in clinical practice isdisentangling the symptoms of anxiety disorders from thoseof depressive disorders, particularly as GAD so often occursconcurrently with depression.[10] He noted that both GADand major depressive disorder (MDD) were associated withsleep disturbances, concentration problems, fatigue, andpsychomotor/arousal symptoms. However, these disordersalso have very specific symptoms that can help to distinguishbetween them. Specific symptoms of MDD include suicidality,loss of appetite/weight, feelings of guilt/worthlessness, andloss of interest/pleasure. In contrast, specific symptoms ofanxiety disorders include muscle tension, compulsions,worry, phobic avoidance and panic attacks. Often, a doctorcan ‘‘see’’ when a patient is depressed by their manner andposture – they may seem flat, sad, and sluggish. In contrast,chronic anxiety is not so easy to ‘‘see’’ – patients may seemalert, eager and vigilant, and this presentation may not strikethe physician as being a signal of underlying psychopathology.

It may be less problematic to distinguish between thedifferent anxiety disorders. The British Association forPsychopharmacology (BAP) has provided guidance for physi-cians to help them explore a suspected anxiety disorder and todifferentiate between the different variants (Figure 5).[11] Thecardinal sign of GAD is uncontrollable worry in multipleareas of life, much of which is unfounded and has no rationalbasis. Pejoratively, others may consider such people ‘‘neuro-tic’’, and this label too can impact the physician’s assessment


PRACTICE POINTERS

I’m sure many clinicians, like me, find neurobiologi-cal research somewhat daunting. As we consult withour patients and try to reduce their anxiety symptomsand treat concurrent disorders and symptoms, few of uswill be wondering whether a polymorphism of thePLXNA2 gene might be the underlying cause.Thankfully, however, as we focus on doing our bestfor our patients, scientists like Professor den Boer arestriving to find hidden keys to unlock new targets fornovel treatments that may one day end up on ourprescription pads as more effective treatments withfewer side effects and better cost-effectiveness.Although this presentation was highly technical, severalpractice pointers emerged for me:N Many patients appear to be genetically or biologically

predisposed to suffer from anxiety. Some patientswill draw comfort from this, and we should use thisknowledge to reassure them that GAD is a seriousdisorder that, much like other medical conditions,has a solid biological foundation.

N The use of benzodiazepines in a chronic condition suchas GAD cannot be justified as a first-line treatment.Thankfully, we now have several agents that are effectivein reducing anxiety, have different side effect profilesand are not associated with the problematic cognitiveimpairment, dependence and withdrawal syndrome wesee with chronic benzodiazepine treatment.

N The SSRIs, SNRIs and pregabalin appear to betoday’s drug treatments of choice in GAD.Psychological therapies such as cognitive behavioraltherapy (CBT) also have an important role if patientsare able to gain access to such treatments.

N Effective treatments for GAD are now available.Therefore, our priorities in clinical practice must beto identify our unidentified patients with GAD andensure that they are appropriately managed.



of the patient. One confounding factor in using such asimplistic approach is often that GAD presents concurrentlywith other anxiety disorders,[10] and the apparent predomi-nance of one disorder does not preclude the existence ofanother.

The use of screening tools (e.g., GAD-7, ASQ-15) to alertthe physician to the possibility that GAD may be present,particularly among challenging patients, could help toimprove recognition of the disorder in psychiatric andprimary care settings. The GAD-7 screening tool (Figure 6)may be especially helpful in primary care for identifyingprobable cases of GAD and alerting the physician that furtherdiagnostic assessments may be required.[12] A score of 10 orhigher on the GAD-7 screening tool would indicate that a

more complete investigation of the possibility of GAD oranother anxiety disorder may be warranted.

REFERENCES1. Rickels K, Rynn MA. What is generalized anxiety disorder? J Clin

Psychiatry. 2001;62 (suppl 11):4–12.2. American Psychiatric Association. Diagnostic and Statistical Manual of

Mental Disorders (4th Edition, Text Revision). Washington DC, 2000.


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 varietyof events and situations

N Anxiety is generalized and persistent and not associated with a particularenvironmental 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 severalmonths

C. The presence for most days over the previous 6 months of threeor more (only one for children) of the following symptoms:

N Symptoms should involve elements of:

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, inabilityto 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, panicdisorder 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

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

DSM-IV ICD-10

Diagnostic classification Independent category Residual category

Worry/anxiety symptoms Excessive anxiety andworry

Persistent free-floatinganxiety

Duration $6 months Several months

Autonomic hyperactivityand physical symptoms

Not essential Must be present

Functional impairment Must be present Not specified

*Both the DSM-IV and ICD-10 diagnostic criteria are being updated, withrevised versions due to be published in 2013.Reference 1

Anxiety

Depression

Pain

Sleepdisturbance

Somaticillness/

complaints

% of patients with GAD (n=666)0 20 40 60

Figure 4. Primary complaint at presentation among patients with GAD inthe primary care setting*.*Generalized Anxiety and Depression in Primary Care (GAD-P) studyinvolving 558 primary care physician practices in Germany that screened17,739 consecutive primary care patients.Reference 5



3. World Health Organization (WHO). The ICD-10 Classification of Mentaland Behavioural Disorders. Geneva, 1992.

4. Altamura AC, Dell’osso B, D’Urso N, et al. Duration of untreated illnessas a predictor of treatment response and clinical course in generalizedanxiety disorder. CNS Spectr. 2008;13(5):415–22.

5. Wittchen HU, Kessler RC, Beesdo K, Krause P, Hofler M, Hoyer J.Generalized anxiety and depression in primary care: prevalence,recognition, and management. J Clin Psychiatry. 2002;63(Suppl 8):24–34.

6. Jorge RE, Leston JE, Arndt S, Robinson RG. Cluster headaches:association with anxiety disorders and memory deficits. Neurology.1999;53(3):543–7.

7. Puca F, Genco S, Prudenzano MP, et al. Psychiatric comorbidity and psychosocialstress in patients with tension-type headache from headache centres in Italy.The Italian Collaborative Group for the Study of PsychopathologicalFactors in Primary Headaches. Cephalalgia. 1999;19(3):159–64.

8. Tollefson GD, Luxenberg M, Valentine R, et al. An open label trial ofalprazolam in comorbid irritable bowel syndrome and generalized anxietydisorder. J Clin Psychiatry. 1991;52(12):502–8.

9. Gros DF, Antony MM, McCabe RE, Swinson RP. Frequency and severityof the symptoms of irritable bowel syndrome across the anxiety disordersand depression. J Anxiety Disord. 2009;23(2):290–6.

10. Carter RM, Wittchen HU, Pfister H, et al. One-year prevalence ofsubthreshold and threshold DSM-IV generalized anxiety disorder in anationally representative sample. Depress Anxiety. 2001;13(2):78–88.

11. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines forthe pharmacological treatment of anxiety disorders: recommendationsfrom the British Association for Psychopharmacology. J Psychopharmacol.2005;19(6):567–96.

12. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure forassessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7.


Specific anxiety-related symptoms& impaired function

Also moderate/severedepression?

No

Yes

Trauma history &flashbacks

Check for PTSD Check for OCD Check for GADCheck for SocialAnxiety Disorder

Check for specificphobia

Check for PanicDisorder

Fear of socialscrutiny

Discrete/object situation

Some uncued/spontaneous

Obsessions ±compulsion

Uncontrollable worry inseveral areas

Predominant symptom focus

Intermittent panic/anxiety attacks and avoidance

Persistent anxiety symptoms despiteadequate trial of antidepressant treatment

Treatdepression?

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

Over the last 2 weeks, how often have youbeen bothered by the following problems?

Notat all

1. Feeling nervous, anxious or on edge 0

Severaldays

1

Morethan halfthe days

2

Nearlyeveryday

3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

0 1 2 3

2. Not being able to stop or control worrying

3. Worrying too much about different things

4. Trouble relaxing

5. Being so restless that it is hard to sit still

6. Becoming easily annoyed or irritable

7. Feeling afraid as if something awful might happen

If you checked off any problems, how difficult have these problems made it for youto do your work, take care of things at home, or get along with other people?

TotalScore

Not difficultat all

= + +Add

Columns

Somewhatdifficult

Verydifficult

Extremelydifficult

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:REVIEW OF TREATMENT GUIDELINES

Professor Borwin Bandelow from the Department ofPsychiatry and Psychotherapy at the University of Gottingenin Germany, and lead author of the updated treatmentguidelines issued by the World Federation of Societies of BiologicalPsychiatry (WFSBP) in 2008[1], outlined how the guidelineswere developed and discussed key recommendations for thetreatment of GAD. Professor Bandelow stressed that thedevelopment of the guidelines was not supported bypharmaceutical companies, but were developed independentlyby a panel of 30 international experts who reviewed over 500randomized and 130 open-label clinical trials. The evidencewas carefully graded according to strict criteria that tookinto account not only the quality and number of positive/negative studies but also the risk:benefit ratio of eachtreatment, which significantly enhances the clinical relevanceof the guidelines.

According to the WFSBP treatment guidelines, the drugswith the best quality evidence for benefits in GAD patientsand therefore recommended for first-line use are the SSRIs(escitalopram, paroxetine and sertraline), the SNRIs (venla-faxine and duloxetine) and the calcium channel modulatorpregabalin (Table 4, Figure 7). Although the quality ofevidence was considered to be good for TCAs and benzodia-zepines, the guidelines have downgraded these treatments tosecond-line use in light of tolerability and other concerns(Table 4, Figure 7). Quetiapine was considered to have a goodevidence base, but is not currently a recommended treatmentin practice as it does not have a license for GAD in Europe.[1]

From a practical perspective, Professor Bandelow high-lighted the WSFBP recommendation that all first-line agentsshould be used for at least 4–6 weeks before evaluatingefficacy and safety and deciding, in the case of insufficientefficacy, to either change the dose, switch to another first-lineagent, combine first-line agents, or use a second-line option(Figure 7).[1] He said one of the disadvantages of the SSRIs/SNRIs was the latency of effect (2–6 weeks) that necessitatesthis 4–6-week initial trial period. In contrast, he saidpregabalin had a rapid onset of effect, with clinical trialsdemonstrating relief of anxiety symptoms within a matter ofdays.[2]

Professor Bandelow presented some of the studies that ledthe WFSBP guidelines task force to make its recommenda-tions and showed evidence that venlafaxine in doses of 75–225 mg/day significantly improved HAM-A total scores vs.placebo over eight weeks of treatment and produced a $50%improvement from baseline in HAM-A total scores at eightweeks in most published placebo-controlled trials (Figure8).[3–5]

In reviewing the duloxetine studies in GAD[6–9], ProfessorBandelow shared data showing that not only was duloxetinesuperior to placebo in reducing anxiety symptoms (HAM-Atotal scores) in most short-term studies (Figure 9), it was alsosuperior to placebo for relapse prevention in patients withGAD who had initially responded to duloxetine.[10]


PRACTICE POINTERS

This presentation was most informative and I wasreassured to hear that research programs support whatwe often see in clinical practice – anxious patientspresenting with physical symptoms such as palpita-tions, shortness of breath, or ‘‘mysterious’’ stomachpains and other medically unexplained symptoms.

Based on this presentation, a number of take homemessages stand out:N Don’t let patients go undiagnosed and untreated.

Leaving patients without treatment could mean storingup problems for patients and ourselves in the future,and may lead to a poorer response to treatment.

N GAD is almost always concurrent with anotherdisorder(s), including psychiatric disorders (e.g.,depression, another anxiety disorder) and/or medicaldisorders (e.g., diabetes, pain syndromes, headachesor arthritis).

N DSM-IV and ICD-10 diagnostic criteria are helpful inshowing clinicians what types of symptoms might bepresent in GAD and reinforcing the chronic nature ofthose symptoms. However, few of us apply thesecriteria rigorously in day to day clinical practice.Identification in the primary care setting could beimproved by an awareness of the fact that patientsmight have GAD if they have chronic medically-unexplained physical symptoms or residual symp-toms and impairment when treated for depression.

N Because headache, stomach pains, IBS, cardiovascu-lar, and respiratory symptoms are clearly linked withGAD, we should probe for anxiety symptoms inpatients presenting with these complaints.

N To disentangle anxiety from depression, we shouldlook for the cardinal symptoms that help us todifferentiate between the two conditions. However,both often co-exist, and identifying GAD in patientswith depression is challenging.

N Stress symptoms secondary to environmental stres-sors, like with the adjustment disorders, are differentfrom GAD symptoms but may overlap.

N Chronic benzodiazepine use may actually fuel anxietydue to withdrawal symptoms, and the anxiolyticbenefits of benzodiazepines can often diminish withlong term use.

N Elderly patients with GAD need special attention;they do not always present in the same way asyounger patients with GAD. We need to learn how torecognize GAD in the elderly population.

N Although the diagnosis of GAD is based on clinicalhistory (i.e. there are no markers, blood tests, EEGetc.), practices should consider using GAD screeningtools (such as GAD-7 and ASQ-15) in patients whoare suspected of having GAD; this may prompt thephysician to further evaluate the patient using a morecomprehensive and objective diagnostic process.



According to Professor Bandelow, pregabalin has the mostcomprehensive database supporting the efficacy and toler-ability of any drug in GAD. He reviewed some of the many

studies that have been conducted to assess the efficacy andsafety of pregabalin in the treatment of GAD[2, 11–17]. Inthese studies, pregabalin has been shown to be significantlymore effective than placebo in reducing the HAM-A totalscore (Figure 10) and was shown to reduce the risk ofrelapse.[18] In one recently published study includingpregabalin (300–600 mg/day; n5121), venlafaxine XR (75–225 mg/day; n5122) and placebo (n5127) over an eight weekperiod, statistically significant improvements in HAM-A totalscores were seen as early as day 4 in the pregabalin group(p#0.001 vs. placebo; p,0.05 vs. venlafaxine).[2]

When discussing the treatment of GAD in the elderly, hepresented one of the only well controlled studies specificallyconducted in this vulnerable group of patients, whichdemonstrated that pregabalin at a mean dose of 270 mg/daywas effective and generally well tolerated in this popula-tion.[16] Professor Bandelow also presented data from arecent placebo-controlled study in patients with refractoryGAD who were suboptimal responders to SSRIs/SNRIs andhad a significant improvement in their HAM-A total scorewhen pregabalin was added as an adjunctive treatment.[17]This study is the first well controlled study to demonstrate theefficacy of an agent as an adjunctive treatment in patients withrefractory GAD.

Finally, he reviewed a range of mostly unpublished studiesconducted with the atypical antipsychotic quetiapine, andhe suggested that although the treatment is not licensed foruse in GAD, there was evidence from one published study[19]and from congress poster presentations that quetiapinemonotherapy is an effective anxiolytic in GAD with a rapid


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/expertopinion; 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

FIRST-LINEPregabalin

SSRIsSNRIs

4–6Weeks

Response?

SECOND LINE

Benzodiazepines (2nd line because of abuse potential)

– Treatment-resistant patients with no history of dependence

– Add-on to SSRIs/SNRIs in first few weeks until onset of efficacy of

antidepressant

TCAs

– Imipramine effective, but potentially lethal in overdose and

tolerability less than first-line

Partial

Further4–6 weeks

ContinueChange dose

orswitch

No Yes

Figure 7. World Federation of Societies of Biological Psychiatry GADtreatment guidelinesSSRIs recommended as first-line: escitalopram, paroxetine, sertraline.SNRIs recommended as first-line: venlafaxine, duloxetine.Reference 1



onset of action. He added that in a recently completedstudy[20], quetiapine was not significantly more effectivethan placebo as an adjunctive treatment in refractory GAD.

In terms of the disadvantages and side effects of the variousrecommended GAD treatments, Professor Bandelow notedthe latency of effect and the risk of discontinuationsyndromes with both SSRIs and SNRIs; the initial ‘‘jitteriness’’,nausea, restlessness, and sexual dysfunction with SSRIs;the risk of hypertension and other side effects with SNRIs;and the risk of dizziness and somnolence with pregabalin(Table 5).[21]

REFERENCES1. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of

Biological Psychiatry (WFSBP) guidelines for the pharmacologicaltreatment of anxiety, obsessive-compulsive and post-traumatic stressdisorders - first revision. World J Biol Psychiatry. 2008;9(4):248–312.

2. Kasper S, Barry H, Nivoli G, et al. Efficacy of pregabalin and venlafaxine-XR in generalized anxiety disorder: results of a double-blind, placebo-controlled, 8-week trial. Int Clin Psychopharmacol. 2009;24(2):87–96.

3. Davidson JR, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, andtolerability of venlafaxine extended release and buspirone in outpatientswith generalized anxiety disorder. J Clin Psychiatry. 1999;60(8):528–35.

4. Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxineextended-release capsules in nondepressed outpatients with generalized


Pbo Dulox60

Dulox120

Dulox60_120

Dulox60_120

Dulox60_120

Dulox20

Ven XR75_225

Ven XR75_225

Pbo Pbo Pbo

******

Treatment (mg/day)

80

Koponen et al. 20079 weeks

*P<0.05, **P�0.01, ***P�0.001 vs. placebo

Nicolini et al. 200910 weeks

60

70

50

40

30

20

10

0

% o

f pa

tien

ts

***

********

Rynn et al. 200810 weeks

Hartford et al. 200710 weeks

N=175 N=168 N=170 N=159 N=168 N=161 N=162 N=170 N=84 N=158 N=169N=164

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

Pbo

N=98

Ven 75 Ven75–225

Ven 150 Ven 75 Ven 150

**P<0.05 vs. placebo

Busp 30 Pbo Pbo

Treatment (mg/day)

Davidson et al. 19998 weeks

Gelenberg‡ et al. 200012 weeks

Allgulander et al. 20018 weeks

80

60

70

50

40

30

20

10

0

% o

f pa

tien

ts

N=127 N=130N=93 N=134 N=137N=87 N=87 N=124

*

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



anxiety disorder: A 6-month randomized controlled trial. JAMA. 2000;283(23):3082–8.

5. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) inthe treatment of generalised anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Br J Psychiatry. 2001;179:15–22.

6. Koponen H, Allgulander C, Erickson J, et al. Efficacy of duloxetine for thetreatment of generalized anxiety disorder: implications for primary carephysicians. Prim Care Companion J Clin Psychiatry. 2007;9(2):100–107.

7. Rynn M, Russell J, Erickson J, et al. Efficacy and safety of duloxetine in thetreatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety. 2008;25(3):182–9.

8. Hartford J, Kornstein S, Liebowitz M, et al. Duloxetine as an SNRItreatment for generalized anxiety disorder: results from a placebo andactive-controlled trial. Int Clin Psychopharmacol. 2007;22(3):167–74.

9. Nicolini H, Bakish D, Duenas H, et al. Improvement of psychic andsomatic symptoms in adult patients with generalized anxiety disorder:examination from a duloxetine, venlafaxine extended-release andplacebo-controlled trial. Psychol Med. 2009;39(2):267–76.

10. Davidson JR, Wittchen HU, Llorca PM, et al. Duloxetine treatment forrelapse prevention in adults with generalized anxiety disorder: adouble-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2008;18(9):673–81.

11. Pohl RB, Feltner DE, Fieve RR, Pande AC. Efficacy of pregabalin in thetreatment of generalized anxiety disorder: double-blind, placebo-

controlled comparison of BID versus TID dosing. J Clin Psychopharmacol.2005;25(2):151–8.

12. Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalizedanxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003;160(3):533–40.

13. Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind,placebo-controlled, fixed-dose, multicenter study of pregabalin inpatients with generalized anxiety disorder. J Clin Psychopharmacol. 2003;23(3):240–9.

14. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment ofgeneralized anxiety disorder: a 4-week, multicenter, double-blind,placebo-controlled trial of pregabalin and alprazolam. Arch GenPsychiatry. 2005;62(9):1022–30.

15. Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safetyof pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled com-parison of pregabalin and venlafaxine. J Clin Psychiatry. 2006;67(5):771–82.

16. Montgomery S, Chatamra K, Pauer L, et al. Efficacy and safety ofpregabalin in elderly people with generalised anxiety disorder. Br JPsychiatry. 2008;193(5):389–94.

17. Miceli J, Ramey T, Weaver J, et al. Adjunctive pregabalin treatment afterpartial response in generalized anxiety disorder (GAD): results of adouble-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*.

Drug classSedation/Psychomotor

impairmentWeight

gainSexual

dysfunctionGI sideeffects

Abusepotential

Discontinuation/Withdrawalsyndrome

Risk of druginteraction{

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 rangeof adverse events, risk of drug–drug interactions and risk of discontinuation symptoms. GI: Gastrointestinal.Reference 21

Pbo(n=83)

PGB200

(BID)

PGB400

(BID)

PGB450

(TID)

Pbo PGB400

PGB600

Ven IR75

Pbo PGB300_600

Ven XR75_225

* **

******

Treatment (mg/day)

80

Pohl et al. 20056 weeks

Montgomery et al. 20066 weeks

*P<0.05, **P�0.01, ***P�0.001 vs. placebo†P<0.05 vs. venlafaxine

Kasper et al. 20098 weeks

60

70

50

40

30

20

10

0

% o

f pa

tien

ts

*†

N=83 N=75 N=85 N=85 N=100 N=94 N=104 N=110 N=28 N=121 N=125

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



American Psychiatric Association; 16–21 May 2009, San Francisco, USA.Abstract NR4-015.

18. Feltner D, Wittchen HU, Kavoussi R, et al. Long-term efficacy ofpregabalin in generalized anxiety disorder. Int Clin Psychopharmacol.2008;23(1):18–28.

19. Bandelow B, Chouinard G, Bobes J, et al. Extended-release quetiapinefumarate (quetiapine XR): a once-daily monotherapy effective ingeneralized anxiety disorder. Data from a randomized, double-blind,placebo- and active-controlled study. Int J Neuropsychopharmacol. 2009 Aug20:1–16. [Epub ahead of print]

20. Astrazenecaclincialtrials.com accessed 26 November 2009, Study 16:Palladium. NCT00534599

21. Montgomery SA. Pregabalin for the treatment of generalised anxietydisorder. Expert Opin Pharmacother. 2006;7(15):2139–54.

ANXIETY DISORDER/GAD EDUCATION:EXPERIENCES FROM EUROPE AND THEDEVELOPING WORLD

The final plenary presentations at the meeting were given byProfessor Christer Allgulander from the Department ofClinical Neuroscience at Karolinska Institute in Stockholm,Sweden and Professor Dan Stein from the Department ofPsychiatry and Mental Health at the University of Cape Townin South Africa. Both experts came to the meeting to sharetheir experience of extensive programs to educate primarycare and allied health professionals about the importance ofrecognizing and treating GAD and other anxiety disorders.

Studies in primary care have consistently revealed thatdespite its high prevalence, around one-third of all individuals

with GAD remain unrecognized,[1–3] and that those who arediagnosed are frequently untreated, under-treated, or inap-propriately treated with benzodiazepines or other hypnotics(Figure 11).[4–6] There is a pressing need to educatephysicians about how to diagnose and treat GAD to ensurethat patients do not suffer in silence and to make themanagement of patients with GAD a more rewardingexperience for clinicians.

The Swedish Experience

Professor Allgulander has worked extensively withprimary care teams in Sweden and believes there are anumber of barriers to the recognition and treatment ofpsychiatric disorders in this setting. Patient-relatedfactors include presentation with predominantly somaticrather than psychological symptoms, the co-occurrence ofmedical and psychiatric problems, and the stigma associatedwith mental health issues.[7] Physician-related factorsinclude insufficient consultation time, inadequate interviewand diagnostic skills, insufficient undergraduate and post-graduate training, and a lack of knowledge about newtreatments.[7]

In a major effort to improve the outcomes for GAD patientsin primary care in Sweden, a nationwide educational programhas been developed and implemented. The ‘‘GAD 60Minutes’’ program was developed by GAD experts andenables a network of psychiatrists working at a local level


PRACTICE POINTERS

Evidence-based guidelines for the treatment of GAD, such as those described by Professor Bandelow, are invaluable forfront-line clinicians such as those of us in primary care. From my point of view, the most obvious practice pointers fromthis 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 weektreatment duration prior to reviewing patient response may be an especially helpful point, as I suspect that 4–6 weeks islonger 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 willnot respond; doctors need to be prepared to try several treatments in some patients. There is no way of predicting whowill 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 SSRIsand 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 tothe treatment options for GAD. It is also clinically important that it has been demonstrated to be effective as an adjunctto SSRIs/SNRIs in refractory patients.

N SSRIs and SNRIs may relieve the depressive symptoms in patients with concurrent Major Depression and GAD, but insome 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 andescalate the dose based on the balance between tolerability and efficacy in the individual patient. This type of treatmentplan 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 severalmonths. Expert consensus recommends a duration of drug therapy of at least 12–24 months, although evidence for thisrecommendation is currently lacking.

N Psychosocial interventions such as cognitive behavioral therapy (CBT) have an important role to play in the treatment ofGAD. Patients should ideally be offered CBT either as an initial approach to treatment or in combination withpharmacotherapy.



to deliver educational seminars to primary care practicesaround the country. The program is CME-accredited andinvolves the attendance of lunchtime seminars by primarycare physicians (PCPs), during which they are educated aboutGAD and its treatment and are trained to screen patients(Figure 12), conduct diagnostic interviews, and developcomprehensive treatment programs.

Professor Allgulander believes that this approach tophysician education really works and that similar programscould be implemented in other countries. He suggested thatthe lives of doctors will most certainly improve if they canimprove the lives of their GAD patients.

The South African Experience

Professor Stein contrasted the experience in Sweden withthat in South Africa where there is only one psychiatrist per100,000 people. He stressed, however, that education aboutanxiety disorders remained a priority for him because anxietyand other neuropsychiatric disorders contributed significantlyto the burden of disease in South Africa, posttraumatic stressdisorder was highly prevalent, and comorbid psychiatricdisorders were a major issue for the large numbers ofindividuals with HIV/AIDS.

Unfortunately, he said, delivering good quality care inanxiety disorders was not perceived to be a national publichealth priority. This situation was further compounded by thefact that stigmatization is a major problem, that many remotecommunities have poor access to services, and that there wererelatively few resources for mental health services acrossSouth Africa.

Despite these challenges, Professor Stein described thesuccess of several initiatives aimed at reaching and educatingpatients with psychiatric conditions. He described the patientorganization South African Depression & Anxiety Group, whichdelivers education and guidance through its web site, and hasbeen extremely successful in bringing information to people

across the country, even in remote areas. He also mentionedthat the umbrella organization Mental Health and InformationCentre had contributed greatly to increasing awareness ofmental health issues and reducing the stigma associated witha broad range of mental health conditions.

Recognizing the need to further educate primary carephysicians and allied health professionals, Professor Steinapplauded the Swedish model and suggested that similardedicated programs were needed in his country. He said thathis own efforts at educating PCPs about GAD typicallyfocused on emphasizing the biological basis of the conditionand on communicating the fact that most GAD can be quiteeasily diagnosed and easily treated…once you know how.

REFERENCES1. Wittchen HU, Kessler RC, Beesdo K, et al. Generalized anxiety and

depression in primary care: prevalence, recognition, and management. JClin Psychiatry. 2002;63 (suppl 8):24–34.

2. Weiller E, Bisserbe JC, Maier W, Lecrubier Y. Prevalence and recognition ofanxiety syndromes in five European primary care settings. A report fromthe WHO study on Psychological Problems in General Health Care. Br JPsychiatry Suppl. 1998;(34)18–23.

3. Munk-Jørgensen P, Allgulander C, Dahl AA, et al. Prevalence of generalizedanxiety disorder in general practice in Denmark, Finland, Norway, andSweden. Psychiatr Serv. 2006;57(12):1738–44.

4. Kohn R, Saxena S, Levav I, Saraceno B. The treatment gap in mental healthcare. Bull World Health Organ. 2004;82(11):858–66.

5. Lecrubier Y, Weiller E. GAD: Current treatment and costs. EurNeuropsychopharmacol. 2000;10 (suppl 3):170–71.

6. Allgulander C, Nilsson B. A nationwide study in primary health care: Oneout of four patients suffers from anxiety and depression. Lakartidningen.2003;100(10):832–8. Article in Swedish.

7. Hickie IB. Primary care psychiatry is not specialist psychiatry in generalpractice. Med J Aust. 1999;170(4):171–3.

8. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessinggeneralized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7.


Schizophrenia

Obsessive compulsive disorder

Bipolar disorder

Dysthymia

Major depression

Panic disorder

Generalized anxiety disorder

Alcohol misuse

0 20 40 60 80 100Median treatment gap (%)

Figure 11. Percentage difference between the number of people needingtreatment for mental illness and the number of people receiving treatment(treatment gap) in the WHO European Region{.{Based on 13 studies of service utilization rates for selected psychiatricdisorders in community-based surveys.WHO: World Health Organization.Reference 4

Patient with suspectedanxiety in the waiting room

Patient completes the HospitalAnxiety and Depression Scale

(HADS; 14 items)

Patient completes the GAD-7screening questionnaire

If GAD-7 score�10 undertakediagnostic procedure to

confirm presence orabsence of GAD

Figure 12. Example of screening for GAD in patients with suspected anxietysymptoms in clinical practice. GAD-7 from reference 8



SUMMARY AND CONCLUSIONS

Generalized Anxiety Disorder (GAD) is a common, chronicand debilitating condition that affects large numbers ofindividuals of all ages. The cardinal symptoms of GAD areexcessive worry and anticipation of the worst. However,medically unexplained symptoms as well as psychic symp-toms that may be misinterpreted as other mental disordersare also present in many sufferers, and it is often thesesymptoms that drive patients to seek help. Sometimes, it is apatient’s behavior rather than a symptom as such that maysignal the presence of GAD, e.g., perceived aggression whensomeone is persistently very irritable.

Patients with GAD frequently present in primary care, andmany patients with other psychiatric disorders in specialistsettings also have GAD. However, a combination of factorsoften conspire to prevent an early, accurate diagnosis, which inturn leads to under- or inappropriate treatment. Becauseeffective psychological and pharmacological treatments arenow available, it is important that GAD patients be recognizedand treated. GAD patients who are well managed can have theirsymptoms ameliorated and their well-being restored.

Primary care physicians have a major opportunity to make asignificant impact on GAD outcomes and to gain the

satisfaction of seeing the lives of their anxious patientsimprove. To do so, efforts must be made to enhanceknowledge and hone the skills necessary to diagnose thecondition and develop successful management plans.Educational initiatives undertaken in some countries haveillustrated that a cascade approach to tackling primary careeducation can reap rewards for both patients and physicians.Primary care physicians are well advised to take advantage ofopportunities to learn and develop their skills in themanagement of GAD, and it seems likely that any futureefforts to educate and inform will be well received.

Disclosures: The Managing Anxiety in Practice (MAP2) meetingwas held at the World Forum Congress Centre, The Hague, TheNetherlands, 11–12 December 2009. It was organized by IntramedEurope International Business Centre and supported by Pfizer Ltd.The views expressed by presenters did not necessarily reflect theviews of Pfizer Ltd. Not all drugs discussed at this meeting werelicensed (in all countries) for the indications discussed; this fact wasmade explicit during the course of the meeting.

Editorial assistance was provided by Alison Jordan and Janet Brayand funded by Pfizer Ltd. Dr. Parmentier was compensated for thedevelopment of this article by Pfizer Ltd. He has been compensatedfor his work as an advisor to Pfizer. He has also worked togetherwith the following organizations that could be perceived as possibleconflicts of interest: Wyeth, Servier.

About the author: Dr. Henk Parmentier originates from TheNetherlands and is a General Practitioner (GP) in London with aspecial interest in mental health. He is the UK representative of theWONCA (World Organization of National Colleges, Academies andAcademic Associations of General Practitioners/Family Physicians)Working Party on Mental Health and a visiting Research Fellow inthe Primary Care Section of the Institute of Psychiatry at King’sCollege in London. Dr. Parmentier is a member of the ExecutiveCommittee of Primhe, the Primary Care Mental Health & Educationcharity in the UK,which helps primary care professionals to achieveand deliver better standards of mental healthcare.


PRACTICE POINTERS

There seems little doubt that more needs to be done toeducate front-line staff to identify the signs andsymptoms of GAD in patients. The screening methodused in Sweden, whereby patients complete variousquestionnaires in the waiting room before they see theirdoctor, could be valuable in other countries. This type ofsystem would highlight a potentially important role forcommunity nurses in administering and interpretingsuch tools, providing of course that they are trained to doso. National training programs in GAD would probablybe well received in many other countries because as wehave heard, most primary care physicians get very littleexposure to this condition in their formal training eventhough many patients in their care have GAD. With thatin mind, relevant practice pointers include:N Investigate what training in GAD, if any, is available for

your staff. If no national or local programs are in place,consider working with your secondary-care psychiatricteam to develop a short course that could be run locallyand include other primary care practices.

N Take responsibility for your own education and keepabreast of the latest developments in the treatment ofGAD. Take advantage of national or local meetingsthat could help improve your diagnostic andmanagement skills.

N A very practical and effective method of GAD trainingmight be short lunch time educational sessionsinvolving local primary care practices and localpsychiatrists followed by discussions based on cases.



Date post:	07-Jul-2015
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