CNS Drugs 2009 23 C2) 103-120

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Current Considerations in theTreatment of GeneralizedAnxiety DisorderMartin . KatzmanSTART (Stress, Trauma, Anxiety, Rehabilitation, and Treatment) Clinic for Mood and Anxiety Disorders,Toronto, Ontario, Canada

ContentsAbstract 103

1. Co-Morbidity 1052. Impact of Generalized Anxiety Disorder (GAD) on Patients 1053. Symptoms of GAD 106A. Diagnosis and Assessment of GAD 1075, Phormacoiogicai and Genetic Basis of GAD 1076, Treatment ot GAD 108

6.1 Treatment Guidelines 1086.2 Seiective Serotonin Reuptoke tntiibitors 109.3 Serotonin Noradrenaiine Reuptake Inhibitors 1106.4 Pregabalin HI6.5 Buspirone 1116.6 imipramine m6.7 Benzodiazepines 1116.8 Limitations of First-Line Treatment Options 112

7, Treatment Response and Remission 1128, Use of Nonpharmacological Approaches for Patients with GAD 1129, Atypicai Antipsychotics in GAD 113

10. Discussion 11511, Conciusions 116

Abstract Generalized anxiety disorder (GAD) is a chronic disorder that frequentlyco-occurs with a variety of co-morbidities in patients with somatic conditionsand other mental disorders. GAD is highly prevalent and is one of the mostcommon anxiety disorders seen by primary care physicians. The individualand societal cost associated with GAD is high and the marked level of impair-ment experienced by patients with this disorder is equivalent in magnitudeto that reported in patients with major depressive disorder. Furthermore,patients with GAD are at risk of suicide or suicide attempts, and are frequentusers of healthcare services. Thus, GAD is a serious and chronic conditionthat requires appropriate long-term treatment.

The focus of acute treatment for patients with GAD is the improvement ofsymptoms, while the primary goal oflong-term clinical management is remis-sion, i.e. the complete resolution of both symptoms and functional impairment.

104 Kalzman

The consensus across current treatment guidelines is that first-line treatmentfor patients with GAD should consist of an antidepressant. either a selectiveserotonin reuptake inhibitor (SSRI) such as sertraline. paroxetine or escita-lopram, or a selective serotonin noradrenaline (norepinephrine) reuptakeinhibitor (SNRI) such as venlafaxine or duloxetine. However, the SSRIs andSNRIs have efficacy limitations, such as lack of response in many patients, a2- to 4-week delay before the onset of symptom relief, lack of full remission,and risk of relapse. In addition, there are troublesome adverse effects asso-ciated with both the SSRIs and SNRIs.

Evidence from early clinical studies of the atypical antipsychotics in thetreatment of anxiety and GAD indicate that they may have a potential rolein the treatment of GAD, either as monotherapy or as augmentation tostandard treatment.

Generalized anxiety disorder (GAD) is a chronicdisorder that is highly prevalent; in the US the12-month and lifetime prevalence rates of GADwere estimated to be 3.1% and 5.7%, respec-tively.f'-'l In primary care, the prevalence ofGAD is typically higher than that observed in thecommunity, making it one of the most commonanxiety disorders seen by primary care physi-cians. For example, in a large European primarycare study {n= 13677), 8.3% of patients whopresented to their general practitioner were diag-nosed as having GAD.'"*!

Patients with GAD are frequent users ofhealthcare services. In a US study of high utilizersof healthcare services, DSM-III-Rf^l diagnoseswere made on a sample of 119 distressed highutilizers, 22% of whom had a diagnosis ofGAD.t^' More recently, the Mental Health Sup-plement to the Ontario Health Survey (a surveyof 8116 Canadian respondents aged 15-64 years)showed that four or more visits made to a pri-mary care physician over a 12-month periodindicated a 35% chance of the patient havingGAD.t'l This survey also showed that patientswho sought help from mental health servicesin the past year had a 50% chance of havingGAD.

GAD follows a chronic course during the first5 years that may last up to 20 years, and is asso-ciated with low rates of remission and moderaterates of relapse/recurrence following remission.f^'In the US National Comorbidity Survey (NCS)conducted in 8098 subjects aged 15-54 years.

GAD was twice as common among women as itwas among men and. as age increased, so did thelifetime prevalence.'''' Multivadate logistic regres-sion analysis showed that being older than24 years of age, separated, widowed, divorced,unemployed or a homemaker were significantcorrelates of GAD.^l

Epidemiology studies consistently indicatethat GAD may occur at any point in a person'slifetime,''*'' but is relatively uncommon beforethe age of 20 years, with a mean age at onset of21 years.'"'-"' However, the age of onset has abimodal distribution - onset occurs earlier whenGAD is the primary presentation and later whenGAD is secondary.'"'

While GAD represents an illness that mayhave presented with significant GAD symptomswhen patients are aged in their 20s, childhoodrisk factors have been identified, such as inter-nalizing problems, conduct problems and asomewhat more inhibited temperament.''-' Chil-dren with family members who have an anxietydisorder have a higher risk of developing over-anxious disorder of childhood and GAD. Forexample, adults with anxiety disorders have chil-dren with greater than expected rates of behav-ioural inhibition (60-76%).f'-^"'*'' Furthermore, ina study of a clinically derived sample of 31 chil-dren (60 parents) and an epidemiologicallyderived (longitudinal) sample of 40 children(75 parents), it was found that inhibited childrenhad parents with greater than expected rates ofanxiety disorders (75% if the child was inhibited

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The Role of Atypical Antipsychotics in GAD 105

and anxious; 29% if the child was inhibited Table I, Lifetime prevalence of co-morbidilies associated withgeneralized anxiety disorcteH^-^i

Schwartz et al.t'^' reported that the parents ofchildren with stable behavioural inhibition hadhigher rates of multiple childhood anxiety dis-orders (25% vs 3.6%) and that the higher rates ofanxiety disorder continued into their adulthood(35% vs 7.3%). Similarly, Biederman et alj'-'l re-ported that compared with healthy children, be-haviourally inhibited children had an increasedrisk for at least one anxiety disorder (22% vs 0%),for over-anxious disorder or childhood GAD(27.8% vs 0%) and for phobic disorders (31.8% vs5.3%).

In addition, data from a prospective, longitu-dinal community study conducted in 3021adolescents and young adultsf'**! have shown that>50% of patients with GAD have had a majordepressive episode by the age of 18 years.''^^

1. Co-Morbidity

GAD is often co-morbid with mood and an-xiety disorders (table \)P-~^^ In the US commu-nity-based NCS conducted in 8098 persons (aged15-54 years). 90.4% of respondents with lifetimeGAD reported having at least one other lifetimemental health disorder.f^--''

More recently, a German community studyof 4181 adults (aged 18-65 years) estimated the12-month prevalence of GAD according toDSM-IVf"I criteria to be \.5%S~^i Of the12-month GAD cases. 93% had another DSM-IVdisorder, 59% fulfilled the criteria for major de-pressive disorder (MOD) and 56% fulfilled thecriteria for any other anxiety disorder.'-^^ Specificphobia (29%) and social phobia (29%) were theanxiety disorders that were most frequently co-morbid with GAD.f- '^l The proportion of patientswith 12-month GAD and any co-morbid DSM-IV eating disorder, eo-morbid alcohol abuse/dependence and drug abuse/dependence were2.5%, 6.4% and 1.4%, respectively. Furthermore,a prospective community-based study in youngadults found that GAD is negatively associatedwith being overweight.'-*'

GAD may occur as the primary disorder (i.e.pre-dating other disorders) or as a secondary

Co-mofbidityMajor depressive disorderDysthymiaSpecific (simple) phobiaSocial phobia (social anxiety disorder)AgoraphobiaPanic disorderManiaSubstance abuseAlcohol use ot dependenceDrug use or dependence

Prevalence {%)60,9-82.437.7-39.533.6-35.134.0-34.4207-25.721.8-23.57.9-10.5

33.137.627.6

disorder (i.e. developing after other disorders).'-^1For example. MDD most often develops in thesame year or after the onset of GAD, whereassocial phobia typically pre-dates the onset ofGAD (figure 1 ).[-=]

Bipolar disorder and GAD are also commonlyco-morbid, with the proportion of patients withbipolar disorder having a lifetime GAD diagnosisreported to be 18.4%.'^^!

2. Impact of Generalized AnxietyDisorder (GAD) on PatientsThe quality of life and level of functioning in

patients with GAD is, in reality, lower than thatperceived by others. Henning et al.t-'^ l found thatpatients with GAD reported statistically sig-nificantly less satisfaction with their quality of lifethan non-anxious controls (mean total Quality ofLife Inventory [QOLIp**! score 0.06 vs 2.47;p

106 Kxilzmau

Pre-dates GADa Same yearn Post-dates GADCo-morbid disorder

Drug disorder

Alcohol disorder

Social phobia

Simple phobia

Agoraphobia

Panic disorder

Dysthymia

Major depressive disorder

0 20 40 60 80 100Lifetime co-morbid DSM-ill-R cases {%)

Fig. 1. The relative onset of mood and anxiety disorders that occurco-morbidly with generalized anxiety disorder (GAD) [reproducedfrom Stein,'^^' wtth permission from Physicians Postgraduate Press.Copyright 2001],

GAD and MDD (n = 40) after controlling for age,gender and other psychopathology.'-"*' In fact,respondents with pure GAD had significantlylower quality of life scores on several of the ShortForm-36 Health Survey scales'^ '^ than respon-dents with pure MDD. The results of this surveyconfirm the status of GAD as an independentdiagnosis.

In addition to the high level of impairment,patients with GAD are at risk of suicide or suicideattempts. In the European Study on the Epide-miology of Mental Disorders (a large communitysurvey of 21 425 respondents), GAD was foundto be strongly related to suicidality, with a rateratio of 2.3 for lifetime attempts and 1,8 for life-time ideation.'- '^'' This compares with rate ratiosfor major depressive episodes of 4.8 and 2.9 for life-time attempts and lifetime ideation, respectively.

The development of other psychiatric dis-orders is another possible consequence of GAD;even without a past history of GAD, patientsexperiencing a current episode of the disorderhave an increased risk of developing other mentaldisorders.'*^ '^ Furthermore, it has been shownthat a prior history of GAD increases the riskof developing MDD.'^ ^^ '' The impact of psychia-tric co-morbidity is great; patients with GAD anda co-morbid psychiatric condition experience

increased psychological and social impairment,have an extended course and poorer outcome,and arc higher utilizers of healthcare resourcesthan patients with GAD alone.'-^ '-^ '^ ' A similareffect is seen when GAD occurs with a co-morbidsomatic condition.t-^ "^ -^ **'

The economic burden of GAD is also high. Ina German study of 3021 respondents (aged 14-24years), subjects with GAD had a greater numberof days lost from work in the past month thansubjects with no mental disorder (8 days vs

The Role of Atypical Antipsychotics in GAD 107

uncertainty and GADJ"**'! Intolerance of un-certainty may also be considered to be a keyfeature t"^

4. Diagnosis and Assessment of GAD

Different diagnostic criteria for GAD are usedin diTcrent countries; in Europe the InternationalStatistical Classification of Diseases, lOth revi-sion (ICD-10)f'**'l and, more recently, the secondedition of the ICD-lOl''^' tend to be employed.ICD-10 has a broader spectrum of associatedsymptoms than the DSM-IV criteria used in theUS (table II).f---501 DSM-IV criteria are the mostfrequently used in clinical trials. These criteriastipulate that patients must have excessive anxi-ety and worry for 6 months, plus three or more ofsix specific symptoms {table II). DSM-V guide-lines are currently being developed, with publi-cation expected in 2011. GAD is one disorderwhose diagnostic criteria may be revised; itis thought that the DSM-IV requirements of6-month duration, excessive worry and threeassociated symptoms may exclude a substantialnumber of people with clinically significant an-xiety from being diagnosed as having GAD.^ ^^ ""!

To aid accurate diagnosis (and to rule outother possible diagnoses), the patient's medicaland family histories should be assessed, takingnote of recent life events and other health pro-blems such as depression and substance or alco-hol abuse/dependence. It is also important toconsider that patients with GAD have probablymade multiple visits to their primary carephysician or may have consulted differenttypes of physicians, such as gastrointestinalspecialists, and have a history of assessmentsand consultations where no definitive diagnosiswas made.

The main tool used in the clinical setting toassess the severity of symptoms of GAD is theHamilton Anxiety Scale (HAM-A).f^*'l However,the HAM-A isa 14-item, clinician-rated scale andis quite time consuming to perform. Recently,scales specific for GAD have been developed,such as the Generalized Anxiety Disorder In-ventory (GADI)[-* -^l and the GAD-7J"! Worrymay be the most important factor in predicting

the severity of GAD, specifically In the inductionof symptoms of GAD, and the Penn State WorryQuestionnaire (PSWQ), a 16-item, self-ratedquestionnaire that assesses pathological worryand captures the excessiveness and uncontroll-ability characteristic of pathological worry, is animportant tool for assessing thisj^"*! It has astrong sensitivity and specificity in distinguishingpatients with GAD from those without GAD.Table III summarizes the major advantages anddisadvantages of these scales.

5. Pharmacoiogicai and Genetic Basisof GAD

There is a variety of evidence implicating thedysfunction of GABA, noradrenergic and sero-tonergic systems in the expression of GAD.'^ ^-^^lThis includes evidence that, in patients withGAD, the number of platelet a^-adrenergic re-ceptors is reduced, and there are reduced plateletserotonin sites and reduced serotonin levels inCSF. Also, the benzodiazepine receptors in peri-pheral tissues are reduced.f'^ -^''*'' Patients withGAD respond to treatment with benzodiaze-pines, further supporting the fact that these

Table II. International Statistical Classification of Diseases, 10threvision (ICD-10} and DSM-IV diagnostic criteria for generalizedanxiety disorder (GAD)ICD-10 criteriai-'s 'SI

For a diagnosis of GAD, patients must have anxiety that isgeneralized and persistent but not restricted to, or even stronglypredominating in, any particular environmental circumstances, i.e. itis 'free-floating'. Dominant symptoms are variable but includepersistent nervousness, trembling, muscular tensions and epigastricdisoomfort. Fears that the patient or a relative will shortly become illor have an accident are often expressedDSM-IV criteriai^^iFor a diagnosis of GAD, patients must have excessive anxiety andworry for 6 months, plus have three or more of the followingsymptoms:

restlessnessfatiguedifficulty concentratingirritabilitymuscle tensionsleep disturbance

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108 Katzman

Table III. Summary of the main disease severity scales that may be used to assess generalized anxiety disorder (GAD)Scale and type Advantages DisadvantagesClinician ratedHarnJIton Anxiety Scale

Self ratedGAD Inventory (GADO's i^

GAD-7"'

Penn State Worry Questionnaire{PSWOjiS"!Intolerance of Uncertainty Scale

Current 'gold standard' scale and reference scalein clinical trialsAssesses severity of anxiety symptoms

Specific for GADAssesses symptom profile and severityBrief, 7-item scaleSpecific for GADGood screening toolGood measure ol pathological worry

Good measure of a potentially importantaetiological factor in GAD

Time consuming; takes 10-15 minutes to complete(14-item scale)Needs a trained rater

Time consuming (18-item scale)Not yet well establishedNot yet well established

Time consuming (16-item scale)Specific for general worryDoes not specifically measure severityHas not been assessed as an outcome measure

patients may have a deficiency in the GABA/benzodiazepine system. These three neuro-transmitter systems are involved in the body'sresponse to stress (processing fear and anxietyresponses).

The involvement of the serotonin 5-HT,d, re-ceptor subtype has been demonstrated in patientswith GAD in clinical trials of buspirone, and maybe the result of a neurochemical imbalance in-volving serotonin. Serotonin is widely distributedthroughout the brain, particularly in regions asso-ciated with anxiety.f^ "^ ! The selective serotoninreuptake inhibitors (SSRIs) bind to the serotonintransporter to prevent the reuptake of serotoninfrom the synaptie cleft.

The mode of action of SSRIs in GAD, al-though not fully elucidated, is thought to be si-milar to that occurring in panic disorder, in whichtwo opposing theories are currently suggested toexplain the role of serotonin dysfunction: (i) sero-tonin excess, where the action of serotonin isanxiogenic; and (ii) serotonin deficit, where theaction of serotonin is anxiolytic.t''"! In the former,patients have an increased level of serotoninrelease or have supersensitive post-synaptic re-eeptors. This theory suggests an explanation forthe time course of early adverse events associatedwith the later beneficial action of SSRIs; i.e. theinitial exacerbation of symptoms following SSRIadministration may well be related to an in-creased level of serotonin in the synapse acting on

the supersensitive post-synaptie receptors. This isthen followed by a gradual downregulation ofthese receptors.

For the second theory, following treatmentwith an SSRI, the initial exacerbation of symp-toms occurs because of a decrease in serotoninrelease by an action on the pre-synaptic in-hibitory 5-HTiA autoreceptor. Antidepressaniresponse occurs following the gradual desensiti-zation of these autoreceptors and the resultantincrease in serotonin levels.

The role of the serotonin and noradrenalinesystems in both GAD and MDD suggests thaithere may be a neurobiological link between thesetwo disorders. This may explain the high level ofco-morbidity between GAD and MDD, althoughthe two are distinct and separate conditions.Twin and family-based studies have shown aclear genetic influence in GAD, with a heritabilityof approximately 15-40%.[*''*'-' Recent evidencefrom a Swedish twin study of 23 280 members ofsame-sex twin pairs indicates that GAD andMDD are closely related genetically.f^^l

6. Treatment of GAD

6,1 Treatment GuidelinesWhile the focus of acute treatment for GAD

must include the improvement of symptoms, theprimary goal of long-term clinical management

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The Role of Atypical Antipsychotics in GAD 109

of patients with GAD is remission, i.e. the com-plete resolution of both symptoms and functionalimpairment. Recurrence prevention is anotherlong-term consideration. It is also important toconsider patient-specific goals, e.g. the improve-ment of troubling symptoms, including problemswith sleep or concentration, chronic agitation,irritability, recurrent headaches or muscle pain.Factors such as anticipated adverse effects, ahistory of prior response in the patient or a familymember, patient preference and cost shouldbe considered when deciding which treatment toinitiate.

Globally, there are several guideline commit-tees that have reported their recommendationsand treatment algorithms for patients with GAD,including the World Federation of Societies ofBiological Psychiatry,'^' the British Associationfor PsychopharmacologyJ^*'' the National In-.stitute for Health and Clinical Excellence,''''^ '^ andthe Canadian Psychiatric Association (CPA)(table IV).l''^ t

In general, the consensus across treatmentguidelines is that first-line pharmacotherapy forpatients with GAD should consist of an anti-depressant, cither an SSRI, such as paroxetineand escitalopram, or a selective serotonin nora-drenaline inhibitor (SNRI), such as venlafaxine

or duloxetine (in the US). The CPA guidelines arethe most recent and these attribute the highestlevel (level 1 : meta-analysis or replicated random-ized clinical trial including a placebo arm) to theevidence supporting the use of paroxetine, esci-talopram and venlafaxine as first-line treatmentoptions for GAD.I-^ '^ The CPA consider thatclinical trial data are sufficient to suggest thatthe SSRI sertraline may be an effective first-line treatment option; however, this agent is notcurrently licensed for GAD.'''^' The CPA re-commends imipramine, buspirone, benzodiaze-pines and pregabalin as second-line treatmentoptions. Clinical trial evidence for these agents isstrong (level 1); however, the CPA considers thatthe clinical experience with these agents does notsupport their use as first-line options because ofadverse effects (imipramine, benzodiazepines),lack of efficacy (buspirone) or paucity of data(pregabalin).

The available evidence for agents that showefficacy in the treatment of GAD is considered inmore detail in sections 6.2-6.7.

6.2 Selective Serotonin Reuptoke inhibitorsParoxetine was the first SSRI to be licensed for

the treatment of GAD and is consequently the

Table IV. Major organizations that have published guidelines/recommendations for the treatment of generalized anxiety disorder (GAD)Organization (year of guideiines) Guideiine FJrsl-line pharmacotherapy options tor GADWorid Federation ot Societies otBiological Psychiatry (2002)

Brttisti Association torPsychopharmacology (2005)

National institute for Health andClinical Excellence (2004)

Canadian Psychiatric Association(2006)

Guideiines for the pharmacological treatmentof anxiety, obsessive-compuisive and post-traumatic stress disorders'^'Evidence-based guideiines for thepharmacoiogicai treatment of anxiety

Management ot anxiety (panic disorder, with orwithout agoraphobia, and generalized anxietydisorder) in adults in primary, secondary andcommunity care'*^'Management of anxiety discwders''*^

SSRI: paroxetineSNRI: veniafaxine

Acute treatment:SSRfs: paroxetine, escitalopram, sertralineSNRi: ventafaxineBenzodiazepines: aiprazoiam, diazepamTCA: imipramineBuspironeAniihistamines: hydroxyzineLonger-term treatment:SSRIs: paroxetine. escitaiopramSSRI: paroxetineSNRI: veniafaxineBenzodiazepines (not to be used t)eyond 2-4 wk)Antihistamines: hydroxyzineSSRis: paroxetine, escitaiopram, sertraiineSNRIs: veniataxine

SNRU serotonin noradrenaiine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.

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no Katzman

most studied in this indication. The efficacy ofparoxetine in the treatment of DSM-IV GAD hasbeen established in four randomized, double-blind, plaeebo-eontrolled studies (three short-term studies and a study of 6 months' duration) inmore than 1800 patients.f*^ !^ Of the three short-term studies, two found a statistically significantdifference between paroxetine and placebo inthe primary outcome variable of change inHAM-A total score. In the largest of the short-term studies (566 outpatients with GAD and noother axis I disorder), response ('very niuehimproved' or 'much improved' on the ClinicalGlobal Impression-Improvement [CGI-I][^ **1 score)at 8 weeks was achieved by 62% and 68% of pa-tients in the 20 and 40 mg/day paroxetine groups,respectively, and by 46% in the placebo group.[''''^Remission rates (defined as a HAM-A score of

The Role of Atypical Antipsychotics in GAD 111

remission rates at week 24 for venlafaxine-treatedpatients to be lower (27.9%) and similar to pla-cebo (18.9%) [p-0.1 l].i**"I

Duloxetine has recently been approved in theUS for the treatment of GAD.'**"! Its efficacy hasbeen demonstrated in three randomized, placebo-controlled studies (two 10-week fiexible-dosestudies and one 9-week fixed-dose study) con-ducted in over 1100 patients with GAD.t**-] Thepooled results from these studies showed thatduloxetine significantly improved the HAM-Atotal score from baseline to endpoint comparedwith placebo (mean improvement 11.1 vs 8.0;p< 0.001). Furthermore, in a 10-week active-comparator study in nearly 500 patients withGAD, duloxetine and venlafaxine both producedsignificantly greater improvements from baselinein HAM-A total score compared with placebo.Compared to placebo, the efficacy of duloxetineand venlafaxine was similar. Discontinuation-emergent adverse events were significantly greaterin the venlafaxine group (26.9%; p = 0.04), butnot the duloxetine group (19.4%; p = 0.448), com-pared with placebo.'^ -^^

6 4 PregoboiinThe antiepileptic pregabalin is approved in

Europe for the treatment of GAD. It is not con-sidered a first-line option for GAD and is cur-rently only recommended for patients who do notachieve full remission or who are intolerant toSSRIs or SNRIs.[^**5i The efficacy of pregabalin(400 or 600 mg/day) was demonstrated in a 6-week,randomized, double-blind, active-comparator studyin outpatients with moderate to severe DSM-IVGAD (n = 421).l'^ '^] There were significantly greaterimprovements in HAM-A total score at endpointwith both pregabalin and venlafaxine (75 mg/day)than with placebo. The proportion of patientswith a >50% reduction in HAM-A score atendpoint was comparable for treatment withpregabalin 400 mg/day and venlafaxine 75 mg/day.Only pregabalin produced significant improve-ment, compared with placebo, in all a prioriand secondary measures. Discontinuation rateswere greater for venlafaxine than for pregabalin.These results confirm the findings of four

previous placebo-controlled studies of pregabalinin ! !

6.5 Buspirone

Buspirone is the only azapirone licensed forthe treatment of anxiety. Its efficacy in GAD hasbeen studied in several trials: 6 studies versusplacebo, 12 studies versus benzodiazepines, and1 study versus venlafaxine (reviewed by Chessicket al.t^^). A Cochrane systematic review of theresults from these studies found that the efficacyof buspirone in the treatment of GAD wassuperior to placebo, but similar to that of thebenzodiazepines.f^^' In addition, in 365 out-patients with GAD without co-morbid MDD,venlafaxine and buspirone were more effectivethan placebo, and venlafaxine was significantlysuperior to buspirone on the Hospital Anxietyand Depression (HAD) anxiety subscale.f******''Limitations of buspirone include its slow onset ofaction of at least 2 weeks.f^ **l In addition, it hasbeen suggested that the efficacy of azapirones inpatients previously treated with benzodiazepinesmay be limited:^^'' their efficacy in these patientsrequires further investigation. Common adverseeffects reported with buspirone include headache,nausea, dizziness and gastrointestinal problems.^ " '^1

6.6 imipramine

Imipramine, a TCA, has been shown to beeffective in treating the symptoms of anxietyin patients with GAD from the third week oftherapy.'^- However, the incidence of adverseevents was higher in imipramine-treated patientsthan in patients treated with the benzodiazepinediazepam.

6.7 Benzodiazepines

There is evidence that benzodiazepines areeffective in the treatment of GAD, particularly asthey offer rapid relief of anxiety symptoms.t'^^lAdverse eTects are usually mild and can includesedation and psychomotor impairment.t^-'l How-ever, the long-term use of benzodiazepines inGAD is not recommended because of concernsover dependen ce; f*'^*'^ '! withdrawal symptoms

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112 Katzmaii

have been reported in up to 44% of patients whohave received benzodiazepines for as few as 4-6weeksJ'^ -^ ' Furthermore, benzodiazepines are noteffective for the symptoms of MDD, which isoften co-morbid in patients with GAD, and mayalso cause MDD in the long term.

6.8 Limitations of First-Line Treatment OptionsDespite being considered first-line treatment

options in GAD, SSRIs and SNRIs have efficacylimitations, including lack of response in manypatients (response rates in GAD clinical trials areapproximately 60-70%t^ ^-^^- '^*l), a 2- to 4-weekdelay before the onset of symptom reliefj^ "*! slowresponse (it may be 6-12 weeks before significantimprovements are achieved),^''^l lack of full re-mission, i.e. residual symptoms remain in ahigh proportion of patients (30-60% of patientsdo not achieve remission^ '^''" -^'-^ '*!) and risk ofrelapse (relapse rates in GAD clinical trials are

In addition, the adverse effects associated withboth SSRIs and SNRIs include sexual dysfunc-tion, nausea, gastrointestinal problems, headacheand sweating.[ '^-'^ ^''^ '1 In addition, for the SSRIs,adverse effects (occurring at varying frequencies)include increased nervousness, vomiting andweight gain (with paroxetine). With SNRIs, ad-ditional adverse effects include potential bloodpressure changes (with duloxetine and venlafax-ine) and insomnia.f^ *^ -*^ '^

A further issue with SSRfs and SNRIs is thatabrupt discontinuation of therapy with theseagents may lead to discontinuation or withdrawalsymptoms.f'"*'* '^ Therefore, when stopping treat-ment, it is important that SSRIs or venlafaxineare gradually tapered over a period of a fewweeks in order to diminish the occurrence of dis-continuation symptoms.['1 Unfortunately, thisis not always possible as patients may indepen-dently decide to discontinue their treatment.

In October 2004, the US FDA instructedmanufacturers of antidepressants (includingSSRIs and SNRIs) to amend product labelling toinclude a black-box warning and expandedwarning statements regarding an increased risk ofsuicidality (suicidal thinking and behaviour) in

paediatric and adolescent patients receiving theseagents.f'"'l In May 2007, the FDA proposed up-dates to the existing black-box warnings for allantidepressants to include information about theincreased risks of suicidal thinking and behaviourduring initial treatment in patients aged 18-24years.'"^-' In a recent study of patients withoutpsychosis who were hospitalized because of asuicide attempt, the authors found that fluoxetinewas associated with the lowest risk of suicide(relative risk [RR] 0.52; 95% CI 0.30, 0.93),whereas venlafaxine was associated with thehighest risk (RR 1.61; 95% CI 1.01. 2.57).[i"-''

7. Treatment Response and Remission

For many patients with GAD. initial pharma-cotherapy will not lead to remission (definedas a HAM-A total score of

The Role of Atypical Antipsychotics in GAD 113

available literature on this topic is beyond thescope of this paper; however, a brief overview isgiven below.

There are a limited number of studies in-vestigating the non pharmacological treatmentof GAD. Most of these focus on cognitive-behavioural therapy (CBT). CBT is a psycho-therapeutic approach designed to alter behaviourand cognition that produces and maintainsemotional distress.t'"**' CBT for GAD may in-clude psychoeducation, symptom managementtechniques, cognitive restructuring, worry expo-sure and self-monitoring. Recently., a Cochranesystematic review of studies assessing psycho-logical therapies in patients with GAD identified22 studies (1060 subjects) that were eligible forinclusion in meta-analyses.f'*'*'! The resultsshowed that CBT-based psychological therapieswere effective in reducing anxiety over the shortterm in patients with GAD. The authors con-cluded that available evidence comparing otherpsychological therapies with CBT was limited;therefore, conclusions about which psychologicaltherapy is more effective could not be drawn.

Three earlier studies of CBT in GAD havebeen published.'"^''"'"^! In all the studies includedin these meta-analyses, the symptoms of GADwere reduced. In addition, the effects of treat-ment continued or improved in the 6-12 monthsfollowing treatmentj'''"^^l

More recently, a study in 45 patients withGAD demonstrated that at 6-month follow-up,CBT was equally effective as applied relaxationtherapy.f'"''l In addition, recent trials in elderlypatients with GAD have shown CBT to be ef-fective. For example, in 85 patients with GAD(aged >60 years), response was higher in the CBTgroup (45%) than in the control group (8%).["''Similarly, two pilot studies in older patients withGAD also demonstrated significant symptomimprovements with CBT.'' "^

The advantages of CBT over pharmaco-therapy include patient preference and lack oftroubling adverse eTects. Unfortunately, CBT isnot widely available, requires specialist trainingand entails weekly contact with the patient for12-20 weeks, with the latter two factors havingimplications on both cost and availability.

9. Atypical Antipsychotics in GAD

Evidence is emerging that atypical anti-psychotics are effective in the treatment ofpatients with anxiety disorders, either as mono-therapy or as augmentation to standard treat-ment. Aripiprazole, olanzapine, quetiapine,risperidone and ziprasidone have all been studiedin patients with anxiety disorders or depressionand anxiety.["'"'~1 Specifically in patientswith GAD, olanzapine (n-24),'"^l risperidone(n = 40)["^l and quetiapine (n=:40)r"^] have beeninvestigated in clinical trials as augmentationtherapy and were shown to be effective in thisrole. Furthermore, quetiapine (n = 38)["^' andziprasidone (n = 13)t"^l have been studied asmonotherapy for the treatment of patients withGAD. The design and efficacy data from thesestudies of the atypical antipsychotics in GAD aresummarized in table v.[""""" Although thenumbers of patients included in these studies aresmall, the results support the potential role ofatypical antipsychotics in the treatment of GAD.

In a randomized, double-blind, placebo-controlled study of olanzapine augmentation offluoxetine, both the HAM-A and CGI-Severityof Illness response rates were statistically sig-nificantly higher than those observed in patientswho received placebo, i.e. no augmentation.t"^'Although no other differences in efficacy param-eters were seen between the treatment groups, theauthors concluded that olanzapine augmentationin patients with treatment-resistant GAD mayhave a beneficial anxiolytic effect. However, theincreased weight observed with olanzapine inthis study may be a potential problem in somepatients.

Risperidone augmentation of anxiolytictherapies (including SSRIs, SNRIs, buspirone,benzodiazepines, gabapentin and combinationsof these drugs) has also been shown to be statis-tically significantly more effective than placebo,as assessed by the HAM-A, in patients withsymptomatic GAD.t"'^! The aim of this random-ized, doubie-bhnd, placebo-controlled study wasto explore the efficacy and safety of adjunctiverisperidone in this patient population. From thepositive results shown (effectiveness and good

3009 Adis Doto Information BV, AH lights reserved. CNS Drugs 2009; 23 (2)

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The Role of Atypical Antipsychotics in GAD 115

tolerability of risperidone augmentation), theauthors recommend that additional studies beconducted in a larger sample size and for a longerduration.

In an open-label study, Katzman et al.^"^'demonstrated that augmentation with quetiapinein patients with treatment-resistant or non-remitted GAD (i.e. patients treated for at least8 weeks with an adequate dose of antidepressant)resulted in statistically significant reductions inHAM-A total scores from baseline to week 12(-21.7; p

116 Katzman

used. Ultimately, the goal is remission and to givepeople with GAD a level playing field and a fullchance of normal health.

11. ConclusionsTreatment guidelines recommend that first-

hne treatment for patients with GAD shouldconsist of an antidepressant, such as an SSRI oran SNRI. The efficacy limitations of these agents,e.g. lack of response in many patients, lack of fullremission and risk of relapse, means that there isa need for alternative treatment options. Earlyclinical studies of the atypical antipsychotics,either as monotherapy or as augmentation tostandard treatment for patients with GAD, in-dicate that they may have a potential role in thetreatment of this anxiety disorder and furtherrandomized controlled studies are warranted.

AcknowledgementsThe auttior would like to thank Jocelyn Woodcock,

MPhil, from Complete Medical Communications, who pro-vided editorial assistance in tlie preparation of this review. Anunrestricted educational grant was provided by AstraZeneca.Dr Martin Kalzmun has received grants from Lundbeck,Wyeth, GlaxoSmithKline, Eli Lilly. AstraZeneca, Solve,Genome Health and Pfizer. Dr Katzman has also consultedfor GlaxoSmilhKline, Wyeth, Lundbeck, AslraZeneca, EULilly, Janssen. Brislol-Myers Squibb and Shire, and has re-ceived honoraria from Wyeth, GlaxoSmithKline. Lundbeck,AstraZeneca. Eli Lilly, Janssen, Solve, Bristol Myers-Squibband Abbott.

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Correspondence: Dr Martin A. Katzman, START Clinic forMood and the Anxiety Disorders, 900 - 790 Bay St, Toronto.Ontario M5G 1N8, Canada.E-mail: mkatzman@startdinic.ca

2009 Adis Data Information BV. All tights feserved. CNS Drugs 2009; 23 (2)