International Journal of Psychiatry in Clinical Practice, 2006; 10(Suppl 1): 10 /15
ORIGINAL ARTICLE
Generalized anxiety disorder: how to treat, and for how long?
RAYMOND W. LAM
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Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
Abstract Generalized anxiety disorder (GAD) is a common, chronic and disabling anxiety disorder with considerable comorbidity with depression as well as with other anxiety disorders. Although tricyclic antidepressants and benzodiazepines have been found to be efficacious in patients with GAD, tolerability problems and other risks limit their use in clinical practice. In placebo-controlled, acute (B/8 weeks) trials, several medications, including the selective serotonin reuptake inhibitors ([SSRIs] escitalopram, paroxetine, and sertraline) and others (venlafaxine, buspirone, pregabalin), have demonstrated efficacy in patients with GAD. Indeed, current guidelines for the treatment of GAD recommend SSRIs as first-line pharmacological therapy because of their efficacy and tolerability profiles. Although GAD is a chronic condition that is usually present for years, with symptoms typically fluctuating in intensity over time, there have been few randomized, controlled trials of pharmacotherapy beyond the acute phase of treatment. However, data from recent relapse-prevention studies and longer-term maintenance studies with paroxetine, venlafaxine and escitalopram strongly support the value of continued treatment for at least a further 6 months. This article focuses on pharmacological treatment, and reviews recently available data from acute, long-term and relapse-prevention trials in patients with GAD. In addition, issues relating to the natural course of GAD are highlighted as important considerations to guide selection of pharmacotherapy.
Key Words: Anxiety disorders, serotonin reuptake inhibitors, escitalopram, tolerability
Introduction Generalized anxiety disorder (GAD) is a common psychiatric condition characterised by excessive, persistent (lasting 6 months or longer) uncontrollable worry or anxiety about events or activities (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) (American Psychiatric Association). Epidemiological studies estimate that the lifetime prevalence of GAD in the general population is 2.8 /6.6% [1 /4]. In the National Comorbidity Survey (NCS), a large (n /9,282) general population survey of American adults aged at least 18 years, the overall 12-month prevalence of all anxiety disorders was estimated to be 18.1% [3]. In this population cohort, the prevalence of GAD within the previous 12-month period was 5.7%, as compared with an estimated prevalence of 12.1% for social anxiety disorder and 4.7% for panic disorder. The age of onset of GAD is different from that of other anxiety disorders, which often begin in childhood, adolescence or early adulthood, with most cases presenting in adults aged between 35 and 45 years [1,5]. Indeed, it is probably the most common
anxiety disorder in adults aged more than 55 years [2,6]. Despite the relatively high prevalence of GAD, there are sparse data on the natural course of the condition. Retrospective studies suggest that it is a chronic condition with an episodic pattern, in which periods of relapse and remission are evident for up to 20 years [7]. Data from the Epidemiologic Catchment Area (ECA) study revealed an average duration of illness between 6.5 and 10.4 years [8], with 40% of patients reporting the presence of symptoms for more than 5 years. In fact, although the age of onset is often in mid-to-late adulthood, up to 50% of individuals presenting with GAD reported experiencing some symptoms of the illness during childhood or adolescence [9]. Without treatment, extended periods of remission are unlikely. Prospective data from a naturalistic follow-up study, the Harvard-Brown Anxiety Research Program (HARP), suggest a low remission rate, with a probability of only 0.38 at 5 years (Figure 1) [10]. In this prospective, observational, longitudinal study of patients with anxiety disorders, of the patients with GAD (n /167), only 40% experienced at least partial remission (reduction in symptoms for at least
Correspondence: Raymond W. Lam, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2A1. Tel: /1 604 822 7325. Fax: /1 604 822 7922. E-mail: [email protected]
ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500600552396
Treatment of generalized anxiety disorder
11
Comorbidity Pure GAD appears to be relatively uncommon and patients with GAD suffer from a high degree of comorbidity with other anxiety or psychiatric disorders. In the HARP study 83% of patients had another anxiety disorder, including 36% who had concurrent panic disorder [10]. Patients with GAD commonly present with coexisting depression [19].
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Influence of aging
Figure 1. Probability of full and partial remission or full remission only during 5 years in the Harvard-Brown Anxiety Research Program (HARP). PSR, psychiatric status rating [10].
8 weeks) during the 5-year follow-up period, and only 38% experienced full remission (occasional or no symptoms for at least eight consecutive weeks), confirming the low response rates in this condition. Although GAD is among the most common mental disorders seen in primary care, the condition is often missed or misdiagnosed [11] because patient attribution of symptoms and the stigma related to mental illness may mask the condition [12,13]. Current guidelines for the treatment of patients with GAD recommend selecting evidence-based pharmacotherapy, psychotherapy, or both, while taking into account patient preference and the facilities available to support the patient in their immediate locality [14 /18]. However, a number of key issues relating to the clinical course of GAD also need to be considered when deciding on the most appropriate and effective course of treatment [13]. Waxing and waning course A challenging characteristic of GAD is that the severity of symptoms can fluctuate considerably during a person’s lifetime. Such variability may lead to a continuous decline in the patient’s quality of life. Chronicity The chronic nature of the condition means that patients often require maintenance therapy for many years. For this reason, tolerability of selected therapies is an important consideration.
GAD is more prevalent in older than in younger patients. Thus, selection of treatment regimens should also take into account both comorbid and other unrelated diagnoses already present in the geriatric patient. Older patients are also more likely to be on other medications, so the potential for drug /drug interactions must also be considered. Stressful life events Retrospective studies link the occurrence of stressful or negative life events with an increased risk of GAD [20]. In recent years there has been a trend towards an increasing use of antidepressants for treating anxiety disorders, rather than the previously commonly used benzodiazepines. However, optimum treatment regimens are still unclear and careful and acute, long-term and relapse-prevention studies are needed in order to assess the most effective modes of treatment for patients with GAD. Although a number of systematic reviews have recently assessed the evidence-based pharmacotherapy of GAD [18,21,22], this article seeks to highlight recent developments in the pharmacological treatment of GAD, which have become available since these reviews were written. Current data available Data from a number of randomized, placebocontrolled trials provide evidence for the beneficial effects of several compounds, including benzodiazepines (e.g., alprazolam, diazepam), tricyclic antidepressants (TCAs; imipramine), selective serotonin reuptake inhibitors (SSRIs; escitalopram, paroxetine, sertraline), and the serotonin noradrenaline reuptake inhibitor (SNRI) venlafaxine XR, in the acute treatment of GAD [18,22]. While TCAs and benzodiazepines have been found to be efficacious in patients with GAD in a number of trials, their use in current clinical practice is limited by issues of tolerability and their risk /benefit ratio. The SSRIs are advantageous for treating GAD, as they are well tolerated and also effective against the comorbid psychiatric disorders seen with this condition. Indeed, evidence supports that 50 /75% of patients with anxiety disorders experience significant benefit
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after adequate dose and duration of therapy with an SSRI [23/25], and these agents are now accepted as first-line therapy in GAD. Despite the relatively large amount of data available from placebo-controlled studies for the acute treatment of GAD, there is a definite paucity of data regarding long-term maintenance and relapse prevention in patients with this disorder. Indeed, only paroxetine [26] and escitalopram [27,28] have shown efficacy in placebo-controlled studies with these designs. Furthermore, few acute- or long-term comparator-controlled studies have been conducted. Various forms of psychological treatment, including cognitive behavioral therapy (CBT) have also been evaluated in the acute, long-term and relapseprevention phases of treatment of GAD, and there are data to show that this approach may be beneficial, especially when used in combination with effective pharmacotherapy. Acute treatment of GAD Escitalopram, a highly selective SSRI, has been evaluated in the acute treatment of GAD in four placebo-controlled clinical studies [28 /31]. The efficacy of escitalopram in acute treatment was established in three randomized studies. Although results of the first study were published separately [28], results from all three studies were later published as a pooled analysis because their study designs were similar [30,31]. In these three studies, patients with GAD (n /856) were randomized to treatment with escitalopram (10 mg/ day) or placebo for 8 weeks. After 4 weeks, the escitalopram dose could be increased to 20 mg/day if required. In each individual study, escitalopram was superior to placebo (last observation carried forward analysis [LOCF]; P B/0.05) as assessed by the mean change in Hamilton anxiety rating scale (HAM-A) total score from baseline to week 8. Escitalopram was also superior to placebo with regard to the secondary outcome variables, which included the HAM-A psychic and somatic anxiety sub-scales, the Clinical Global Impression of improvement and severity scales (CGI-I and CGI-S) and the Hamilton depression rating scale (HAM-D) anxiety sub-scale. In the pooled analysis of all three studies, escitalopram (10 mg/day) was superior to placebo (P B/0.001) with an effect size of 2.5 points on the HAM-A scale; an effect that is not only statistically significant, but also clinically relevant. The dose /response relationship of escitalopram (5, 10 and 20 mg/day) in acute treatment was examined in a 12-week, randomized, fixed-dose, placebo-controlled study (n /681) [29]. Paroxetine (20 mg/day) was also included as a comparator. Comparison of escitalopram with placebo showed that in the intent-to-treat (ITT) LOCF analysis, the higher escitalopram doses (10 and 20 mg)
were superior to placebo from week 8 onwards (Figure 2), while the 5-mg dose of escitalopram was superior to placebo at week 12. Escitalopram 10 mg/day, was statistically superior to placebo in the LOCF analysis (P B/0.05); the 20-mg dose was superior to both placebo and paroxetine. Evidence for the efficacy of venlafaxine, an SNRI, in the acute phase of GAD has been demonstrated in five randomized placebo-controlled studies, two of which involved an active comparator (diazepam or buspirone) [32]. Pooled analysis of these five studies (n /1,839) showed a statistically significant effect size for venlafaxine compared with placebo (P B/0.001) [32]. Another medication, demonstrating efficacy in the acute phase of GAD, is pregabalin, a structural analogue of g-aminobutyric acid (GABA) with anti-convulsant, anxiolytic and analgesic properties. In three randomized, double-blind, placebocontrolled treatment studies (two of which incorporated an active comparator) pregabalin was superior to placebo in relieving acute symptoms of GAD [33 /35] and had similar overall efficacy to alprazolam [34] or venlafaxine [35]. Long-term trials in GAD Although several agents have demonstrated beneficial effects in patients with GAD during acute-phase treatment, on average only 60% of patients achieve a satisfactory response to acute treatment, and of these patients a high proportion continue to experience problematic persistent symptoms [21]. This, together with the known chronic nature of GAD,
Figure 2. Dose /response relationship of escitalopram compared with placebo and paroxetine (20 mg/day) in patients with GAD. The figure shows the mean change in HAM-A from baseline. Compared with placebo a significantly greater effect was seen for escitalopram 10 and 20 mg (*P B/0.05) from 8 /12 weeks and for escitalopram 5 mg ($P B/0.05) after 12 weeks. In the last observation carried forward (LOCF) analysis, escitalopram 10 mg was significantly more effective than paroxetine 20 mg (%P B/0.05) [29].
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Treatment of generalized anxiety disorder means that long-term pharmacotherapy is needed for most patients. Despite this, there is scant evidence regarding long-term evaluation of pharmacological therapies in patients with GAD. Longitudinal analysis of pooled data from two similar studies, which evaluated the long-term efficacy of venlafaxine, revealed a significant improvement in response and remission rates compared with placebo during 6 months of treatment [36]. In these two double-blind, placebo-controlled studies (n /792), the criteria for response (]/50% improvement from baseline HAM-A score) was met by 66% of venlafaxine-treated patients, compared with 39% of those in the placebo group (P B/0.001). Similarly, remission rates at 6 months were significantly higher with venlafaxine than with placebo (43 versus 19%; P B/0.001). Remission rates are an important indicator of treatment success, as they show the proportion of patients who fully recover rather than the proportion of patients who simply experience clinical improvement in symptoms (response rate). Sustained remission was observed in 19% of the venlafaxine group versus 8% of the placebo group (P B/0.001), demonstrating the stability of the response. The benefit of continued treatment with escitalopram for up to 6 months was demonstrated in a randomized, double-blind, flexible dose comparative study [37]. Patients with GAD received 1 week of placebo treatment and 24 weeks of double-blind flexible-dose treatment with either escitalopram (10/20 mg/day) or paroxetine (20 /50 mg/day), followed by a 2-week, double-blind, down-titration period [37]. Although a similar decline in mean HAM-A scores of 15.3 and 13.3 points was observed in the escitalopram- (n /60) and paroxetine-treated groups (n /61), respectively, treatment with escitalopram was numerically superior to the treatment with paroxetine. At week 24, more patients on escitalopram achieved response than those on paroxetine. At week 24, the response rate (HAM-A 50% reduction) was greater in the escitalopram group than in the paroxetine group (78.3 versus 62.3%). In addition, the tolerability profile appeared to favor escitalopram over paroxetine. There were significantly fewer (P B/0.05) patients who dropped out of the trial because of adverse events with escitalopram than with paroxetine (6.6 versus 22.6%), and a lower incidence of sexual adverse events (including ejaculation disorder, anorgasmia and reduced libido).
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tients (n /560) showing an improvement in CGI-I score of at least 2 points (to 5/3) were subsequently randomized to receive treatment for 24 weeks, with either paroxetine or placebo. The likelihood of relapse during the double-blind treatment period, as defined by an increase in the CGI-I score to ]/4, was almost 5 times greater in placebo- than in paroxetine-treated patients (estimated hazard ratio /0.213; P B/0.001). A clear benefit of escitalopram relative to placebo was observed in risk of relapse and time to relapse in a long-term evaluation of GAD patients who had responded to acute treatment [27]. Patients with GAD (n /491) who responded to 12 weeks of openlabel treatment with escitalopram (20 mg/day) were randomly assigned to 24 /76 weeks of double-blind treatment with escitalopram (20 mg/day) or placebo. Risk of relapse (defined as either an increase in total HAM-A score to ]/15, or an unsatisfactory treatment response as judged by the investigator) was 4 times higher in the placebo- compared with the escitalopram-treated patients. Indeed, the proportion of patients with relapse was significantly lower with escitalopram than with placebo (19 versus 56%; P B/0.001), demonstrating the efficacy of escitalopram in preventing relapse during long-term treatment of GAD (Figure 3). Conclusions Improved clinical outcomes for patients with GAD require effective management of all aspects of the condition, and consideration of both the chronic course of the disease and the high occurrence of comorbid conditions, particularly depression and other anxiety disorders. Retrospective, naturalistic studies indicate that the chronic pattern of the
Relapse prevention trials in GAD The efficacy of paroxetine in the prevention of relapse in patients who had responded to acute treatment was demonstrated a 32-week, randomized, double-blind, placebo-controlled study [26]. In an initial open-label treatment period all patients received paroxetine (20 /50 mg) for 8 weeks. Pa-
Figure 3. Escitalopram reduces the likelihood of relapse in patients with GAD who had responded to acute treatment [27]. 18.8% of patients treated with escitalopram relapsed, compared with 56.1% of placebo-treated patients.
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untreated disease, with low rates of remission and moderate rates of relapse following remission, may persist for 20 years or more. Therefore, the successful treatment of GAD needs to provide acute relief from symptoms, together with effective maintenance therapy to achieve full remission. Consideration of treatment tolerability, especially during long-term maintenance use, is consequently also of critical importance. To date, few treatments have demonstrated efficacy in the acute and the long-term treatment phases and in the prevention of relapse; only escitalopram and paroxetine have efficacy data for these phases of treatment. Future studies should address the development of effective treatment strategies that provide an improved long-term outcome for patients with GAD.
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The author is on advisory/speaker boards and/or has received research funds from: AstraZeneca, Canadian Network for Mood and Anxiety Treatments, Cephalon, Eli Lilly, GlaxoSmithKline, JanssenOrtho, Litebook Inc., Lundbeck, Roche, SanofiAventis, Servier and Wyeth.
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. Generalized anxiety disorder (GAD) is a common, chronic and disabling condition with considerable comorbidity, especially with depression . Tolerability issues for the tricyclic antidepressants and benzodiazepines limit their efficacy in GAD . The selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SSRIs) demonstrate substantial efficacy in patients with GAD . Current treatment guidelines recommend the SSRIs as first-line treatment for GAD . Data from acute, long-term and relapseprevention trials strongly support the role of the SSRIs, such as escitalopram, as effective pharmacological therapy of GAD
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[32] Gorman JM. Treatment of generalized anxiety disorder. J Clin Psychiatry 2002;63(Suppl 8):17 /23. [33] Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003;23:240 /9. [34] Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry 2005;62:1022 / 30. [35] Kasper S, Blagden M, Seghers S, et al. A placebo controlled study of pregabalin and venlafaxine treatment of GAD. Poster presented at: Annual Meeting of the American Psychiatric Association; May 21, 2002, Philadelphia, PA, USA; 2002. [36] Montgomery SA, Mahe V, Haudiquet V, Hackett D. Effectiveness of venlafaxine, extended release formulation, in the short-term and long-term treatment of generalized anxiety disorder: Results of a survival analysis. J Clin Psychopharmacol 2002;22:561 /7. [37] Bielski RJ, Bose A, Change CC. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry 2005;17: 65 /9. /
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ORIGINAL ARTICLE
Generalized anxiety disorder: how to treat, and for how long?
RAYMOND W. LAM
Int J Psych Clin Pract Downloaded from informahealthcare.com by Universitat de Girona on 11/04/14 For personal use only.
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
Abstract Generalized anxiety disorder (GAD) is a common, chronic and disabling anxiety disorder with considerable comorbidity with depression as well as with other anxiety disorders. Although tricyclic antidepressants and benzodiazepines have been found to be efficacious in patients with GAD, tolerability problems and other risks limit their use in clinical practice. In placebo-controlled, acute (B/8 weeks) trials, several medications, including the selective serotonin reuptake inhibitors ([SSRIs] escitalopram, paroxetine, and sertraline) and others (venlafaxine, buspirone, pregabalin), have demonstrated efficacy in patients with GAD. Indeed, current guidelines for the treatment of GAD recommend SSRIs as first-line pharmacological therapy because of their efficacy and tolerability profiles. Although GAD is a chronic condition that is usually present for years, with symptoms typically fluctuating in intensity over time, there have been few randomized, controlled trials of pharmacotherapy beyond the acute phase of treatment. However, data from recent relapse-prevention studies and longer-term maintenance studies with paroxetine, venlafaxine and escitalopram strongly support the value of continued treatment for at least a further 6 months. This article focuses on pharmacological treatment, and reviews recently available data from acute, long-term and relapse-prevention trials in patients with GAD. In addition, issues relating to the natural course of GAD are highlighted as important considerations to guide selection of pharmacotherapy.
Key Words: Anxiety disorders, serotonin reuptake inhibitors, escitalopram, tolerability
Introduction Generalized anxiety disorder (GAD) is a common psychiatric condition characterised by excessive, persistent (lasting 6 months or longer) uncontrollable worry or anxiety about events or activities (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) (American Psychiatric Association). Epidemiological studies estimate that the lifetime prevalence of GAD in the general population is 2.8 /6.6% [1 /4]. In the National Comorbidity Survey (NCS), a large (n /9,282) general population survey of American adults aged at least 18 years, the overall 12-month prevalence of all anxiety disorders was estimated to be 18.1% [3]. In this population cohort, the prevalence of GAD within the previous 12-month period was 5.7%, as compared with an estimated prevalence of 12.1% for social anxiety disorder and 4.7% for panic disorder. The age of onset of GAD is different from that of other anxiety disorders, which often begin in childhood, adolescence or early adulthood, with most cases presenting in adults aged between 35 and 45 years [1,5]. Indeed, it is probably the most common
anxiety disorder in adults aged more than 55 years [2,6]. Despite the relatively high prevalence of GAD, there are sparse data on the natural course of the condition. Retrospective studies suggest that it is a chronic condition with an episodic pattern, in which periods of relapse and remission are evident for up to 20 years [7]. Data from the Epidemiologic Catchment Area (ECA) study revealed an average duration of illness between 6.5 and 10.4 years [8], with 40% of patients reporting the presence of symptoms for more than 5 years. In fact, although the age of onset is often in mid-to-late adulthood, up to 50% of individuals presenting with GAD reported experiencing some symptoms of the illness during childhood or adolescence [9]. Without treatment, extended periods of remission are unlikely. Prospective data from a naturalistic follow-up study, the Harvard-Brown Anxiety Research Program (HARP), suggest a low remission rate, with a probability of only 0.38 at 5 years (Figure 1) [10]. In this prospective, observational, longitudinal study of patients with anxiety disorders, of the patients with GAD (n /167), only 40% experienced at least partial remission (reduction in symptoms for at least
Correspondence: Raymond W. Lam, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2A1. Tel: /1 604 822 7325. Fax: /1 604 822 7922. E-mail: [email protected]
ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500600552396
Treatment of generalized anxiety disorder
11
Comorbidity Pure GAD appears to be relatively uncommon and patients with GAD suffer from a high degree of comorbidity with other anxiety or psychiatric disorders. In the HARP study 83% of patients had another anxiety disorder, including 36% who had concurrent panic disorder [10]. Patients with GAD commonly present with coexisting depression [19].
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Influence of aging
Figure 1. Probability of full and partial remission or full remission only during 5 years in the Harvard-Brown Anxiety Research Program (HARP). PSR, psychiatric status rating [10].
8 weeks) during the 5-year follow-up period, and only 38% experienced full remission (occasional or no symptoms for at least eight consecutive weeks), confirming the low response rates in this condition. Although GAD is among the most common mental disorders seen in primary care, the condition is often missed or misdiagnosed [11] because patient attribution of symptoms and the stigma related to mental illness may mask the condition [12,13]. Current guidelines for the treatment of patients with GAD recommend selecting evidence-based pharmacotherapy, psychotherapy, or both, while taking into account patient preference and the facilities available to support the patient in their immediate locality [14 /18]. However, a number of key issues relating to the clinical course of GAD also need to be considered when deciding on the most appropriate and effective course of treatment [13]. Waxing and waning course A challenging characteristic of GAD is that the severity of symptoms can fluctuate considerably during a person’s lifetime. Such variability may lead to a continuous decline in the patient’s quality of life. Chronicity The chronic nature of the condition means that patients often require maintenance therapy for many years. For this reason, tolerability of selected therapies is an important consideration.
GAD is more prevalent in older than in younger patients. Thus, selection of treatment regimens should also take into account both comorbid and other unrelated diagnoses already present in the geriatric patient. Older patients are also more likely to be on other medications, so the potential for drug /drug interactions must also be considered. Stressful life events Retrospective studies link the occurrence of stressful or negative life events with an increased risk of GAD [20]. In recent years there has been a trend towards an increasing use of antidepressants for treating anxiety disorders, rather than the previously commonly used benzodiazepines. However, optimum treatment regimens are still unclear and careful and acute, long-term and relapse-prevention studies are needed in order to assess the most effective modes of treatment for patients with GAD. Although a number of systematic reviews have recently assessed the evidence-based pharmacotherapy of GAD [18,21,22], this article seeks to highlight recent developments in the pharmacological treatment of GAD, which have become available since these reviews were written. Current data available Data from a number of randomized, placebocontrolled trials provide evidence for the beneficial effects of several compounds, including benzodiazepines (e.g., alprazolam, diazepam), tricyclic antidepressants (TCAs; imipramine), selective serotonin reuptake inhibitors (SSRIs; escitalopram, paroxetine, sertraline), and the serotonin noradrenaline reuptake inhibitor (SNRI) venlafaxine XR, in the acute treatment of GAD [18,22]. While TCAs and benzodiazepines have been found to be efficacious in patients with GAD in a number of trials, their use in current clinical practice is limited by issues of tolerability and their risk /benefit ratio. The SSRIs are advantageous for treating GAD, as they are well tolerated and also effective against the comorbid psychiatric disorders seen with this condition. Indeed, evidence supports that 50 /75% of patients with anxiety disorders experience significant benefit
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after adequate dose and duration of therapy with an SSRI [23/25], and these agents are now accepted as first-line therapy in GAD. Despite the relatively large amount of data available from placebo-controlled studies for the acute treatment of GAD, there is a definite paucity of data regarding long-term maintenance and relapse prevention in patients with this disorder. Indeed, only paroxetine [26] and escitalopram [27,28] have shown efficacy in placebo-controlled studies with these designs. Furthermore, few acute- or long-term comparator-controlled studies have been conducted. Various forms of psychological treatment, including cognitive behavioral therapy (CBT) have also been evaluated in the acute, long-term and relapseprevention phases of treatment of GAD, and there are data to show that this approach may be beneficial, especially when used in combination with effective pharmacotherapy. Acute treatment of GAD Escitalopram, a highly selective SSRI, has been evaluated in the acute treatment of GAD in four placebo-controlled clinical studies [28 /31]. The efficacy of escitalopram in acute treatment was established in three randomized studies. Although results of the first study were published separately [28], results from all three studies were later published as a pooled analysis because their study designs were similar [30,31]. In these three studies, patients with GAD (n /856) were randomized to treatment with escitalopram (10 mg/ day) or placebo for 8 weeks. After 4 weeks, the escitalopram dose could be increased to 20 mg/day if required. In each individual study, escitalopram was superior to placebo (last observation carried forward analysis [LOCF]; P B/0.05) as assessed by the mean change in Hamilton anxiety rating scale (HAM-A) total score from baseline to week 8. Escitalopram was also superior to placebo with regard to the secondary outcome variables, which included the HAM-A psychic and somatic anxiety sub-scales, the Clinical Global Impression of improvement and severity scales (CGI-I and CGI-S) and the Hamilton depression rating scale (HAM-D) anxiety sub-scale. In the pooled analysis of all three studies, escitalopram (10 mg/day) was superior to placebo (P B/0.001) with an effect size of 2.5 points on the HAM-A scale; an effect that is not only statistically significant, but also clinically relevant. The dose /response relationship of escitalopram (5, 10 and 20 mg/day) in acute treatment was examined in a 12-week, randomized, fixed-dose, placebo-controlled study (n /681) [29]. Paroxetine (20 mg/day) was also included as a comparator. Comparison of escitalopram with placebo showed that in the intent-to-treat (ITT) LOCF analysis, the higher escitalopram doses (10 and 20 mg)
were superior to placebo from week 8 onwards (Figure 2), while the 5-mg dose of escitalopram was superior to placebo at week 12. Escitalopram 10 mg/day, was statistically superior to placebo in the LOCF analysis (P B/0.05); the 20-mg dose was superior to both placebo and paroxetine. Evidence for the efficacy of venlafaxine, an SNRI, in the acute phase of GAD has been demonstrated in five randomized placebo-controlled studies, two of which involved an active comparator (diazepam or buspirone) [32]. Pooled analysis of these five studies (n /1,839) showed a statistically significant effect size for venlafaxine compared with placebo (P B/0.001) [32]. Another medication, demonstrating efficacy in the acute phase of GAD, is pregabalin, a structural analogue of g-aminobutyric acid (GABA) with anti-convulsant, anxiolytic and analgesic properties. In three randomized, double-blind, placebocontrolled treatment studies (two of which incorporated an active comparator) pregabalin was superior to placebo in relieving acute symptoms of GAD [33 /35] and had similar overall efficacy to alprazolam [34] or venlafaxine [35]. Long-term trials in GAD Although several agents have demonstrated beneficial effects in patients with GAD during acute-phase treatment, on average only 60% of patients achieve a satisfactory response to acute treatment, and of these patients a high proportion continue to experience problematic persistent symptoms [21]. This, together with the known chronic nature of GAD,
Figure 2. Dose /response relationship of escitalopram compared with placebo and paroxetine (20 mg/day) in patients with GAD. The figure shows the mean change in HAM-A from baseline. Compared with placebo a significantly greater effect was seen for escitalopram 10 and 20 mg (*P B/0.05) from 8 /12 weeks and for escitalopram 5 mg ($P B/0.05) after 12 weeks. In the last observation carried forward (LOCF) analysis, escitalopram 10 mg was significantly more effective than paroxetine 20 mg (%P B/0.05) [29].
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Treatment of generalized anxiety disorder means that long-term pharmacotherapy is needed for most patients. Despite this, there is scant evidence regarding long-term evaluation of pharmacological therapies in patients with GAD. Longitudinal analysis of pooled data from two similar studies, which evaluated the long-term efficacy of venlafaxine, revealed a significant improvement in response and remission rates compared with placebo during 6 months of treatment [36]. In these two double-blind, placebo-controlled studies (n /792), the criteria for response (]/50% improvement from baseline HAM-A score) was met by 66% of venlafaxine-treated patients, compared with 39% of those in the placebo group (P B/0.001). Similarly, remission rates at 6 months were significantly higher with venlafaxine than with placebo (43 versus 19%; P B/0.001). Remission rates are an important indicator of treatment success, as they show the proportion of patients who fully recover rather than the proportion of patients who simply experience clinical improvement in symptoms (response rate). Sustained remission was observed in 19% of the venlafaxine group versus 8% of the placebo group (P B/0.001), demonstrating the stability of the response. The benefit of continued treatment with escitalopram for up to 6 months was demonstrated in a randomized, double-blind, flexible dose comparative study [37]. Patients with GAD received 1 week of placebo treatment and 24 weeks of double-blind flexible-dose treatment with either escitalopram (10/20 mg/day) or paroxetine (20 /50 mg/day), followed by a 2-week, double-blind, down-titration period [37]. Although a similar decline in mean HAM-A scores of 15.3 and 13.3 points was observed in the escitalopram- (n /60) and paroxetine-treated groups (n /61), respectively, treatment with escitalopram was numerically superior to the treatment with paroxetine. At week 24, more patients on escitalopram achieved response than those on paroxetine. At week 24, the response rate (HAM-A 50% reduction) was greater in the escitalopram group than in the paroxetine group (78.3 versus 62.3%). In addition, the tolerability profile appeared to favor escitalopram over paroxetine. There were significantly fewer (P B/0.05) patients who dropped out of the trial because of adverse events with escitalopram than with paroxetine (6.6 versus 22.6%), and a lower incidence of sexual adverse events (including ejaculation disorder, anorgasmia and reduced libido).
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tients (n /560) showing an improvement in CGI-I score of at least 2 points (to 5/3) were subsequently randomized to receive treatment for 24 weeks, with either paroxetine or placebo. The likelihood of relapse during the double-blind treatment period, as defined by an increase in the CGI-I score to ]/4, was almost 5 times greater in placebo- than in paroxetine-treated patients (estimated hazard ratio /0.213; P B/0.001). A clear benefit of escitalopram relative to placebo was observed in risk of relapse and time to relapse in a long-term evaluation of GAD patients who had responded to acute treatment [27]. Patients with GAD (n /491) who responded to 12 weeks of openlabel treatment with escitalopram (20 mg/day) were randomly assigned to 24 /76 weeks of double-blind treatment with escitalopram (20 mg/day) or placebo. Risk of relapse (defined as either an increase in total HAM-A score to ]/15, or an unsatisfactory treatment response as judged by the investigator) was 4 times higher in the placebo- compared with the escitalopram-treated patients. Indeed, the proportion of patients with relapse was significantly lower with escitalopram than with placebo (19 versus 56%; P B/0.001), demonstrating the efficacy of escitalopram in preventing relapse during long-term treatment of GAD (Figure 3). Conclusions Improved clinical outcomes for patients with GAD require effective management of all aspects of the condition, and consideration of both the chronic course of the disease and the high occurrence of comorbid conditions, particularly depression and other anxiety disorders. Retrospective, naturalistic studies indicate that the chronic pattern of the
Relapse prevention trials in GAD The efficacy of paroxetine in the prevention of relapse in patients who had responded to acute treatment was demonstrated a 32-week, randomized, double-blind, placebo-controlled study [26]. In an initial open-label treatment period all patients received paroxetine (20 /50 mg) for 8 weeks. Pa-
Figure 3. Escitalopram reduces the likelihood of relapse in patients with GAD who had responded to acute treatment [27]. 18.8% of patients treated with escitalopram relapsed, compared with 56.1% of placebo-treated patients.
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untreated disease, with low rates of remission and moderate rates of relapse following remission, may persist for 20 years or more. Therefore, the successful treatment of GAD needs to provide acute relief from symptoms, together with effective maintenance therapy to achieve full remission. Consideration of treatment tolerability, especially during long-term maintenance use, is consequently also of critical importance. To date, few treatments have demonstrated efficacy in the acute and the long-term treatment phases and in the prevention of relapse; only escitalopram and paroxetine have efficacy data for these phases of treatment. Future studies should address the development of effective treatment strategies that provide an improved long-term outcome for patients with GAD.
of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatric Scand 2004;109(Suppl 420):21 /7. Wittchen HU, Carter RM, Pfister H, et al. Disabilities and quality of life in pure and comorbid generalized anxiety disorder and major depression in a national survey. Int Clin Psychopharmacol 2000;13:319 /28. Beekman AT, Bremmer MA, Deeg DJ, et al. Anxiety disorders in late life: a report from the longitudinal Aging Study Amsterdam. Int J Geriatr Psychiatry 1998;13:717 /26. Barlow DH, Blanchard EB, Vermilyea JA, et al. Generalized anxiety disorder: Description and reconceptualization. Am J Psychiatr 1986;143:40 /4. Blazer DG, Hughes D, George LK, et al. Generalized anxiety disorder. In: Robins LN, Regier DA, editors. Psychiatric disorders in America: The ECA study. New York: The Free Press; 1991. p 180 /203. Le Roux H, Gatz M, Wetherell JL. Age at onset of generalized anxiety disorder in older adults. Am J Geriatr Psychiatry 2005;13:23 /30. Yonkers KA, Dyck IR, Warshaw M, Keller MB. Factors predicting the clinical course of generalized anxiety disorder. Br J Psychiatr 2000;176:544 /9. Weiller E, Bisserbe JC, Maier W, et al. Prevalence and recognition of anxiety syndromes in five European primary care settings: A report from the WHO study on psychological problems in general health care. Br J Psychiatr Suppl 1998; 34:18 /23. Culpepper L. Generalized anxiety disorder in primary care: Emerging issues in management and treatment. J Clin Psychiatry 2002;63(Suppl 8):35 /42. Keller MB. The long-term clinical course of generalized anxiety disorder. J Clin Psychiatr 2002;63(Suppl 8):11 /6. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessivecompulsive and posttraumatic stress disorders. World J Biol Psychiatry 2002;3:171 /99. Davidson JR. Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry 2001;62(Suppl 11):46 /50. NICE. 2004. Clinical Guideline 22. Anxiety management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary, and community care. Issue date December 2004. www.nice.orh.uk/CG022NICEguideline Allgulander C, Bandelow B, Hollander E, et al. World Council of Anxiety. WCA recommendations for the longterm treatment of generalized anxiety disorder. CNS Spectr 2003;8(Suppl 1):53 /61. Baldwin DS, Polkinghorn C. Evidence-based pharmacotherapy of generalized anxiety disorder. Int J Neuropsychopharmacol 2005;8:293 /302. Wittchen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:355 /64. Blazer D, Hughes D, George LK. Stressful life events and the onset of a generalized anxiety syndrome. Am J Psychiatry 1987;144:1178 /83. Rynn MA, Brawman-Mintzer O. Generalized anxiety disorder: acute and chronic treatment. CNS Spectr 2004;9: 716 /23. Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev 2003;2:CD003592. Ballenger JC. Overview of different pharmacotherapies for attaining remission in generalized anxiety disorder. J Clin Psychiatry 2001;62(Suppl 19):11 /9. Brunello N, den Boer JA, Judd LL, et al. Social phobia: Diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment. J Affect Disord 2000;60: 61 /74. /
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The author is on advisory/speaker boards and/or has received research funds from: AstraZeneca, Canadian Network for Mood and Anxiety Treatments, Cephalon, Eli Lilly, GlaxoSmithKline, JanssenOrtho, Litebook Inc., Lundbeck, Roche, SanofiAventis, Servier and Wyeth.
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Statement of interest
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. Generalized anxiety disorder (GAD) is a common, chronic and disabling condition with considerable comorbidity, especially with depression . Tolerability issues for the tricyclic antidepressants and benzodiazepines limit their efficacy in GAD . The selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SSRIs) demonstrate substantial efficacy in patients with GAD . Current treatment guidelines recommend the SSRIs as first-line treatment for GAD . Data from acute, long-term and relapseprevention trials strongly support the role of the SSRIs, such as escitalopram, as effective pharmacological therapy of GAD
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