Pharmacological treatment for generalized anxiety disorder in adults: an update.

Review

Pharmacological treatment for generalized anxiety disorder in adults: an update 1.

Introduction

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General approach to treatment and management of treatment failure

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Currently available pharmacotherapeutic options

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Conclusion

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Expert opinion

Jennifer A Reinhold & Karl Rickels† †

University of Pennsylvania, School of Medicine, Department of Psychiatry, Mood and Anxiety Disorders Treatment and Research Program, Philadelphia, PA, USA

Introduction: Modest response and remission rates for the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, coupled with mounting evidence that the tolerability of the antidepressants (ADs) may have been overstated in the literature, has contributed to changes in prescribing patterns for generalized anxiety disorder (GAD). New interest in the absence of evidence that supports these standard therapies as superior to benzodiazepines stimulated a review of the literature. Areas covered: A literature search was conducted in the MedLine database with search terms ‘generalized anxiety disorder’ and ‘treatment’ for purposes of including relevant literature related to pharmacologic treatment of GAD. Aside from a review of pivotal literature, the authors also included newer studies that evaluated novel drug treatments. Last, the database was searched for benzodiazepine comparisons to standard therapy secondary to concerns that such literature is sparse. The review of newer modalities and the decision to include related literature was also based on the strength of the evidence and the status of their approval for the treatment of GAD. Expert opinion: Although ADs remain the most frequently prescribed medications for GAD, alternative and off-label therapies such as pregabalin, the atypical antipsychotics and vortioxetine are garnering interest. Based on the evidence available to us, it is our recommendation that along with the ADs, benzodiazepines be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician. Keywords: atypical antipsychotics, benzodiazepines, generalized anxiety disorder, pharmacotherapy, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors Expert Opin. Pharmacother. (2015) 16(11):1669-1681

1.

Introduction

Generalized anxiety disorder (GAD) is characterized by a complex clinical course which includes periods of symptom exacerbation and improvement [1-5]. Central to the presentation of GAD is the manifestation of cognitive, emotional and physiological symptoms which confer some degree of social and/or occupational functional impairment. Clinical presentation is highly variable among patients, which contributes to the difficulty in recognizing and treating GAD in primary care. Somatic concerns most frequently are the impetus for evaluation and can potentially obscure the underlying psychic symptomatology, as the proposed rate of correct recognition and diagnosis of GAD in primary care is estimated at 34% [6]. Pervasive, pathologic, uncontrollable worry is a core feature of GAD and is generally considered to be intolerance of uncertainty. This maladaptive, exaggerated fear response, along with the associated autonomic arousal, typically occurs in 10.1517/14656566.2015.1059424 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Current practice guidelines recommend that pharmacologic treatment of generalized anxiety disorder (GAD) consist of an antidepressant (selective serotonin reuptake inhibitor [SSRI] or serotonin-norepinephrine reuptake inhibitor [SNRI] most commonly). Strategies for improving an inadequate response to drug therapy include dose optimization, a within-class switch, a between-class switch or augmentation with an additional drug. The benzodiazepine (BZ) discontinuation/withdrawal syndrome has been well documented; however, the SSRIs may also result in a discontinuation syndrome, particularly in cases of abrupt discontinuation. There is a paucity of literature that directly compares the BZs to the pharmacologic standards of care (SSRIs or SNRIs), and therefore, there may not be adequate evidence to support their place in therapy as first line. Newer modalities (vilazodone, vortioxetine and agomelatine) have shown promise in treating GAD, although none are yet approved in the US for this purpose.

This box summarizes key points contained in the article.

response to impending perceived threats -- whether extant or unrealistic. This may propagate patterns of reinforcement during which patients anticipate a consequence and develop avoidance behaviors in response [7]. It has been suggested that it is not uncommon for patients with GAD to suffer from symptoms for months to years without seeking treatment or receiving treatment. A recent study evaluated the latency to first pharmacological treatment in adult patients who were ultimately diagnosed with GAD. A host of multifactorial psychosocial and environmental elements contribute to the delay in diagnosis and pharmacologic intervention; namely age of onset, family history, trauma, attitudes and quality of medical services. It is postulated that a longer delay in recognition and treatment is a critical predictor of clinical outcomes. In the evaluated sample, patients with GAD presented with the greatest age of onset (GAD possesses the latest average age of onset of the anxiety disorders) and that in general the latency to first intervention was over 81 months (almost 7 years) [8]. Further complicating successful diagnosis and treatment is the high rate of psychiatric comorbidity among patients with GAD. It is estimated that 90% of patients with GAD also have at least one additional comorbid psychiatric diagnosis, most commonly major depressive disorder (61%) [9-11]. Lifetime prevalence rates for GAD in the US average 5.7%, but are highest (7.7%) in the 45- to 59-year-old demographic group and are higher in women as compared to men [12,13]. The Diagnostic and Statistical Manual 5 (DSM-5) has further refined the diagnostic criteria for GAD. The worry must be considered excessive, difficult to control and must be present for a minimum of 6 months. Two of the six 1670

somatic symptoms must also be present (restlessness, fatigability, impaired concentration, irritability, muscle tension, sleep disturbance) -- a reduction from the DSM-IV-TR requirement of three of six symptoms [14,15]. The diagnosis is less restrictive and possibly more meaningful in the International Statistical Classification of Diseases and Related Health Problems (ICD-10) [16]. A literature search was conducted in MedLine without a date range restriction to identify articles that review currently approved pharmacologic therapies for GAD, pivotal clinical studies that evaluated approved drugs, contemporary studies that evaluated new drug therapies for a possible role in treating GAD and studies that compared benzodiazepines (BZs) to standard drug therapies. In addition to reviewing the landmark trials that established certain drugs as first- or secondline therapies, the authors intended to review some of the newer pharmacologic treatment modalities. In the manuscript we have limited our review to drugs that are officially indicated for GAD and did not include drugs that are still in the process of approval or have been denied approval in the US. Last, there has been a resurgence of interest in the role of BZs in the treatment of GAD which has been spurred by an assertion by experts that little to no evidence exist to support the superiority of antidepressants (ADs) over BZs. Therefore, the authors also included an evaluation of published BZ comparisons to ADs.

General approach to treatment and management of treatment failure

2.

The ultimate therapeutic goal for GAD is remission -- a complete resolution of anxious symptoms and a return to premorbid functionality and quality of life. Remission may be gauged by a number of validated assessment tools, including the Hamilton Rating Scale for Anxiety (HAM-A) to assess severity, the Clinical Global Impression-Improvement (CGI-I) scale to assess overall improvement and the Sheehan Disability Scale (SDS) to assess functionality. Remission is defined as a HAM-A score of £ 7 or a CGI-I score of 1. A response to therapy is defined as a ‡ 50% improvement in HAM-A score, and a ‘much improved’ or ‘very much improved’ rating on the CGI-I and is considered a meaningful improvement in symptoms and function [17-19]. Today practice guidelines suggest that in the acute phase of treatment, a single drug, typically an AD, is initiated with the expectation that it will be continued at least until symptoms resolve, and ideally for 12 months beyond symptom resolution [2,20]. The selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line pharmacotherapeutic options in the US and internationally, this despite the fact that BZs elicit a rapid anxiolytic response as they are highly lipophilic and are also commonly used as first-line treatment by many non-psychiatrists [21]. After an adequate trial of an SSRI or SNRI (4 -- 8 weeks), response to treatment should

Expert Opin. Pharmacother. (2015) 16(11)


Pharmacological treatment for GAD in adults: an update

be assessed. Assuming that a response or an early remission has occurred and the treatment is well tolerated, the drug may be continued for an additional 12 months or indefinitely as determined by length of illness and number of episodes. If a response is not realized or the drug is not tolerated, a withinclass switch to another SSRI or SNRI, respectively, is appropriate. A switch to a different class (SSRI to SNRI or vice versa), to a BZ, to pregabalin (in Europe only, as pregabalin is not approved for GAD in the US), to buspirone or to imipramine may promote a response [22]. Augmentation is also an option. Evidence continues to mount in support of the role of second-generation antipsychotics (APs) as monotherapy and adjunctive therapy in anxiety [23]. There is a misconception among non-psychiatrists that the atypical APs (AAPs) are safer than the BZs, which may underlie the more frequent use of AAPs in primary care as compared to psychiatry. However, there is significant concern about the extensive, consistent metabolic effects of the AAPs and how this may limit their utility in a preponderance of patients [24]. The evidence to support the use of the ADs, agomelatine, vilazodone or vortioxetine in GAD is inconsistent. On symptomatic and functional remission, the maintenance phase begins and the focus shifts to relapse prevention. In addition to the immediate goal of response and the intermediate goal of remission, prevention of relapse is a key therapeutic consideration. Patients who continue to endorse residual symptoms after successful treatment (achievement of remission) are at increased risk of relapse and recurrence. This underscores the importance of continuing treatment beyond the resolution of symptoms [2,3,20]. Response to treatment is estimated to occur in 50 -- 60% of patients; however, remission is achieved by ~ 30 -- 50% [2,19]. Randomized clinical trials suggest that 40 -- 60% of patients respond to placebo and 60 -- 75% respond to SSRIs as assessed by the CGI. Newer studies have demonstrated similar results for the SNRIs and pregabalin [22]. However, the same is true for the BZs [25]. BZs are also initiated for purposes of augmentation during the first 4 weeks of therapy with a standard AD, and then are gradually tapered on realization of the effect of the AD.

Currently available pharmacotherapeutic options

3.

The compendium of recommended pharmacotherapeutic interventions has developed meaningfully in the past few decades. Drug classes that were experimental for the treatment of GAD 10 years ago have risen to first-line options and newer, novel drug products are now beginning to amass a litany of literature that serves as an evidence base for clinical practice [26]. Secondary to the proposed neurobiological basis for anxiety, drug therapies with evidence of clinical usefulness tend to target serotonin, norepinephrine, GABA or combinations thereof. Internationally, the SSRIs, SNRIs and pregabalin are regarded as first-line options for GAD but

not the BZs. US guidelines have not yet incorporated pregabalin into the first-line status nor is the drug labeled for this indication in the US, although it is considered an alternative therapy [23]. Second-generation AAPs are now commonly used as a replacement of the BZs to augment traditional first-line therapy and are frequently used as monotherapy by non-psychiatrists in some patient populations, albeit with some reservation. Selective serotonin reuptake inhibitors SSRIs are thought to exert their AD and anxiolytic effect through inhibition of serotonin reuptake at the synaptic cleft. One of the most studied drug classes for depression and anxiety disorders, the efficacy and safety of SSRIs has been demonstrated in dozens of randomized controlled trials [27-42]. SSRIs are generally regarded as first-line medications for short- and long-term treatment, according to domestic and international practice guidelines. There usually is a delay of 2 -- 4 weeks until onset of therapeutic effect, which may be discouraging and may impact patient compliance. Longterm (32-week) remission rates in paroxetine-treated patients are as high as 73%, with 11% relapsing [19]. In an 8-week, double-blind, placebo-controlled study, paroxetine 20 and 40 mg groups demonstrated a statistically and clinically significant change in the HAM-A and psychic anxiety subscale as compared to placebo. About 62% of patients in the intentto-treat 20 mg arm and 68% of patients in the intent-to-treat 40 mg arm met the criteria for response by week 8 (p < 0.001). For patients completing the study response rates were as high as 80%. Remission was achieved in the intent-to-treat analysis in 36% of the paroxetine 20 mg group and 42% of the paroxetine 40 mg group by week 8 (p = 0.004) [33]. A second study reported a > 70% response rate by week 8 compared to placebo and a > 40% remission rate [34]. In patients with moderate-to-severe GAD, sertraline 50 -- 100 mg/day has demonstrated superiority over placebo in improving HAM-A score. Statistical significance in improvement of HAM-A score psychic and somatic subscales was evident by week 4 (52% sertraline vs 34% placebo). Clinical response criteria were met by 55% of patients in the sertraline group as compared to 32% in the placebo group by week 12 [40]. Escitalopram has been evaluated for the long-term treatment of GAD and prevention of relapse. A randomized, double-blind, placebo-controlled study reported significantly superior results in terms of improvements in HAM-A total score, HAM-A somatic and psychic subscales and quality of life measures for escitalopram at every time point starting at week 1. By week 4, 50% of patients in the escitalopram arm had responded and 68% by week 8. Remission was achieved by 36% of escitalopram patients as compared to 16% of placebo (p < 0.01) [36]. Pooled analyses further support the sustained superior efficacy of escitalopram as compared to placebo [37]. A study that evaluated escitalopram’s impact on relapse found that the risk of relapse was more than four times 3.1


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greater in the placebo arm versus escitalopram [38]. A 24-week study that compared escitalopram with paroxetine found that the efficacy as measured by changes in HAM-A score did not differ; however, treatment-emergent adverse effects were significantly more frequent in the paroxetine group [35]. Class adverse effects include weight gain, somnolence, gastrointestinal sequelae and agitation. The risk and extent of weight gain varies within this class, as some compounds promote weight gain and some are considered weight-neutral [43]. Sexual dysfunction, often a presenting symptom in anxious patients, may be exacerbated or instigated by SSRIs in up to 40 or 50% of patients (sometimes as high as > 70%). This statistic is likely representative of an underreporting. Another unfortunate pharmacologic phenomenon of the SSRI class is its ability to cause agitation and jitteriness in the acute phase of treatment, particularly if the speed of the dose titration is escalated [39]. This, coupled with the adverse effect profile, might be responsible for early treatment failure with SSRIs. The SSRIs are associated with a discontinuation syndrome on abrupt cessation and sometimes even with gradual taper, which parallels that of the BZs. More recent evaluation of this collection of psychiatric and somatic symptoms which emerge on discontinuation suggests that the severity may be greater than originally realized; so much so that it has been suggested that the ‘discontinuation syndrome’ seems to be similar to the BZ ‘withdrawal syndrome’. There is a variability of severity among the members of this class; however, the risk exists with all SSRIs. Symptoms generally emerge within a few days of discontinuing the drug and may persist anywhere from a few days to > 6 weeks. The likelihood of developing a discontinuation syndrome does not appear to be related to length of treatment consistently [44,45]. Serotonin-norepinephrine reuptake inhibitors Members of the SNRI class inhibit the reuptake of both serotonin and norepinephrine, although the selectivity for these monoamines and balance in respect to extent of inhibition varies among the SNRIs. Venlafaxine XR, the first drug to be licensed specifically for the treatment of GAD, has consistently demonstrated superior efficacy versus placebo in improving anxiety symptoms by measure of a reduction in HAM-A total scores in the short and long-term [46-48]. Response rates for venlafaxine XR have approached 70%. In a comparison of venlafaxine versus paroxetine in the improvement of HAM-A score, both drugs demonstrated significance over time but no difference between groups was observed. Rates of response and remission also did not differ between paroxetine and venlafaxine by week 8 [49]. In an 8-week randomized, double-blind, placebo-controlled trial, when compared to escitalopram, venlafaxine XR performed better in terms of improving HAM-A score. However, escitalopram was better tolerated [50]. Rickels et al. studied venlafaxine’s impact on time to relapse by extending treatment to 6 and to 12 months in patients

who responded. After 6 months of open-label flexible-dose venlafaxine XR, patients who responded were randomized to venlafaxine XR again or placebo in a double-blind, placebocontrolled relapse phase and then a final 6-month randomized, double-blind, placebo-controlled relapse phase. Over the course of the subsequent 6-month blinded treatment period immediately following the open-label phase (12 total months), 53.7% of patients who switched to placebo relapsed as compared to 9.8% of the venlafaxine group (p < 0.001). After 12 months of treatment with venlafaxine, the relapse rate was 6.7% for the venlafaxine group (total therapy time = 18 months) and 20% for the placebo group (months 6 -- 18). This study supported the use of venlafaxine for at least 12 months in patients who respond. Remission rates as high as 78% were observed in patients who completed 6 months of treatment with venlafaxine XR [20,47,51]. Duloxetine 60 -- 120 mg and venlafaxine XR 75 -- 225 mg have demonstrated similar response rates in clinical studies. As compared to baseline, the mean change in HAM-A score was significant in both the duloxetine and venlafaxine groups versus placebo (p < 0.001 in both comparisons). The onset of improvement with duloxetine and venlafaxine was earlier than placebo and the rate of improvement was not different among the active groups [52]. A 10-week randomized, placebo-controlled, double-blind study reaffirmed the comparability of duloxetine and venlafaxine XR in which the two active arms did not differ in respect to efficacy. Both drugs improved core psychiatric and somatic symptoms [53]. Duloxetine has also been evaluated for the prevention of relapse in a 26-week continuation phase which included duloxetine responders as compared to placebo. At the end of 26 weeks of additional treatment, 13.7% of duloxetine-treated patients experienced a relapse as compared to 41.8% of placebotreated patients (p £ 0.001) [54].

3.2

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Benzodiazepines Prior to the advent of suggesting tricyclic ADs (TCAs) for treating anxiety disorders [55,56] and prior to the discovery of SSRIs and SNRIs, BZs were considered standard therapy for anxiety [57]. In the late 1970s in the US, it was estimated that between 55 and 94% of patients diagnosed with an anxiety disorder were treated with a BZ. In recent clinical practice globally, BZs are most often employed for the short-term management of the acute phase of anxiety (first 2 -- 4 weeks) as well as any subsequent exacerbations of anxiety during stable treatment with an AD. Their rapid onset of effect and good tolerability make them conducive to alleviating anxious symptoms when immediate anxiolytic effects are necessary [58]. Secondary to the delay in therapeutic effect of the ADs, initiation of a BZ along with an AD mitigates the anxious symptoms immediately and provides symptomatic relief until the realization of the effect of the AD. Additionally, the initial increase in anxiety and subjective jitteriness associated with the use of serotonergic medications has been well documented, further supporting the role of BZs early in treatment. 3.3




Domestic and international guidelines specifically recommend avoiding long-term administration of BZDs for the treatment of anxiety disorders secondary to safety and tolerability concerns as well as a perception of less impressive efficacy compared to ADs. The World Federation of Biological Psychiatry, National Institute for Health Care and Excellence, British Association for Psychopharmacology, Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology guidelines all recommend initiation of an SSRI or SNRI in patients with GAD and recommend against adjunctive BZ treatment beyond the first 4 weeks of therapy. Their collective position suggests reserving BZs for patients who have not responded to firstline medications (some further specify a specific number of treatment failures). The published literature over the past few decades, in combination with the guidelines that it inspired, cite concerns related to risk of sedation, cognitive impairment, tolerance, dependence and risk of abuse as further evidence to recommend against long-term use of BZs [59]. In contrast newer generation ADs are considered superior in regard to efficacy and tolerability. There was a progressive philosophical shift toward primary utilization of the newer ADs and away from chronic administration of BZs. In clinical practice, however, the prescribing of BZs has continued for both short- and long-term treatments, seemingly in contrast with published guidelines [21]. There is a renewed interest in reappraising the clinical utility and safety of BZs, as several psychiatrists and researchers have questioned the validity of published reports as well as identified that there is an undeniable paucity of studies directly comparing BZs with ADs (with some overlap among the studies) [60,61]. It has been suggested that the efficacy and safety of ADs may be overestimated and the efficacy and safety of BZDs underestimated. This assertion provided the impetus for a meta-analysis published in 2013 which systematically reviewed the literature in an effort to determine if the recommendations for treatment are supported by data [60]. A total of 22 studies were reviewed: 18 involving TCAs, 1 involving phenelzine, 3 involving newer ADs. The TCA-focused studies involved imipramine as compared to alprazolam [62], opipramol compared to alprazolam [63] and imipramine compared to diazepam and trazodone [56]. In the Hoehn-Saric et al. study, alprazolam 0.5 -- 6 mg/day was found to be significantly more effective in resolution of physical symptoms as compared to imipramine 25 -- 200 mg/day, whereas imipramine was more effective in alleviating the psychic symptoms. The Rickels et al. study reported that imipramine yielded greater improvement in psychiatric symptoms as compared to diazepam, but yielded similar improvement in somatic symptoms. Moller et al. found no meaningful difference in either symptom subset when comparing opipramol and alprazolam. Only three studies have been published that directly compare BZs to newer ADs. The first compared diazepam and venlafaxine XR and found no difference in response rates between venlafaxine XR,

diazepam and placebo. Discontinuations attributed to adverse effects were more frequent in the venlafaxine XR group [64]. The second, a 4-week study, compared lorazepam, paroxetine and placebo. The active arms realized improvement in the psychiatric symptoms but only the lorazepam arm had significant improvement in the physical symptoms [65]. The third study, although evaluating patients with panic disorder, compared clonazepam and paroxetine and found that in addition to improved efficacy in the clonazepam group, there were also significantly fewer adverse effects. This was demonstrated in the short term (8 weeks) and the long term (3 years) [66,67]. Clonazepam, however, elicited a therapeutic response sooner and was better tolerated in the long-term. Tolerance developed to the sedative effects of clonazepam but not its therapeutic effects, but conversely, the sexual dysfunction and weight gain associated with paroxetine continued throughout the long-term study [67]. Although panic disorder and GAD have different clinical courses, this article was included in the review because there are so few studies that directly compare BZs with ADs for the treatment of anxious disorders in general. In an effort to be as inclusive as possible and describe the full complement of literature available, the article that evaluated patients with panic disorder has been included. These recent publications suggest that, based on published data, the superiority of ADs over BZs in terms of efficacy and tolerability has not been established in either GAD or panic disorder [60,61]. It is further proposed that the comparative advantage of SSRIs over BZs has also not been established and therefore the guidance and paradigm shift to prefer the newer ADs was premature and without an adequate evidence base [68]. Evaluation of the literature suggests consistent, reliable efficacy of BZs in improving the central features of GAD -- both the psychiatric and somatic. BZs elicit an earlier response than the ADs and provided that a response occurs by the eighth week, it tends to be sustained throughout the length of treatment [68,69]. Although sedation, cognitive impairment and interference with psychomotor function are realistic concerns as evidenced by the literature, they are generally limited to initiation of therapy and on dosage increase. In some patients, particularly the elderly, cognitive impairment may present to a greater degree and may persist beyond the length of time expected in a younger patient. Tolerance tends to develop to the sedative adverse effects after 1 or 2 weeks, yet the therapeutic anxiolytic effects endure. It should be noted that in 1988 and 1993 two long-term studies evaluating BZs were conducted: one in the treatment of GAD [69] and one in the treatment of panic disorder [70]. In these studies, the value of BZs was established for 6 -- 8 months of maintenance treatment. And although tolerability to the sedative effects occurred early, no tolerance to the anxiolytic or anti-panic effects developed. The risk of tolerance, abuse and withdrawal has been a critical factor in relegating BZs to last-line therapy for chronic management of GAD. A realistic concern, non-addictive physical dependence, which is a physiological adaptation at


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the receptor level, may occur after long-term administration of BZs. A gradual taper minimizes the risk of a drug withdrawal on discontinuation, and abrupt discontinuations should be avoided [71]. The risk of abuse is also an unfortunate reality; however, the evidence suggests that abuse of BZs is rare in the absence of an established substance abuse history [72]. SSRIs and SNRIs are also associated with a discontinuation phenomenon that has been referred to as an AD discontinuation syndrome which arguably mimics that of a BZD withdrawal [44,45]. The withdrawal symptoms associated with SSRI discontinuation tend to be discounted in practice. Adverse effects that emerge during treatment initiation include gastrointestinal effects, nausea, vomiting, headache, dizziness, agitation, restlessness and increased anxiety. These effects generally dissipate after a few days to weeks; however, they may persist in some patients precipitating early discontinuation before realization of anxiolytic effects. Long-term treatment with SSRIs and some SNRIs is associated with sexual dysfunction in both men and women, which does not subside with chronic therapy. Sexual dysfunction, a common symptom of GAD and major depressive disorder, represents a significant quality of life parameter independently. Drug therapy that further exacerbates an existing symptom or precipitates it de novo may ultimately worsen therapeutic outcomes in some patient populations. It was postulated that perhaps it is the SSRIs and the SNRIs that are inconsistent in efficacy and unpredictable in regard to intolerable adverse effects, and that no legitimate advantage exists [68]. Tricyclic ADs One of the oldest drug classes used to treat GAD the TCAs have been largely supplanted by newer, more tolerable ADs that are markedly less toxic in overdose. Anticholinergic and antiadrenergic effects such as orthostasis, dry mouth, sedation and constipation have profoundly impacted patient tolerability. Imipramine has the most compelling data in terms of efficacy relative to other drug therapies and has served as the comparator in numerous active-controlled studies. In a landmark 1993 study conducted by Rickels et al., the anxiolytic effects of imipramine, trazodone, diazepam and placebo were compared in non-depressed patients with GAD. Imipramine resulted in moderate-to-marked improvement between weeks 2 and 8 of therapy in 73% of patients as compared to 69% for trazodone, 66% for diazepam and 44% for placebo. Diazepam-treated patients experienced the most improvement in anxious symptoms during the first 2 weeks of treatment; with the most significant improvements in the somatic complaints. Imipramine and trazodone performed comparably in terms of psychiatric symptom improvement, but resulted in higher rates of adverse effects as compared to diazepam. It was this research that was instrumental in exploring the potential utility of ADs in GAD, despite the fact that the AD arms reported an increase in adverse effects as compared to diazepam and placebo [56]. 3.4

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Buspirone Buspirone’s effectiveness in treating GAD as compared to the BZs has been demonstrated in several studies [73-79], including studies demonstrating, in contrast to the BZs, no interactions with alcohol [80]. This makes it a preferred anxiolytic for anxious patients who do not want to avoid even minimal alcohol intake while on anxiolytic medication. Its delayed onset of action and lack of sedation, may contribute to its perceived relative lack of efficacy in most comorbid conditions such as panic disorder, for example, (with the exception of MDD) has relegated buspirone to a possible second and not first choice for GAD treatment [68,80-83]. Because of its moderate AD efficacy [81,84] it is often preferred to the BZs when GAD patients, as they frequently do, also endorse secondary depressive symptoms. 3.5

Pregabalin Modulation of GABA-A receptors impacts the fear response, panic and anxiety. Prototypical early antiepileptics such as BZs and barbiturates exhibit both anti-seizure and anxiolytic effects by stimulating the GABA-A receptors at the a1 and a2 subunits [85]. Three similarly designed randomized, placebo and active comparator-controlled double-blinded studies evaluated the efficacy of pregabalin versus placebo or lorazepam for the treatment of GAD. The pregabalin groups and the lorazepam group all experienced greater reductions in HAM-A score by week 4 compared to placebo, with no observed statistically significant differences among the active groups. Pregabalin at its highest study dose (600 mg) produced statistically superior reductions in the psychic and somatic anxiety HAM-A subscales compared to placebo, with the lowest dosage (300 mg) providing the best results. The improvements in HAM-A score produced by the active groups were apparent by week 1 of the study. Response rates for pregabalin (46%) and lorazepam (61%) were statistically superior to placebo (27%) [86-88]. In a 4-week double-blind, placebo-controlled trial, pregabalin was compared to alprazolam. By week 1, the alprazolam group and all of the pregabalin groups (300, 450, 600 mg) separated from placebo in respect to improvement in the HAM-A score. All active groups had meaningful reductions in the psychic and somatic symptoms subscales [89]. Pregabalin has also been compared to venlafaxine XR 75 -- 225 mg and a treatment difference in favor of pregabalin occurred by day 4 and persisted until the end of the 8-week study [90]. Failure of an initial therapy, partial response to an initial therapy and tolerance to the anxiolytic effects of a drug are realistic clinical challenges. A recent study evaluated the role of pregabalin after a partial response to an SSRI or SNRI in a randomized, double-blind, placebo-controlled design. Compared to placebo, the pregabalin-treated group experienced a greater reduction in HAM-A score, achieved higher responder 3.6




rates (47.5 vs 35.2%, p = 0.00145) and had a shorter time to sustained response [91]. Although not approved in the US for the treatment of anxiety, the relative efficacy and early onset of effect of pregabalin versus commonly used BZs has been established and this may represent a new therapeutic intervention for GAD. Pregabalin is renally excreted, and therefore poses a low risk of drug--drug interactions and is associated with minimal adverse effects (dizziness, temporary diarrhea, weight gain, insomnia) and has established long-term, safety and tolerability [92]. Of particular note is the risk of clinically significant weight gain. Increases of > 7% of baseline body weight have been reported even in the short-term studies. The weight gain by 4 weeks of treatment in some studies ranges from 1.1 to 2.2 kg, separates meaningfully from placebo, and appears to be dose-dependent [87-89]. Newer or novel modalities: agomelatine, vilazodone and vortioxetine

3.7

Agomelatine is a novel AD compound which acts as an agonist at melatonergic (MT1, MT2) receptors and an antagonist at serotonergic (5-HT2C) receptors. Both the AD and anxiolytic effects of agomelatine appear to be mediated through the synergistic action at these receptors as compared to either one independently. Although not available in the US, agomelatine has been studied in three randomized, double-blind, placebo-controlled studies: a 12-week study versus placebo, a 6-month relapse prevention study compared to placebo and a 12-week analysis versus escitalopram. All three studies, which were conducted by the same author, report statistically significant improvements in HAM-A score, improvements in both in the somatic and psychic subscales, response and remission rates and sleep quality [93-95]. A recent 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled, fixed-dose study evaluated vilazodone in the treatment of GAD. Vilazodone 40 mg/day, but not 20 mg/day, was statistically superior to placebo by week 8 in regard to improvements in the HAM-A. The difference as compared to placebo was evident by week 2 of the study. The most commonly occurring adverse effects were nausea, diarrhea, dizziness and vomiting. The rates of HAM-A response are comparable to those of traditional ADs. Vilazodone was relatively well tolerated with no serious adverse effects reported. Sexual functioning was modestly negatively impacted, which is consistent with the depression studies [96]. Vilazodone has been well studied and its utility in the treatment of major depressive disorder has been established [97,98]. Currently, there is not sufficient evidence to support its use in GAD, although additional studies may be forthcoming. Vortioxetine is a multimodal AD. A bis-arylsulfonyl compound, it acts as an inhibitor of serotonin reuptake by antagonizing the 5-HT3, 5-HT7 and 5-HT1D receptors, agonizing the 5-HT1A receptor, partially agonizing the 5-HT1B receptor

and inhibiting the 5-HT transporter. Vortioxetine’s activity at multiple receptors results in modulation of the serotonergic, noradrenergic, dopaminergic and histaminic systems which results in AD effects. Vortioxetine, labeled for the treatment of major depressive disorder in the US, was evaluated for use in anxious patients in four randomized, double-blind, placebo-controlled studies. The results of these analyses were inconsistent and somewhat contradictory. Of the four clinical trials evaluating vortioxetine in patients with GAD, one reports that vortioxetine is superior to placebo, two found no difference and the last found that vortioxetine is useful in relapse prevention. Two identical 8-week, randomized, placebo-controlled trials evaluated the effects of vortioxetine 5 mg/day on change from baseline in HAM-A score, CGI-I score, SDS score and response rate at week 8. Only one of the two studies found that vortioxetine separated from placebo. A 12-week relapse prevention study suggested that vortioxetine 5 or 10 mg/day was efficacious in preventing relapse as compared to placebo and was well tolerated. The most recent study, a randomized, double-blind, fixed-dose study compared vortioxetine 2.5 and 10 mg/day to placebo and found that there was no meaningful difference among any of the study arms [99-102]. Given the lack of consistent efficacy data, neither agomelatine nor vortioxetine are likely to be considered appropriate therapeutic modalities at this time. Atypical antipsychotics Historically, AP medications were generally reserved for the treatment of psychotic symptoms or disorders; however, there has been a resurgence in interest in evaluating them for nonpsychotic complaints. Modest response and remission rates associated with the traditional ADs have stimulated the effort to explore alternative pharmacotherapeutic interventions; one of which is the atypical AP class. The efficacy of the AAPs as augmenters of SSRIs in the treatment of MDD has been established in the treatment of major depressive disorder, and both aripiprazole and quetiapine have been labeled as adjunctive therapies [103-112]. Of the 11 available AAPs there are studies evaluating the benefit of five of them in GAD (aripiprazole, quetiapine, risperidone, ziprasidone and olanzapine), although none of them carry official indications for the treatment of anxiety disorders [104]. The AAPs have primarily been studied in short-term trials as adjunctive therapies in treatment-resistant GAD; however, some monotherapy studies have been conducted. The unfavorable and often permanent adverse effect profiles limit their use as first-line long-term drugs of choice. Extended-release quetiapine, risperidone, ziprasidone and olanzapine have been evaluated for a possible role in the treatment of GAD; particularly when it has become refractory to standard therapy. The evidence is sparse and inconsistent, unfortunately, in regard to the efficacy of these drugs in GAD. Extended-release quetiapine has been the most extensively studied as both monotherapy and adjunctive therapy in patients with pure GAD as well as bipolar disorder or 3.8


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schizophrenia with comorbid GAD or MDD. The majority of studies do not support the efficacy of quetiapine over placebo, although some suggest that there is some utility [103-112]. Although demonstrated in numerous studies, the benefit of AAPs in the treatment of GAD has not been consistently established. Concerns related to the metabolic effects of these drugs have limited their use and also have served as the impetus for additional focused studies which assess their impact on metabolism and other pathways. A recent analysis suggests that clozapine, quetiapine and aripiprazole induce the expression of adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, which indicates that both glucose and fat metabolism may be affected by these drugs [113]. The AAPs theoretically induce metabolic dysregulation through a multitude of behavioral and neurochemical pathways. Alterations in satiety, food cravings and enhanced sensitivity to external eating cures are hypothesized to underlie the weight gain in part. The observed weight gain in most studies becomes evident as early as week 1 and typically rapidly accelerates through about week 12, at which time a plateau is usually reached [114]. The short-term use of AAPs has also been associated with metabolic disturbances. There is evidence to suggest that AAPs influence glucose sensitivity and induce insulin resistance even after a single dose [24,115]. The AAP-associated increased risk of insulin resistance, glucose dysregulation and development of type 2 diabetes has been well established; and this risk is postulated to be partially independent of weight gain [24]. Olanzapine has induced insulin resistance in patients early on in therapy even in the absence of weight gain. The underlying neurochemical basis for AAP-associated weight gain may involve antagonistic properties of 5-HT2C and H1 receptors and this is further supported as the AAPs with the highest affinity for these receptors (clozapine and olanzapine) are associated with the most weight gain [114]. Aside from weight gain and blood glucose dysregulation, AAPs have also been implicated in contributing to dyslipidemia [116,117]. In addition to the metabolic sequelae associated with AAPs, the risk of cardiac arrhythmia, particularly in higher risk patients, is a realistic concern. All of the AAPs have the potential to prolong the QT interval, but the highest likelihood of doing so resides with ziprasidone, which is not typically used in GAD treatment. Despite the lesser likelihood of the other members of the AAP class to prolong the QT interval and hence facilitate an arrhythmia, the use of AAPs in patients with a congenital or acquired prolonged QT interval or in patients who are taking medications concomitantly that can also prolong the QT interval is not recommended [118-120]. In the 1960s and 1970s, one of the authors (KR) studied several first-generation APs for the treatment of anxiety disorders (DSM 2), comparing them with the marketed anxiolytics. Prochlorperazine was compared against placebo and meprobamate [121] and the following APs against the BZ chlordiazepoxide and fluphenazine and placebo: [122], haloperidol [123], molindone [124], clomacran [125], loxapine [126] and 1676

prochlorperazine. Other APs were compared against placebo only. It is most interesting that these first-generation APs produced similar efficacy results than the present generation of AAPs. In general, their response showed better efficacy than placebo (but mostly at a nonsignificant level) but less efficacy than the BZs. Adding to these meager efficacy findings their more complex and serious adverse effect profile than the BZs, they were used very little in anxiety disorders. 4.

Conclusion

The pharmacologic management of GAD is complex and highly variable, and the course of treatment is dependent on individual patient’s characteristics, needs and expectations. The current treatment guidelines advocate for the first-line use of the ADs (SSRIs, SNRIs) based on efficacy, safety, lack of abuse potential and the perceived absence of discontinuation effects. These guidelines place the BZs into a secondary role, namely only for acute treatment, or for use in combination with ADs for the first 4 weeks of AD treatment to help the patients to improve more swiftly and get the patients over the initial adverse effects of the ADs. This initial augmentation of ADs is based on the observation that the ADs have a delayed onset of anti-anxiety effects and it takes 8 -- 12 weeks to obtain a significant anxiolytic effect if the patient is an AD responder. However, neither efficacy nor safety and tolerability of the newer ADs have been compared in controlled trials with the much older BZs. In contrast to the ADs, the BZs have a rapid onset of action which is maximized by week 4, thereby expediting the time by which maximum benefit is realized, allowing the physician to asses rather early in treatment whether the patient should continue on treatment or be shifted to another treatment agent. Owing to the arguably low response and remission rates associated with current first-line drug therapy options, alternative approaches are being evaluated. Traditional approaches include modifying the dose of the standard AD, switching drugs within or among classes or augmenting the initial drug or combining drugs with different mechanisms of action. Newer drug options are labeled for the treatment of GAD outside of the US and are more routinely being used for this purpose even if not specifically indicated (pregabalin, agomelatine, vilazodone, vortioxetine). Although evaluated for use in GAD, none of these compounds are currently indicated for its treatment in the US. 5.

Expert opinion

ADs are an appropriate first-line option, particularly in patients who are able to tolerate the adverse effects that may emerge at the onset of therapy and persist throughout. As evidenced by the literature and clinical experience, BZs tend to be better tolerated as compared to the ADs in general. The




troublesome treatment-emergent adverse effects associated with most ADs, such as sexual dysfunction, usually do not abate with continued therapy and may contribute to worsened clinical outcomes. The recent interest in reappraising the role of BZs in the treatment of GAD is based on a lack of direct comparisons of BZDs with ADs as well as evidence that suggests that the efficacy may be comparable, the tolerability may be better, and the discontinuation effects may be similar. Medication prescribing surveys indicate that BZs are prescribed at least as much as the ADs, primarily by nonpsychiatrists in the treatment of GAD. There is also increasing concern that many patients on ADs, when stopping their medication abruptly, experience similar discontinuation symptoms as patients treated with BZs. Based on the evidence available to us, it is our recommendation that, along with the ADs, BZs be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician. However, it is most important that treatment with the first agent used, be it AD or BZ, be discontinued if the patient does not Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Jennifer A Reinhold1 BA PharmD BCPS BCPP & Karl Rickels†2 MD † Author for correspondence 1 Associate Professor of Clinical Pharmacy, University of the Sciences in Philadelphia, Department of Pharmacy Practice/Pharmacy Administration, 600 South 43rd Street, Philadelphia, PA 19104-4495, USA 2 Stuart and Emily Mudd Professor of Human Behavior and Psychiatry, University of Pennsylvania, School of Medicine, Department of Psychiatry, Mood and Anxiety Disorders Treatment and Research Program, 3535 Market Street, Suite 670, Philadelphia, PA 19104, USA Tel: +1 215 746 6417; Fax: +1 215 746 6551; E-mail: [email protected]

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Controlled comparison of pharmacological and psychological treatment of generalized anxiety disorder in primary care.

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Personality features related to generalized anxiety disorder.

Generalized anxiety disorder: some biochemical aspects.

Predictors of change in quality of life in older adults with generalized anxiety disorder.

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A literature review of quetiapine for generalized anxiety disorder.

Generalized anxiety disorder: how to treat, and for how long?

Pregabalin: a review of its use in adults with generalized anxiety disorder.

Change in Decentering Mediates Improvement in Anxiety in Mindfulness-Based Stress Reduction for Generalized Anxiety Disorder.