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Pharmacotherapy of generalized anxiety disorder: focus and update on pregabalin Expert Rev. Neurother. 14(1), 29–38 (2014)
Charlotte Both1, Georg Kojda1 and Christian LangeAsschenfeldt*2 1 Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany 2 Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany *Author for correspondence: Tel.: +49 211 922 4215 Fax: +49 211 922 4213 [email protected] [email protected]
Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders and clinically characterized by both psychological anxiety and somatic symptoms (muscular tension and autonomic symptoms). Next to serotonergic antidepressants, the Ca2+ channel a2d ligand pregabalin is an approved first-line treatment of GAD in many countries. Pregabalin is considered effective against psychological and somatic anxiety symptoms alike. However, occurrence of discontinuation syndromes and a growing number of reports regarding abuse or dependence during the last years are concerns, particularly in patients with a history of addictive behavior. Here we review key issues of GAD and the pharmacology and pharmacokinetics of pregabalin. Above all, we evaluate evidence from available randomized placebo-controlled as well as head-to-head clinical trials with other drugs regarding its efficacy and safety in the GAD treatment. KEYWORDS: anxiolytic • drug therapy • generalized anxiety disorder • pregabalin • randomized controlled trials
Generalized anxiety disorder (GAD) is characterized by persistent, excessive and unfocused worry or anxiety which is not connected to recent stressful events. The lifetime prevalence of GAD is 5.7% [1,2], women are affected twice as compared to men. The disorder may occur during the whole life span; however, its incidence peaks at the third and fourth decade. Fears are often related to common and everyday aspects and activities. In GAD, anxiety is usually accompanied by muscular tension, restlessness and a feeling ‘on edge’ as well as autonomic symptoms such as palpitations, abdominal complaints, sweating, nausea and dry mouth. Diagnosis is operationalized, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria, as outlined in BOX 1. GAD is considered as a chronic illness. The latency between onset of symptoms and diagnosis may be years to even decades [3]. The predominant reasons for this are wrong (i.e., somatic) diagnoses and insufficient treatment strategies which may aggravate the course. The resulting substantial delay of treatment has important prognostic implications since in
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10.1586/14737175.2014.853617
GAD, a long duration of untreated illness is considered a predictor for an unfavorable outcome of drug therapy [4,5]. The etiology of GAD is viewed as multifactorial comprising behavioral, genetic and neurobiological components [6]. From a neural network perspective, pathological anxiety has been linked to an imbalance between the prefrontal cortex and the amygdala and reactivity of the amygdala has been associated with symptom severity [7,8]. The amygdalae are part of the limbic system and represent a neuroanatomical key structure in mediating the regulation of emotion and anxiety in the mammal brain. Moreover, it is an important area of projection of noradrenergic neurons with a high density of serotonin (5-HT) receptors, thus interfacing these two neurotransmitter systems pertinent to affective regulation [9]. Especially the 5-HT neurotransmitter system has been implicated in GAD pathophysiology since, in older studies administration of the non-specific 5-HT1 and 5-HT2 agonist metachlorophenylpiperazine, enhances anxiety [10]. Moreover, an association exists between this disorder, polymorphisms of the 5-HT2A receptor
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Box 1. Overview of the new diagnostic criteria of generalized anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. • Excessive anxiety and worry (apprehensive expectation), occur-
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•
•
•
•
ring more days than not for at least 6 months, about a number of events or activities (such as work or school performance The individual finds it difficult to control the worry The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months): – Restlessness or feeling keyed up or on edge – Being easily fatigued – Difficulty concentrating or mind going blank – Irritability – Muscle tension – Sleep disturbance The anxiety, worry or physical symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism) The disturbance is not better explained by another mental disorder (e.g., anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder, contamination or other obsessions in obsessive-compulsive
(HTR2A) and certain 5-HT transporter genes, respectively, which even seem to predict drug treatment response [11]. Last but not least, neuroendocrinological studies revealed a dysregulation of the HPA axis with higher basal cortisol levels that appear to be statedependent [12]. In addition, adverse environmental experiences are prominent risk factors for GAD, underscoring the role of psychosocial stressors in the sense of the frequently encountered vulnerability-stress model of neuropsychiatric disorders [13]. Based on such pathophysiological models, during the past two to three decades, an array of treatment strategies has been proposed and tested against anxiety disorders and particularly GAD. The latest achievement in GAD pharmacotherapy is the approval of the Ca2+ channel modulator and anticonvulsant pregabalin. In this paper, after providing a brief overview of today’s treatment strategies of GAD, we present current knowledge of the pharmacology as well as efficacy, safety and pharmacoeconomic aspects of this substance. We used MEDLINE search as methodological tool for this narrative review. Treatment principles & drug classes used in GAD pharmacotherapy
and most widely used. Pharmacological treatment should be commenced if symptoms cause significant functional impairment which is usually the case when GAD is diagnosed. Today, treatment efficacy is assessed by clinical response, defined as remission or symptom reduction of >50% on standard instruments such as the Hamilton Rating Scale for Anxiety (HAM-A). Altogether, in a recent review, probability of response to first-line treatment with any guideline-recommended agent (see below) was calculated 67.7% and remission occurred in 39.7% [14]. Antidepressants, anxiolytics (above all benzodiazepines), anticonvulsants and second generation antipsychotics (SGA), respectively, have all been evaluated for the treatment of GAD. Evidence-based therapeutic options according to the guidelines of the World Federation of Societies of Biological Psychiatry [15] are listed in TABLE 1. Since GAD is a chronic condition, there is usually a need for long-term treatment (i.e., 12 months) [3,16]. Thus, the ideal drug to treat GAD would be efficacious in acute as well as long-term treatment, provide sufficient relapse prevention and enhance the efficacy of a concomitant psychological therapy, respectively. Antidepressants
Besides benzodiazepines, tricyclic antidepressants (TCAs) were among the first drug classes used to treat GAD. However, mainly due to their strong anticholinergic and antiadrenergic adverse effects, safety and tolerability issues limit their use. The risk/benefit ratio markedly improved also in GAD treatment with the broad introduction of selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs). Many clinical guidelines now particularly recommend SSRIs such as escitalopram, paroxetine and sertraline as well as the SNRIs venlafaxine and duloxetine as first-line treatment for GAD [3] (TABLE 1). It has to be considered, though, that SSRIs and SNRIs have their own adverse effects, mainly nausea, sexual dysfunction, (often initial) restlessness, sleep disturbances and the potential of withdrawal symptoms upon discontinuation [16]. However, the tolerability profiles of both drug classes have differences such as more frequent sexual dysfunctions with SSRIs which in addition carry a greater risk of platelet dysfunction and consecutive bruising or rare bleeding. In turn, venlafaxine may be associated with blood pressure dysregulation. A more recently investigated treatment option is agomelatine, a melatonergic agonist (MT1 and MT2 receptors) and 5HT2C antagonist. Agomelatine 25–50 mg/day showed efficacy in recent clinical trials in GAD [17] and there is also evidence for relapse prevention [18] and efficacy against anhedonia in major depressive disorder [19]. Trazodone is another antidepressant sometimes used off-label in the treatment of GAD [20]. Taken together, especially the antidepressants listed in TABLE 1 are both effective and relatively safe options in GAD treatment. As already stated, also with antidepressants, tapering is advisable at the end of treatment in order to minimize discontinuation symptoms [3].
Treatment principles
Benzodiazepines
Therapeutic options include drug treatment and psychotherapy. Of the latter, cognitive behavioral therapy (CBT) is best studied
Benzodiazepines act as agonists on a specific binding site at the GABAA receptor complex, thus potentiating the effect of the
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Pharmacotherapy of generalized anxiety disorder
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Table 1. Therapeutic options for generalized anxiety disorder pharmacotherapy according to World Federation of Societies of Biological Psychiatry Guidelines. Recommendation grade
Category of evidence
Drug
Comments
1
A
SSRI: escitalopram, paroxetine, sertraline Selective SNRI: venlafaxine, duloxetine Calcium channel modulator: pregabalin
First-line treatment First-line treatment First-line treatment (not first choice with comorbid addiction)
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Second generation antipsychotic: quetiapine 2
A
Benzodiazepines: diazepam, lorazepam Anithistaminic: hydroxyzine
Not suitable for monotherapy and individuals with history of addiction
4
C
Tricyclic antidepressants: clomipramine, imipramine
Frequency of adverse events higher than in newer antidepressants; potential cardiac toxicity, overdose lethality, cognitive impairment
5
D
Others: buspirone
SNRI: Serotonin-norepinephrine reuptake inhibitors; SSRI: Selective serotonin reuptake inhibitors. Data taken from [15].
inhibitory neurotransmitter GABA. They exert anxiolytic (mainly via the a2 subunit) as well as sedative, amnestic and anticonvulsive (mainly via the a1 subunit) effects. Benzodiazepines are particularly effective in short-term treatment combatting psychological and somatic symptoms of GAD alike [21]. Best evaluated substances to date are alprazolam, diazepam and lorazepam. However, this drug class should be avoided in the long-term due to dependency concerns, the development of tolerance, and discontinuation as well as rebound symptoms which increase the risk of relapse [22]. Nevertheless, benzodiazepines are suitable to treat acute overwhelming anxiety and are often used as adjuvants in the initial treatment phase of GAD, for example, with SSRI or SNRI antidepressants, given the delayed onset of action of the latter drugs and due to their ability to attenuate early serotonergic side effects (see above) [23].
Patients with GAD tend to have a specific cognitive bias towards increased attention to threat-related information and misinterpretation of ambiguous stimuli as threatening [28]. Such habitual thought patterns can be disrupted or reduced by CBT which has proven efficacy by several meta-analyses [29]. In GAD with moderate to severe symptoms, CBT is often combined with drug treatment, although data are scarce [30]. Repetitive transcranial magnetic stimulation (rTMS) has also been investigated as a therapeutic option in GAD. In one open study, fMRI-guided low-frequency rTMS was effective [31] and this effect persisted over a 6 month follow-up period [32]. However, these data need to be confirmed with larger sample sizes and by using a sham-controlled design. Pregabalin Introduction
Other drugs
Psychotropic drugs other than antidepressants, benzodiazepines and pregabalin are considered to be of minor significance for the treatment of GAD. However, they may have a role as adjunctive therapeutics or in treatment-refractory patients. Clinical trials with SGAs have shown mixed results and suffer from suboptimal study designs [24]. Best studied in this drug class is quetiapine which, particularly in its extended-release formulation, might be considered for augmentation in partial responders to first-line drugs [25]. Other options include the partial agonist of the 5-HT1A receptor buspirone, and the antihistaminic drug hydroxyzine, both of which are US FDA-approved for the treatment of GAD and have relatively good evidence of efficacy [26]. Further (unlicensed) alternatives such as ondansetron and riluzole can be regarded as experimental options with the lowest grade of evidence [27]. Non-pharmacological treatment
Several psychological therapies have been proven effective in the treatment of GAD. The best studied psychotherapy in this indication is CBT which is symptom-focused and time-limited.
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Pregabalin was approved by the European Medicines Agency in March 2006 for the treatment of GAD. So far, there is no approval for this indication in the USA. Pregabalin was already licensed for the treatment of both partial epilepsy and neuropathic pain [33]. Evidence is also available for efficacy in the treatment of alcohol and benzodiazepine dependence [34–36]. Especially at higher doses (exceeding 150 mg/day), the anxiolytic demonstrated significant efficacy in reducing both somatic and psychological symptoms with an early onset (TABLE 2) [37]. According to current international guidelines, pregabalin, along with SSRIs and SNRIs, is recommended as first-line treatment for GAD [16,38]. Pharmacology
Like gabapentine, pregabalin is a non-natural, branched-chain amino acid. Already 30 years ago, gabapentin was shown to inhibit the release of monoamine neurotransmitters such as norepinephrine, dopamine and serotonin. Similar effects were assumed and later proven also for pregabalin [39]. Though pregabalin is a chemical GABA analogue (3-isobutyl-GABA) (FIGURE 1), it lacks activity on GABA receptors [40]. Instead, like gabapentine, 31
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Table 2. Randomized controlled trials of acute generalized anxiety disorder treatment with pregabalin. Efficacy compared to placebo
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Study (year)
Dose (mg/d)
Duration (weeks)
HAM-A reduction† (of) Pregabalin §
Response‡ (%; n total)
Placebo
Pregabalin
Placebo
Ref.
Pande et al. (2003)
150 600
4
-9.2 (23) -10.3 (23)§
-6.8 (23)
No data 46 (68)§
27 (64)
[55]
Feltner et al. (2003)
150 600
4
-10.9 (25){ -13.2 (25)§
-9.3 (25)
52.2 (69){ 59.0 (61){
44 (66)
[49]
Rickels et al. (2005)
300 450 600
4
-12.2 (25)§ -11.0 (25)§ -11.8 (25)§
-8.4 (25)
61 (89)§ 47 (87){ 53 (85)§
34 (85)
[54]
Pohl et al. (2005)
200 400 450
6
-12.4 (25)§ -12.9 (25)§ -12.4 (25)§
-9.3 (25)
53 (78)§ Up to (89)§ 56 (88)§
34 (86)
[64]
Montgomery et al. (2006)
400 600
6
-14.7 (26)§ -14.1 (27)§
-11.6 (27)
61.0 (94)§ 58.0 (104){
45 (100)
[50]
Montgomery et al. (2008)
150 600
8
-12.8 (27)§
-10.7 (26)
52.6 (177)§
41.1 (96)
[77]
Kasper et al. (2009)
300 600
8
-14.5 (28)§
-11.7 (27)
59 (121){
46 (128){
[51]
Efficacy compared to lorazepam (6 mg/d) Study (year)
Dose (mg/d)
Duration (weeks)
Response† (%; n total)
HAM-A reduction (of) Pregabalin {
Lorazepam §
Pregabalin
Lorazepam
Ref.
Pande et al. (2003)
150 600
4
-9.2 (23) -10.3 (23){
-12.0 (24)
No data 46 (68)§
61 (62)§
[55]
Feltner et al. (2003)
150 600
4
-10.9 (25) -13.2 (25){
-11.6 (25)§
52.2 (69){ 59.0 (61){
55 (64){
[49]
Efficacy compared to alprazolam (1.5 mg/d) Study (year)
Rickels et al. (2005)
Dose (mg/d) 300 450 600
Duration (weeks) 4
HAM-A reduction (of)† Pregabalin {
-12.2 (25) -11.0 (25){ -11.8 (25){
Alprazolam §
-10.9 (25)
Response‡ (%; n total) Pregabalin {
Alprazolam 43 (85){
61 (89) 47 (87){ 53 (85){
Ref.
[54]
Efficacy compared to venlafaxine (75 mg/d) Study (year)
Dose (mg/d)
Duration (weeks)
HAM-A reduction (of) Pregabalin §
Venlafaxine §
Response† (%; n total) Pregabalin {
Ref.
Venlafaxine
Montgomery et al. (2006)
400 600
6
-14.7 (26) -14.1 (27)§
-14.1 (26)
61.0 (94) 58.0 (104){
62 (110)§
[50]
Kasper et al. (2009)
300 600#
8
-14.5 (28)††
-12.0 (27)§,{
59 (121){
44 (125){
[51]
†
HAM-A scores were rounded up to whole numbers. Response: HAM-A reduction of 50% (n total indicates the total number of patients included). Significance to placebo. { No significance to placebo or competitor. # Mean dose 424 ± 118 mg/d. †† Significance to competitor. HAM-A: Hamilton rating scale for anxiety. TABLE adapted from [16]. ‡ §
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Pharmacotherapy of generalized anxiety disorder
pregabalin belongs to a new class of drugs known as ‘Ca2+ channel a2d ligands’ [39]. The four individually genetically encoded a2d proteins (a2d-1 to a2d-4) are structural elements of various types of voltage-dependent calcium channels and, among other effects, modulate Ca2+ influx via the 10 subtypes of a1 subunits. Presynaptically localized P/Q-type and N-type Ca2+ channels are thought to be predominantly involved in the release of excitatory neurotransmitters and there is experimental evidence of inhibition of both Ca2+ channel subtypes by a2d ligands [39]. Thus, high affinity binding of pregabalin to a2d-1 and a2d-2 results in decreased Ca2+ influx at presynaptic voltage sensitive Ca2+ channels [41] and a consecutive reduction of neurotransmitter release including norepinephrine and glutamate (FIGURE 1) [40]. This inhibitory effect counteracts a state of neuronal hyperexcitability, which occurs in various neuropsychiatric conditions such as in anxiety disorders [42], and thus accounts for pregabalin’s anxiolytic-like effect. By contrast, under physiological conditions, neurotransmitter release appears to be not substantially reduced by pregabalin via this mechanism. However, some experimental data indicate that pregabalin reduces the synaptic transmission calcium-independently via another yet unknown mechanism [39]. Pharmacokinetics
Pregabalin is a water-soluble drug (‡0.1 g/ml) with quick intestinal resorption (oral bioavailability ‡90%) via amino acid transporters. Peak plasma concentration (Cmax = 3.8 mg/ml) is reached within 0.62 h (tmax). Food consumption reduces oral bioavailability and has been shown to decrease Cmax to 2.6 mg/ml and increase tmax to 3.2 h [43]. Pregabalin crosses the blood–brain barrier and 1–30% of the pregabalin plasma concentration distributes to the central nervous system where it peaks within 8 h [43]. Experimental animal studies indicate that pregabalin passes into the breast milk, and such distribution is assumed for humans as well [44,45]. The volume of distribution is small (0.5 l/kg), corresponding to the volume of unbound body water. Hepatic metabolization of pregabalin is calculated 10% were headache, dizziness, dry mouth, nausea and weight gain. The latter is also frequently observed in long-term treatment with pregabalin in patients with neurological conditions, such as epilepsy and neuropathic pain [60,61]. One study showed a median body weight increase in epilepsy patients of 4 kg in 6 months [62]. Weight gain appears to occur to a greater extend at dosages ‡300 mg [61]. Thus, caution is recommended with patients at risk of metabolic syndrome. There is evidence from carcinogenicity studies in mice for a possible risk of hemangiosarcoma, however, no human cases have yet been described [63]. Based on the pharmacokinetic profile with almost exclusive renal excretion, hepatic impairment is not a contraindication. However, for this reason, doses should be adjusted accordingly in patients with renal dysfunction. Withdrawal, abuse & dependency
Particularly in patients with GAD, there is a risk of withdrawal symptoms, especially after abrupt discontinuation of pregabalin in doses >150 mg [49,55,64]. Withdrawal symptoms can be anxiety, restlessness, irritability and nervousness as well as insomnia, or rebound effects can manifest [40]. Hence, slow tapering regimens after chronic pregabalin treatment are required. Premarketing trials had produced conflicting results regarding pregabalin’s addictive potential and the debate is still ongoing. The first case reports of pregabalin abuse or dependence were published in 2010 [65,66]. A retrospective analysis of data from the Swedish National Register of Adverse Drug Reactions (SWEDIS) revealed 16 positive spontaneous reports during the years 2008 and 2009. The authors concluded that pregabalin may likely be associated with a potential for abuse [67]. More recently, an assessment of anecdotal online reports suggested an already widespread abuse of pregabalin as a recreational drug, most likely due to reported euphoric and dissociative effects [68]. Data from a recent analysis of spontaneous case reports to the German Federal Institute for Drugs and Medical Devices (BfArM) suggest that middle age, male sex and a history of polytoxicomania, respectively, may be risk factors for pregabalin abuse [69]. Caution is advised, however, in all patients with comorbid substance abuse disorders which often overlap with GAD [70]. Cost-effectiveness
As already stated, GAD is one of the most frequently encountered mental disorders in the primary care setting, and its recognition is rather low since the disorder is diagnosed relatively late in its course, which results in significant use of healthcare resources. Moreover, it has been shown that GAD substantially reduces occupational and social functioning leading to an increased economic burden [71]. Pharmacoeconomic issues are therefore important in GAD management. According to the current NICE guideline, sertraline and other SSRIs and Expert Rev. Neurother. 14(1), (2014)
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Pharmacotherapy of generalized anxiety disorder
venlafaxine are the most cost-effective options in GAD treatment [101]. However, studies in the Spanish and Portuguese healthcare system, respectively, using a patient-level simulation model to estimate clinical and economic outcomes of pharmacotherapy both demonstrated cost-effectiveness of pregabalin versus venlafaxine [72,73]. A post-hoc analysis of Spanish data concluded that pregabalin is cost-effective versus SSRI or SNRI also in benzodiazepine-refractory patients [74]. Very recently, the same authors published a pharmacoeconomic analysis of pregabalin versus usual care in daily practice which was defined as treatment with any antidepressant, a benzodiazepine or an anticonvulsant other than pregabalin. In this 6-month study with treatment refractory GAD out-patients, effectiveness was expressed as quality-adjusted life-years gained. It was concluded that pregabalin was cost-effective against usual care in the Spanish healthcare setting [75]. Conclusions
GAD is a chronic disorder that often remains undetected for a long time. One reason (of many) is the primary presentation with often changing, mainly somatic symptoms such as muscle tension, tremors, dizziness, nausea or abdominal pain. Thus, the underlying psychiatric condition may not be recognized for a long time. Current recommendations of the World Federation of Societies of Biological Psychiatry have evaluated escitalopram, paroxetine, duloxetine, venlafaxine and pregabalin with the highest level of evidence (1A [TABLE 1]). The clinical trials conducted to date have shown that pregabalin monotherapy is a useful pharmacotherapeutic intervention in GAD. However, it is not more effective than the benzodiazepines alprazolam or lorazepam and previous comparisons with venlafaxine also revealed conflicting results. Whereas the antidepressant drugs act via reuptake inhibition of neurotransmitters and benzodiazepines via allosteric modulation of the GABAA receptors, pregabalin is the first inhibitor of neuronal Ca2+ channels available for this indication. Due to different mechanisms of action, a combination therapy of pregabalin and/or benzodiazepines and/or antidepressants could improve response rates in GAD pharmacotherapy. Indeed, recent evidence suggests an efficacy of adjunctive pregabalin at least after suboptimal response to SSRI and SNRI treatment, respectively.
Review
and/or contraindications, pregabalin appears to be a useful option. Pregabalin works by a completely different mechanism of action, that is, inhibition of P/Q-type and N-type calcium channels through binding to their structural elements a2d-1 and a2d-2. According to the results of clinical trials, pregabalin is as efficacious as the above mentioned antidepressants, although its use has been associated with abuse and addiction. Dosages of pregabalin with proven efficacy in GAD range from 150 to 600 mg; however, studies have not shown substantial increase of effect sizes at 600 mg. The dose range is similar to that used in the treatment of neuropathic pain (300–600 mg) and in clinical trials of alcohol withdrawal (200–450 mg). However, the unique mechanism of action offers new treatment opportunities in case of insufficient treatment with antidepressants or even in the first place. The former options include both switching to pregabalin and/or adding it to antidepressants but the efficacy and safety of such treatment strategies have to be confirmed in future clinical trials. Five-year view
More research into the differential indication of pregabalin versus antidepressants versus benzodiazepines or other drugs, respectively, should be done in future clinical GAD trials. It can be surmised, for example, that GAD patients with comorbid depression would be more eligible to SSRI or SNRI therapy while patients with predominant somatic anxiety symptoms and sleeping problems may respond better to pregabalin. However, evidence is lacking at this point and clarifying this issue would substantially improve patient care and most likely shorten times to remission or response if the best suitable compound is chosen in the first place. Moreover, a common problem is treatment resistance. There is a need to learn more about effective switching and augmentation strategies and respective evidence should result in the development of treatment algorithms of refractory GAD, comparable to the results of the STAR*D trials for depression [76]. Last but not least, an important emerging issue that warrants further research is pregabalin abuse and dependency, particularly in relation to GAD. Efforts should be made to better identify patients potentially at risk of addiction and to map treatment alternatives for this population.
Expert commentary
Financial & competing interests disclosure
Anxiety disorders are among the most frequent group of psychiatric illnesses. Once diagnosed, they can be treated by either psychotherapy, for example, cognitive behavioral therapy, or by drugs if symptoms cause significant functional impairment and/or psychotherapy is not effective. Most drugs with proven efficacy in GAD and a high level of recommendation are antidepressants. Specifically, SSRIs such as sertraline or escitalopram, and SNRIs such as duloxetine and venlafaxine are considered first-line treatment options. However, in case of intolerability of those drugs due to side effects
C Lange-Asschenfeldt has received lecture fees and/or travel support from Novartis, AstraZeneca and Servier, and research funding from Pfizer and Bristol Myers-Squibb. G Kojda has received lecture fees from Boehringer and Mundipharma, consulting fees from Pfizer and research funding from Actavis, Schwarz Pharma, Pfizer and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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Key issues • Generalized anxiety disorder (GAD) is characterized by persistent, excessive and unfocused worry or anxiety, usually accompanied by muscular tension, restlessness and autonomic symptoms such as palpitations, abdominal complaints, sweating, nausea and dry mouth. • Therapeutic options include psychological and drug treatment. Of the latter, cognitive behavioral therapy is best studied and most widely used. Antidepressants, anxiolytics (above all, benzodiazepines), anticonvulsants and second generation antipsychotics have all been evaluated for the treatment of GAD. • Pregabalin was approved by the European Medicines Agency in March 2006 for the treatment of GAD. According to current international guidelines, pregabalin, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recom-
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mended as first-line treatment for GAD. • Pregabalin was significantly superior to placebo in all clinical trials as assessed by a significant decrease in the Hamilton Rating Scale for Anxiety. However, it is not more effective than the benzodiazepines alprazolam or lorazepam and venlafaxine. • Pregabalin showed significant effectiveness in reducing both somatic and psychological anxiety symptoms. • Side effects of pregabalin are usually considered mild to moderate. Dizziness and somnolence, headache, dry mouth, nausea and weight gain were most common and frequent side effects. • There is a risk of withdrawal symptoms after cessation of pregabalin treatment, especially in a dose ‡150 mg/d. Withdrawal symptoms can be anxiety, restlessness, irritability, nervousness, insomnia or rebound effects. • Current recommendations of the World Federation of Societies of Biological Psychiatry have evaluated escitalopram, paroxetine, duloxetine, venlafaxine and pregabalin with the highest level of evidence.
family history of mental disorders, and birth risk factors in patients with social anxiety disorder. Eur. Arch. Psychiatry Clin. Neurosci 254(6), 397–405 (2004).
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Pharmacotherapy of generalized anxiety disorder: focus and update on pregabalin Expert Rev. Neurother. 14(1), 29–38 (2014)
Charlotte Both1, Georg Kojda1 and Christian LangeAsschenfeldt*2 1 Department of Pharmacology and Clinical Pharmacology, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany 2 Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany *Author for correspondence: Tel.: +49 211 922 4215 Fax: +49 211 922 4213 [email protected] [email protected]
Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders and clinically characterized by both psychological anxiety and somatic symptoms (muscular tension and autonomic symptoms). Next to serotonergic antidepressants, the Ca2+ channel a2d ligand pregabalin is an approved first-line treatment of GAD in many countries. Pregabalin is considered effective against psychological and somatic anxiety symptoms alike. However, occurrence of discontinuation syndromes and a growing number of reports regarding abuse or dependence during the last years are concerns, particularly in patients with a history of addictive behavior. Here we review key issues of GAD and the pharmacology and pharmacokinetics of pregabalin. Above all, we evaluate evidence from available randomized placebo-controlled as well as head-to-head clinical trials with other drugs regarding its efficacy and safety in the GAD treatment. KEYWORDS: anxiolytic • drug therapy • generalized anxiety disorder • pregabalin • randomized controlled trials
Generalized anxiety disorder (GAD) is characterized by persistent, excessive and unfocused worry or anxiety which is not connected to recent stressful events. The lifetime prevalence of GAD is 5.7% [1,2], women are affected twice as compared to men. The disorder may occur during the whole life span; however, its incidence peaks at the third and fourth decade. Fears are often related to common and everyday aspects and activities. In GAD, anxiety is usually accompanied by muscular tension, restlessness and a feeling ‘on edge’ as well as autonomic symptoms such as palpitations, abdominal complaints, sweating, nausea and dry mouth. Diagnosis is operationalized, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria, as outlined in BOX 1. GAD is considered as a chronic illness. The latency between onset of symptoms and diagnosis may be years to even decades [3]. The predominant reasons for this are wrong (i.e., somatic) diagnoses and insufficient treatment strategies which may aggravate the course. The resulting substantial delay of treatment has important prognostic implications since in
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10.1586/14737175.2014.853617
GAD, a long duration of untreated illness is considered a predictor for an unfavorable outcome of drug therapy [4,5]. The etiology of GAD is viewed as multifactorial comprising behavioral, genetic and neurobiological components [6]. From a neural network perspective, pathological anxiety has been linked to an imbalance between the prefrontal cortex and the amygdala and reactivity of the amygdala has been associated with symptom severity [7,8]. The amygdalae are part of the limbic system and represent a neuroanatomical key structure in mediating the regulation of emotion and anxiety in the mammal brain. Moreover, it is an important area of projection of noradrenergic neurons with a high density of serotonin (5-HT) receptors, thus interfacing these two neurotransmitter systems pertinent to affective regulation [9]. Especially the 5-HT neurotransmitter system has been implicated in GAD pathophysiology since, in older studies administration of the non-specific 5-HT1 and 5-HT2 agonist metachlorophenylpiperazine, enhances anxiety [10]. Moreover, an association exists between this disorder, polymorphisms of the 5-HT2A receptor
2014 Informa UK Ltd
ISSN 1473-7175
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Box 1. Overview of the new diagnostic criteria of generalized anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. • Excessive anxiety and worry (apprehensive expectation), occur-
•
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•
•
•
•
ring more days than not for at least 6 months, about a number of events or activities (such as work or school performance The individual finds it difficult to control the worry The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months): – Restlessness or feeling keyed up or on edge – Being easily fatigued – Difficulty concentrating or mind going blank – Irritability – Muscle tension – Sleep disturbance The anxiety, worry or physical symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism) The disturbance is not better explained by another mental disorder (e.g., anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder, contamination or other obsessions in obsessive-compulsive
(HTR2A) and certain 5-HT transporter genes, respectively, which even seem to predict drug treatment response [11]. Last but not least, neuroendocrinological studies revealed a dysregulation of the HPA axis with higher basal cortisol levels that appear to be statedependent [12]. In addition, adverse environmental experiences are prominent risk factors for GAD, underscoring the role of psychosocial stressors in the sense of the frequently encountered vulnerability-stress model of neuropsychiatric disorders [13]. Based on such pathophysiological models, during the past two to three decades, an array of treatment strategies has been proposed and tested against anxiety disorders and particularly GAD. The latest achievement in GAD pharmacotherapy is the approval of the Ca2+ channel modulator and anticonvulsant pregabalin. In this paper, after providing a brief overview of today’s treatment strategies of GAD, we present current knowledge of the pharmacology as well as efficacy, safety and pharmacoeconomic aspects of this substance. We used MEDLINE search as methodological tool for this narrative review. Treatment principles & drug classes used in GAD pharmacotherapy
and most widely used. Pharmacological treatment should be commenced if symptoms cause significant functional impairment which is usually the case when GAD is diagnosed. Today, treatment efficacy is assessed by clinical response, defined as remission or symptom reduction of >50% on standard instruments such as the Hamilton Rating Scale for Anxiety (HAM-A). Altogether, in a recent review, probability of response to first-line treatment with any guideline-recommended agent (see below) was calculated 67.7% and remission occurred in 39.7% [14]. Antidepressants, anxiolytics (above all benzodiazepines), anticonvulsants and second generation antipsychotics (SGA), respectively, have all been evaluated for the treatment of GAD. Evidence-based therapeutic options according to the guidelines of the World Federation of Societies of Biological Psychiatry [15] are listed in TABLE 1. Since GAD is a chronic condition, there is usually a need for long-term treatment (i.e., 12 months) [3,16]. Thus, the ideal drug to treat GAD would be efficacious in acute as well as long-term treatment, provide sufficient relapse prevention and enhance the efficacy of a concomitant psychological therapy, respectively. Antidepressants
Besides benzodiazepines, tricyclic antidepressants (TCAs) were among the first drug classes used to treat GAD. However, mainly due to their strong anticholinergic and antiadrenergic adverse effects, safety and tolerability issues limit their use. The risk/benefit ratio markedly improved also in GAD treatment with the broad introduction of selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs). Many clinical guidelines now particularly recommend SSRIs such as escitalopram, paroxetine and sertraline as well as the SNRIs venlafaxine and duloxetine as first-line treatment for GAD [3] (TABLE 1). It has to be considered, though, that SSRIs and SNRIs have their own adverse effects, mainly nausea, sexual dysfunction, (often initial) restlessness, sleep disturbances and the potential of withdrawal symptoms upon discontinuation [16]. However, the tolerability profiles of both drug classes have differences such as more frequent sexual dysfunctions with SSRIs which in addition carry a greater risk of platelet dysfunction and consecutive bruising or rare bleeding. In turn, venlafaxine may be associated with blood pressure dysregulation. A more recently investigated treatment option is agomelatine, a melatonergic agonist (MT1 and MT2 receptors) and 5HT2C antagonist. Agomelatine 25–50 mg/day showed efficacy in recent clinical trials in GAD [17] and there is also evidence for relapse prevention [18] and efficacy against anhedonia in major depressive disorder [19]. Trazodone is another antidepressant sometimes used off-label in the treatment of GAD [20]. Taken together, especially the antidepressants listed in TABLE 1 are both effective and relatively safe options in GAD treatment. As already stated, also with antidepressants, tapering is advisable at the end of treatment in order to minimize discontinuation symptoms [3].
Treatment principles
Benzodiazepines
Therapeutic options include drug treatment and psychotherapy. Of the latter, cognitive behavioral therapy (CBT) is best studied
Benzodiazepines act as agonists on a specific binding site at the GABAA receptor complex, thus potentiating the effect of the
30
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Review
Table 1. Therapeutic options for generalized anxiety disorder pharmacotherapy according to World Federation of Societies of Biological Psychiatry Guidelines. Recommendation grade
Category of evidence
Drug
Comments
1
A
SSRI: escitalopram, paroxetine, sertraline Selective SNRI: venlafaxine, duloxetine Calcium channel modulator: pregabalin
First-line treatment First-line treatment First-line treatment (not first choice with comorbid addiction)
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Second generation antipsychotic: quetiapine 2
A
Benzodiazepines: diazepam, lorazepam Anithistaminic: hydroxyzine
Not suitable for monotherapy and individuals with history of addiction
4
C
Tricyclic antidepressants: clomipramine, imipramine
Frequency of adverse events higher than in newer antidepressants; potential cardiac toxicity, overdose lethality, cognitive impairment
5
D
Others: buspirone
SNRI: Serotonin-norepinephrine reuptake inhibitors; SSRI: Selective serotonin reuptake inhibitors. Data taken from [15].
inhibitory neurotransmitter GABA. They exert anxiolytic (mainly via the a2 subunit) as well as sedative, amnestic and anticonvulsive (mainly via the a1 subunit) effects. Benzodiazepines are particularly effective in short-term treatment combatting psychological and somatic symptoms of GAD alike [21]. Best evaluated substances to date are alprazolam, diazepam and lorazepam. However, this drug class should be avoided in the long-term due to dependency concerns, the development of tolerance, and discontinuation as well as rebound symptoms which increase the risk of relapse [22]. Nevertheless, benzodiazepines are suitable to treat acute overwhelming anxiety and are often used as adjuvants in the initial treatment phase of GAD, for example, with SSRI or SNRI antidepressants, given the delayed onset of action of the latter drugs and due to their ability to attenuate early serotonergic side effects (see above) [23].
Patients with GAD tend to have a specific cognitive bias towards increased attention to threat-related information and misinterpretation of ambiguous stimuli as threatening [28]. Such habitual thought patterns can be disrupted or reduced by CBT which has proven efficacy by several meta-analyses [29]. In GAD with moderate to severe symptoms, CBT is often combined with drug treatment, although data are scarce [30]. Repetitive transcranial magnetic stimulation (rTMS) has also been investigated as a therapeutic option in GAD. In one open study, fMRI-guided low-frequency rTMS was effective [31] and this effect persisted over a 6 month follow-up period [32]. However, these data need to be confirmed with larger sample sizes and by using a sham-controlled design. Pregabalin Introduction
Other drugs
Psychotropic drugs other than antidepressants, benzodiazepines and pregabalin are considered to be of minor significance for the treatment of GAD. However, they may have a role as adjunctive therapeutics or in treatment-refractory patients. Clinical trials with SGAs have shown mixed results and suffer from suboptimal study designs [24]. Best studied in this drug class is quetiapine which, particularly in its extended-release formulation, might be considered for augmentation in partial responders to first-line drugs [25]. Other options include the partial agonist of the 5-HT1A receptor buspirone, and the antihistaminic drug hydroxyzine, both of which are US FDA-approved for the treatment of GAD and have relatively good evidence of efficacy [26]. Further (unlicensed) alternatives such as ondansetron and riluzole can be regarded as experimental options with the lowest grade of evidence [27]. Non-pharmacological treatment
Several psychological therapies have been proven effective in the treatment of GAD. The best studied psychotherapy in this indication is CBT which is symptom-focused and time-limited.
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Pregabalin was approved by the European Medicines Agency in March 2006 for the treatment of GAD. So far, there is no approval for this indication in the USA. Pregabalin was already licensed for the treatment of both partial epilepsy and neuropathic pain [33]. Evidence is also available for efficacy in the treatment of alcohol and benzodiazepine dependence [34–36]. Especially at higher doses (exceeding 150 mg/day), the anxiolytic demonstrated significant efficacy in reducing both somatic and psychological symptoms with an early onset (TABLE 2) [37]. According to current international guidelines, pregabalin, along with SSRIs and SNRIs, is recommended as first-line treatment for GAD [16,38]. Pharmacology
Like gabapentine, pregabalin is a non-natural, branched-chain amino acid. Already 30 years ago, gabapentin was shown to inhibit the release of monoamine neurotransmitters such as norepinephrine, dopamine and serotonin. Similar effects were assumed and later proven also for pregabalin [39]. Though pregabalin is a chemical GABA analogue (3-isobutyl-GABA) (FIGURE 1), it lacks activity on GABA receptors [40]. Instead, like gabapentine, 31
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Table 2. Randomized controlled trials of acute generalized anxiety disorder treatment with pregabalin. Efficacy compared to placebo
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Study (year)
Dose (mg/d)
Duration (weeks)
HAM-A reduction† (of) Pregabalin §
Response‡ (%; n total)
Placebo
Pregabalin
Placebo
Ref.
Pande et al. (2003)
150 600
4
-9.2 (23) -10.3 (23)§
-6.8 (23)
No data 46 (68)§
27 (64)
[55]
Feltner et al. (2003)
150 600
4
-10.9 (25){ -13.2 (25)§
-9.3 (25)
52.2 (69){ 59.0 (61){
44 (66)
[49]
Rickels et al. (2005)
300 450 600
4
-12.2 (25)§ -11.0 (25)§ -11.8 (25)§
-8.4 (25)
61 (89)§ 47 (87){ 53 (85)§
34 (85)
[54]
Pohl et al. (2005)
200 400 450
6
-12.4 (25)§ -12.9 (25)§ -12.4 (25)§
-9.3 (25)
53 (78)§ Up to (89)§ 56 (88)§
34 (86)
[64]
Montgomery et al. (2006)
400 600
6
-14.7 (26)§ -14.1 (27)§
-11.6 (27)
61.0 (94)§ 58.0 (104){
45 (100)
[50]
Montgomery et al. (2008)
150 600
8
-12.8 (27)§
-10.7 (26)
52.6 (177)§
41.1 (96)
[77]
Kasper et al. (2009)
300 600
8
-14.5 (28)§
-11.7 (27)
59 (121){
46 (128){
[51]
Efficacy compared to lorazepam (6 mg/d) Study (year)
Dose (mg/d)
Duration (weeks)
Response† (%; n total)
HAM-A reduction (of) Pregabalin {
Lorazepam §
Pregabalin
Lorazepam
Ref.
Pande et al. (2003)
150 600
4
-9.2 (23) -10.3 (23){
-12.0 (24)
No data 46 (68)§
61 (62)§
[55]
Feltner et al. (2003)
150 600
4
-10.9 (25) -13.2 (25){
-11.6 (25)§
52.2 (69){ 59.0 (61){
55 (64){
[49]
Efficacy compared to alprazolam (1.5 mg/d) Study (year)
Rickels et al. (2005)
Dose (mg/d) 300 450 600
Duration (weeks) 4
HAM-A reduction (of)† Pregabalin {
-12.2 (25) -11.0 (25){ -11.8 (25){
Alprazolam §
-10.9 (25)
Response‡ (%; n total) Pregabalin {
Alprazolam 43 (85){
61 (89) 47 (87){ 53 (85){
Ref.
[54]
Efficacy compared to venlafaxine (75 mg/d) Study (year)
Dose (mg/d)
Duration (weeks)
HAM-A reduction (of) Pregabalin §
Venlafaxine §
Response† (%; n total) Pregabalin {
Ref.
Venlafaxine
Montgomery et al. (2006)
400 600
6
-14.7 (26) -14.1 (27)§
-14.1 (26)
61.0 (94) 58.0 (104){
62 (110)§
[50]
Kasper et al. (2009)
300 600#
8
-14.5 (28)††
-12.0 (27)§,{
59 (121){
44 (125){
[51]
†
HAM-A scores were rounded up to whole numbers. Response: HAM-A reduction of 50% (n total indicates the total number of patients included). Significance to placebo. { No significance to placebo or competitor. # Mean dose 424 ± 118 mg/d. †† Significance to competitor. HAM-A: Hamilton rating scale for anxiety. TABLE adapted from [16]. ‡ §
32
Expert Rev. Neurother. 14(1), (2014)
Review
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Pharmacotherapy of generalized anxiety disorder
pregabalin belongs to a new class of drugs known as ‘Ca2+ channel a2d ligands’ [39]. The four individually genetically encoded a2d proteins (a2d-1 to a2d-4) are structural elements of various types of voltage-dependent calcium channels and, among other effects, modulate Ca2+ influx via the 10 subtypes of a1 subunits. Presynaptically localized P/Q-type and N-type Ca2+ channels are thought to be predominantly involved in the release of excitatory neurotransmitters and there is experimental evidence of inhibition of both Ca2+ channel subtypes by a2d ligands [39]. Thus, high affinity binding of pregabalin to a2d-1 and a2d-2 results in decreased Ca2+ influx at presynaptic voltage sensitive Ca2+ channels [41] and a consecutive reduction of neurotransmitter release including norepinephrine and glutamate (FIGURE 1) [40]. This inhibitory effect counteracts a state of neuronal hyperexcitability, which occurs in various neuropsychiatric conditions such as in anxiety disorders [42], and thus accounts for pregabalin’s anxiolytic-like effect. By contrast, under physiological conditions, neurotransmitter release appears to be not substantially reduced by pregabalin via this mechanism. However, some experimental data indicate that pregabalin reduces the synaptic transmission calcium-independently via another yet unknown mechanism [39]. Pharmacokinetics
Pregabalin is a water-soluble drug (‡0.1 g/ml) with quick intestinal resorption (oral bioavailability ‡90%) via amino acid transporters. Peak plasma concentration (Cmax = 3.8 mg/ml) is reached within 0.62 h (tmax). Food consumption reduces oral bioavailability and has been shown to decrease Cmax to 2.6 mg/ml and increase tmax to 3.2 h [43]. Pregabalin crosses the blood–brain barrier and 1–30% of the pregabalin plasma concentration distributes to the central nervous system where it peaks within 8 h [43]. Experimental animal studies indicate that pregabalin passes into the breast milk, and such distribution is assumed for humans as well [44,45]. The volume of distribution is small (0.5 l/kg), corresponding to the volume of unbound body water. Hepatic metabolization of pregabalin is calculated 10% were headache, dizziness, dry mouth, nausea and weight gain. The latter is also frequently observed in long-term treatment with pregabalin in patients with neurological conditions, such as epilepsy and neuropathic pain [60,61]. One study showed a median body weight increase in epilepsy patients of 4 kg in 6 months [62]. Weight gain appears to occur to a greater extend at dosages ‡300 mg [61]. Thus, caution is recommended with patients at risk of metabolic syndrome. There is evidence from carcinogenicity studies in mice for a possible risk of hemangiosarcoma, however, no human cases have yet been described [63]. Based on the pharmacokinetic profile with almost exclusive renal excretion, hepatic impairment is not a contraindication. However, for this reason, doses should be adjusted accordingly in patients with renal dysfunction. Withdrawal, abuse & dependency
Particularly in patients with GAD, there is a risk of withdrawal symptoms, especially after abrupt discontinuation of pregabalin in doses >150 mg [49,55,64]. Withdrawal symptoms can be anxiety, restlessness, irritability and nervousness as well as insomnia, or rebound effects can manifest [40]. Hence, slow tapering regimens after chronic pregabalin treatment are required. Premarketing trials had produced conflicting results regarding pregabalin’s addictive potential and the debate is still ongoing. The first case reports of pregabalin abuse or dependence were published in 2010 [65,66]. A retrospective analysis of data from the Swedish National Register of Adverse Drug Reactions (SWEDIS) revealed 16 positive spontaneous reports during the years 2008 and 2009. The authors concluded that pregabalin may likely be associated with a potential for abuse [67]. More recently, an assessment of anecdotal online reports suggested an already widespread abuse of pregabalin as a recreational drug, most likely due to reported euphoric and dissociative effects [68]. Data from a recent analysis of spontaneous case reports to the German Federal Institute for Drugs and Medical Devices (BfArM) suggest that middle age, male sex and a history of polytoxicomania, respectively, may be risk factors for pregabalin abuse [69]. Caution is advised, however, in all patients with comorbid substance abuse disorders which often overlap with GAD [70]. Cost-effectiveness
As already stated, GAD is one of the most frequently encountered mental disorders in the primary care setting, and its recognition is rather low since the disorder is diagnosed relatively late in its course, which results in significant use of healthcare resources. Moreover, it has been shown that GAD substantially reduces occupational and social functioning leading to an increased economic burden [71]. Pharmacoeconomic issues are therefore important in GAD management. According to the current NICE guideline, sertraline and other SSRIs and Expert Rev. Neurother. 14(1), (2014)
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Pharmacotherapy of generalized anxiety disorder
venlafaxine are the most cost-effective options in GAD treatment [101]. However, studies in the Spanish and Portuguese healthcare system, respectively, using a patient-level simulation model to estimate clinical and economic outcomes of pharmacotherapy both demonstrated cost-effectiveness of pregabalin versus venlafaxine [72,73]. A post-hoc analysis of Spanish data concluded that pregabalin is cost-effective versus SSRI or SNRI also in benzodiazepine-refractory patients [74]. Very recently, the same authors published a pharmacoeconomic analysis of pregabalin versus usual care in daily practice which was defined as treatment with any antidepressant, a benzodiazepine or an anticonvulsant other than pregabalin. In this 6-month study with treatment refractory GAD out-patients, effectiveness was expressed as quality-adjusted life-years gained. It was concluded that pregabalin was cost-effective against usual care in the Spanish healthcare setting [75]. Conclusions
GAD is a chronic disorder that often remains undetected for a long time. One reason (of many) is the primary presentation with often changing, mainly somatic symptoms such as muscle tension, tremors, dizziness, nausea or abdominal pain. Thus, the underlying psychiatric condition may not be recognized for a long time. Current recommendations of the World Federation of Societies of Biological Psychiatry have evaluated escitalopram, paroxetine, duloxetine, venlafaxine and pregabalin with the highest level of evidence (1A [TABLE 1]). The clinical trials conducted to date have shown that pregabalin monotherapy is a useful pharmacotherapeutic intervention in GAD. However, it is not more effective than the benzodiazepines alprazolam or lorazepam and previous comparisons with venlafaxine also revealed conflicting results. Whereas the antidepressant drugs act via reuptake inhibition of neurotransmitters and benzodiazepines via allosteric modulation of the GABAA receptors, pregabalin is the first inhibitor of neuronal Ca2+ channels available for this indication. Due to different mechanisms of action, a combination therapy of pregabalin and/or benzodiazepines and/or antidepressants could improve response rates in GAD pharmacotherapy. Indeed, recent evidence suggests an efficacy of adjunctive pregabalin at least after suboptimal response to SSRI and SNRI treatment, respectively.
Review
and/or contraindications, pregabalin appears to be a useful option. Pregabalin works by a completely different mechanism of action, that is, inhibition of P/Q-type and N-type calcium channels through binding to their structural elements a2d-1 and a2d-2. According to the results of clinical trials, pregabalin is as efficacious as the above mentioned antidepressants, although its use has been associated with abuse and addiction. Dosages of pregabalin with proven efficacy in GAD range from 150 to 600 mg; however, studies have not shown substantial increase of effect sizes at 600 mg. The dose range is similar to that used in the treatment of neuropathic pain (300–600 mg) and in clinical trials of alcohol withdrawal (200–450 mg). However, the unique mechanism of action offers new treatment opportunities in case of insufficient treatment with antidepressants or even in the first place. The former options include both switching to pregabalin and/or adding it to antidepressants but the efficacy and safety of such treatment strategies have to be confirmed in future clinical trials. Five-year view
More research into the differential indication of pregabalin versus antidepressants versus benzodiazepines or other drugs, respectively, should be done in future clinical GAD trials. It can be surmised, for example, that GAD patients with comorbid depression would be more eligible to SSRI or SNRI therapy while patients with predominant somatic anxiety symptoms and sleeping problems may respond better to pregabalin. However, evidence is lacking at this point and clarifying this issue would substantially improve patient care and most likely shorten times to remission or response if the best suitable compound is chosen in the first place. Moreover, a common problem is treatment resistance. There is a need to learn more about effective switching and augmentation strategies and respective evidence should result in the development of treatment algorithms of refractory GAD, comparable to the results of the STAR*D trials for depression [76]. Last but not least, an important emerging issue that warrants further research is pregabalin abuse and dependency, particularly in relation to GAD. Efforts should be made to better identify patients potentially at risk of addiction and to map treatment alternatives for this population.
Expert commentary
Financial & competing interests disclosure
Anxiety disorders are among the most frequent group of psychiatric illnesses. Once diagnosed, they can be treated by either psychotherapy, for example, cognitive behavioral therapy, or by drugs if symptoms cause significant functional impairment and/or psychotherapy is not effective. Most drugs with proven efficacy in GAD and a high level of recommendation are antidepressants. Specifically, SSRIs such as sertraline or escitalopram, and SNRIs such as duloxetine and venlafaxine are considered first-line treatment options. However, in case of intolerability of those drugs due to side effects
C Lange-Asschenfeldt has received lecture fees and/or travel support from Novartis, AstraZeneca and Servier, and research funding from Pfizer and Bristol Myers-Squibb. G Kojda has received lecture fees from Boehringer and Mundipharma, consulting fees from Pfizer and research funding from Actavis, Schwarz Pharma, Pfizer and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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35
Review
Both, Kojda & Lange-Asschenfeldt
Key issues • Generalized anxiety disorder (GAD) is characterized by persistent, excessive and unfocused worry or anxiety, usually accompanied by muscular tension, restlessness and autonomic symptoms such as palpitations, abdominal complaints, sweating, nausea and dry mouth. • Therapeutic options include psychological and drug treatment. Of the latter, cognitive behavioral therapy is best studied and most widely used. Antidepressants, anxiolytics (above all, benzodiazepines), anticonvulsants and second generation antipsychotics have all been evaluated for the treatment of GAD. • Pregabalin was approved by the European Medicines Agency in March 2006 for the treatment of GAD. According to current international guidelines, pregabalin, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recom-
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mended as first-line treatment for GAD. • Pregabalin was significantly superior to placebo in all clinical trials as assessed by a significant decrease in the Hamilton Rating Scale for Anxiety. However, it is not more effective than the benzodiazepines alprazolam or lorazepam and venlafaxine. • Pregabalin showed significant effectiveness in reducing both somatic and psychological anxiety symptoms. • Side effects of pregabalin are usually considered mild to moderate. Dizziness and somnolence, headache, dry mouth, nausea and weight gain were most common and frequent side effects. • There is a risk of withdrawal symptoms after cessation of pregabalin treatment, especially in a dose ‡150 mg/d. Withdrawal symptoms can be anxiety, restlessness, irritability, nervousness, insomnia or rebound effects. • Current recommendations of the World Federation of Societies of Biological Psychiatry have evaluated escitalopram, paroxetine, duloxetine, venlafaxine and pregabalin with the highest level of evidence.
family history of mental disorders, and birth risk factors in patients with social anxiety disorder. Eur. Arch. Psychiatry Clin. Neurosci 254(6), 397–405 (2004).
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