Drug Evaluation
Agomelatine in treating generalized anxiety disorder
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Koen Demyttenaere University Psychiatric Center KU Leuven, Campus Gasthuisberg, Leuven, Belgium
1.
Introduction
2.
Overview market
3.
Agomelatine
4.
Clinical efficacy: studies with agomelatine in GAD
5.
Meta-analysis of the two short-term studies
6.
Relapse prevention study
7.
Safety and tolerability
8.
Conclusion
9.
Expert opinion
Introduction: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a lifetime prevalence of 4.3 -- 5.9% in the general population. Many drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines, antidepressants (selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants), anticonvulsants, azapirones, antihistamines, atypical antipsychotics, complementary/alternative medicine, psychotherapy and Internet-based services. Agomelatine is an antidepressant approved by the European Agency; it is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist indicated in the treatment of major depressive episodes. Areas covered: The present article looks at the short-term efficacy of Agomelatine assessed in two short-term placebo-controlled studies. It also looks at the long-term efficacy evaluated in one relapse prevention study. Expert opinion: Agomelatine is an effective treatment option for both GAD and somatic anxiety. The trial, which includes an escitalopram arm, shows comparable efficacy in GAD between both antidepressants, whereas the restoration of sleep was significantly better with agomelatine. The low discontinuation rate illustrates the good tolerability and lab results show a low incidence of transient elevations in liver enzymes. Whereas uptitrated patients on a 50 mg dose have a lower chance of reaching the desired outcome than the lower 25 mg dose, those reaching this outcome have a better chance of treatment continuation. Keywords: agomelatine, generalized anxiety disorder Expert Opin. Investig. Drugs (2014) 23(6):857-864
1.
Introduction
Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a cognitive core symptom (worry) associated with affective and physical manifestations of hypervigilance and tension [1]. Intolerance to uncertainty and constant checking (not on objects as in obsessive-compulsive disorder but rather on relational situations and achievements, with procrastination being a consequence), all being avoidance strategies, are core psychological mechanisms [2]. The diagnostic and statistical manual (DSM) definition of GAD has often been criticized [3]. First, how should the excessiveness of worry be defined? Second, how should the worries about a number of events be defined: more worry domains, like people/relationships, and miscellaneous topics such as minor matters and routine daily activities and daily hassles? Third, should ‘difficult to control’ really be included in the criteria as only 4% of patients with excessive worry were found still able to control the worry? Fourth, is the 6-month duration the optimal cut-off as recall would be more reliable for a shorter period like 3 months (but how to balance evidence and policy considerations, including overdiagnosis and fear of prevalence inflation)? Fifth, since only two of the associated symptoms were found to be specific (‘feeling restless or keyed up or on edge’ and ‘muscular tension’), dropping ‘being easily fatigued’, ‘difficulty concentrating’, ‘irritability’ and ‘sleep disturbance’ could be helpful in reducing comorbidity. Criticism 10.1517/13543784.2014.911840 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description
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Route of administration Chemical structure
Agomelatine Phase III Generalized anxiety disorder 5 Hydroxytryptamine receptor agonist Oral
CH3
N H
O
criteria, and that is a methodological problem; on the other hand, the scale is more convergent with the reasons why patients seek help for GAD, and this is an important advantage [9]. Response is usually defined as a 50% decrease from baseline and remission as a HAM-A score of seven or less (although, based on a plotting of HAM-A scores against the clinical global impressions of severity (CGI-S) score, a score of nine or less has also been proposed) [12]. There was a recent attempt to validate a new scale for GAD on the agomelatine (Box 1) database comprising eight DSM-IV GAD symptoms, assessing not only severity but also frequency and intensity; the authors found a very high correlation with the HAMA and with the CGI-S. They also found a two-factor solution (psychic and somatic anxiety); however, divergent validity still has to be proven [13].
O H3C
Pivotal trial(s)
2.
[27-29]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
of the concept of GAD also focuses on the high comorbidity in GAD, therefore questioning the validity of GAD as a separate disorder. The most frequent comorbid conditions are mood disorders (70.6%), although in 37% of cases, GAD was preceding the onset of the comorbid disorder [4]. A last question on the diagnosis of GAD is whether the in DSM-5 newly-defined specifier for depressive disorders (i.e., ‘with anxious distress’) will improve or impair the differentiation between mood disorders (major depression, persistent depressive disorder) and GAD [1]. GAD has a lifetime prevalence of 4.3 -- 5.9% in the general population and a 1-month prevalence of 7.9 -- 9% in general medical practice [5-7]. The median delay in seeking help is about 9 years [8]. Although the core symptom is worry, it is the associated somatic symptoms that most often prompt patients to seek help; indeed, only 13.3% of patients with GAD and seeking help in primary care present with anxiety as a primary complaint; the others present mainly with somatic complaints, pain and sleep disturbances [9]. The course of GAD is chronic: a 12-year prospective study showed that the probability of recovery was only 0.58 [9]. Occupational impairment was mentioned by 66.7% of these patients and was as important as in patients with major depression, where impairment was mentioned by 68.4% (and by 81.1% of patients with comorbid GAD-major depressive episode) [10]. Assessment of severity in GAD and of change during treatment is mainly performed with a 14-item observer-rated Hamilton Rating Scale for Anxiety (HAM-A), which has a total score as well as 2 subscores (psychic anxiety 7 items and somatic anxiety 7 items) [11]. The content of the scale (including 7 items referring to somatic muscular anxiety, somatic sensory anxiety, cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary and autonomic symptoms) is therefore strongly divergent from the DSM 858
Overview market
Various drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines (alprazolam, diazepam and lorazepam), selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, paroxetine, sertraline, fluvoxamine and escitalopram), serotonin noradrenaline reuptake inhibitors (venlafaxine, duloxetine), tricyclic antidepressants (imipramine), anticonvulsants (pregabalin), azapirones (buspirone), antihistamines (hydroxyzine), atypical antipsychotics (quetiapine), complementary/alternative medicine (kava-kava and homeopathic preparation), psychotherapy (cognitive behavioral therapy [CBT], short-term psychodynamic therapy [STPP]) and Internet-based services [14]. Effect sizes versus placebo for pregabalin, hydroxyzine, venlafaxine, benzodiazepines and SSRIs have been shown to be 0.50, 0.45, 0.42, 0.38 and 0.36, respectively [15]. The effects of psychotherapy (CBT or STPP), although significant, seem to be lower than in other anxiety disorders [16]. The existence of several treatment options is clinically desirable but raises the difficult question of which treatment option is best for the patient. Comparing the efficacy of pharmacotherapy and psychotherapy is difficult for several reasons: patient selection bias (not all patients are open to both pharmacotherapy and psychotherapy), the difficulty of running a randomized clinical trial in psychotherapy (waiting list controls), lower baseline severity in psychotherapy trials, methodological differences (most pharmacotherapy trials use last observation carried forward, many psychotherapy trials report outcome in completers), different end point choices (more and more psychotherapy trials focus on worry, for example, using the Penn State Worry Questionnaire, hence focusing on the core of the therapy) and less on the patient’s concerns [17]. Benzodiazepines have been reported to have relatively greater efficacy in treating somatic anxious symptoms, whereas medications that modulate monoamine neurotransmission have typically (but not always) been reported to reduce psychic anxiety symptoms to a greater extent than somatic symptoms [18]. This is important as patients mainly seek help for the somatic symptoms of GAD [10].
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Agomelatine
Table 1. Agomelatine clinical development program in generalized anxiety disorder. Study number
Study design and type of control
Number of patients included
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Short-term efficacy: placebo-controlled studies CL2-040 Multicenter 121 patients DB, R, PC, Parallel with GAD
CL3-071
Multicenter 412 patients DB, R, PC with GAD Parallel with an active control group Long-term efficacy: randomized withdrawal study CL3-050 Multicenter 477 patients Period 1 : open with GAD Period 2 : DB, R, PC, Parallel Period 3 : DB, R, PC, Parallel re-randomized safety follow-up period (DESS scale)
Doses mg/day
Dose titration time & criteria*
Ago: 25 -- 50
Week 2 HAMA total score decrease £ 20% from baseline and CGI-I item 2 ‡ 4 Week 4 HAMA total score decrease £ 20% from baseline and CGI-I item 2 ‡ 4
Ago: 25 -- 50 Escit: 10 -- 20
Ago: 25 -- 50
Week 4 HAMA total score decrease £ 30% from baseline and CGI-I item 2 ‡ 3
Duration of treatment
Objective(s) of the study
12 weeks
Short-term efficacy Safety (up to 13 weeks)
12 weeks
Short-term efficacy Safety (up to 14 weeks)
Period 1z: 16 weeks Period 2: 26 weeks Period 3: 1 week
Relapse prevention Safety (up to 44 weeks)
*Predefined criteria kept blinded to the investigator and the patient through Interactive Response System (IRS). z This study begins with an open-label treatment period of 16 weeks with agomelatine 25 -- 50 mg, followed by a 26-week double-blind period comparative phase of agomelatine versus placebo in 2 parallel arms. At week 16, if the patients do not fulfill the randomization criteria, they continued to be treated with agomelatine (25 mg or 50 mg depending on their dosage after week 4) until the end of the study or their withdrawal. Ago: Agomelatine; CGI-I: Clinical global impression of improvement; DB: Double-blind; DESS scale: Discontinuation Emergent Signs and Symptoms scale; Escit: escitalopram; GAD: Generalized anxiety disorder; HAM-A: Hamilton Anxiety Scale A; PC: Placebo-controlled; R: Randomized.
3.
Agomelatine
. study CL2-040: a 12-week, randomized, double-blind,
Agomelatine is an antidepressant approved by the European Agency and is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist indicated in the treatment of major depressive episodes [19]. It has been demonstrated that agomelatine has anxiolytic properties in validated paradigms of anxiety behavior in rats, and that at least in some of the animal experiments, both the melatonin agonism and the 5-HT2C properties of the compound are involved: the tested animal models were the Vogel conflict procedure, the elevated plus-maze procedure, the conditioned footshock-induced ultrasonic vocalizations test, the social defeat stress test, the predator stress test and the fear learning process [20-24]. It was also found to be effective in treating the anxiety symptoms associated with depression [25,26]. The present paper summarizes and discusses the 3 pivotal studies demonstrating the efficacy of agomelatine versus placebo in 2 short-term and 1 long-term (relapse prevention).
Clinical efficacy: studies with agomelatine in GAD
4.
The short-term efficacy was assessed in two short-term placebo-controlled studies:
placebo-controlled study comparing agomelatine 25 -50 mg to placebo [27]. Dose titration was possible at week 2. . study CL3-071: a 12-week, randomized, double-blind, placebo-controlled study comparing agomelatine 25 -- 50 mg to placebo, using escitalopram 10 -- 20 mg as active control for assay sensitivity [28]. Dose titration was possible at week 4. The long-term efficacy was evaluated in one relapse prevention study CL3-50: a randomized, 26-week double-blind, withdrawal study comparing agomelatine 25 -- 50 mg to placebo after an initial response to a 16-week treatment period with agomelatine 25 -- 50 mg [29]. Dose titration was possible at week 4 (Table 1). Patients entering the placebo-controlled efficacy studies on agomelatine were required to satisfy the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition revised (DSM-IV-TR) diagnostic criteria for GAD [30]. The mini neuropsychiatric interview was used to diagnose GAD and any potential comorbid disorders [31]. A minimum severity of anxiety on the HAM-A (total score ‡ 22) and a score of > 2 on both HAM-A items 1 (anxious mood) and 2 (tension) and a Montgomery--Asberg depression rating scale total score
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Table 2. Baseline characteristics of the randomized patients in the 3 studies.
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Study number
Age (years) Sex ratio % (M/F) HAM-A total score Psychic anxiety score Somatic anxiety score CGI-S of illness score HAD anxiety score HAD depression score MADRS total score HAM-A total score ‡ 25 n (%) HAM-A total score ‡ 25 and CGI-S ‡ 5 n (%)
CL2-040
CL3-071
CL3-050
All (n = 121)
All (n = 412)
All (n = 228)
41.7 ± 12.2 31/69 28.8 ± 4.1 15.9 ± 2.2 12.9 ± 3.1 4.8 ± 0.6 15.1 ± 2.5 7.2 ± 2.5 11.7 ± 2.5 104 (86) 77 (64)
42.6 ± 12.4 28/72 28.4 ± 3.8 15.2 ± 2.2 13.3 ± 3.1 4.7 ± 0.6 14.8 ± 2.5 6.6 ± 3.6 12.2 ± 2.5 355 (86) 225 (55)
46.4 ± 14.6 38/62 27.6 ± 3.6 14.5 ± 2.4 13.1 ± 3.0 4.7 ± 0.6 14.0 ± 2.9 7.3 ± 3.4 11.6 ± 2.5 183 (80) 135 (59)
Mean ± SD unless otherwise specified. CGI-S: Clinical global impression of severity; HAD: Hospital anxiety and depression; HAM-A: Hamilton anxiety scale A; MADRS: Montgomery-Asberg depression rating scale.
of £ 16 was defined for entry into all studies [11,32]. In addition, the sum of HAM-A item 1 and item 2 was required to be ‡ 5 in CL3-071 and CL3-050 studies. In one study (CL2-040), patients were required to have a minimum severity of ‡ 11 on hospital anxiety and depression (HAD) scale Anxiety score, and in CL2-040 and CL3-071 studies, to have a HAD Anxiety > Depression score [33]. In all studies, patients with a decrease greater than 20% on the HAM-A total score between selection and inclusion, were excluded. Severe GAD was defined in two ways: HAM-A total score ‡ 25 or HAM-A total score ‡ 25 & CGI-S ‡ 5. The primary efficacy outcome measure was the HAM-A total score for all studies. Secondary efficacy outcome measures for anxiety were the HAM-A psychic and somatic anxiety scores. Secondary outcome measures were the CGI-S and CGI improvement (CGI-I); the factors of the self-rated Leeds Sleep Evaluation Questionnaire (LSEQ): getting to sleep, quality of sleep and awakening from sleep; the Sheehan Disability Scale (SDS) and the self-rated HAD scale [11,34-36]. In all studies, the responder analysis was based on the percentage of patients who achieved a ‡ 50% reduction in the total HAM-A score from baseline. An alternative definition of responders CGI-I score of 1 or 2 (much or very much improved) was also used. The remission analyses were based on the percentage of patients who achieved a HAM-A total score £ 7 [12]. The baseline characteristics are given in Table 2.
Meta-analysis of the two short-term studies 5.
The meta-analysis demonstrated a significant difference of 4.26 (95% CI 2.53 -- 5.98) in favor of agomelatine on the primary outcome criterion HAM-A total score compared with placebo (p = 0.04). The HAM-A responder rate demonstrated 860
a significant estimate difference of 25.17% (95% CI 15.60 -34.74) in favor of agomelatine (64.82 vs 39.68%; p < 0.001). The HAM-A remitter rate demonstrated a significant estimate difference of 17.44% (95% CI 15.60 -- 34.74) in favor of agomelatine (36.69 vs 19.85%; p < 0.001). Both HAM-A psychic and HAM-A somatic subscores were significantly more improved (p < 0.001 for both) on agomelatine than on placebo (difference with placebo of 2.12 (95% CI 0.97 -- 3.27) and 1.96 (95% CI 1.04 -- 2.87), respectively). The statistically significant superiority was also found in patients with more severe GAD: the difference between agomelatine and placebo was 4.38 (95% CI 2.45 -- 6.31; p < 0.001) in patients with a baseline HAM-A ‡ 25 and was 5.13 (95% CI 2.67 -- 7.59; p < 0.001) in patients with a baseline HAM-A ‡ 25 and a CGI-S ‡ 5. The underpowered CL2-040 study was positive on the primary end points (HAM-A) but was not reaching statistical significance on some of the secondary end points (HAM-A psychic subscore, CGI-I, occupational impairment, social impairment, analysis in the subgroup of patients with severe GAD), most probably due to the small sample size (63 patients on agomelatine, 58 on placebo). In the larger CL3-071 study, statistical significance was reached for the primary and all the secondary variables. The secondary outcome measures all showed statistically significant superiority of agomelatine over placebo. This was true for CGI-S and CGI-I (0.57; 95% CI 0.30 -- 0.84; p < 0.001 and 0.51; 95% CI 0.26 -- 0.77; p = 0.003) and for the 3 SDS scores (impairment in occupational functioning: 1.16; 95% CI 0.63 -- 1.68; p < 0.001; impairment in social functioning: 1.20; 95% CI 0.15 -- 2.25; p = 0.02; and impairment in family functioning: 1.17 mm; 95% CI 0.30 -- 2.03; p = 0.008). In study CL3 -- 071 (agomelatine, escitalopram, placebo), it is interesting to notice that, compared to placebo, the sleep scores (LSEQ: getting off to sleep,
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Agomelatine
quality of sleep, sleep awakening) improved significantly more with agomelatine but not with escitalopram (p = 0.002, p < 0.001 and p = 0.05 vs p = 0.36, p = 0.35 and p = 0.66, respectively). The potential benefit of one-step uptitration to 50 mg/day in patients with poor early or non-response to 25 mg (i.e., no improvement or deterioration on CGI-I and < 20% improvement on HAM-A) was estimated versus placebo in the two short-term studies, and was administered at week 2 in study CL2-040 and at week 4 in study CL3-071. No further changes in the dosing of study medication were permitted afterward. The rate of dosage uptitration to 50 mg/day was higher in study CL2-040 (41.9%) than in study CL3-071 (15.5%), a difference that might be driven by the different time points for the one-step uptitration. The meta-analysis showed that the decrease in HAM-A between baseline and end point was 15.6 points for all patients on agomelatine and 10.6 for all patients on placebo. But this decrease in uptitrated patients was 14.5 points for agomelatine and 13.0 points for placebo in the CL2-040study but only 7.9 points for agomelatine and 5.5 points for placebo in the CL3-071 study. Response rates for uptitrated patients were 50% for agomelatine and 40% for placebo in the CL2-040 study but only 25% for agomelatine and 12% for placebo in the CL3-071 study, and remission rates for uptitrated patients were 27% for agomelatine and 16% for placebo in the CL2-040 study, but only 15% for agomelatine and 3% for placebo in the CL3-071 study. 6.
Relapse prevention study
A total of 477 patients were included in the study. After an initial open 16-week treatment phase, patient responders to agomelatine (25 -- 50 mg, according to criteria predefined in the study protocol) were randomized to a 6-month double-blind placebo-controlled treatment period. In the full analysis set (FAS), the percentage of patients with a relapse (defined either by a HAM-A total score ‡ 15, or by clinical judgment of a lack of efficacy) during the double-blind period was lower in the agomelatine group (19.5%) than in placebo group (30.7%). The incidence over time of patients having relapse was significantly lower with agomelatine compared with placebo (p = 0.046, log-rank test stratified for country), the risk of relapse being reduced by 41.8% (HR [SE] = 0.582 [0.159] and 95% CI = [0.341; 0.995], p = 0.045, adjusted COX model for country). The significant long-term efficacy of agomelatine in preventing relapses compared with placebo in the FAS was supported by the secondary clinically relevant efficacy analyses in more severely anxious patients (sub-FAS with baseline HAM-A total score ‡ 25 and baseline CGI-S ‡ 5). In this subset of patients, the risk of relapse over time was significantly reduced by 59.3% on agomelatine compared with placebo (p = 0.006, adjusted COX model for country).
The low number of early relapses (up to 6 -- 8 weeks after randomization) reported by patients switched to placebo suggests the absence of withdrawal symptoms after abrupt cessation of agomelatine. The one-step uptitration design proposed in study CL3-050 for patients with insufficient improvement at week 4 (open label phase) was based on the following criteria at week 4: HAM-A total score decrease to < 30% from baseline and CGI-I item 2 ‡ 3. Based on these criteria, 41.1% of patients were receiving an increased dose of agomelatine. In patients treated with agomelatine 25 mg and randomized at week 16 to remain on agomelatine 25 mg, the relapse rate was 21.3%, while it was 30.4% for those randomized to placebo. These rates are similar to those observed in the overall population. For patients treated with agomelatine 50 mg and randomized at week 16 to remain on agomelatine 50 mg or on the placebo, the relapse rate was 15.2 and 31.4%, respectively. While those results point to a possible dose effect, the low number of patients having received the highest dose (33 and 35 patients, respectively) does not allow concluding.
7.
Safety and tolerability
Treatment discontinuations In the CL2-040 study, 92.1% of patients on agomelatine and 93.1% of patients on placebo completed the study. In the CL3-071 study, the rate of discontinuation over the 12-week evaluation period was not different between groups (13.9% for agomelatine, 20.6 % for placebo and 16.6% for escitalopram). The main reason for treatment discontinuation was lack of efficacy, and such discontinuations were less frequent in the agomelatine or the escitalopram groups than in the placebo group (8.4% for agomelatine, 13.2% for placebo and 4.3% for escitalopram). The discontinuations due to adverse event were low and occurred less frequently on agomelatine (2.0%) than on escitalopram (7.2%) compared with placebo (2.1%). In the CL3-050 study (relapse prevention), 74.6% of patients on agomelatine and 64.0% of patients on placebo completed the 26-week double-blind period (main reason for dropout was lack of efficacy: 19.3% for agomelatine vs 30.7% for placebo). 7.1
Laboratory safety Liver function testing resulted in abnormalities (AST & ALT > 3ULN) in the following rates: in the CL2-040 study, 2/63 on agomelatine and 0/58 on placebo; in the CL3-071study, 2/139 on agomelatine, 0/131 on placebo and 2/141 on escitalopram; in the CL3-050 study (relapse prevention), 2/113 on agomelatine and 1/114 on placebo. All these values returned to baseline levels after discontinuation of the drug/placebo. 7.2
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8.
Conclusion
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In conclusion, two short-term studies and one relapse prevention study with agomelatine show evidence that agomelatine is an effective treatment option for GAD, as well as for psychic and somatic anxiety. The trial with escitalopram as an active comparator shows that, compared with placebo, the restoration of sleep is significantly better with agomelatine than with escitalopram. The low discontinuation rates illustrate the good tolerability of agomelatine and escitalopram. 9.
Expert opinion
The 3 studies (2 short-term and 1 relapse prevention) demonstrate the efficacy of agomelatine in GAD. The low dropout rate also illustrates the good tolerability of this compound. It is interesting to notice that the efficacy is for both psychic and somatic anxiety as SSRIs/serotonin and norepinephrine reuptake inhibitors have been shown to reduce psychic anxiety to a greater extent than somatic anxiety and that psychotherapeutical approaches also tend to focus most on ‘worrying’, again part of the psychic anxiety. Benzodiazepines, on the contrary, have been shown to be more efficacious for somatic anxiety than for psychic anxiety [17,18]. This is an important finding as it suggests that agomelatine, probably because of its different pharmacodynamics characteristics, reduces both psychic and somatic anxiety, the latter being the primary reason that patients with GAD seek help [10]. Therefore, the existence of a new and pharmacologically different treatment option is clinically desirable. One of the items on the somatic anxiety subscale is insomnia; therefore, an interesting finding from the CL3-071 study (agomelatine, escitalopram, placebo) is that the quality of sleep (both ‘getting off to sleep’ and ‘quality of sleep’ as assessed with the LSEQ) is significantly improved with agomelatine but not with escitalopram from week 2 onward. Sleep disturbance is indeed a diagnostic criterion in GAD, causing impairment in daytime functioning. It is reported by at least two-thirds of patients who have GAD [37]. One double-blind study investigated the change in subjective sleep latency in patients with disturbed sleep and GAD treated for 8 weeks with escitalopram or with escitalopram and eszopiclone [37]. Patients on adjunct eszopiclone had a mean improvement in sleep latency of 25 minutes compared with 11 minutes in those taking adjunct placebo (p < 0. 001); total sleep time was subjectively increased by 61 minutes in the eszopiclone group and by 35 minutes in the placebo group (p < 0.001); and the response rate in anxiety symptoms was 63% in the group receiving escitalopram plus eszopiclone
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versus 49% in those receiving escitalopram plus placebo (p = < 0.0001). In a study in healthy volunteers, pregabalin appeared to have an effect on sleep and sleep architecture that distinguishes it from benzodiazepines (alprazolam); enhancement of slow-wave sleep was found, while reductions in slow-wave sleep have frequently been reported in patients with GAD [38] These studies emphasize the importance of addressing sleep in GAD and illustrate the efficacy of agomelatine in regulating sleep. A more careful look at the effect of uptitration upon outcome gives some clinically important observations. The one-step uptitration was based on predefined criteria : no improvement or deterioration on CGI-I and < 20% improvement on HAM-A in the short-term studies; HAM-A total score decrease < 30 % from baseline and CGI-I item 2 ‡ 3 in the open phase of the relapse prevention study. This resulted in 41.9% of patients taking 50 mg in the CL2-040study (uptitration after 2 weeks), in 15.5% of patients taking 50 mg in the CL3-071 study and in 41.1% of patients taking 50 mg in the CL3-050 study (uptitration after 4 weeks during open phase and patients in the active arm of the relapse prevention phase continued at the dosing of the open phase). The results from the short-term studies illustrate that patients with an uptitration have a worse final outcome, especially when the uptitration is after 4 weeks, but the results from the relapse prevention study illustrate that patients (becoming responders after an uptitration) have a higher risk reduction of relapse by continuing their active treatment (51% risk reduction for 50 mg and 29.9% reduction for 25 mg). This leads to the clinically very important suggestion that although uptitrated patients reach the desired outcome less easily, once they get it, they are better protected by continuation of treatment.
Declaration of interest K Demyttenaere is a member of the agomelatine advisory board and speaker’s bureau for Servier. He has also received a research grant from the Fonds voor Wetenschappelijk Onderzoek -- Flanders (FWO), and Eli Lilly & Co. He is also on the advisory boards for AstraZeneca, Johnson & Johnson, Lundbeck, Naurex, Shire, Takeda and Servier as well as the speaker’s bureau of AstraZeneca, Eli Lilly & Co, Lundbeck, and Servier. The author has 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.
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Tuma J, Strubbe JH, Mocae¨r E, Koolhaas JM. Anxiolytic-like action of the antidepressant agomelatine (S 20098) after a social defeat requires the integrity of the SCN. Eur Neuropsychopharmacol 2005;15:545-55
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Conboy L, Tanrikut C, Zoladz PR, et al. The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats. Int J Neuropsychopharmacol 2009;12:329-41
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Stein DJ, Fincham D, Seedat S, et al. The DSM-IV-based generalized anxiety disorder severity scale : preliminary validation using data from a trial of agomelatine versus placebo. J Nerv Ment Dis 2009;32:611-28
Carter RM, Wittchen HU, Pfister H, Kessler RC. One-year prevalence of subthreshold and threshold DSM-IV generalized anxiety disorder in a nationally representative sample. Depress Anxiety 2001;13:78-88
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Allgulander C. Generalizeed anxiety disorder : between now and DSM-V. Psychiatr Clin North Am 2009;32:611-28 Suggestions and challenges for the definition of GAD.
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Diaz-Mataix L, Mocae¨r E, Seguin L, LeDoux JE. Agomelatine reduces fear long term memory but not acquisition or short term fear memories. Involvement of melatonergic and 5HT2C receptors. Abstract, ECNP 2013
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Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe -- a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005;15:357-76
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Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. J Psychopharmacol 2007;21:864-72
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Kasper S, Hajak G, Wulff K, et al. Efficacy of the novel antidepressant agomelatine on the circadian rest-activity cycle and depressive and anxiety symptoms in patients with major depressive disorder: a randomized double-blind comparison with sertraline. J Clin Psychiatry 2010;71(2):271-80
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Meyer T, Miller ML, Metzger R, Borkovec TD. Development and validation of the Penn State Worry Scale. Behav Res Ther 1990;28(6):487-95
Demyttenaere K. Agomelatine : a narrative review. Eur Neuropsychopharmacol 2011;21:S703-9
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Affiliation Koen Demyttenaere MD PhD University Psychiatric Center KU Leuven, campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium E-mail: [email protected]
Agomelatine in treating generalized anxiety disorder
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Koen Demyttenaere University Psychiatric Center KU Leuven, Campus Gasthuisberg, Leuven, Belgium
1.
Introduction
2.
Overview market
3.
Agomelatine
4.
Clinical efficacy: studies with agomelatine in GAD
5.
Meta-analysis of the two short-term studies
6.
Relapse prevention study
7.
Safety and tolerability
8.
Conclusion
9.
Expert opinion
Introduction: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a lifetime prevalence of 4.3 -- 5.9% in the general population. Many drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines, antidepressants (selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants), anticonvulsants, azapirones, antihistamines, atypical antipsychotics, complementary/alternative medicine, psychotherapy and Internet-based services. Agomelatine is an antidepressant approved by the European Agency; it is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist indicated in the treatment of major depressive episodes. Areas covered: The present article looks at the short-term efficacy of Agomelatine assessed in two short-term placebo-controlled studies. It also looks at the long-term efficacy evaluated in one relapse prevention study. Expert opinion: Agomelatine is an effective treatment option for both GAD and somatic anxiety. The trial, which includes an escitalopram arm, shows comparable efficacy in GAD between both antidepressants, whereas the restoration of sleep was significantly better with agomelatine. The low discontinuation rate illustrates the good tolerability and lab results show a low incidence of transient elevations in liver enzymes. Whereas uptitrated patients on a 50 mg dose have a lower chance of reaching the desired outcome than the lower 25 mg dose, those reaching this outcome have a better chance of treatment continuation. Keywords: agomelatine, generalized anxiety disorder Expert Opin. Investig. Drugs (2014) 23(6):857-864
1.
Introduction
Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a cognitive core symptom (worry) associated with affective and physical manifestations of hypervigilance and tension [1]. Intolerance to uncertainty and constant checking (not on objects as in obsessive-compulsive disorder but rather on relational situations and achievements, with procrastination being a consequence), all being avoidance strategies, are core psychological mechanisms [2]. The diagnostic and statistical manual (DSM) definition of GAD has often been criticized [3]. First, how should the excessiveness of worry be defined? Second, how should the worries about a number of events be defined: more worry domains, like people/relationships, and miscellaneous topics such as minor matters and routine daily activities and daily hassles? Third, should ‘difficult to control’ really be included in the criteria as only 4% of patients with excessive worry were found still able to control the worry? Fourth, is the 6-month duration the optimal cut-off as recall would be more reliable for a shorter period like 3 months (but how to balance evidence and policy considerations, including overdiagnosis and fear of prevalence inflation)? Fifth, since only two of the associated symptoms were found to be specific (‘feeling restless or keyed up or on edge’ and ‘muscular tension’), dropping ‘being easily fatigued’, ‘difficulty concentrating’, ‘irritability’ and ‘sleep disturbance’ could be helpful in reducing comorbidity. Criticism 10.1517/13543784.2014.911840 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description
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Route of administration Chemical structure
Agomelatine Phase III Generalized anxiety disorder 5 Hydroxytryptamine receptor agonist Oral
CH3
N H
O
criteria, and that is a methodological problem; on the other hand, the scale is more convergent with the reasons why patients seek help for GAD, and this is an important advantage [9]. Response is usually defined as a 50% decrease from baseline and remission as a HAM-A score of seven or less (although, based on a plotting of HAM-A scores against the clinical global impressions of severity (CGI-S) score, a score of nine or less has also been proposed) [12]. There was a recent attempt to validate a new scale for GAD on the agomelatine (Box 1) database comprising eight DSM-IV GAD symptoms, assessing not only severity but also frequency and intensity; the authors found a very high correlation with the HAMA and with the CGI-S. They also found a two-factor solution (psychic and somatic anxiety); however, divergent validity still has to be proven [13].
O H3C
Pivotal trial(s)
2.
[27-29]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
of the concept of GAD also focuses on the high comorbidity in GAD, therefore questioning the validity of GAD as a separate disorder. The most frequent comorbid conditions are mood disorders (70.6%), although in 37% of cases, GAD was preceding the onset of the comorbid disorder [4]. A last question on the diagnosis of GAD is whether the in DSM-5 newly-defined specifier for depressive disorders (i.e., ‘with anxious distress’) will improve or impair the differentiation between mood disorders (major depression, persistent depressive disorder) and GAD [1]. GAD has a lifetime prevalence of 4.3 -- 5.9% in the general population and a 1-month prevalence of 7.9 -- 9% in general medical practice [5-7]. The median delay in seeking help is about 9 years [8]. Although the core symptom is worry, it is the associated somatic symptoms that most often prompt patients to seek help; indeed, only 13.3% of patients with GAD and seeking help in primary care present with anxiety as a primary complaint; the others present mainly with somatic complaints, pain and sleep disturbances [9]. The course of GAD is chronic: a 12-year prospective study showed that the probability of recovery was only 0.58 [9]. Occupational impairment was mentioned by 66.7% of these patients and was as important as in patients with major depression, where impairment was mentioned by 68.4% (and by 81.1% of patients with comorbid GAD-major depressive episode) [10]. Assessment of severity in GAD and of change during treatment is mainly performed with a 14-item observer-rated Hamilton Rating Scale for Anxiety (HAM-A), which has a total score as well as 2 subscores (psychic anxiety 7 items and somatic anxiety 7 items) [11]. The content of the scale (including 7 items referring to somatic muscular anxiety, somatic sensory anxiety, cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary and autonomic symptoms) is therefore strongly divergent from the DSM 858
Overview market
Various drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines (alprazolam, diazepam and lorazepam), selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, paroxetine, sertraline, fluvoxamine and escitalopram), serotonin noradrenaline reuptake inhibitors (venlafaxine, duloxetine), tricyclic antidepressants (imipramine), anticonvulsants (pregabalin), azapirones (buspirone), antihistamines (hydroxyzine), atypical antipsychotics (quetiapine), complementary/alternative medicine (kava-kava and homeopathic preparation), psychotherapy (cognitive behavioral therapy [CBT], short-term psychodynamic therapy [STPP]) and Internet-based services [14]. Effect sizes versus placebo for pregabalin, hydroxyzine, venlafaxine, benzodiazepines and SSRIs have been shown to be 0.50, 0.45, 0.42, 0.38 and 0.36, respectively [15]. The effects of psychotherapy (CBT or STPP), although significant, seem to be lower than in other anxiety disorders [16]. The existence of several treatment options is clinically desirable but raises the difficult question of which treatment option is best for the patient. Comparing the efficacy of pharmacotherapy and psychotherapy is difficult for several reasons: patient selection bias (not all patients are open to both pharmacotherapy and psychotherapy), the difficulty of running a randomized clinical trial in psychotherapy (waiting list controls), lower baseline severity in psychotherapy trials, methodological differences (most pharmacotherapy trials use last observation carried forward, many psychotherapy trials report outcome in completers), different end point choices (more and more psychotherapy trials focus on worry, for example, using the Penn State Worry Questionnaire, hence focusing on the core of the therapy) and less on the patient’s concerns [17]. Benzodiazepines have been reported to have relatively greater efficacy in treating somatic anxious symptoms, whereas medications that modulate monoamine neurotransmission have typically (but not always) been reported to reduce psychic anxiety symptoms to a greater extent than somatic symptoms [18]. This is important as patients mainly seek help for the somatic symptoms of GAD [10].
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Agomelatine
Table 1. Agomelatine clinical development program in generalized anxiety disorder. Study number
Study design and type of control
Number of patients included
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Short-term efficacy: placebo-controlled studies CL2-040 Multicenter 121 patients DB, R, PC, Parallel with GAD
CL3-071
Multicenter 412 patients DB, R, PC with GAD Parallel with an active control group Long-term efficacy: randomized withdrawal study CL3-050 Multicenter 477 patients Period 1 : open with GAD Period 2 : DB, R, PC, Parallel Period 3 : DB, R, PC, Parallel re-randomized safety follow-up period (DESS scale)
Doses mg/day
Dose titration time & criteria*
Ago: 25 -- 50
Week 2 HAMA total score decrease £ 20% from baseline and CGI-I item 2 ‡ 4 Week 4 HAMA total score decrease £ 20% from baseline and CGI-I item 2 ‡ 4
Ago: 25 -- 50 Escit: 10 -- 20
Ago: 25 -- 50
Week 4 HAMA total score decrease £ 30% from baseline and CGI-I item 2 ‡ 3
Duration of treatment
Objective(s) of the study
12 weeks
Short-term efficacy Safety (up to 13 weeks)
12 weeks
Short-term efficacy Safety (up to 14 weeks)
Period 1z: 16 weeks Period 2: 26 weeks Period 3: 1 week
Relapse prevention Safety (up to 44 weeks)
*Predefined criteria kept blinded to the investigator and the patient through Interactive Response System (IRS). z This study begins with an open-label treatment period of 16 weeks with agomelatine 25 -- 50 mg, followed by a 26-week double-blind period comparative phase of agomelatine versus placebo in 2 parallel arms. At week 16, if the patients do not fulfill the randomization criteria, they continued to be treated with agomelatine (25 mg or 50 mg depending on their dosage after week 4) until the end of the study or their withdrawal. Ago: Agomelatine; CGI-I: Clinical global impression of improvement; DB: Double-blind; DESS scale: Discontinuation Emergent Signs and Symptoms scale; Escit: escitalopram; GAD: Generalized anxiety disorder; HAM-A: Hamilton Anxiety Scale A; PC: Placebo-controlled; R: Randomized.
3.
Agomelatine
. study CL2-040: a 12-week, randomized, double-blind,
Agomelatine is an antidepressant approved by the European Agency and is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist indicated in the treatment of major depressive episodes [19]. It has been demonstrated that agomelatine has anxiolytic properties in validated paradigms of anxiety behavior in rats, and that at least in some of the animal experiments, both the melatonin agonism and the 5-HT2C properties of the compound are involved: the tested animal models were the Vogel conflict procedure, the elevated plus-maze procedure, the conditioned footshock-induced ultrasonic vocalizations test, the social defeat stress test, the predator stress test and the fear learning process [20-24]. It was also found to be effective in treating the anxiety symptoms associated with depression [25,26]. The present paper summarizes and discusses the 3 pivotal studies demonstrating the efficacy of agomelatine versus placebo in 2 short-term and 1 long-term (relapse prevention).
Clinical efficacy: studies with agomelatine in GAD
4.
The short-term efficacy was assessed in two short-term placebo-controlled studies:
placebo-controlled study comparing agomelatine 25 -50 mg to placebo [27]. Dose titration was possible at week 2. . study CL3-071: a 12-week, randomized, double-blind, placebo-controlled study comparing agomelatine 25 -- 50 mg to placebo, using escitalopram 10 -- 20 mg as active control for assay sensitivity [28]. Dose titration was possible at week 4. The long-term efficacy was evaluated in one relapse prevention study CL3-50: a randomized, 26-week double-blind, withdrawal study comparing agomelatine 25 -- 50 mg to placebo after an initial response to a 16-week treatment period with agomelatine 25 -- 50 mg [29]. Dose titration was possible at week 4 (Table 1). Patients entering the placebo-controlled efficacy studies on agomelatine were required to satisfy the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition revised (DSM-IV-TR) diagnostic criteria for GAD [30]. The mini neuropsychiatric interview was used to diagnose GAD and any potential comorbid disorders [31]. A minimum severity of anxiety on the HAM-A (total score ‡ 22) and a score of > 2 on both HAM-A items 1 (anxious mood) and 2 (tension) and a Montgomery--Asberg depression rating scale total score
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Table 2. Baseline characteristics of the randomized patients in the 3 studies.
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Study number
Age (years) Sex ratio % (M/F) HAM-A total score Psychic anxiety score Somatic anxiety score CGI-S of illness score HAD anxiety score HAD depression score MADRS total score HAM-A total score ‡ 25 n (%) HAM-A total score ‡ 25 and CGI-S ‡ 5 n (%)
CL2-040
CL3-071
CL3-050
All (n = 121)
All (n = 412)
All (n = 228)
41.7 ± 12.2 31/69 28.8 ± 4.1 15.9 ± 2.2 12.9 ± 3.1 4.8 ± 0.6 15.1 ± 2.5 7.2 ± 2.5 11.7 ± 2.5 104 (86) 77 (64)
42.6 ± 12.4 28/72 28.4 ± 3.8 15.2 ± 2.2 13.3 ± 3.1 4.7 ± 0.6 14.8 ± 2.5 6.6 ± 3.6 12.2 ± 2.5 355 (86) 225 (55)
46.4 ± 14.6 38/62 27.6 ± 3.6 14.5 ± 2.4 13.1 ± 3.0 4.7 ± 0.6 14.0 ± 2.9 7.3 ± 3.4 11.6 ± 2.5 183 (80) 135 (59)
Mean ± SD unless otherwise specified. CGI-S: Clinical global impression of severity; HAD: Hospital anxiety and depression; HAM-A: Hamilton anxiety scale A; MADRS: Montgomery-Asberg depression rating scale.
of £ 16 was defined for entry into all studies [11,32]. In addition, the sum of HAM-A item 1 and item 2 was required to be ‡ 5 in CL3-071 and CL3-050 studies. In one study (CL2-040), patients were required to have a minimum severity of ‡ 11 on hospital anxiety and depression (HAD) scale Anxiety score, and in CL2-040 and CL3-071 studies, to have a HAD Anxiety > Depression score [33]. In all studies, patients with a decrease greater than 20% on the HAM-A total score between selection and inclusion, were excluded. Severe GAD was defined in two ways: HAM-A total score ‡ 25 or HAM-A total score ‡ 25 & CGI-S ‡ 5. The primary efficacy outcome measure was the HAM-A total score for all studies. Secondary efficacy outcome measures for anxiety were the HAM-A psychic and somatic anxiety scores. Secondary outcome measures were the CGI-S and CGI improvement (CGI-I); the factors of the self-rated Leeds Sleep Evaluation Questionnaire (LSEQ): getting to sleep, quality of sleep and awakening from sleep; the Sheehan Disability Scale (SDS) and the self-rated HAD scale [11,34-36]. In all studies, the responder analysis was based on the percentage of patients who achieved a ‡ 50% reduction in the total HAM-A score from baseline. An alternative definition of responders CGI-I score of 1 or 2 (much or very much improved) was also used. The remission analyses were based on the percentage of patients who achieved a HAM-A total score £ 7 [12]. The baseline characteristics are given in Table 2.
Meta-analysis of the two short-term studies 5.
The meta-analysis demonstrated a significant difference of 4.26 (95% CI 2.53 -- 5.98) in favor of agomelatine on the primary outcome criterion HAM-A total score compared with placebo (p = 0.04). The HAM-A responder rate demonstrated 860
a significant estimate difference of 25.17% (95% CI 15.60 -34.74) in favor of agomelatine (64.82 vs 39.68%; p < 0.001). The HAM-A remitter rate demonstrated a significant estimate difference of 17.44% (95% CI 15.60 -- 34.74) in favor of agomelatine (36.69 vs 19.85%; p < 0.001). Both HAM-A psychic and HAM-A somatic subscores were significantly more improved (p < 0.001 for both) on agomelatine than on placebo (difference with placebo of 2.12 (95% CI 0.97 -- 3.27) and 1.96 (95% CI 1.04 -- 2.87), respectively). The statistically significant superiority was also found in patients with more severe GAD: the difference between agomelatine and placebo was 4.38 (95% CI 2.45 -- 6.31; p < 0.001) in patients with a baseline HAM-A ‡ 25 and was 5.13 (95% CI 2.67 -- 7.59; p < 0.001) in patients with a baseline HAM-A ‡ 25 and a CGI-S ‡ 5. The underpowered CL2-040 study was positive on the primary end points (HAM-A) but was not reaching statistical significance on some of the secondary end points (HAM-A psychic subscore, CGI-I, occupational impairment, social impairment, analysis in the subgroup of patients with severe GAD), most probably due to the small sample size (63 patients on agomelatine, 58 on placebo). In the larger CL3-071 study, statistical significance was reached for the primary and all the secondary variables. The secondary outcome measures all showed statistically significant superiority of agomelatine over placebo. This was true for CGI-S and CGI-I (0.57; 95% CI 0.30 -- 0.84; p < 0.001 and 0.51; 95% CI 0.26 -- 0.77; p = 0.003) and for the 3 SDS scores (impairment in occupational functioning: 1.16; 95% CI 0.63 -- 1.68; p < 0.001; impairment in social functioning: 1.20; 95% CI 0.15 -- 2.25; p = 0.02; and impairment in family functioning: 1.17 mm; 95% CI 0.30 -- 2.03; p = 0.008). In study CL3 -- 071 (agomelatine, escitalopram, placebo), it is interesting to notice that, compared to placebo, the sleep scores (LSEQ: getting off to sleep,
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Agomelatine
quality of sleep, sleep awakening) improved significantly more with agomelatine but not with escitalopram (p = 0.002, p < 0.001 and p = 0.05 vs p = 0.36, p = 0.35 and p = 0.66, respectively). The potential benefit of one-step uptitration to 50 mg/day in patients with poor early or non-response to 25 mg (i.e., no improvement or deterioration on CGI-I and < 20% improvement on HAM-A) was estimated versus placebo in the two short-term studies, and was administered at week 2 in study CL2-040 and at week 4 in study CL3-071. No further changes in the dosing of study medication were permitted afterward. The rate of dosage uptitration to 50 mg/day was higher in study CL2-040 (41.9%) than in study CL3-071 (15.5%), a difference that might be driven by the different time points for the one-step uptitration. The meta-analysis showed that the decrease in HAM-A between baseline and end point was 15.6 points for all patients on agomelatine and 10.6 for all patients on placebo. But this decrease in uptitrated patients was 14.5 points for agomelatine and 13.0 points for placebo in the CL2-040study but only 7.9 points for agomelatine and 5.5 points for placebo in the CL3-071 study. Response rates for uptitrated patients were 50% for agomelatine and 40% for placebo in the CL2-040 study but only 25% for agomelatine and 12% for placebo in the CL3-071 study, and remission rates for uptitrated patients were 27% for agomelatine and 16% for placebo in the CL2-040 study, but only 15% for agomelatine and 3% for placebo in the CL3-071 study. 6.
Relapse prevention study
A total of 477 patients were included in the study. After an initial open 16-week treatment phase, patient responders to agomelatine (25 -- 50 mg, according to criteria predefined in the study protocol) were randomized to a 6-month double-blind placebo-controlled treatment period. In the full analysis set (FAS), the percentage of patients with a relapse (defined either by a HAM-A total score ‡ 15, or by clinical judgment of a lack of efficacy) during the double-blind period was lower in the agomelatine group (19.5%) than in placebo group (30.7%). The incidence over time of patients having relapse was significantly lower with agomelatine compared with placebo (p = 0.046, log-rank test stratified for country), the risk of relapse being reduced by 41.8% (HR [SE] = 0.582 [0.159] and 95% CI = [0.341; 0.995], p = 0.045, adjusted COX model for country). The significant long-term efficacy of agomelatine in preventing relapses compared with placebo in the FAS was supported by the secondary clinically relevant efficacy analyses in more severely anxious patients (sub-FAS with baseline HAM-A total score ‡ 25 and baseline CGI-S ‡ 5). In this subset of patients, the risk of relapse over time was significantly reduced by 59.3% on agomelatine compared with placebo (p = 0.006, adjusted COX model for country).
The low number of early relapses (up to 6 -- 8 weeks after randomization) reported by patients switched to placebo suggests the absence of withdrawal symptoms after abrupt cessation of agomelatine. The one-step uptitration design proposed in study CL3-050 for patients with insufficient improvement at week 4 (open label phase) was based on the following criteria at week 4: HAM-A total score decrease to < 30% from baseline and CGI-I item 2 ‡ 3. Based on these criteria, 41.1% of patients were receiving an increased dose of agomelatine. In patients treated with agomelatine 25 mg and randomized at week 16 to remain on agomelatine 25 mg, the relapse rate was 21.3%, while it was 30.4% for those randomized to placebo. These rates are similar to those observed in the overall population. For patients treated with agomelatine 50 mg and randomized at week 16 to remain on agomelatine 50 mg or on the placebo, the relapse rate was 15.2 and 31.4%, respectively. While those results point to a possible dose effect, the low number of patients having received the highest dose (33 and 35 patients, respectively) does not allow concluding.
7.
Safety and tolerability
Treatment discontinuations In the CL2-040 study, 92.1% of patients on agomelatine and 93.1% of patients on placebo completed the study. In the CL3-071 study, the rate of discontinuation over the 12-week evaluation period was not different between groups (13.9% for agomelatine, 20.6 % for placebo and 16.6% for escitalopram). The main reason for treatment discontinuation was lack of efficacy, and such discontinuations were less frequent in the agomelatine or the escitalopram groups than in the placebo group (8.4% for agomelatine, 13.2% for placebo and 4.3% for escitalopram). The discontinuations due to adverse event were low and occurred less frequently on agomelatine (2.0%) than on escitalopram (7.2%) compared with placebo (2.1%). In the CL3-050 study (relapse prevention), 74.6% of patients on agomelatine and 64.0% of patients on placebo completed the 26-week double-blind period (main reason for dropout was lack of efficacy: 19.3% for agomelatine vs 30.7% for placebo). 7.1
Laboratory safety Liver function testing resulted in abnormalities (AST & ALT > 3ULN) in the following rates: in the CL2-040 study, 2/63 on agomelatine and 0/58 on placebo; in the CL3-071study, 2/139 on agomelatine, 0/131 on placebo and 2/141 on escitalopram; in the CL3-050 study (relapse prevention), 2/113 on agomelatine and 1/114 on placebo. All these values returned to baseline levels after discontinuation of the drug/placebo. 7.2
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Conclusion
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In conclusion, two short-term studies and one relapse prevention study with agomelatine show evidence that agomelatine is an effective treatment option for GAD, as well as for psychic and somatic anxiety. The trial with escitalopram as an active comparator shows that, compared with placebo, the restoration of sleep is significantly better with agomelatine than with escitalopram. The low discontinuation rates illustrate the good tolerability of agomelatine and escitalopram. 9.
Expert opinion
The 3 studies (2 short-term and 1 relapse prevention) demonstrate the efficacy of agomelatine in GAD. The low dropout rate also illustrates the good tolerability of this compound. It is interesting to notice that the efficacy is for both psychic and somatic anxiety as SSRIs/serotonin and norepinephrine reuptake inhibitors have been shown to reduce psychic anxiety to a greater extent than somatic anxiety and that psychotherapeutical approaches also tend to focus most on ‘worrying’, again part of the psychic anxiety. Benzodiazepines, on the contrary, have been shown to be more efficacious for somatic anxiety than for psychic anxiety [17,18]. This is an important finding as it suggests that agomelatine, probably because of its different pharmacodynamics characteristics, reduces both psychic and somatic anxiety, the latter being the primary reason that patients with GAD seek help [10]. Therefore, the existence of a new and pharmacologically different treatment option is clinically desirable. One of the items on the somatic anxiety subscale is insomnia; therefore, an interesting finding from the CL3-071 study (agomelatine, escitalopram, placebo) is that the quality of sleep (both ‘getting off to sleep’ and ‘quality of sleep’ as assessed with the LSEQ) is significantly improved with agomelatine but not with escitalopram from week 2 onward. Sleep disturbance is indeed a diagnostic criterion in GAD, causing impairment in daytime functioning. It is reported by at least two-thirds of patients who have GAD [37]. One double-blind study investigated the change in subjective sleep latency in patients with disturbed sleep and GAD treated for 8 weeks with escitalopram or with escitalopram and eszopiclone [37]. Patients on adjunct eszopiclone had a mean improvement in sleep latency of 25 minutes compared with 11 minutes in those taking adjunct placebo (p < 0. 001); total sleep time was subjectively increased by 61 minutes in the eszopiclone group and by 35 minutes in the placebo group (p < 0.001); and the response rate in anxiety symptoms was 63% in the group receiving escitalopram plus eszopiclone
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versus 49% in those receiving escitalopram plus placebo (p = < 0.0001). In a study in healthy volunteers, pregabalin appeared to have an effect on sleep and sleep architecture that distinguishes it from benzodiazepines (alprazolam); enhancement of slow-wave sleep was found, while reductions in slow-wave sleep have frequently been reported in patients with GAD [38] These studies emphasize the importance of addressing sleep in GAD and illustrate the efficacy of agomelatine in regulating sleep. A more careful look at the effect of uptitration upon outcome gives some clinically important observations. The one-step uptitration was based on predefined criteria : no improvement or deterioration on CGI-I and < 20% improvement on HAM-A in the short-term studies; HAM-A total score decrease < 30 % from baseline and CGI-I item 2 ‡ 3 in the open phase of the relapse prevention study. This resulted in 41.9% of patients taking 50 mg in the CL2-040study (uptitration after 2 weeks), in 15.5% of patients taking 50 mg in the CL3-071 study and in 41.1% of patients taking 50 mg in the CL3-050 study (uptitration after 4 weeks during open phase and patients in the active arm of the relapse prevention phase continued at the dosing of the open phase). The results from the short-term studies illustrate that patients with an uptitration have a worse final outcome, especially when the uptitration is after 4 weeks, but the results from the relapse prevention study illustrate that patients (becoming responders after an uptitration) have a higher risk reduction of relapse by continuing their active treatment (51% risk reduction for 50 mg and 29.9% reduction for 25 mg). This leads to the clinically very important suggestion that although uptitrated patients reach the desired outcome less easily, once they get it, they are better protected by continuation of treatment.
Declaration of interest K Demyttenaere is a member of the agomelatine advisory board and speaker’s bureau for Servier. He has also received a research grant from the Fonds voor Wetenschappelijk Onderzoek -- Flanders (FWO), and Eli Lilly & Co. He is also on the advisory boards for AstraZeneca, Johnson & Johnson, Lundbeck, Naurex, Shire, Takeda and Servier as well as the speaker’s bureau of AstraZeneca, Eli Lilly & Co, Lundbeck, and Servier. The author has 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.
Expert Opin. Investig. Drugs (2014) 23(6)
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Affiliation Koen Demyttenaere MD PhD University Psychiatric Center KU Leuven, campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium E-mail: [email protected]
