Katzman, Martin A.a,b,c,d,e; Brawman-Mintzer, Olgaf; Reyes, Efren B.g; Olausson, Bength; Liu, Sherryi; Eriksson, Hansh
The persistent and unremitting symptoms of generalized anxiety disorder (GAD) mean that the burden of illness is substantial and patients often suffer from diminished social functioning and quality of life (Henning et al., 2007). GAD is associated with an increased risk of suicide or suicide attempts (Sareen et al., 2005; Bernal et al., 2007) and a marked degree of impairment equivalent to that observed in patients with major depressive disorder (MDD) (Kessler et al., 1999).
GAD is a prevalent and chronic psychiatric disorder leading to significant impairment and disability. Recent data indicate that GAD has a lifetime prevalence of 5.3%, although this is thought to be a conservative estimate (Kessler et al., 2005), with prevalence rates higher in the primary care setting (Ansseau et al., 2005).
The diagnosis, course, and treatment of GAD is frequently complicated by the presence of other comorbid psychiatric disorders and/or medical conditions, such as MDD, other anxiety disorders, cardiovascular, gastrointestinal, and respiratory disease (Wittchen et al., 1994). Growing evidence suggests that anxiety plays a role in the development of depression, and that the treatment of the former may help in the prevention of the latter (Flannery-Schroeder, 2006). Given this, the early diagnosis and efficacious treatment of GAD is important for optimizing patient outcomes.
Current pharmacological treatment options for GAD include selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), benzodiazepines, tricyclic antidepressants (TCAs), and antihistamines (Bandelow et al., 2002; Baldwin et al., 2005; Canadian Psychiatric Association, 2006). The response rates to treatment are highly variable, ranging between 40 and 70% (Rickels et al., 1993; Gelenberg et al., 2000; Pollack et al., 2001; Baldwin and Nair, 2005). In addition, SSRIs, SNRIs, and TCAs have been associated with a relatively slow onset of action (Pollack, 2001; Canadian Psychiatric Association, 2006). Treatment is further complicated in some patients by the potentially unfavorable tolerability profiles of some antidepressants, such as nausea and sexual dysfunction associated with SSRIs and SNRIs, as well as discontinuation symptoms (Kennedy et al., 2001).
The challenge of finding efficacious and tolerable treatments for patients with GAD is reflected in the difficulty of achieving remission of GAD symptoms. Only one-third of patients achieve remission within a year of follow-up and those patients achieving an initial response often suffer relapses (Andrews et al., 2000), hence there is an unmet need in the pharmacological treatment of patients with GAD.
The atypical antipsychotic quetiapine immediate release has shown efficacy in the treatment of anxiety and depressive symptoms in post-traumatic stress disorder, obsessive-compulsive disorder, and treatment-resistant depression (Hamner et al., 2003; Denys et al., 2004; Doree et al., 2007; Yargic et al., 2004; Bogan et al., 2005; Devarajan et al., 2006). Quetiapine has also shown efficacy in patients with GAD as monotherapy (Galynker et al., 2005) and as adjunctive therapy (Katzman et al., 2008). Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy has also been shown to be effective in the treatment of GAD in the short term (Atkinson et al., 2008; Merideth et al., 2008; Bandelow et al., 2010).
A potential explanation for the effect of quetiapine on anxiety symptoms may be its actions on the dopamine, serotonin, and norepinephrine neurotransmitter systems, or a combination of these effects. The majority of pharmacologic therapies utilized to treat anxiety disorders enhance serotonergic and/or noradrenergic neurotransmission. Quetiapine and norquetiapine (active metabolite) have moderate-to-high affinity for serotonin, 5HT2A, and dopamine D2 receptors; norquetiapine is also a potent inhibitor of the norepinephrine transporter (NET) (Jensen et al., 2008). The clinical relevance of these findings is further supported by positron emission tomography data showing NET occupancy in quetiapine-treated individuals (Goldstein et al., 2008), which has not been shown by other atypical antipsychotics at clinically relevant doses (Goldstein et al., 2007). NET inhibition is a property shared by a number of traditional antidepressants, such as SNRIs, and is believed to contribute to the therapeutic effect (Nyberg et al., 2008).
Although the efficacy of quetiapine XR in the acute treatment of GAD has been shown, the chronic nature of the disorder necessitates long-term treatment for these patients.
The objective of this study was to assess the efficacy of once-daily quetiapine XR maintenance monotherapy by evaluating the recurrence of anxiety symptoms in patients with GAD.
Study design and treatment
This was a multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study (Platinum; D1448C00012) to evaluate the efficacy (time to event) and safety of quetiapine XR for up to 52 weeks of maintenance treatment in adult patients with GAD. Patients were enrolled between March 2006 and March 2007.
The study consisted of four defined treatment periods (Fig. 1): an enrollment and washout period (28 days), an open-label run-in period (4–8 weeks), an open-label stabilization period (12 weeks), and a randomized period. Patients continued in the randomized period for up to 52 weeks or until they met criteria for an anxiety event (as described below), or when the required number of events [46 late (≥14 days post-randomization) events] had occurred and the study was terminated by the sponsor. Therefore, efficacy results are calculated on data from the randomized period, and safety results are calculated for both the open-label and randomized periods.
During the open-label run-in period, quetiapine XR was administered at 50 mg/day on day 1 and day 2, 150 mg/day on day 3 and day 4, and could be increased to 300 mg/day on day 5 or thereafter. Patients started the open-label stabilization period on the same dose of quetiapine XR as they exited the open-label run-in period. Patients meeting randomization criteria (i.e. patients who remained stable for at least 12 weeks) were allocated to a double-blind treatment: to continue with blinded quetiapine XR or switch to matching placebo at the same dose as taken at the last visit of the open-label stabilization period. The permitted doses of quetiapine XR were 50, 150, and 300 mg/day, and the dose could be increased or decreased based on the clinical judgment of the investigator.
The study protocol was approved by the relevant local ethics committees, conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and written informed consent was provided by each patient (or the patient's legally authorized representative) before initiation of any study-related procedures.
To be enrolled in the study, patients had to be aged 18–65 years, and were required to have a diagnosis of GAD according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV TR) criteria (American Psychiatric Association, 1994). Patients were prevented from enrolling if they were suffering from depressive symptoms, defined as having a Montgomery-Åsberg Depression Rating Scale (MADRS) (Montgomery and Åsberg, 1979) total score ≥17. Patients were excluded from the study if they had any DSM-IV Axis I disorder other than GAD within 6 months of enrollment, the presence or history of schizophrenia and other psychotic disorders according to DSM-IV TR, any DSM-IV TR Axis II disorder likely to interfere with the patient's ability to participate in the study, serious suicidal, homicidal risk, or substance or alcohol abuse or dependence within 6 months before enrollment, or clinically significant deviation from the reference range in laboratory test results.
The clinical inclusion criteria for enrollment to the study were a Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1959) total score ≥20, HAM-A Items 1 and 2 scores ≥2, and a Clinical Global Impression-Severity of Illness (CGI-S) (National Institutes of Mental Health, 1970) score ≥4. To proceed from the stabilization period to the randomized period, patients were required to have a HAM-A total score ≤12, a CGI-S score ≤3, and a MADRS total score ≤16. Patients who were hospitalized for anxiety symptoms, attempted suicide or were at risk of a suicide attempt, had a HAM-A total score ≥15 at two consecutive visits, a CGI-S score ≥5, or initiated prohibited pharmacological treatment for anxiety during the randomization period, were discontinued from the study.
Primary analysis and definition of an anxiety event
The primary variable was the time from randomization to an anxiety event. Before initiation of the study, it was decided that the study a priori would be completed when a pre-determined number of anxiety events [≥46 (to ensure adequate power of 85%)] had been observed ≥14 days post-randomization (to allow for any events because due to randomization to placebo and therefore withdrawal of active treatment in some patients). The term ‘anxiety event’ summarizes a recurrence of anxiety symptoms, and is defined as an occurrence of one of the following conditions: a HAM-A total score≥15 at two consecutive visits, a CGI-S score≥5 (markedly ill) at a study visit, hospitalization because of anxiety symptoms, initiation of prohibited medication to treat anxiety symptoms, and self-medication with exclusionary medications to treat anxiety symptoms for 1 week or greater. Lost to follow-up was not considered to be an anxiety event (in the primary analysis) and the patient's time to an event was recorded at the time of lost to follow-up.
The uniformity of the treatment effect of quetiapine XR compared with placebo was established using additional analyses of the primary efficacy outcome variable for the subpopulations of all-cause (including lost to follow-up) discontinuation and late onset discontinuation (time to all-cause discontinuation censoring events during the first 13 days).
Secondary efficacy analysis
The secondary efficacy analyses aimed to address maintenance of effect while patients were stable, hence secondary efficacy analyses focused on changes from randomization.
The mean change from randomization to the last visit before an anxiety event (or the last visit for those patients who did not experience an anxiety event) was assessed in HAM-A total score, HAM-A psychic and somatic anxiety cluster scores, CGI-S total score, Pittsburgh Sleep Quality Index (PSQI) global score (Buysse et al., 1989), Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) score (Endicott et al., 1993), and Sheehan Disability Scale (SDS) global functional impairment score (Sheehan, 1996) at study end.
A shortened version of the Q-LES-Q was used in this study, comprising 16 items with the same content as the last section (General Activities) of the regular version of the Q-LES-Q. The first 14 items were used to derive a percentage maximum total score, and the remaining two were single items, measuring satisfaction with medication and overall quality of life, respectively.
Tolerability analyses considered both changes from enrollment and changes from randomization, and therefore included data from both the open-label periods and the randomized period.
The tolerability of quetiapine XR was assessed by monitoring the number and severity of reported adverse events (AEs) and withdrawals throughout the open-label and randomized periods of the study.
Suicidality was monitored throughout the study. This included suicide attempts, suicide ideation, completed suicides, and suicidal behavior. Suicidal behavior included behavioral AEs or serious AEs (SAEs) in which the investigator could not rule out underlying suicidal thinking (for e.g. a motor vehicle accident), or behaving in a dangerous or unsafe way and other self-injurious behavior. Based on these AEs, a narrative for each patient was reviewed by three medical reviewers who classified each AE according to the Columbia University Classification (Endicott and Spitzer, 1987). The codes for the Columbia University Classification were: i, completed suicide; ii, suicide attempt; iii, preparatory actions towards imminent suicidal behavior; iv, suicidal ideation; v, self-injurious behavior, intent unknown; vi, not enough information, death; vii, self-injurious behavior, no suicidal intent; viii, other; and ix, not enough information, non-death.
Effect on depressive symptoms was monitored by the change in MADRS total score (Montgomery and Åsberg, 1979) from enrollment, at weeks 0, 1, 2, and 4 (and week 8 if necessary) of the open-label run-in period, weeks 0, 4, 8, 12, 14, 16, and 18 of the open-label stabilization period and then at randomization, weeks 1, 2, and 4 and every 4 weeks thereafter of the randomized period.
Laboratory measurements including hematology, clinical chemistry (p-glucose, s-insulin and HbA1c), lipids, thyroid function, and prolactin levels were made at enrollment, week 4 (and week 8 if necessary) of the open-label run-in period, and weeks 0, 4, 8, and 16 of the open-label stabilization period and then at randomization, weeks 12, 24, 36, 48, and 52 of the randomized period. Fasting blood samples were collected at enrollment, week 12 and every 12 weeks thereafter until the end of the randomized period.
An electrocardiogram (ECG) was performed at enrollment, at randomization, and at week 28 and 52 of the randomized period. Measurements of vital signs (blood pressure and pulse rate) were performed at enrollment, weeks 0, 1, 2, and 4 (and week 8 if necessary) of the open-label run-in period, weeks 0, 4, 8, 12, 14, 16, and 18 of the open-label stabilization period and then at randomization, weeks 1, 2, and 4, and every 4 weeks thereafter of the randomized period. Changes in body weight were recorded from enrollment at weeks 4, 8, and 16 of the open-label stabilization period and then at randomization, weeks 12, 24, 36, 48, and 52 of the randomized period.
The incidence and severity of extrapyramidal symptoms (EPS) were assessed by measuring the change in Simpson-Angus Scale (SAS) (Simpson and Angus, 1970), Barnes Akathisia Rating Scale (BARS) (Barnes, 1989), and Abnormal Involuntary Movement Scale (AIMS) (Guy, 1976) at weeks 0 and 4 (and week 8 if necessary) of the open-label run-in period, weeks 0, 4, 8, 12, and 16 of the open-label stabilization period and then at weeks 0, 4, and every 4 weeks thereafter of the randomized period.
A Cox proportional hazards model was used to analyze the primary efficacy outcome, time to an anxiety event during the randomized treatment period. Region was used as a stratification variable. Comparisons of interest explaining uniformity of quetiapine XR treatment effects versus placebo in specific subpopulations are presented as hazard ratio (HR) and associated 95% confidence interval (CI).
The change from baseline for the secondary efficacy variables was analyzed in a two-step approach. First, for each patient, all total scores were summarized as the average of assessments between randomization and an anxiety event or end of study. This summary statistic excluded the assessment at randomization and any assessments during (or after) an anxiety event. The average change score with respect to randomization was then calculated. Second, the average total change score was analyzed using an analysis of covariance with total score at randomization as a covariate and treatment and region as fixed effects. All assessments between randomization and up to, but excluding, the anxiety event were included in the analyses. The HRs of quetiapine XR versus placebo and corresponding 95% CIs were calculated using the same Cox proportional hazards model as for the main analysis.
All data analyses were performed using one or more of the following data sets: the open-label safety analysis set included all patients who entered the open-label period and received study drug (an additional subgroup included patients who received treatment only during the open-label period and was designated as ‘open-label only’), the randomized safety analysis set included all patients who received randomized study treatment during the randomized period, and the intention-to-treat (ITT) analysis set included all randomized patients who received study drug during the randomized period.
A total of 1248 patients were enrolled in the study and 1224 patients from 128 centers in Canada, the United States, Europe, Asia, and Australia were included in the open-label treatment period. The most common reasons for discontinuation from the open-label period were AEs and unwillingness to continue (Fig. 2).
A total of 433 patients were randomized at the end of the open-label period (Fig. 2), of which 432 patients received quetiapine XR (N=216) or placebo (N=216). Baseline demographics for the open-label and ITT populations are presented in Table 1 and clinical characteristics are presented for both the open-label and randomized populations in Table 2.
As mentioned earlier, the protocol specified that the study would reach completion when a pre-determined number of anxiety events [46 (≥14 days post-randomization)] had been observed. When the pre-specified number of events was reached, 259 patients were still participating in the randomized period (162 patients in the quetiapine XR group and 97 patients in the placebo group) and 200 patients were still receiving open-label treatment (and were therefore discontinued and unable to enter the randomized-treatment period).
No patients completed 52 weeks of randomized treatment before the study termination (Fig. 2).
The mean dose and duration of treatment for both the open-label and randomized periods are given in Table 3. The distribution of doses at the end of the open-label treatment period for those patients who were subsequently randomized to continue with quetiapine XR treatment was 26.4% for the 50 mg/day dose group, 49.1% for the 150 mg/day dose group, and 24.5% for the 300 mg/day dose group.
The duration of exposure during the randomized period was approximately 56% higher in the quetiapine XR groups (106.9 mean days in the quetiapine XR group compared with 68.6 mean days in the placebo group), which would potentially impact on time-dependent safety measures such as AEs and laboratory values. The percentage of patients remaining in the randomized period at 12 weeks was higher in the quetiapine XR group (56.0%) compared with the placebo group (33.3%).
The majority of patients were receiving the same dose of quetiapine XR at the end of the study as at the end of the open-label period. A total of 89.5% of patients who finished the open-label period on 50 mg/day quetiapine XR remained on the same dose throughout the randomized period. Similar results were observed for quetiapine XR 150 mg/day (94.3%) and 300 mg/day (92.5%).
Primary endpoint: analysis of time-to-recurrence of anxiety event (recurrence of anxiety symptoms)
During the randomized treatment period, quetiapine XR significantly increased the time to recurrence of anxiety symptoms (anxiety event) compared with the placebo group, with an estimated HR of 0.19 (95% CI=0.12–0.31; P<0.001). The number of patients with anxiety events were 84 (38.9%) and 22 (10.2%) in the placebo and quetiapine XR treatment groups, respectively. The Kaplan–Meier curves showed consistency with the Cox proportional hazard analysis of time to occurrence of an anxiety event (Fig. 3).
Moreover, quetiapine XR significantly increased the time to recurrence of anxiety symptoms (anxiety event) compared with the placebo group when analyzed by the last open-label dose, with estimated HRs of 0.21 (95% CI=0.08–0.51; P<0.001) for quetiapine XR 50 mg/day versus placebo, 0.17 (95% CI=0.08–0.36; P<0.001) for quetiapine XR 150 mg/day versus placebo, and 0.22 (95% CI=0.09–0.51; P<0.001) for quetiapine XR 300 mg/day versus placebo.
Quetiapine XR significantly reduced the number of all-cause discontinuations during the randomized period, with 119 (55.1%) and 54 (25.0%) all-cause discontinuations in the placebo and quetiapine XR treatment groups (P<0.001), respectively. The time to occurrence of discontinuation was significantly longer in the quetiapine XR group compared with the placebo group, with an estimated HR of 0.32 (95% CI=0.23–0.44; P<0.001). Quetiapine XR was also shown to have a greater effect than placebo in increasing time to occurrence of a late onset discontinuation (>13 days post-randomization), with an estimated HR of 0.43 (95% CI=0.30–0.62; P<0.001).
Secondary efficacy endpoints
The maintenance of effect measures for secondary variables, assessed as the mean change from randomization to the last visit before an anxiety event (or the last visit for those patients who did not experience an anxiety event), are presented in Table 4.
Quetiapine XR showed a significant reduction from randomization to study end in HAM-A total score for quetiapine XR (−0.14, P<0.001) compared with placebo (1.90; Table 4). Significant reductions from randomization to study end in HAM-A psychic cluster score (P<0.001) and HAM-A somatic cluster score (P<0.001) showed that quetiapine XR was effective at maintaining the anxiolytic effect compared with placebo (Table 4).
Quetiapine XR was significantly more effective at maintaining the improvement in CGI-S mean scores (P<0.001) from randomization to study end compared with placebo (Table 4).
Quetiapine XR was significantly more effective in maintaining the quality of sleep compared with placebo (P<0.001), as shown by the improvement in PSQI global score from randomization to study end (Table 4). A significant difference was observed for the patient-reported outcomes of Q-LES-Q (P<0.05) and SDS (P<0.05) from randomization to study end for quetiapine XR compared with placebo (Table 4), representing maintenance in patient functioning and quality of life, enjoyment, and satisfaction.
Open-label period: the incidence of AEs during the open-label period was 86.9% with the most commonly reported AEs (≥5%) being dry mouth (30.5%), somnolence (29.7%), sedation (26.6%), dizziness (13.9%), fatigue (13.6%), constipation (10.6%), headache (9.6%), nausea (7.3%), and dyspepsia (5.0%) (Table 5). The incidence of non-fatal SAEs was 1.2% and no deaths occurred. None of the 15 SAEs were considered treatment related and eight of these events caused patients to withdraw from the study.
The overall incidence of AEs leading to discontinuation was 19.4%, of which the most commonly reported were sedation (6.6%), somnolence (3.4%), fatigue (1.6%), dizziness (1.4%), irritability (1.0%), and constipation (0.8%) (Table 5). The onset of most AEs leading to discontinuation was reported in the first week of treatment with quetiapine XR.
The incidence of AEs potentially related to EPS was 7.4%, the most common of which were restlessness (2.6%), akathisia (2.4%), and tremor (1.9%). None of these events were considered serious, most were considered mild-to-moderate in intensity and most were considered treatment related. Most of the cases of restlessness and akathisia did not lead to discontinuation. During the open-label period, a small mean reduction in SAS total score and BARS global assessment score (both −0.1) and a small mean decrease in AIMS total score (−0.1) were observed. A total of 77.4% of patients showed no change, 15.2% showed improvement, and 7.3% showed worsening in SAS total score. A total of 87.5% of patients showed no change, 10.9% showed improvement, and 1.7% showed worsening in BARS global assessment score. A total of 89.6% of patients showed no change, 7.4% showed improvement, and 2.9% showed worsening in AIMS total score (Items 1–7).
The AEs of somnolence and sedation were mostly mild-to-moderate in intensity. The majority of these AEs occurred in the first week (somnolence, 2.5%; sedation, 5.3%), although some of the patients did not discontinue treatment until several weeks after the start of the AE.
There were no AEs potentially related to QT prolongation. Two patients experienced AEs potentially related to neutropenia/agranulocytosis (neutrophil count decrease) that were considered to be potentially treatment related; there was one case of neutropenia that was not considered to be treatment related and six cases of syncope that were all considered to be treatment related (one leading to discontinuation).
Randomized period: the incidence of AEs during the randomized period was similar in the quetiapine XR (51.9%) and the placebo (51.4%) groups, as was the rate of treatment-related AEs (24.1 and 22.2% in the quetiapine XR and placebo groups, respectively). The most commonly reported AEs (≥5% in any group) are shown in Table 6. The overall incidence of non-fatal SAEs was the same for both the treatment groups (1.4%), resulting in the discontinuation of two patients in the quetiapine XR group and one patient in the placebo group. No SAEs were reported by more than one patient and no fatal AEs occurred.
Discontinuations because of AEs were low and similar in both treatment groups. Excluding recurrence of anxiety symptoms or sponsor termination of the study (number of pre-specified events reached), the overall rate of discontinuation during the randomized period was 2.3 and 2.8% in the quetiapine XR and placebo groups, respectively.
The most frequent reasons for discontinuation in the quetiapine XR group during the randomized period, excluding termination by the sponsor, were recurrence of anxiety symptoms (10.2%), followed by patients' unwillingness to continue (5.6%), lost to follow-up (3.2%), and AEs (2.3%). Table 6 shows the AEs leading to discontinuation in the quetiapine XR group.
The most frequent reason for discontinuation in the placebo group during the randomized period was recurrence of anxiety symptoms (38.9%), followed by unwillingness to continue (7.4%), AE (3.7%), and patients lost to follow-up (3.2%). The most commonly reported AE leading to discontinuation was insomnia (1.9%) (Table 6). A higher incidence of insomnia was observed in the placebo group during the first week after randomization (after the abrupt discontinuation of open-label quetiapine XR treatment) than during the rest of the randomized treatment period. Of the four reported cases of insomnia leading to discontinuation in weeks 1–2, three occurred in the first week and one occurred in the second week; none of these patients experienced a recurrence of anxiety symptoms.
The most common AEs potentially associated with EPS were restlessness (quetiapine XR, 1.9%; placebo, 0.0%), tremor (quetiapine XR, 0.9%; placebo, 0.5%), and akathisia (quetiapine XR, 0.5%; placebo, 0.9%). None of these AEs were considered serious, none led to discontinuation, and most were considered treatment related.
During the randomized period, mean changes in SAS total score, BARS global assessment score, and AIMS total score (Items 1–7) for the quetiapine XR group and the placebo group were: 0.0 and 0.1; −0.1 and 0.0; 0.0 and 0.1, respectively. A total of 84.8 and 86.7% of patients showed no change, 9.5 and 5.2% showed improvement, and 5.7 and 8.1% showed worsening in SAS total score in the quetiapine XR and placebo groups, respectively. A total of 95.7 and 94.8% of patients showed no change, 1.4 and 0.5% showed improvement, and 2.9 and 4.8% showed worsening in BARS global assessment score in the quetiapine XR and placebo groups, respectively. A total of 96.7 and 92.4% of patients showed no change, 1.0 and 2.4% showed improvement, and 2.4 and 5.2% showed worsening in AIMS total score (Items 1–7) in the quetiapine XR and placebo groups, respectively.
No patients in the placebo group reported AEs of somnolence and sedation, whereas two (0.9%) and five (2.3%) patients in the quetiapine XR group reported somnolence and sedation, respectively. All cases of somnolence and sedation were mild-to-moderate in intensity.
There were no AEs potentially related to QT prolongation or agranulocytosis, one case of neutropenia that was considered to be possibly quetiapine XR treatment related, and one case of syncope in the placebo group.
Emergent AEs in the 2 weeks post randomization: the majority of the AEs reported during the randomized period occurred during the first 2 weeks (57.4%). Of the most common AEs (>5% in any group; Table 5), the rates of occurrence during the first week for patients switched from quetiapine XR treatment to placebo were: nausea, 13.0%; insomnia, 10.2%; headache, 6.9%; fatigue, 1.9%; nasopharyngitis, 0.9%, and dizziness, 0.5%. Other frequently reported AEs were diarrhea (2.8%), chills (2.4%), back pain (1.9%), upper respiratory tract infection (1.4%), abnormal dreams (1.4%), hyperhidrosis (1.4%), and vomiting (1.4%).
Risk of suicide, Columbia-type analysis, and SAEs
Open-label period: using the Columbia-type analysis, two patients (0.2%) were classified as having suicidal behavior/ideation [one (0.1%) was classified as having suicidal behavior, one (0.1%) was classified as having suicidal ideation], and five (0.4%) were classified as having possible suicidal behavior/ideation. AEs potentially related to suicidality were also recorded; one patient had an SAE of attempted suicide during the open-label period 53 days after the start of treatment, and one patient experienced suicidal ideation 27 days after the start of treatment. Neither event was considered to be treatment related.
Randomized period: the overall incidence of suicidal behavior/ideation as assessed by Columbia-type analysis was low and similar in the quetiapine XR and placebo groups. One (0.5%) quetiapine XR-treated patient was classified as having suicidal behavior, no patients were classified as having suicidal ideation, and three (1.4%) placebo-treated patients and two (0.9%) quetiapine-XR-treated patients were classified as having possible suicidal behavior/ideation. One patient in the quetiapine XR treatment group displayed suicidal behavior and discontinued during the randomized period. This event was considered an SAE, occurred 68 days after randomization, and was not considered to be treatment related.
Treatment with quetiapine XR decreased depressive symptoms as shown by a mean change from baseline in MADRS total score of −7.1 during the open-label period. Furthermore, quetiapine XR was shown to have a greater effect than placebo (P<0.001) in control of depressive symptoms as demonstrated by a mean change from randomization to last visit before an anxiety event (or the last visit for those patients who did not experience an anxiety event) in MADRS total score of 0.7 and 5.6 in the quetiapine XR and placebo treatment groups, respectively.
Weight, vital signs, and laboratory findings
Open-label period: the incidence of patients with a weight increase of ≥7% was 8.8%. A mean weight gain of 1.4 kg was observed (Table 7).
The incidence of patients moving from ≤2 metabolic risk factors to ≥3 metabolic risk factors was 9.5%. Metabolic risk factors were: waist circumference (men >102 cm, women >88 cm, or body mass index ≥30 kg/m2 if waist was not measured), supine blood pressure [≥130 mmHg (systolic) or ≥85 mmHg (diastolic)], triglycerides (≥150 mg/dl), high-density lipoprotein (HDL)-cholesterol (men <40 mg/dl, women <50 mg/dl) and fasting glucose (≥100 mg/dl).
A small mean increase in supine pulse rate and mean decrease in systolic blood pressure were observed and there were no clinically relevant changes in ECG data (Table 7).
There was an increase in insulin levels (1.8 μIU/ml) during the open-label period; however, interpretation of these results was obscured by the large standard deviations in plasma concentrations (Table 7). Mean changes in glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, HDL-cholesterol, triglyceride, and prolactin levels are shown in Table 7.
Randomized period: patients in the quetiapine XR group showed a mean decrease in weight of −0.4 kg (Table 7), with mean changes in weight greater for females compared with males. The incidence of weight increases or decreases of ≥7% was similar for patients in the quetiapine XR group (1.46 and 5.83%, respectively) compared with the placebo group (1.49 and 5.97%, respectively). The mean change from open-label baseline to the end of the randomized period was 0.9 kg in the placebo group and 1.3 kg in the quetiapine XR group. No consistent pattern of weight increase or decrease ≥7% by baseline body mass index category was observed.
The incidence of patients moving from ≤2 metabolic risk factors to ≥3 metabolic risk factors during randomized treatment was higher for the quetiapine XR group (17.4%) compared with the placebo group (7.9%). The incidence of patients with a shift from less than three metabolic risk factors was consistent with the known safety profile for quetiapine (Table 7). No clinically significant mean changes in supine vital signs or ECG data were observed (Table 7).
There were no mean changes judged to be clinically meaningful in hematology, hepatic clinical chemistry, or electrolyte levels during the randomized period. Changes in glucose regulation data were small and similar in both the quetiapine XR and placebo treatment groups (Table 7). A higher proportion of patients in the quetiapine XR group had shifts to clinically important values for elevated total cholesterol, LDL-cholesterol, and triglycerides, and reduced HDL-cholesterol compared with the placebo group (Table 7). Changes in prolactin levels were small, with a decrease in the placebo group (−0.67 ng/ml) and an increase in the quetiapine XR group (0.69 ng/ml).
This is the first large-scale study to examine the efficacy and tolerability of quetiapine XR, or any atypical antipsychotic, in the long-term (>12 weeks) maintenance monotherapy treatment for patients with stabilized GAD.
Once-daily quetiapine XR monotherapy significantly reduced the risk of relapse of anxiety symptoms in patients with GAD compared with placebo, as shown by the time to recurrence of anxiety symptoms. Although the long-term efficacy of several traditional GAD treatments (escitalopram, duloxetine, pregabalin, and paroxetine) to prevent relapse has been demonstrated in placebo-controlled trials (Stocchi et al., 2003; Allgulander et al., 2006; Davidson et al., 2008; Feltner et al., 2008), data supporting the use of atypical antipsychotics in the treatment of GAD are limited to small augmentation trials showing efficacy in terms of improvement of HAM-A total score for risperidone (Brawman-Mintzer et al., 2005; Simon et al., 2006), quetiapine (Katzman et al., 2008), and olanzapine (Pollack et al., 2006), and reduction in CGI-S score by olanzapine (Pollack et al., 2006) and aripiprazole (Hoge et al., 2008). Therefore, the finding that quetiapine XR is effective in reducing the risk of recurrence of anxiety symptoms is important when placed in the context of the chronic and fluctuating nature of the illness (Yonkers et al., 1996; Wittchen et al., 2000), and the high levels of relapse (Andrews et al., 2000).
The maintenance of improvement in anxiety symptoms during the randomized period was also shown by improvements in HAM-A total score and HAM-A somatic and psychic cluster scores. Recent research has shown a potential causal link between GAD and the subsequent development of MDD and other depressive disorders (Bittner et al., 2004; Flannery-Schroeder, 2006), suggesting that the management of anxiety symptoms in patients with GAD may help to prevent the development of depressive episodes (Flannery-Schroeder, 2006). This is a potentially important implication given the high levels of comorbid depression associated with GAD, and the negative impact of depressive symptoms on the course of the illness and long-term prognosis (Pollack, 2005; DeVane et al., 2005). The initial stabilization (open-label) treatment with quetiapine XR decreased depressive symptoms. Moreover, quetiapine XR was shown to be more effective than placebo in maintaining control of depressive symptoms during the randomized period as shown by the changes in MADRS total score. However, because of the exclusion of patients with comorbid depression, which is standard procedure in clinical trials of anxiety disorders, the patient population in this study may not be truly representative of the vast majority of patients with GAD in clinical practice since the prevalence of comorbid MDD is approximately 60% (Carter et al., 2001).
Fatigue and impaired sleep cycle are two of the symptoms commonly associated with GAD, and patients are far more likely to seek treatment for vague somatic illness, pain, and sleep disturbance than for anxiety (Wittchen et al., 2002). It is therefore noteworthy that quetiapine XR was significantly more effective than placebo in maintaining quality of sleep, as shown by changes in PSQI scores. Patients with GAD also experience a significantly reduced quality of life that is comparable with patients with MDD and associated with a considerable human and economic burden (Hoffman et al., 2008). There is provisional evidence that the effective treatment of anxiety symptoms may translate into improvements in quality of life (Hoffman et al., 2008). In this study, quetiapine XR was significantly better at maintaining quality of life improvements than placebo during randomized treatment, as shown by change in Q-LES-Q and SDS scores.
Quetiapine XR was generally well tolerated with a safety profile consistent with that seen earlier in other studies with quetiapine and its known pharmacological profile (Arvanitis et al., 1997; Timdahl et al., 2007). The most common AEs associated with quetiapine XR during stabilization (open-label) treatment were dry mouth, sedation, and somnolence, with sedation and somnolence being the most common cause for discontinuation due to AEs. There was a shift in pattern during randomized treatment, with headache, nasopharyngitis, nausea, and insomnia reported as the most common AEs associated with quetiapine XR; insomnia was the most common cause for discontinuation because of AEs.
Although the exposure to treatment was considerably greater in the quetiapine XR group compared with the placebo group, the incidence of treatment-emergent AEs during randomized treatment was comparable between the groups. Moreover, the incidence of nausea and sexual dysfunction, commonly associated with SSRIs and SNRIs (Kennedy et al., 2001), was lower in quetiapine XR-treated patients than placebo-treated patients and did not result in any discontinuations during the randomized treatment period.
The incidence of sedation-related and somnolence-related AEs in patients treated with quetiapine XR were lower during the randomized period than during the open-label period (run-in and stabilization), with the majority occurring in the first week of open-label treatment. A long-term study of venlafaxine in patients with GAD reported a higher incidence of somnolence-related AEs (37%) during the short-term (≤56 days) phase compared with the long-term (>56–196 days) phase (10%) (Gelenberg et al., 2000). In a study of paroxetine for GAD, somnolence was reported to be the most common cause for discontinuation from the study (incidence of 3.7% for 20 mg paroxetine and 1.5% for 40 mg paroxetine) (Rickels et al., 2003). Moreover, the early occurrence of somnolence and sedation during the stabilization (open-label) period of quetiapine XR treatment, and the reduction in the incidence of somnolence in the randomized treatment period, suggests that the effect may be transitory for some patients. It should, however, be noted that 235 patients discontinued the study because of AEs during the open-label period and did not receive randomized treatment.
Although AEs potentially related to EPS were reported, the incidence of akathisia was lower in the quetiapine XR treatment group than the placebo group during the randomized treatment period (quetiapine XR, 0.5%; placebo, 0.9%). Restlessness (quetiapine XR, 1.9%; placebo, 0.0%) and tremor (quetiapine XR, 0.9%; placebo, 0.5%) occurred at a slightly higher frequency in patients treated with quetiapine XR; however, these symptoms can also be explained by conditions such as restless leg syndrome, as well as muscle tension and autonomic hyperarousal attributed to GAD.
There was a modest mean increase in weight during the stabilization (open-label) period, with no discernible difference between the mean decreases in weight seen in both groups during the randomized treatment period. The incidence of patients with a ≥7% change in weight during the stabilization (open-label) period was 8.8%, and was less than 1.5% during randomized treatment with quetiapine XR. These results indicate that weight gain appears to occur early in treatment with quetiapine XR.
Consistent with the findings from short-term studies of quetiapine XR in patients with GAD (Atkinson et al., 2008; Merideth et al., 2008; Bandelow et al., 2010), a mean increase was observed in glucose and triglycerides during the stabilization (open-label) period. In the randomized period, mean increases in glucose were small and similar in the quetiapine XR and placebo groups. Furthermore, there was a subsequently greater mean decrease in triglycerides in the placebo group compared with quetiapine XR during the randomization period. There was also a shift to clinically low values in HDL-cholesterol after randomization in a higher proportion of patients in the quetiapine XR group.
Although some patients may experience greater efficacy with higher doses, the potential for increased weight gain and other AEs seen during the stabilization (open-label) period indicates that patients at increased risk of weight gain or other specific AEs should be identified and monitored throughout treatment.
The limitations of this study must also be noted and include the absence of an active-comparator arm, the failure to adjust statistical analyses for multiplicity, the exclusion of patients with comorbid depression, and the early termination of the study (because of the pre-determined number of anxiety events being reached), which resulted in 200 patients discontinuing before entering the randomized treatment period.
Despite the range of currently available treatments, remission rates for patients with GAD are poor and relapse is common (Andrews et al., 2000). Given that the ability of any drug to maintain remission or prevent relapse can be compromised by a less than favorable tolerability and adherence profile (DeVane et al., 2005), quetiapine XR may be an important treatment option for patients that have an inadequate response to first-line treatment. However, it is worth noting that following abrupt discontinuation of quetiapine XR, some clinical evidence of withdrawal symptoms was detected. During the 2 weeks after randomization, a higher incidence of AEs was observed in the placebo group, in particular nausea, insomnia, and headache, although few were serious or led to discontinuation. A ≥14 days post-randomization period was used before observation of anxiety events to ensure that any changes noted were in fact loss of efficacy/recurrence of anxiety symptoms and not because of withdrawal of active treatment. Furthermore while this time was chosen, it may be that a minor amount of the symptomatic presentation was in some way related to withdrawal, but occurred 2 weeks later.
In summary, the data presented here show that quetiapine XR at doses of 50, 150, and 300 mg/day is more effective than placebo in reducing the risk of recurrence of anxiety symptoms in patients with stable GAD. Moreover, quetiapine XR was effective in maintaining the improvement in anxiety symptoms and was generally well tolerated by the patient population.
The authors thank Catherine Hoare, Ph.D., from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. The following investigators were involved in this study: Lawrence Adler, Diab Almhana, Donald Anderson, Gregory Asnis, Sarah Atkinson, Roy Autry, Michael Banov, Benny Barnhart, Bruce Berg, Brian Bortnick, Olga Brawman-Mintzer, Ronald Brenner, Edward Burdick, Joel Diamond, Nizar El-Khalili, John Heussy, Miguel Flores, Michael Greenbaum, Paul Gross, David Meyer, Valentin Isacescu, William Jeter, Michael Johnson, Zerrin Kayatekin, Gustavo Kinrys, Thomas Marbury, Paul Markovitz, Jorge Porras, Craig McCarthy, Irina Mezhebovsky, Amy Mulroy, John Prater, Alfredo Rivera, Angelo Sambunaris, Veronique Sebastian, Andrew Sedillo, Eric Smith, Phebe Tucker, Amit Vijapura, Robert Buynak, Kettlie Daniels, David Grubb, Margarita Nunez, Haydn Thomas, Reinaldo Verson, Daniel Vine, Ethan Kass, Andrew Goddard, Matthew Menza, Bijan Bastani (USA); Richard Bergeron, Gilbert Dru, Carlos Galarraga-Carrero, Martin Katzman, Roumen Milev, Michael Van Ameringen, Martin Tremblay, Serge Lessard, Pratap Chokka (Canada); Thomas George, Michael Theodoros, Bruce Lawford, Phillip Morris, Peter Farnbach, Jayashri Kulkarni (Australia); Hannu Koponen, Ulla Lepola, Liisa Lahdelma, Markku Timonen, Marko Sorvaniemi, Riitta Riihikangas (Finland); Klaus-Christian Steinwachs, Eugen Schlegel, Heike Benes, Gunther Karlbauer, H.-J. Gertz (Germany); Gábor Feller, Gábor Vincze, Sándor Koffler (Hungary); Kang-Seob Oh, Jin-Pyo Hong, Jeong-Ho Chae, Bum-Hee Yu (South Korea); B Bodalia, J Langan, Christopher Strang, Barry D Silvert, John Calvert, Krishna Korlipara, James Simpson, Alun Cooper, Ravi Pawa, John Robinson (United Kingdom); Konstantin Zhukov, Boris Tsygankov, Mikhail Ivanov, Boris Karvasarskii, Vladimir Vilianov, Valeriy Krasnov, Leonid Bardenshtein, Nataliya Dobrovolskaya (Russia); Ikke Siregar, Ashwin Kandouw, Anak Kusumawardhani (Indonesia); Efren Reyes, Alma Jimenez, Agnes Padilla (The Philippines). This study (Platinum; D1448C00012) was funded by AstraZeneca.
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