A Literature Review of Quetiapine for Generalized Anxiety Disorder Tiffany-Jade M. Kreys,1,* and Stephanie V. Phan2 1
California Northstate University, College of Pharmacy, Elk Grove, California; 2University of Georgia College of Pharmacy, Southwest Georgia Clinical Campus, Albany, Georgia
To evaluate the efficacy and tolerability of quetiapine for the treatment of generalized anxiety disorder (GAD), a literature search of the Medline database was conducted from inception to May 2014. The search was not restricted by language. Keywords used in the search were quetiapine and generalized anxiety disorder or anxiety. All studies assessing the use of quetiapine as monotherapy or adjunct therapy for the primary management of GAD in adults 18–65 years of age were included in this review. The nine studies included in this review were three studies evaluating the use of quetiapine extended release (XR) as monotherapy for acute GAD treatment, one study evaluating quetiapine XR monotherapy for maintenance treatment of GAD, and five studies evaluating quetiapine (2 XR, 3 immediate release) as adjunct therapy for acute GAD treatment. Quetiapine displayed both efficacy and tolerability in all monotherapy trials evaluating its use for acute and long-term treatment of GAD. Despite some limitations to and heterogeneity among the five adjunct therapy studies, three studies showed that quetiapine resulted in statistically significant changes in the Hamilton Anxiety Rating Scale or Clinical Global Impressions-Severity of Illness Scale scores. Although future studies of longer duration with broader inclusion criteria are needed to further evaluate the benefits and risks of quetiapine for GAD, in patients failing to respond to conventional antidepressant therapy, quetiapine may be a potential treatment option. With appropriate monitoring and management of adverse effects, the potential benefits of quetiapine in patients with treatment-refractory GAD may outweigh the risks associated with its use. KEY WORDS quetiapine, Seroquel, generalized anxiety disorder, anxiety. (Pharmacotherapy 2015;35(2):175–188) doi: 10.1002/phar.1529 Generalized anxiety disorder (GAD) is one of the most common anxiety disorders seen by primary care physicians, with an annual and lifetime prevalence in the United States of 3.1% and 5.7% of the general population, respectively.1, 2 GAD is a chronic, recurring illness associated with psychiatric and medical comorbidities that affect both the severity of the disorder and its
No financial assistance was used to assist in the preparation of this manuscript. Neither author has a conflict of interest to disclose. *Address for correspondence: Tiffany-Jade M. Kreys, Assistant Professor, College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
personal and societal burden.3, 4 More than 70% of patients with a reported history of a suicide attempt have had an anxiety disorder.1, 5 According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), 5th edition, GAD is characterized by excessive and difficultto-control anxiety or worry about numerous activities and/or events for at least a 6-month period.6 At least three of the following six symptoms must accompany the anxiety or worry: restlessness, easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbances.6 Treatment goals for GAD focus on ameliorating psychic and somatic symptoms and restoring the patient’s quality of life. Antidepressants, specifically selective serotonin reuptake inhibitors
176
PHARMACOTHERAPY Volume 35, Number 2, 2015
(SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), are conventionally used as first-line therapy for GAD.2 However, due to a latency of effect with SSRIs and SNRIs (i.e., 2– 4 wks), high rates of nonresponse to antidepressants (i.e., 30–40%), and side effects (i.e., sexual dysfunction), additional treatment options are needed.2 Benzodiazepines are an effective treatment of GAD. However, the risk of tolerance, dependence, and adverse effects (e.g., sedation and cognitive and psychomotor impairment) limits their use to short-term (up to 4 wk) treatment of increased anxiety that may occur upon antidepressant initiation.7, 8 Aside from these instances, benzodiazepines are generally reserved for patients with treatment-refractory GAD.7 Thus additional treatments are needed to further manage patients with GAD who do not respond to more conventional treatments. First-generation antipsychotics (FGAs) have been used since the 1970s to manage anxiety disorders. However, because of methodological flaws in clinical studies and concerns about the development of tardive dyskinesia (TD) with long-term use, the use of FGAs in GAD has been curtailed.8 As a result, second-generation antipsychotics (SGAs) such as quetiapine, which are associated with a lower risk of extrapyramidal side effects (EPS) and TD, have been evaluated for the treatment of GAD. The risk of metabolic abnormalities with the SGAs is a concern, specifically because GAD often requires long-term pharmacotherapy. AstraZeneca filed a supplemental new drug application in 2008 for U.S. Food and Drug Administration (FDA) approval of quetiapine extended-release (XR) monotherapy for the treatment of GAD.9 The Psychopharmacologic Drugs Advisory Committee of the FDA met in 2009 to discuss issues with expanding the labeled indications to include GAD.10 The committee was concerned about exposing a larger patient population to the metabolic side effects and risk of TD associated with quetiapine XR.10 In addition, the committee suggested the added indication would expand use among general practitioners who may lack expertise in monitoring motor adverse effects.10 The need for long-term safety data about the metabolic, cardiovascular, and motor side effects, specifically TD, associated with quetiapine use was highlighted.10 The majority voted “yes” when asked if quetiapine XR monotherapy was effective for GAD. However, all voted unanimously that safety data were lacking for quetiapine XR monotherapy of GAD, and the request
for monotherapy for GAD was denied.10 Nevertheless, quetiapine is used off label in clinical practice for the treatment of anxiety disorders.11 Data are available from several short-term studies and one maintenance study that assess the efficacy and safety of quetiapine immediate release (IR) or XR as monotherapy or adjunct treatment to antidepressants for GAD. Quetiapine Pharmacology Although the precise anxiolytic mechanism of action of quetiapine is not known, several mechanisms similar to the tricyclic antidepressants and SNRIs have been proposed. At low doses, quetiapine is a potent antagonist of the a1 receptors responsible for regulating sympathetic nervous system response.12 The active metabolite of quetiapine, N-desalkyl quetiapine or norquetiapine, has moderate affinity for the norepinephrine reuptake transporter (NERT) and is ~100 times more potent at inhibiting the NERT than the parent drug.13 The binding affinity of norquetiapine for the 5-hydroxytryptamine 1A (5-HT1A) receptor is similar to buspirone, which is FDA approved for GAD.14, 15 Thus the anxiolytic effects of quetiapine may be due to norepinephrine reuptake inhibition and/or 5-HT1A partial agonism. Quetiapine and norquetiapine are both antagonists of the dopamine D2, serotonin 5-HT2, histamine H1, a1b-adrenergic, and muscarinic receptors, but they display different binding affinities for each receptor.16 The low risk of EPS and TD associated with the use of quetiapine may be attributed to its high selectivity to 5-HT2 receptors compared with D2 receptors, and its antipsychotic effects mediated through low dopamine receptor occupancy.13 Quetiapine selectively antagonizes dopamine in the mesolimbic system, which treats the positive symptoms of schizophrenia while sparing dopamine receptors in the nigrostriatal pathway, thereby further reducing the risk of EPS and TD.13 The FDA-approved indications, dosing, and pharmacokinetic parameters of quetiapine immediate release (IR) and XR are compared in Table 1.16, 17 Of note, quetiapine XR reaches peak plasma concentrations at 6 hours compared with 1.5 hours with the IR formulation. However, the mean terminal half-lives of both formulations are similar (quetiapine XR: 7 hours; quetiapine IR: 6 hours). Both quetiapine IR and XR, when dosed equivalently (IR: 150 mg twice/day and XR: 300 mg once/ day), display similar bioavailability at steady
QUETIAPINE FOR GENERALIZED ANXIETY DISORDER Kreys et al Table 1. Quetiapine IR and XR Comparison16,
17
Quetiapine IR16
Quetiapine XR17
FDA-approved indications
Schizophrenia Bipolar I disorder, manic episodes Bipolar disorder, depressive episodes
Maximum recommended dose in adult patients by indication
Schizophrenia: 750 mg/day Bipolar I disorder, manic: 800 mg/day Bipolar disorder, depressive: 300 mg/day
Pharmacokinetics Absorption Distribution
Metabolism
Elimination
177
Rapidly absorbed after oral administration Peak plasma concentrations reached in 1.5 hrs 100% bioavailability Widely distributed throughout body with apparent volume of distribution 10 4 L/kg 83% bound to plasma proteins at therapeutic concentrations Extensively metabolized by the liver CYP3A4 is involved in metabolism to active metabolite N-desalkyl quetiapine (norquetiapine) Mean terminal half-life in adults is about 6 hrs with proposed clinical dose range
Schizophrenia Bipolar I disorder, manic or mixed episodes Bipolar disorder, depressive episodes Adjunctive treatment with antidepressants in major depressive disorder Schizophrenia: 800 mg/day Bipolar I disorder, manic or mixed: 800 mg/day (acute monotherapy or adjunctive with lithium or divalproex) Bipolar disorder, depressive: 300 mg/day Major depressive disorder: 300 mg/day (adjunctive with antidepressants) Peak plasma concentrations obtained ~6 hrs following administration
Mean terminal half-life is about 7 hrs for quetiapine and ~12 hrs for norquetiapine
IR = immediate release; XR = extended release.
state.18 The change in formulation has not significantly affected the absorption or elimination of quetiapine.13, 18 Overall, both formulations appear to have similar efficacy and tolerability profiles.18, 19 Data Sources A literature search of the Medline database was conducted from inception to May 2014 to evaluate the efficacy and tolerability of quetiapine for the treatment of GAD as monotherapy or adjunct therapy to antidepressants. The search was not restricted by language. References from retrieved articles were reviewed for relevance and inclusion in the review. All studies assessing the use of quetiapine as monotherapy or adjunct therapy for the primary management of GAD in adults 18–65 years of age were included in this review. Studies were excluded if subjects were not specifically diagnosed with GAD and being treated with quetiapine for GAD. Keywords used in the search were quetiapine and generalized anxiety disorder or anxiety. The nine studies included in this review were three quetiapine XR monotherapy studies for acute GAD treatment, one study of quetiapine XR monotherapy for maintenance
treatment of GAD, and five studies evaluating quetiapine (2 XR, 3 IR) as adjunct therapy for acute GAD treatment. Results from a pooled analysis of the three acute quetiapine XR monotherapy studies were also discussed. Because this analysis pooled data from studies already included in this review, it was not considered a separate study. All studies used the diagnostic criteria for GAD listed in the 4th edition of the DSM; however, the diagnostic criteria did not change between the 4th and 5th editions. Quetiapine for Treatment of Generalized Anxiety Disorder Quetiapine Monotherapy for GAD A total of five studies evaluating the use of quetiapine monotherapy were identified including one case series, three short-term studies, and one maintenance study.20–24 In the case series of 36 patients between 21 and 79 years of age, patients received either risperidone (23 subjects) or quetiapine IR (13 subjects) for GAD with (14 subjects) or without comorbid panic disorder (22 subjects). Twenty-seven patients had comorbid major depressive disorder. Quetiapine IR was initiated at 25 mg once/day at bedtime and
178
PHARMACOTHERAPY Volume 35, Number 2, 2015
titrated to 300 mg/day. The Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HAM-D-17) were used to evaluate symptom improvement. Both agents produced significant differences in baseline HAM-A and HAM-D scores at end point. The mean (standard deviation [SD]) final daily dose of quetiapine was 105.8 (93.1) mg/day. Of the 13 patients taking quetiapine, 10 (77%) were responders, defined as a 50% or more improvement in the HAM-A score. One limitation of this case series is that the results were not differentiated for patients with GAD alone versus those with comorbid panic disorder. In addition, the duration of treatment and time of evaluation was not reported, and specific improvements in psychic and somatic scores and adverse effects were not reported.20 Because of these limitations, results from this case series were omitted when evaluating the appropriateness of quetiapine for GAD. Three 10-week phase III multicenter, randomized, parallel-group, double-blind, placebo-controlled studies evaluated the efficacy and safety of quetiapine for acute treatment of GAD in adults 18–65 years of age.21–23 The studies consisted of an 8-week active treatment phase followed by a 2-week discontinuation phase. Two of the three studies included active controls for assay sensitivity (paroxetine 20 mg/day, escitalopram 10 mg/day); however, these studies were not powered to directly compare quetiapine with the active control.21, 23 Inclusion criteria were similar across studies. Concomitant psychotropic medications were not permitted during the study period with the exception of sleep agents (zolpidem, chloral hydrate, zaleplon, zopiclone), which were permitted twice/week up to week 2 for insomnia. In two of the three studies, psychotherapy was permitted if patients had been receiving it for a minimum of 3 months before randomization.21, 22 The primary efficacy measure was the mean change in the HAM-A total score from randomization to week 8. Each study based sample size calculations on an expected difference of 2.75 points in the HAM-A total score at week 8 between active treatment and placebo and assumed an SD of 7.5 points. In addition, the studies were designed to provide 90% power to demonstrate that study treatments were different from placebo. Table 2 lists the study design and interventions. Primary and secondary outcome measures, specifically response and remission rates, are listed in Table 3 for the monotherapy trials.
One study reported that the mean change in HAM-A total score from randomization to week 8 was statistically significant for all treatment groups (quetiapine XR 50 mg/day, quetiapine XR 150 mg/day, paroxetine 20 mg/day) compared with placebo. A statistically significant difference in HAM-A total score at day 4 was observed with both quetiapine groups; however, paroxetine did not separate from placebo until week 2 of the treatment. The authors concluded that quetiapine XR 50 and 150 mg/day were effective as monotherapy for the treatment of outpatients with GAD. In addition, quetiapine XR appeared to display similar efficacy to paroxetine based on outcome measures, although this study was not designed to directly compare quetiapine with paroxetine. Although it was not specified which psychic or somatic symptoms improved, a post hoc analysis was conducted to assess differences in HAM-A total scores between quetiapine XR-treated patients with and without somnolence. The mean change in HAM-A score was similar in both groups, suggesting that an improvement in the HAM-A score was not simply due to an increase in sedation.21 In another study, a significant reduction in mean HAM-A total scores from baseline to week 8 was observed with quetiapine XR 50 and 150 mg/day group compared with placebo; however, no statistically significant difference in mean HAM-A total scores was observed at week 8 with quetiapine XR 300 mg/day compared with placebo (Table 3). The authors concluded that quetiapine XR 50 mg/day and 150 mg/day were an effective and generally well-tolerated treatment for GAD.22 One study reported that a significant reduction in mean HAM-A total scores at week 8 occurred in the quetiapine XR 150 and 300 mg/ day groups and in the escitalopram group compared with placebo (Table 3). A significant reduction in mean HAM-A total scores was observed at day 4 in both quetiapine groups; however, it should be noted that patients in the quetiapine 300 mg/day arm were still receiving 150 mg/day on day 4. No significant differences in the escitalopram or placebo groups occurred at day 4. The authors concluded that quetiapine XR at doses of 150 and 300 mg/day was effective for the acute treatment of GAD.23 The three quetiapine XR monotherapy trials have similar limitations.21–23 Each trial evaluated fixed doses of quetiapine, which is not representative of actual clinical practice. Thus patients may have received doses that were higher or
QUETIAPINE FOR GENERALIZED ANXIETY DISORDER Kreys et al
179
Table 2. Selected Methodology of Quetiapine IR and XR Monotherapy and Adjunct Therapy Trials Study design
Interventions
Base therapy
Quetiapine monotherapy 10-wk multicenter, double-blind, parallel-group, placebo-and active (paroxetine)-controlled study of outpatients (N=873; 473 completed study)21
Quetiapine XR 50 mg once/day Quetiapine XR 150 mg once/day Paroxetine 20 mg once/day Placebo
NA
10-wk multicenter, randomized, double-blind, placebo-controlled, phase III study of outpatients (N=951; 468 completed study)22
Quetiapine XR 50 mg once/day Quetiapine XR 150 mg once/day Quetiapine XR 300 mg once/day Placebo
NA
10-wk multicenter, randomized, parallel group, double-blind, double-dummy, placebo-controlled and active-controlled (escitalopram) study (N=854; 478 completed study)23
Quetiapine XR 150 mg once/day Quetiapine XR 300 mg once/day Escitalopram 10 mg once/day Placebo
NA
Up to 52 wk multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study (N=432)25 Quetiapine adjunct therapy 12-wk open-label flexible-dose study (N=40; 32 completed study)25
Quetiapine XR up to 300 mg/day
NA
Quetiapine IR dosed 25 mg up to 800 mg once/day (mean dose: 386 mg/day) Quetiapine XR up to the maximum tolerable dose once/day at bedtime (mean dose: 150 mg/day) Phase I: paroxetine 12.5 mg/day flexibly titrated to max of 62.5 mg/day by week 8 Phase II: Quetiapine 25 mg at bedtime flexibly titrated to 200 mg twice/day by week 16 (mean dose: 120.5 mg/day)
Traditional anxiolytic
8-wk randomized placebo-controlled trial (N=20)28
Quetiapine IR 25 mg up to 150 mg/day (mean dose: 50 mg/day)
SSRI
Palladium study: 11-wk multicenter placebo-controlled study of patients with a partial or no response to 8-wk treatment with SSRI or SNRI (N=409; 320 completed study)29
Quetiapine XR 150 mg once/day (could be titrated to 300 mg/day if needed at week 3 or 4) (mean dose: 174.3 mg/day) Placebo
SSRI or SNRI BDZ
12-wk open-label study (N=23 completed study)26 2-phase 18-wk prospective treatment trial of outpatients Phase 1: 10 wks of open-labeled paroxetine Phase 2: nonresponders in phase 1 randomized 1:1 to 8 wks quetiapine or placebo augmentation (phase 1: N=54, 43 completed; phase 2: N=22, 16 completed)27
SSRI or SNRI Paroxetine CR
BDZ = benzodiazepine; CR = controlled release; IR = immediate release; NA = not applicable; SD = standard deviation; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; XR = extended release;
lower than needed. Also, in one trial the onset of somnolence and sedation occurred during the first 7 days of treatment, which may have presented a potential unblinding bias, resulting in the interpretation of enhanced efficacy for quetiapine.23 Each study excluded patients with other psychiatric comorbidities, including depression, which may limit generalizability to the clinical setting because patients with GAD often have other psychiatric comorbidities. Also, in the two studies using an active antidepressant treatment arm, the antidepressant was administered at a
low fixed dose (escitalopram 10 mg/day, paroxetine 20 mg/day).21, 23 Thus the true efficacy and tolerability of the antidepressant arm may not have been fully realized. In addition, the 8-week study durations may have been insufficient to reveal additional benefits associated with longterm treatment and did not permit the evaluation of sustained efficacy and tolerability with longterm quetiapine use. Psychotherapy was permitted in two of the three trials.21, 22 A multicenter, parallel-group, double-blind extension study was conducted of 432 patients
180
PHARMACOTHERAPY Volume 35, Number 2, 2015
Table 3. Primary and Secondary Outcomes of Quetiapine Monotherapy Trials at End Point Intervention
Quetiapine XR 50 mg/day Quetiapine XR 150 mg/day Paroxetine 20 mg/day Placebo21 Quetiapine XR 50 mg/day Quetiapine XR 150 mg/day Quetiapine XR 300 mg/day Placebo22 Quetiapine XR 150 mg/day Quetiapine XR 300 mg/day Escitalopram 10 mg/day Placebo23 maintenance quetiapine trial
Primary outcome measure LSM change in HAM-A total score (95% CI) 13.95 ( 3.12, 0.18) p
California Northstate University, College of Pharmacy, Elk Grove, California; 2University of Georgia College of Pharmacy, Southwest Georgia Clinical Campus, Albany, Georgia
To evaluate the efficacy and tolerability of quetiapine for the treatment of generalized anxiety disorder (GAD), a literature search of the Medline database was conducted from inception to May 2014. The search was not restricted by language. Keywords used in the search were quetiapine and generalized anxiety disorder or anxiety. All studies assessing the use of quetiapine as monotherapy or adjunct therapy for the primary management of GAD in adults 18–65 years of age were included in this review. The nine studies included in this review were three studies evaluating the use of quetiapine extended release (XR) as monotherapy for acute GAD treatment, one study evaluating quetiapine XR monotherapy for maintenance treatment of GAD, and five studies evaluating quetiapine (2 XR, 3 immediate release) as adjunct therapy for acute GAD treatment. Quetiapine displayed both efficacy and tolerability in all monotherapy trials evaluating its use for acute and long-term treatment of GAD. Despite some limitations to and heterogeneity among the five adjunct therapy studies, three studies showed that quetiapine resulted in statistically significant changes in the Hamilton Anxiety Rating Scale or Clinical Global Impressions-Severity of Illness Scale scores. Although future studies of longer duration with broader inclusion criteria are needed to further evaluate the benefits and risks of quetiapine for GAD, in patients failing to respond to conventional antidepressant therapy, quetiapine may be a potential treatment option. With appropriate monitoring and management of adverse effects, the potential benefits of quetiapine in patients with treatment-refractory GAD may outweigh the risks associated with its use. KEY WORDS quetiapine, Seroquel, generalized anxiety disorder, anxiety. (Pharmacotherapy 2015;35(2):175–188) doi: 10.1002/phar.1529 Generalized anxiety disorder (GAD) is one of the most common anxiety disorders seen by primary care physicians, with an annual and lifetime prevalence in the United States of 3.1% and 5.7% of the general population, respectively.1, 2 GAD is a chronic, recurring illness associated with psychiatric and medical comorbidities that affect both the severity of the disorder and its
No financial assistance was used to assist in the preparation of this manuscript. Neither author has a conflict of interest to disclose. *Address for correspondence: Tiffany-Jade M. Kreys, Assistant Professor, College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA 95757; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
personal and societal burden.3, 4 More than 70% of patients with a reported history of a suicide attempt have had an anxiety disorder.1, 5 According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), 5th edition, GAD is characterized by excessive and difficultto-control anxiety or worry about numerous activities and/or events for at least a 6-month period.6 At least three of the following six symptoms must accompany the anxiety or worry: restlessness, easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbances.6 Treatment goals for GAD focus on ameliorating psychic and somatic symptoms and restoring the patient’s quality of life. Antidepressants, specifically selective serotonin reuptake inhibitors
176
PHARMACOTHERAPY Volume 35, Number 2, 2015
(SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), are conventionally used as first-line therapy for GAD.2 However, due to a latency of effect with SSRIs and SNRIs (i.e., 2– 4 wks), high rates of nonresponse to antidepressants (i.e., 30–40%), and side effects (i.e., sexual dysfunction), additional treatment options are needed.2 Benzodiazepines are an effective treatment of GAD. However, the risk of tolerance, dependence, and adverse effects (e.g., sedation and cognitive and psychomotor impairment) limits their use to short-term (up to 4 wk) treatment of increased anxiety that may occur upon antidepressant initiation.7, 8 Aside from these instances, benzodiazepines are generally reserved for patients with treatment-refractory GAD.7 Thus additional treatments are needed to further manage patients with GAD who do not respond to more conventional treatments. First-generation antipsychotics (FGAs) have been used since the 1970s to manage anxiety disorders. However, because of methodological flaws in clinical studies and concerns about the development of tardive dyskinesia (TD) with long-term use, the use of FGAs in GAD has been curtailed.8 As a result, second-generation antipsychotics (SGAs) such as quetiapine, which are associated with a lower risk of extrapyramidal side effects (EPS) and TD, have been evaluated for the treatment of GAD. The risk of metabolic abnormalities with the SGAs is a concern, specifically because GAD often requires long-term pharmacotherapy. AstraZeneca filed a supplemental new drug application in 2008 for U.S. Food and Drug Administration (FDA) approval of quetiapine extended-release (XR) monotherapy for the treatment of GAD.9 The Psychopharmacologic Drugs Advisory Committee of the FDA met in 2009 to discuss issues with expanding the labeled indications to include GAD.10 The committee was concerned about exposing a larger patient population to the metabolic side effects and risk of TD associated with quetiapine XR.10 In addition, the committee suggested the added indication would expand use among general practitioners who may lack expertise in monitoring motor adverse effects.10 The need for long-term safety data about the metabolic, cardiovascular, and motor side effects, specifically TD, associated with quetiapine use was highlighted.10 The majority voted “yes” when asked if quetiapine XR monotherapy was effective for GAD. However, all voted unanimously that safety data were lacking for quetiapine XR monotherapy of GAD, and the request
for monotherapy for GAD was denied.10 Nevertheless, quetiapine is used off label in clinical practice for the treatment of anxiety disorders.11 Data are available from several short-term studies and one maintenance study that assess the efficacy and safety of quetiapine immediate release (IR) or XR as monotherapy or adjunct treatment to antidepressants for GAD. Quetiapine Pharmacology Although the precise anxiolytic mechanism of action of quetiapine is not known, several mechanisms similar to the tricyclic antidepressants and SNRIs have been proposed. At low doses, quetiapine is a potent antagonist of the a1 receptors responsible for regulating sympathetic nervous system response.12 The active metabolite of quetiapine, N-desalkyl quetiapine or norquetiapine, has moderate affinity for the norepinephrine reuptake transporter (NERT) and is ~100 times more potent at inhibiting the NERT than the parent drug.13 The binding affinity of norquetiapine for the 5-hydroxytryptamine 1A (5-HT1A) receptor is similar to buspirone, which is FDA approved for GAD.14, 15 Thus the anxiolytic effects of quetiapine may be due to norepinephrine reuptake inhibition and/or 5-HT1A partial agonism. Quetiapine and norquetiapine are both antagonists of the dopamine D2, serotonin 5-HT2, histamine H1, a1b-adrenergic, and muscarinic receptors, but they display different binding affinities for each receptor.16 The low risk of EPS and TD associated with the use of quetiapine may be attributed to its high selectivity to 5-HT2 receptors compared with D2 receptors, and its antipsychotic effects mediated through low dopamine receptor occupancy.13 Quetiapine selectively antagonizes dopamine in the mesolimbic system, which treats the positive symptoms of schizophrenia while sparing dopamine receptors in the nigrostriatal pathway, thereby further reducing the risk of EPS and TD.13 The FDA-approved indications, dosing, and pharmacokinetic parameters of quetiapine immediate release (IR) and XR are compared in Table 1.16, 17 Of note, quetiapine XR reaches peak plasma concentrations at 6 hours compared with 1.5 hours with the IR formulation. However, the mean terminal half-lives of both formulations are similar (quetiapine XR: 7 hours; quetiapine IR: 6 hours). Both quetiapine IR and XR, when dosed equivalently (IR: 150 mg twice/day and XR: 300 mg once/ day), display similar bioavailability at steady
QUETIAPINE FOR GENERALIZED ANXIETY DISORDER Kreys et al Table 1. Quetiapine IR and XR Comparison16,
17
Quetiapine IR16
Quetiapine XR17
FDA-approved indications
Schizophrenia Bipolar I disorder, manic episodes Bipolar disorder, depressive episodes
Maximum recommended dose in adult patients by indication
Schizophrenia: 750 mg/day Bipolar I disorder, manic: 800 mg/day Bipolar disorder, depressive: 300 mg/day
Pharmacokinetics Absorption Distribution
Metabolism
Elimination
177
Rapidly absorbed after oral administration Peak plasma concentrations reached in 1.5 hrs 100% bioavailability Widely distributed throughout body with apparent volume of distribution 10 4 L/kg 83% bound to plasma proteins at therapeutic concentrations Extensively metabolized by the liver CYP3A4 is involved in metabolism to active metabolite N-desalkyl quetiapine (norquetiapine) Mean terminal half-life in adults is about 6 hrs with proposed clinical dose range
Schizophrenia Bipolar I disorder, manic or mixed episodes Bipolar disorder, depressive episodes Adjunctive treatment with antidepressants in major depressive disorder Schizophrenia: 800 mg/day Bipolar I disorder, manic or mixed: 800 mg/day (acute monotherapy or adjunctive with lithium or divalproex) Bipolar disorder, depressive: 300 mg/day Major depressive disorder: 300 mg/day (adjunctive with antidepressants) Peak plasma concentrations obtained ~6 hrs following administration
Mean terminal half-life is about 7 hrs for quetiapine and ~12 hrs for norquetiapine
IR = immediate release; XR = extended release.
state.18 The change in formulation has not significantly affected the absorption or elimination of quetiapine.13, 18 Overall, both formulations appear to have similar efficacy and tolerability profiles.18, 19 Data Sources A literature search of the Medline database was conducted from inception to May 2014 to evaluate the efficacy and tolerability of quetiapine for the treatment of GAD as monotherapy or adjunct therapy to antidepressants. The search was not restricted by language. References from retrieved articles were reviewed for relevance and inclusion in the review. All studies assessing the use of quetiapine as monotherapy or adjunct therapy for the primary management of GAD in adults 18–65 years of age were included in this review. Studies were excluded if subjects were not specifically diagnosed with GAD and being treated with quetiapine for GAD. Keywords used in the search were quetiapine and generalized anxiety disorder or anxiety. The nine studies included in this review were three quetiapine XR monotherapy studies for acute GAD treatment, one study of quetiapine XR monotherapy for maintenance
treatment of GAD, and five studies evaluating quetiapine (2 XR, 3 IR) as adjunct therapy for acute GAD treatment. Results from a pooled analysis of the three acute quetiapine XR monotherapy studies were also discussed. Because this analysis pooled data from studies already included in this review, it was not considered a separate study. All studies used the diagnostic criteria for GAD listed in the 4th edition of the DSM; however, the diagnostic criteria did not change between the 4th and 5th editions. Quetiapine for Treatment of Generalized Anxiety Disorder Quetiapine Monotherapy for GAD A total of five studies evaluating the use of quetiapine monotherapy were identified including one case series, three short-term studies, and one maintenance study.20–24 In the case series of 36 patients between 21 and 79 years of age, patients received either risperidone (23 subjects) or quetiapine IR (13 subjects) for GAD with (14 subjects) or without comorbid panic disorder (22 subjects). Twenty-seven patients had comorbid major depressive disorder. Quetiapine IR was initiated at 25 mg once/day at bedtime and
178
PHARMACOTHERAPY Volume 35, Number 2, 2015
titrated to 300 mg/day. The Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Rating Scale for Depression (HAM-D-17) were used to evaluate symptom improvement. Both agents produced significant differences in baseline HAM-A and HAM-D scores at end point. The mean (standard deviation [SD]) final daily dose of quetiapine was 105.8 (93.1) mg/day. Of the 13 patients taking quetiapine, 10 (77%) were responders, defined as a 50% or more improvement in the HAM-A score. One limitation of this case series is that the results were not differentiated for patients with GAD alone versus those with comorbid panic disorder. In addition, the duration of treatment and time of evaluation was not reported, and specific improvements in psychic and somatic scores and adverse effects were not reported.20 Because of these limitations, results from this case series were omitted when evaluating the appropriateness of quetiapine for GAD. Three 10-week phase III multicenter, randomized, parallel-group, double-blind, placebo-controlled studies evaluated the efficacy and safety of quetiapine for acute treatment of GAD in adults 18–65 years of age.21–23 The studies consisted of an 8-week active treatment phase followed by a 2-week discontinuation phase. Two of the three studies included active controls for assay sensitivity (paroxetine 20 mg/day, escitalopram 10 mg/day); however, these studies were not powered to directly compare quetiapine with the active control.21, 23 Inclusion criteria were similar across studies. Concomitant psychotropic medications were not permitted during the study period with the exception of sleep agents (zolpidem, chloral hydrate, zaleplon, zopiclone), which were permitted twice/week up to week 2 for insomnia. In two of the three studies, psychotherapy was permitted if patients had been receiving it for a minimum of 3 months before randomization.21, 22 The primary efficacy measure was the mean change in the HAM-A total score from randomization to week 8. Each study based sample size calculations on an expected difference of 2.75 points in the HAM-A total score at week 8 between active treatment and placebo and assumed an SD of 7.5 points. In addition, the studies were designed to provide 90% power to demonstrate that study treatments were different from placebo. Table 2 lists the study design and interventions. Primary and secondary outcome measures, specifically response and remission rates, are listed in Table 3 for the monotherapy trials.
One study reported that the mean change in HAM-A total score from randomization to week 8 was statistically significant for all treatment groups (quetiapine XR 50 mg/day, quetiapine XR 150 mg/day, paroxetine 20 mg/day) compared with placebo. A statistically significant difference in HAM-A total score at day 4 was observed with both quetiapine groups; however, paroxetine did not separate from placebo until week 2 of the treatment. The authors concluded that quetiapine XR 50 and 150 mg/day were effective as monotherapy for the treatment of outpatients with GAD. In addition, quetiapine XR appeared to display similar efficacy to paroxetine based on outcome measures, although this study was not designed to directly compare quetiapine with paroxetine. Although it was not specified which psychic or somatic symptoms improved, a post hoc analysis was conducted to assess differences in HAM-A total scores between quetiapine XR-treated patients with and without somnolence. The mean change in HAM-A score was similar in both groups, suggesting that an improvement in the HAM-A score was not simply due to an increase in sedation.21 In another study, a significant reduction in mean HAM-A total scores from baseline to week 8 was observed with quetiapine XR 50 and 150 mg/day group compared with placebo; however, no statistically significant difference in mean HAM-A total scores was observed at week 8 with quetiapine XR 300 mg/day compared with placebo (Table 3). The authors concluded that quetiapine XR 50 mg/day and 150 mg/day were an effective and generally well-tolerated treatment for GAD.22 One study reported that a significant reduction in mean HAM-A total scores at week 8 occurred in the quetiapine XR 150 and 300 mg/ day groups and in the escitalopram group compared with placebo (Table 3). A significant reduction in mean HAM-A total scores was observed at day 4 in both quetiapine groups; however, it should be noted that patients in the quetiapine 300 mg/day arm were still receiving 150 mg/day on day 4. No significant differences in the escitalopram or placebo groups occurred at day 4. The authors concluded that quetiapine XR at doses of 150 and 300 mg/day was effective for the acute treatment of GAD.23 The three quetiapine XR monotherapy trials have similar limitations.21–23 Each trial evaluated fixed doses of quetiapine, which is not representative of actual clinical practice. Thus patients may have received doses that were higher or
QUETIAPINE FOR GENERALIZED ANXIETY DISORDER Kreys et al
179
Table 2. Selected Methodology of Quetiapine IR and XR Monotherapy and Adjunct Therapy Trials Study design
Interventions
Base therapy
Quetiapine monotherapy 10-wk multicenter, double-blind, parallel-group, placebo-and active (paroxetine)-controlled study of outpatients (N=873; 473 completed study)21
Quetiapine XR 50 mg once/day Quetiapine XR 150 mg once/day Paroxetine 20 mg once/day Placebo
NA
10-wk multicenter, randomized, double-blind, placebo-controlled, phase III study of outpatients (N=951; 468 completed study)22
Quetiapine XR 50 mg once/day Quetiapine XR 150 mg once/day Quetiapine XR 300 mg once/day Placebo
NA
10-wk multicenter, randomized, parallel group, double-blind, double-dummy, placebo-controlled and active-controlled (escitalopram) study (N=854; 478 completed study)23
Quetiapine XR 150 mg once/day Quetiapine XR 300 mg once/day Escitalopram 10 mg once/day Placebo
NA
Up to 52 wk multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study (N=432)25 Quetiapine adjunct therapy 12-wk open-label flexible-dose study (N=40; 32 completed study)25
Quetiapine XR up to 300 mg/day
NA
Quetiapine IR dosed 25 mg up to 800 mg once/day (mean dose: 386 mg/day) Quetiapine XR up to the maximum tolerable dose once/day at bedtime (mean dose: 150 mg/day) Phase I: paroxetine 12.5 mg/day flexibly titrated to max of 62.5 mg/day by week 8 Phase II: Quetiapine 25 mg at bedtime flexibly titrated to 200 mg twice/day by week 16 (mean dose: 120.5 mg/day)
Traditional anxiolytic
8-wk randomized placebo-controlled trial (N=20)28
Quetiapine IR 25 mg up to 150 mg/day (mean dose: 50 mg/day)
SSRI
Palladium study: 11-wk multicenter placebo-controlled study of patients with a partial or no response to 8-wk treatment with SSRI or SNRI (N=409; 320 completed study)29
Quetiapine XR 150 mg once/day (could be titrated to 300 mg/day if needed at week 3 or 4) (mean dose: 174.3 mg/day) Placebo
SSRI or SNRI BDZ
12-wk open-label study (N=23 completed study)26 2-phase 18-wk prospective treatment trial of outpatients Phase 1: 10 wks of open-labeled paroxetine Phase 2: nonresponders in phase 1 randomized 1:1 to 8 wks quetiapine or placebo augmentation (phase 1: N=54, 43 completed; phase 2: N=22, 16 completed)27
SSRI or SNRI Paroxetine CR
BDZ = benzodiazepine; CR = controlled release; IR = immediate release; NA = not applicable; SD = standard deviation; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; XR = extended release;
lower than needed. Also, in one trial the onset of somnolence and sedation occurred during the first 7 days of treatment, which may have presented a potential unblinding bias, resulting in the interpretation of enhanced efficacy for quetiapine.23 Each study excluded patients with other psychiatric comorbidities, including depression, which may limit generalizability to the clinical setting because patients with GAD often have other psychiatric comorbidities. Also, in the two studies using an active antidepressant treatment arm, the antidepressant was administered at a
low fixed dose (escitalopram 10 mg/day, paroxetine 20 mg/day).21, 23 Thus the true efficacy and tolerability of the antidepressant arm may not have been fully realized. In addition, the 8-week study durations may have been insufficient to reveal additional benefits associated with longterm treatment and did not permit the evaluation of sustained efficacy and tolerability with longterm quetiapine use. Psychotherapy was permitted in two of the three trials.21, 22 A multicenter, parallel-group, double-blind extension study was conducted of 432 patients
180
PHARMACOTHERAPY Volume 35, Number 2, 2015
Table 3. Primary and Secondary Outcomes of Quetiapine Monotherapy Trials at End Point Intervention
Quetiapine XR 50 mg/day Quetiapine XR 150 mg/day Paroxetine 20 mg/day Placebo21 Quetiapine XR 50 mg/day Quetiapine XR 150 mg/day Quetiapine XR 300 mg/day Placebo22 Quetiapine XR 150 mg/day Quetiapine XR 300 mg/day Escitalopram 10 mg/day Placebo23 maintenance quetiapine trial
Primary outcome measure LSM change in HAM-A total score (95% CI) 13.95 ( 3.12, 0.18) p
