Anxiety Disorder
Conditions
Keywords
generalized anxiety disorder, pharmacotherapy, treatment refractory, double-blind
Brief summary
The purpose of this study is to examine the safety and efficacy of quetiapine for generalized anxiety disorder patients who remain symptomatic despite treatment with paroxetine CR.
Detailed description
Generalized anxiety disorder (GAD) is a relatively common condition affecting 5% of the population, with a typically chronic course and associated with significant psychosocial impairment and decreased quality of life (Schweizer, 1995). Although a number of therapeutic agents demonstrate some efficacy in the treatment of generalized anxiety disorder, only a minority of anxious patients experience remission with initial treatment. The purpose of this study is to examine the efficacy of one strategy, the addition of quetiapine, for the treatment of patients with GAD who remain refractory despite an adequate treatment trial with a selective serotonin reuptake inhibitor (SSRI). This is an investigator-initiated augmentation study of an already approved drug for a different indication. Quetiapine is a novel antipsychotic agent with potent effects at the serotonergic, as well as dopaminergic receptor, and a more favorable side effect profile than standard neuroleptics, including a low potential to cause extrapyramidal symptoms. This is a two phase, 18-week research study in which participants who remain symptomatic at the end of one phase (10 weeks) enter into the next phase. In phase I, all participants receive paroxetine CR (Paxil CR) for 10 weeks. Participants who continue to have anxiety symptoms will enter the 8-week Phase II, in which they continue taking Paxil CR and they will also be randomly assigned (by chance, like a flip of a coin) to receive quetiapine (Seroquel) or placebo (contains no active medication).
Interventions
DRUGPlacebo
DRUGContinued Paroxetine CR
DRUGQuetiapine
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 72 Years
Healthy volunteers
No
Inclusion criteria
* Male and female outpatients, age 18-72. * Primary diagnosis of generalized anxiety disorder. * Patients on concurrent benzodiazepines will be entered into the trial if they remain symptomatic despite stable doses for at least one month
Exclusion criteria
* Pregnant or lactating women or other women of child bearing potential not using acceptable means of birth control * Patients with a primary diagnosis of major depression, dysthymia, panic disorder or social phobia. * Patients with current or history of bipolar disorder, schizophrenia or other psychotic conditions * Patients with post-traumatic stress disorder or obsessive-compulsive disorder current in the past 6 months. * Patients with a history of alcohol or substance abuse or dependence within the last six months. * Patients with significant unstable medical illness. * Ongoing psychotherapy directed toward the treatment of generalized anxiety disorder. * History of hypersensitivity to paroxetine CR, paroxetine or quetiapine. * History of cataracts. * Concurrent use of psychotropic medications including buspirone and antidepressants. Patients must have discontinued buspirone or antidepressant therapy at least two weeks prior to study entry, and fluoxetine at least four weeks prior, but no patient will be taken off effective medication. * Concomitant use of herbs and dietary supplements with known psychotropic properties, including St John's Wort, Kava, Valerian, Gingko, Ginseng, ephedra and weight loss supplements. Other than such agents with known psychotropic properties, no over the counter medications are exclusionary.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Baseline and Week 18 | Symptoms of generalized anxiety disorder as measured by the Hamilton Anxiety Scale (HAM-A) at week 18/study endpoint. Each item is scored on a scale from 0 (not present) to 4 (severe) with a total score range of 0-56. Changes in HAM-A scores are calculated as the difference between the baseline HAM-A scores and scores at week 18/study endpoint. The 14-item Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1959) was developed to assess anxiety in a clinical population. It is considered a measure of general anxiety across anxiety disorders, in addition to being a gold standard measure for GAD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission (HAM-A ≤ 7) | Week 18 (Study Endpoint) | Remission was measured as a secondary outcome using a score of less than or equal to 7 on the Hamilton Anxiety Scale (HAM-A). |
| Response, Clinical Global Impression of Improvement (CGI-I) | Week 18 (Phase 2 Endpoint) | Response was measured as a secondary outcome using the Clinical Global Impression of Improvement (CGI-I). Response was defined as a score of 1 \[very much improved\] or 2 \[much improved\] at study endpoint. |
| Depressive Symptoms, Montgomery-Asberg Depression Rating Scale (MADRS) | Week 10 (Phase 1 Endpoint) and Week 18 (Phase 2 Endpoint) | Depressive symptoms were measured at a secondary outcome using the Montgomery-Asberg Depression Rating Scale (MADRS). Each item is scored on a scale of 1-6; The total score range is 0-60, with higher scores indicated higher levels of depression severity. |
| The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). | Week 10 (Phase 1 Endpoint) and Week 18 (Phase 2 Endpoint) | The 16-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) is used to assess quality of life changes with treatment. Total scores range from 14-70, with higher levels of satisfaction yielding higher scores. |
Countries
United States
Participant flow
Recruitment details
One hundred and one individuals were recruited through advertisement and clinical referral from February 2004 to June 2007, signed consent, and participated in a screening visit. Fifty-four individuals (53.5%) with GAD met the study entry criteria and initiated paroxetine CR in phase 1 of the trial.
Pre-assignment details
Seven patients did not complete phase 1. Of phase 1 completers, 21 were not randomized. Twenty-two patients were randomized, 11 to quetiapine and 11 to placebo augmentation. \*Note that the data reported throughout the results section are from Phase 2 only.
Participants by arm
| Arm | Count |
|---|---|
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine Individuals randomized to receive Quetiapine started at 25 mg at bedtime for the first week, then flexibly dosed based on response and tolerability to a maximum of 200 mg BID by week 16. | 11 |
| Placebo Augmentation of Continued Paroxetine Individuals received placebo augmentation of continued paroxetine CR at the week 10 dose level. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Unrelated Medical Illness | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Placebo Augmentation of Continued Paroxetine |
|---|---|---|---|
| Age, Continuous At Phase 2 Baseline | 42.2 years STANDARD_DEVIATION 11.7 | 43.8 years STANDARD_DEVIATION 12.5 | 40.5 years STANDARD_DEVIATION 11.2 |
| CGI-S | 3.77 Units on a scale STANDARD_DEVIATION 0.75 | 3.64 Units on a scale STANDARD_DEVIATION 0.67 | 3.91 Units on a scale STANDARD_DEVIATION 0.83 |
| HAM-A | 16.05 units on a scale STANDARD_DEVIATION 4.8 | 16.27 units on a scale STANDARD_DEVIATION 5.04 | 15.82 units on a scale STANDARD_DEVIATION 4.77 |
| MADRS | 11.91 units on a scale STANDARD_DEVIATION 3.66 | 11.45 units on a scale STANDARD_DEVIATION 1.93 | 12.36 units on a scale STANDARD_DEVIATION 4.8 |
| Q-LES-Q | 45.51 units on a scale STANDARD_DEVIATION 9.77 | 45.13 units on a scale STANDARD_DEVIATION 10.6 | 45.89 units on a scale STANDARD_DEVIATION 8.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 10 Participants | 8 Participants |
| Sex/Gender, Customized Phase 2 Baseline Females | 11 participants | 4 participants | 7 participants |
| Sex/Gender, Customized Phase 2 Baseline Males | 11 participants | 7 participants | 4 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 11 | 8 / 11 | 6 / 50 |
| serious Total, serious adverse events | 2 / 11 | 1 / 11 | 0 / 50 |
Outcome results
Primary
Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint.
Symptoms of generalized anxiety disorder as measured by the Hamilton Anxiety Scale (HAM-A) at week 18/study endpoint. Each item is scored on a scale from 0 (not present) to 4 (severe) with a total score range of 0-56. Changes in HAM-A scores are calculated as the difference between the baseline HAM-A scores and scores at week 18/study endpoint. The 14-item Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1959) was developed to assess anxiety in a clinical population. It is considered a measure of general anxiety across anxiety disorders, in addition to being a gold standard measure for GAD.
Time frame: Baseline and Week 18
Population: Twenty-two patients were randomized, 11 to quetiapine and 11 to placebo augmentation, and all had at least one assessment postrandomization and were included in the phase 2 efficacy analyses; of this group, six randomized to quetiapine (54.5%) and ten to placebo (90.1%) completed the trial.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Baseline | 16.27 units on a scale | Standard Deviation 5.04 |
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Week 18 | 13.64 units on a scale | Standard Deviation 8.36 |
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Change | -2.6 units on a scale | Standard Deviation 5.8 |
| Placebo Augmentation of Continued Paroxetine | Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Change | -0.3 units on a scale | Standard Deviation 5.5 |
| Placebo Augmentation of Continued Paroxetine | Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Baseline | 15.82 units on a scale | Standard Deviation 4.77 |
| Placebo Augmentation of Continued Paroxetine | Hamilton Anxiety Scale (HAM-A) Score at Study Endpoint. | Week 18 | 15.55 units on a scale | Standard Deviation 7.97 |
Comparison: In phase 2, comprising randomized double-blind quetiapine augmentation, change scores were examined with two-tailed, two-sample t tests, utilizing scores at phase 2 randomization as baseline. All analyses were intention to treat (ITT) with the last visit carried forward (LVCF) for subjects that did not complete the study.p-value: <0.05t-test, 2 sided
Secondary
Depressive Symptoms, Montgomery-Asberg Depression Rating Scale (MADRS)
Depressive symptoms were measured at a secondary outcome using the Montgomery-Asberg Depression Rating Scale (MADRS). Each item is scored on a scale of 1-6; The total score range is 0-60, with higher scores indicated higher levels of depression severity.
Time frame: Week 10 (Phase 1 Endpoint) and Week 18 (Phase 2 Endpoint)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Depressive Symptoms, Montgomery-Asberg Depression Rating Scale (MADRS) | Baseline (Week 10) | 11.45 units on a scale | Standard Deviation 1.93 |
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Depressive Symptoms, Montgomery-Asberg Depression Rating Scale (MADRS) | Endpoint (Week 18) | 10.27 units on a scale | Standard Deviation 7.3 |
| Placebo Augmentation of Continued Paroxetine | Depressive Symptoms, Montgomery-Asberg Depression Rating Scale (MADRS) | Baseline (Week 10) | 12.36 units on a scale | Standard Deviation 4.8 |
| Placebo Augmentation of Continued Paroxetine | Depressive Symptoms, Montgomery-Asberg Depression Rating Scale (MADRS) | Endpoint (Week 18) | 11.64 units on a scale | Standard Deviation 5.92 |
Secondary
Remission (HAM-A ≤ 7)
Remission was measured as a secondary outcome using a score of less than or equal to 7 on the Hamilton Anxiety Scale (HAM-A).
Time frame: Week 18 (Study Endpoint)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Remission (HAM-A ≤ 7) | 4 participants |
| Placebo Augmentation of Continued Paroxetine | Remission (HAM-A ≤ 7) | 2 participants |
Secondary
Response, Clinical Global Impression of Improvement (CGI-I)
Response was measured as a secondary outcome using the Clinical Global Impression of Improvement (CGI-I). Response was defined as a score of 1 \[very much improved\] or 2 \[much improved\] at study endpoint.
Time frame: Week 18 (Phase 2 Endpoint)
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | Response, Clinical Global Impression of Improvement (CGI-I) | 6 participants | 0.8 |
| Placebo Augmentation of Continued Paroxetine | Response, Clinical Global Impression of Improvement (CGI-I) | 5 participants | 0.8 |
Secondary
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q).
The 16-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) is used to assess quality of life changes with treatment. Total scores range from 14-70, with higher levels of satisfaction yielding higher scores.
Time frame: Week 10 (Phase 1 Endpoint) and Week 18 (Phase 2 Endpoint)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). | Baseline (Week 10) | 45.13 units on a scale | Standard Deviation 10.64 |
| Quetiapine, 25-400mg/Day Augmentation of Continued Paroxetine | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). | Endpoint (Week 18) | 46.25 units on a scale | Standard Deviation 9.45 |
| Placebo Augmentation of Continued Paroxetine | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). | Baseline (Week 10) | 45.89 units on a scale | Standard Deviation 8.88 |
| Placebo Augmentation of Continued Paroxetine | The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). | Endpoint (Week 18) | 45.11 units on a scale | Standard Deviation 10.55 |