Combination of Paroxetine CR and Quetiapine for the Treatment of Refractory Generalized Anxiety Disorder

Study Overview
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Brief Summary
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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
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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).

Official Title
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Combination of Paroxetine CR and Quetiapine for the Treatment of Refractory Generalized Anxiety Disorder

Conditions
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Anxiety Disorder

Intervention / Treatment
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* Drug: Continued Paroxetine CR
* Drug: Quetiapine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 72 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Paroxetine CR and Placebo<br>Eleven individuals were randomized to plaecbo augmentation of continued paroxetine CR at the week 10 dose level. In the first phase of the study, individuals started at 12.5 mg/day of paroxetine and flexibly titrated up to a maximum of 62.5 mg/day by week 10. Individuals who did not achieve remission and were randomized into the placebo group received placebo augmentation of continued paroxetine CR at the week 10 dose level. | Drug: Continued Paroxetine CR<br> <br> Drug: Placebo<br> <br> |
| Experimental: Quetiapine and continued paroxetine CR<br>Eleven individuals were randomized to quetiapine augmentation of continued paroxetine CR at the week 10 dose level. In the first phase of the study, individuals started at 12.5 mg/day of paroxetine and flexibly tirated up to a maximum of 62.5 mg/day by week 10. Individuals who did not receive remission and were 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. | Drug: Continued Paroxetine CR<br> <br> Drug: Quetiapine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Week 18 (Study Endpoint) | 
| 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. | Week 18 (Phase 2 Endpoint) | 
| 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. | Week 10 (Phase 1 Endpoint) and Week 18 (Phase 2 Endpoint) | 
| 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. | Week 10 (Phase 1 Endpoint) and Week 18 (Phase 2 Endpoint) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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generalized anxiety disorder, pharmacotherapy, treatment refractory, double-blind