Anxiety, Anxiety Disorders, Bipolar Disorder, Substance Use Disorders
Conditions
Keywords
Bipolar Disorder, Anxiety, Anxiety Disorders, Substance Use Disorders
Brief summary
The primary objective is to test the hypothesis that Quetiapine XR (Extended Release) monotherapy and adjunctive therapy is effective in the acute treatment of bipolar depression and comorbid generalized anxiety disorder in patients with bipolar disorder with or without a substance use disorder. The secondary aim is to generate an estimate of effect size to power a definitive large-scale, multi-site collaborative R01 and to configure the use of the primary and secondary outcome measures in the definitive large-scale study.
Detailed description
120 subjects aged 18 and up with Diagnostic and Statistical Manual -IV Generalized Anxiety Disorder and Bipolar Disorder type I or II as identified by extensive clinical interview and the Mini-International Neuropsychiatric Interview (MINI) will be enrolled and randomized. Assignment to each arm will be balanced for BP I vs BP II; male vs female; and with vs without SUD. Potential participants will be recruited by means of Institutional Review Board -approved advertising or from the clinical psychiatric infrastructure. This study is a randomized, double-blind, placebo-controlled, 8-week comparison of quetiapine sustained-release monotherapy or adjunctive mood stabilizer therapy vs. placebo in the acute treatment of comorbid generalized anxiety disorder in patients with bipolar disorder with or without a substance use disorder. Subjects will be assessed weekly for mood changes and side effects.
Interventions
DRUGQuetiapine XR
Days 1-2 - 50 mg/day; Days 3-4 - 150mg/day; Day 5-End of Study - 300mg/day
DRUGPlacebo for quetiapine XR
Days 1-2 - 50 mg/day; Days 3-4 - 150mg/day; Day 5-End of Study - 300mg/day
Sponsors
National Alliance for Research on Schizophrenia and Depression
AstraZeneca
University Hospitals Cleveland Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnostic and Statistical Manual-IV diagnosis of bipolar I or II disorder, and currently depressed as confirmed by the MINI-Plus at Screening. * Diagnostic and Statistical Manual-IV diagnosis of lifetime GAD; * Hamilton Depression Rating Scale -17 items total score ≥ 18; * Hamilton Anxiety Rating Scale total score ≥ 18; * Be male or female at least 18 year old and not older than 65.
Exclusion criteria
* Pregnancy or breast feeding. * Severe medical or neurological problems. * Severe personality disorder. * Currently suicidal risk judged by physician. * Known history of intolerance or hypersensitivity to any of the medications involved in the study. * Treatment with quetiapine at any dose in the 6 months prior to randomization. * Known lack of response to quetiapine in a dosage of at least 50 mg for 4 weeks at any time, as judged by the investigator. * Dependence on opiate, phencyclidine (PCP), and/or barbiturate. * Acute mania as determined by a score \> 12 on the Young Mania Rating Scale at baseline. * Concurrent obsessive compulsive disorder. * Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir * Use of any of the following cytochrome P450 inducers in the 14 days preceding enrollment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids * Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation * Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment * Unstable or inadequately treated medical illness (e.g. diabetes, angina pectoris, hypertension) as judged by the investigator * Involvement in the planning and conduct of the study * Previous enrolment or randomisation of treatment in the present study. * Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements * A patient with diabetes mellitus (DM) fulfilling one of the following criteria: a. Unstable DM defined as enrollment glycosylated hemoglobin (HbA1c) .8.5% b. Admitted to hospital for treatment of DM or DM related illness within the past 12 weeks c. Not under physician care for DM d. Physician responsible for patient's DM care has not indicated that the patient's DM is controlled f. Physician responsible for patient's DM care has not approved the patient's participation in the study g. Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks before randomization. For thiazolidinediones (glitazones) this period should not be less than 8 weeks before randomization h. Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a patient with DM meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the 17 Item Hamilton Rating Scale for Depression (HAM-D-17) Score | Week 0 - Week 8 | A score of 0-7 is considered to be normal. Hamilton Rating Scale total score ranges from 0-57 where higher scores are indicative of more depression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (≥ 50% Improvement) on Hamilton Rating Scale for Depression (HAM-D-17) | Week 0 - Week 8 | A score of 0-7 is considered to be normal. Hamilton Rating Scale total score ranges from 0-57 where higher scores are indicative of more depression. |
| Remission Rate (≤ 7) on Hamilton Rating Scale for Depression (HAM-D-17) | Week 0 - Week 8 | A score of 0-7 is considered to be normal. Hamilton Rating Scale total score ranges from 0-57 where higher scores are indicative of more depression. Remission is defined by the number of participants with Hamilton Rating Scale for Depression score equal to or less than 7. |
| Change in Clinical Global Impressions of Improvement or Severity (CGI-I or S) Score | Week 0 - Week 8 | The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment. 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. |
| Change in the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Score | Week 0 - Week 8 | This assessment degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70 with a higher score indicating less enjoyment and satisfaction. |
| Change in Hamilton Rating Scale for Anxiety (HAM-A) | Week 0 - Week 8 | The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety).Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe |
Countries
United States
Participant flow
Pre-assignment details
The study consent 120 subjects. However, 29 subjects were considered screening failures and were not randomized.
Participants by arm
| Arm | Count |
|---|---|
| Quetiapine XR Days 1-2 - 50 mg/day; Days 3-4 - 150mg/day; Day 5-End of Study - 300mg/day | 46 |
| Placebo for Quetiapine XR Days 1-2 - 50 mg/day; Days 3-4 - 150mg/day; Day 5-End of Study - 300mg/day | 45 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 1 |
| Overall Study | Lack of Efficacy | 3 | 7 |
| Overall Study | Lost to Follow-up | 8 | 8 |
| Overall Study | Non-adherence with study procedures | 1 | 4 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Placebo for Quetiapine XR | Quetiapine XR | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 46 Participants | 91 Participants |
| Age, Continuous | 37.4 years STANDARD_DEVIATION 11.3 | 38.0 years STANDARD_DEVIATION 12 | 37.7 years STANDARD_DEVIATION 11.6 |
| Gender Female | 21 Participants | 22 Participants | 43 Participants |
| Gender Male | 24 Participants | 24 Participants | 48 Participants |
| Region of Enrollment United States | 45 participants | 46 participants | 91 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 46 | 37 / 45 |
| serious Total, serious adverse events | 0 / 46 | 0 / 45 |
Outcome results
Primary
Change in the 17 Item Hamilton Rating Scale for Depression (HAM-D-17) Score
A score of 0-7 is considered to be normal. Hamilton Rating Scale total score ranges from 0-57 where higher scores are indicative of more depression.
Time frame: Week 0 - Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine XR | Change in the 17 Item Hamilton Rating Scale for Depression (HAM-D-17) Score | -9.91 units on a scale | Standard Deviation 16.45 |
| Placebo for Quetiapine XR | Change in the 17 Item Hamilton Rating Scale for Depression (HAM-D-17) Score | -7.41 units on a scale | Standard Deviation 8.13 |
Secondary
Change in Clinical Global Impressions of Improvement or Severity (CGI-I or S) Score
The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment. 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time frame: Week 0 - Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine XR | Change in Clinical Global Impressions of Improvement or Severity (CGI-I or S) Score | -1.10 units on a scale | Standard Deviation 1.16 |
| Placebo for Quetiapine XR | Change in Clinical Global Impressions of Improvement or Severity (CGI-I or S) Score | -0.8 units on a scale | Standard Deviation 1.21 |
Secondary
Change in Hamilton Rating Scale for Anxiety (HAM-A)
The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety).Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe
Time frame: Week 0 - Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine XR | Change in Hamilton Rating Scale for Anxiety (HAM-A) | -9.54 units on a scale | Standard Deviation 7.58 |
| Placebo for Quetiapine XR | Change in Hamilton Rating Scale for Anxiety (HAM-A) | -8.25 units on a scale | Standard Deviation 8.7 |
Secondary
Change in the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Score
This assessment degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70 with a higher score indicating less enjoyment and satisfaction.
Time frame: Week 0 - Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Quetiapine XR | Change in the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Score | 0.11 units on a scale | Standard Deviation 0.22 |
| Placebo for Quetiapine XR | Change in the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) Score | -0.06 units on a scale | Standard Deviation 0.52 |
Secondary
Remission Rate (≤ 7) on Hamilton Rating Scale for Depression (HAM-D-17)
A score of 0-7 is considered to be normal. Hamilton Rating Scale total score ranges from 0-57 where higher scores are indicative of more depression. Remission is defined by the number of participants with Hamilton Rating Scale for Depression score equal to or less than 7.
Time frame: Week 0 - Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Quetiapine XR | Remission Rate (≤ 7) on Hamilton Rating Scale for Depression (HAM-D-17) | 6 Participants |
| Placebo for Quetiapine XR | Remission Rate (≤ 7) on Hamilton Rating Scale for Depression (HAM-D-17) | 6 Participants |
Secondary
Response Rate (≥ 50% Improvement) on Hamilton Rating Scale for Depression (HAM-D-17)
A score of 0-7 is considered to be normal. Hamilton Rating Scale total score ranges from 0-57 where higher scores are indicative of more depression.
Time frame: Week 0 - Week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Quetiapine XR | Response Rate (≥ 50% Improvement) on Hamilton Rating Scale for Depression (HAM-D-17) | 12 participants |
| Placebo for Quetiapine XR | Response Rate (≥ 50% Improvement) on Hamilton Rating Scale for Depression (HAM-D-17) | 11 participants |