Generalized Anxiety Disorder
Conditions
Keywords
Anxiety disorders, Generalized anxiety
Brief summary
The purpose of this study is to find out how an anti-anxiety drug or placebo affects the activity of your brain when you are at rest and when you are viewing emotional material, such as, emotional faces and pictures.
Detailed description
This is an exploratory study to evaluate the usefulness of fMRI as a biomarker to measure the response to a known, FDA approved marketed anxiolytic. As such, this is not a study testing safety and efficacy of an approved medicine; it is a study to evaluate the usefulness of fMRI (a non-significant risk device procedure) to correlate the clinical/behavioral effects of a marketed anxiolytic with brain activity assessed by magnetic resonance imaging. fMRI is a more direct measure of brain function than behavior, outcomes are quantitative and objective. As such, it may be more specific, i.e., may be more sensitive to drug effects or show them earlier than clinical endpoints and enable determination of efficacy in smaller or shorter studies than those required to show effects on clinical endpoints. Finally, imaging may allow differentiation of placebo responders from true drug responders.
Interventions
Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks).
DRUGPlacebo
Placebo, bid, p.o. for 28 +/- 2 days.
Sponsors
Hoffmann-La Roche
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female between 18 - 65 years of age, inclusive 2. In good general health (as determined by medical history, physical examination, laboratory assessments and electrocardiogram (ECG)), especially no findings (including concomitant medications) that would constitute contraindications for treatment with alprazolam 3. Diagnostic and Statistical Manual-IV criteria for Generalized Anxiety Disorder (GAD) (exception: at least 3 months of symptoms) 4. Hamilton Anxiety Scale at screening \>/= 20 5. Montgomery-Asberg Depression Rating Scale (MADRS) at screening \< 25 6. Prior medications washout: * 2-week medication washout prior to randomization for most psychotropic medications * If prior history of fluoxetine use, this drug must have been discontinued at least 5 weeks before randomization 7. For females of non-childbearing potential: either postmenopausal for the past year (confirmed by an follicle stimulating hormone level greater than 40 mIU/mL unless the subject is receiving hormone replacement therapy), or surgically sterile (e.g., tubal ligation, hysterectomy) 8. Males and female subjects of child-bearing potential may be included if using appropriate contraceptive methods: * must use abstinence or two methods of contraception throughout the trial: * should include one primary (e.g., systemic hormonal contraception, vasectomy of the male partner) AND one secondary barrier method (e.g., latex condoms, spermicide) OR * a double barrier method (e.g., latex condom plus spermicide (foam, suppository, gel, cream)) may be used 9. GAD should be the clinically predominant disorder, as judged by the investigator, considering relative severity and impact on functioning
Exclusion criteria
1. Axis I disorder other than stated above with the exception of the following permitted comorbidities: * history of (within past 6 months) or current dysthymia * current (within past 6 months) depressive episode with MADRS at baseline \< 25 * history of major depression as long as no current depressive episode as defined above 2. Drug or alcohol dependence in the past 6 months 3. Positive urine toxicology (drugs of abuse as determined by clinician's assessment of positive urine test) 4. Active suicidal ideation (determined by clinician) 5. For females of childbearing potential: Pregnancy or intent to become pregnant or currently breastfeeding 6. Current use of beta-blockers or stimulants (e.g., Methylphenidate, d-Amphetamine, modafinil, and illicit drugs like cocaine or 3,4-methylenedioxy-N-methylamphetamine \[MDMA\]) 7. Current regular use of antihistamines (except for inhalants which are permitted) 8. Current use of herbal medication for mood or anxiety disorders and unwillingness to discontinue use for the duration of the study 9. Current use of fluoxetine 10. Concomitant psychotropic medications including regular use of sleeping medications (also herbals) * occasional use of sleeping medication, with the exception of benzodiazepines, is permitted as long as it is not taken the evening prior to a visit 11. Past intolerance (including allergic) to, or clear history of non-response to the study medication 12. Current smoker (\> 10 cigarettes/day); habitual caffeine consumption of more than 400 mg/d (approximately 4 cups of coffee or equivalent) 13. Body mass index \> 32.5 kg/m2 14. Contraindication to magnetic resonance imaging based on a standard fMRI screening forms 15. Concurrent participation in an institutional review board (IRB) approved investigational drug trial 16. Any other reason why, per clinician, the patient should not participate in this study (to be included in this assessment are all considerations, warnings, precautions as per current FDA-approved drug label for Xanax®)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | 0,1,28 days | Extent of activation a brain signal when matching emotional face expressions as a percentage of the brain signal when matching geometric designs. The brain signal is the blood oxygen level dependent signal measured by functional magnetic resonance imaging. |
| Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | 0,1,28 days | Extent of activation of a brain signal when anticipating the viewing of an emotional picture as a percentage of brain signal when the viewing of an emotional signal is not anticipated. The brain signal is the blood oxygen level dependent signal as measured by functional magnetic resonance imaging. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Score on the Hamilton Anxiety Scale | 0, 7, 28 days | Measured participant's general anxiety; range 0 - 56; higher scores worse |
| Score on the Penn State Worry Scale | 0, 7, 28 days | Measured participant's extent of worry; range 16 - 80, higher scores worse |
Other
| Measure | Time frame | Description |
|---|---|---|
| Score on Quick Inventory of Depressive Symptomatology | 0, 7, 28 days | Measured the level of a participant's depression; 0 - 48; higher scores worse |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alprazolam Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder.
Alprazolam (Xanax): Drug dose will be fixed across patients: alprazolam 0.5 mg b.i.d escalating to 1.0 mg b.i.d. The treatment duration will be approximately 28 days (4 weeks). | 21 |
| Placebo A placebo comparator will be administered to 12 patients with generalized anxiety disorder
Placebo: Placebo, bid, p.o. for 28 +/- 2 days. | 11 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Alprazolam |
|---|---|---|---|
| Age, Continuous | 36.27 years STANDARD_DEVIATION 14.69 | 37.8 years STANDARD_DEVIATION 14.74 | 38.63 years STANDARD_DEVIATION 14.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 29 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 9 Participants | 29 Participants | 20 Participants |
| Sex: Female, Male Female | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Male | 2 Participants | 12 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 21 | 0 / 11 |
| serious Total, serious adverse events | 0 / 21 | 0 / 11 |
Outcome results
Primary
Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces
Extent of activation a brain signal when matching emotional face expressions as a percentage of the brain signal when matching geometric designs. The brain signal is the blood oxygen level dependent signal measured by functional magnetic resonance imaging.
Time frame: 0,1,28 days
Population: 19 out of 21 participants analyzed due to 2 withdrawing from adverse events.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alprazolam | Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | Day 1 | .0119 Percent signal change in brain acitivity | Standard Deviation 0.105 |
| Alprazolam | Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | Day 28 | .1230 Percent signal change in brain acitivity | Standard Deviation 0.1366 |
| Alprazolam | Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | Day 0 (Baseline) | .1489 Percent signal change in brain acitivity | Standard Deviation 0.1529 |
| Placebo | Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | Day 0 (Baseline) | .1074 Percent signal change in brain acitivity | Standard Deviation 0.1123 |
| Placebo | Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | Day 28 | .1699 Percent signal change in brain acitivity | Standard Deviation 0.1058 |
| Placebo | Signal Change in Brain Activity in the Amygdala When Viewing Emotional Faces | Day 1 | .1404 Percent signal change in brain acitivity | Standard Deviation 0.0987 |
Primary
Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures.
Extent of activation of a brain signal when anticipating the viewing of an emotional picture as a percentage of brain signal when the viewing of an emotional signal is not anticipated. The brain signal is the blood oxygen level dependent signal as measured by functional magnetic resonance imaging.
Time frame: 0,1,28 days
Population: Nineteen of 21 alprazolam participants analyzed to two subjects withdrawing due to adverse events.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alprazolam | Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | Day 0 (Baseline) | .0707 Percent signal change in brain acitivity | Standard Deviation 0.0322 |
| Alprazolam | Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | Day 1 | .0458 Percent signal change in brain acitivity | Standard Deviation 0.0274 |
| Alprazolam | Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | Day 28 | .0596 Percent signal change in brain acitivity | Standard Deviation 0.0426 |
| Placebo | Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | Day 0 (Baseline) | .0724 Percent signal change in brain acitivity | Standard Deviation 0.0522 |
| Placebo | Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | Day 1 | .0645 Percent signal change in brain acitivity | Standard Deviation 0.031 |
| Placebo | Signal Change in Brain Activity in the Insula When Anticipating the Viewing of Emotional Pictures. | Day 28 | .0461 Percent signal change in brain acitivity | Standard Deviation 0.0337 |
Secondary
Score on the Hamilton Anxiety Scale
Measured participant's general anxiety; range 0 - 56; higher scores worse
Time frame: 0, 7, 28 days
Population: Nineteen of 21 participants analyzed due to two participants withdrawing due to adverse events.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alprazolam | Score on the Hamilton Anxiety Scale | Day 0 (Baseline) | 27.79 score on a scale | Standard Deviation 5.99 |
| Alprazolam | Score on the Hamilton Anxiety Scale | Day 7 | 13.58 score on a scale | Standard Deviation 6.94 |
| Alprazolam | Score on the Hamilton Anxiety Scale | Day 28 | 10.85 score on a scale | Standard Deviation 6.01 |
| Placebo | Score on the Hamilton Anxiety Scale | Day 0 (Baseline) | 28.00 score on a scale | Standard Deviation 5.42 |
| Placebo | Score on the Hamilton Anxiety Scale | Day 7 | 22.18 score on a scale | Standard Deviation 6.71 |
| Placebo | Score on the Hamilton Anxiety Scale | Day 28 | 20.18 score on a scale | Standard Deviation 8.74 |
Secondary
Score on the Penn State Worry Scale
Measured participant's extent of worry; range 16 - 80, higher scores worse
Time frame: 0, 7, 28 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alprazolam | Score on the Penn State Worry Scale | Day 0 (Baseline) | 64.74 score on a scale | Standard Deviation 8.31 |
| Alprazolam | Score on the Penn State Worry Scale | Day 7 | 50.26 score on a scale | Standard Deviation 10.57 |
| Alprazolam | Score on the Penn State Worry Scale | Day 28 | 48.11 score on a scale | Standard Deviation 12.28 |
| Placebo | Score on the Penn State Worry Scale | Day 0 (Baseline) | 66.73 score on a scale | Standard Deviation 7.76 |
| Placebo | Score on the Penn State Worry Scale | Day 7 | 62.45 score on a scale | Standard Deviation 7.58 |
| Placebo | Score on the Penn State Worry Scale | Day 28 | 61.36 score on a scale | Standard Deviation 10.33 |
Other Pre-specified
Score on Quick Inventory of Depressive Symptomatology
Measured the level of a participant's depression; 0 - 48; higher scores worse
Time frame: 0, 7, 28 days
Population: Nineteen of 21 participants analyzed due to 2 participants withdrawal due to adverse events.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alprazolam | Score on Quick Inventory of Depressive Symptomatology | Day 0 (Baseline) | 12.42 score on a scale | Standard Deviation 4.9 |
| Alprazolam | Score on Quick Inventory of Depressive Symptomatology | Day 7 | 8.05 score on a scale | Standard Deviation 4.96 |
| Alprazolam | Score on Quick Inventory of Depressive Symptomatology | Day 28 | 6.42 score on a scale | Standard Deviation 3.36 |
| Placebo | Score on Quick Inventory of Depressive Symptomatology | Day 0 (Baseline) | 12.09 score on a scale | Standard Deviation 4.35 |
| Placebo | Score on Quick Inventory of Depressive Symptomatology | Day 7 | 10.09 score on a scale | Standard Deviation 3.83 |
| Placebo | Score on Quick Inventory of Depressive Symptomatology | Day 28 | 9.09 score on a scale | Standard Deviation 3.3 |