Anxiety Disorder
Conditions
Keywords
social anxiety disorder, social phobia, duloxetine, serotonin norepinephrine reuptake inhibitor, SNRI, double blind
Brief summary
The purpose of this study is to examine the safety and efficacy of duloxetine for the treatment of social anxiety disorder.
Detailed description
An expanding body of clinical experience and controlled trials has established the efficacy of serotonin selective reuptake inhibitors (SSRIs) and the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine, for the treatment of social anxiety disorder, with paroxetine, sertraline and venlafaxine extended-release (XR), which are FDA approved for this indication. The newest SNRI, duloxetine, has been shown to be effective at doses of 60mg/day to 120mg/day for anxiety associated with depression, and is anticipated to be a broad spectrum agent for mood and anxiety disorders (Dunner, Goldstein, Mallinckrodt, Lu, & Detke, 2003). However, no data on the efficacy of duloxetine for Social Anxiety Disorder, nor guidance regarding time to response or predictors of response, is yet available. These questions are the focus of this proposal. This is a two phase, 24-week research study in which participants who remain symptomatic at the end of one phase (6 weeks) enter into the next phase. In phase I, all participants receive 60mg/day of duloxetine (Cymbalta) for 6 weeks. Participants who continue to have anxiety symptoms will enter the 18-week Phase II, in which they continue taking 60 mg/day of duloxetine and they will also be randomly assigned (by chance, like a flip of a coin) to receive either an additional 60mg/day of duloxetine or placebo (contains no active medication).
Interventions
DRUGDuloxetine
60 mg duloxetine 1x per day
DRUGPlacebo
60mg placebo 1x per day
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female outpatients \> 18 years of age with a primary psychiatric diagnosis of generalized social anxiety disorder as defined by DSM-IV criteria and an LSAS score \> 50. * Physical examination, electrocardiogram, and laboratory findings without clinically significant abnormalities. * Willingness and ability to comply with the requirements of the study protocol.
Exclusion criteria
* Patient has a history of intolerance or lack of response to a treatment trial of duloxetine at highest tolerated dose (\<120mg/day). * Patients with acute narrow angle glaucoma. * Pregnant women, lactating women, and women of childbearing potential who are not using medically accepted forms of contraception (e.g., IUD, oral contraceptives, barrier devices, condoms and foam, or implanted progesterone rods stabilized for at least 3 months). * Concurrent use of other psychotropic medications. Patients must discontinue regular benzodiazepine or antidepressant therapy at least one week (5 weeks for fluoxetine) prior to baseline. Concomitant beta-blockers are proscribed unless prescribed for a medical indication (e.g., hypertension, at a stable daily dose for \> 1 month). * Patients with a history of failure to satisfactorily respond to \>2 prior adequate treatment trials. * Significant personality dysfunction likely to interfere with study participation. * Serious medical illness or instability for which hospitalization may be likely within the next year. * Seizure disorders with the exception of a history of febrile seizures if they occurred during childhood, were isolated, and did not recur in adulthood. * Concurrent psychotherapy initiated within 2 months of baseline is prohibited. Ongoing psychotherapy of any duration directed specifically toward treatment of the social anxiety disorder is excluded. Prohibited psychotherapy includes cognitive behavioral therapy or psychodynamic therapy that focuses on exploring specific, dynamic causes of the phobic symptomatology and provides skills for their management. General supportive individual, couples, or family therapy greater than 2 months duration is acceptable. * Diagnosis of any of the following mental disorders as defined by the DSM-IV: a lifetime history of schizophrenia or any other psychosis, mental retardation, organic medical disorders or bipolar disorder; eating disorders in the past 6 months; alcohol or substance abuse in the past 3 months or dependence within the past 6 months. * Entry of patients with major depression, dysthymia, panic disorder, generalized anxiety disorder, post-traumatic stress disorder or obsessive-compulsive disorder will be permitted if the social anxiety disorder is judged to be the predominant disorder, in order to increase accrual of a clinically relevant sample. * Patients with significant suicidal ideation (MADRS item 10 score \> 3) or who have enacted suicidal behaviors within 6 months prior to intake will be excluded from study participation and referred for appropriate clinical intervention.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Anxiety Symptoms as Assessed by Liebowitz Social Anxiety Scale | 6 months | The Liebowitz Social Anxiety Scale (LSAS; Liebowitz, 1987) is a 24-item scale that provides separate scores for fear and avoidance in social and performance situations with higher scores representing increased social anxiety. The LSAS contains three total scores: 1) total fear score (0-72), 2) total avoidance score(0-72), 3) and total overall score (0-144). Suggested interpretations: 55-65 Moderate social phobia, 65-80 Marked social phobia, 80-95 Severe social phobia, Greater than 95 - Very severe social phobia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CGI-S | 6 months | The Clinician Global Impression-Severity Scale (CGI-S) is a clinician-rated instrument used to assess global severity of symptoms (Guy, 1976). The CGI ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Baseline collected for Phase 1 at week 0 and for Phase 2 at week 6. |
Countries
United States
Participant flow
Recruitment details
Treatment seeking outpatients aged 18 years and older with a primary diagnosis of Generalized Social Anxiety Disorder (GSAD) were recruited by media advertisement.
Pre-assignment details
Of the 39 participants who completed Phase I of this study, 28 moved on to Phase II. 1 subject was lost to follow up between baseline and week 1.
Participants by arm
| Arm | Count |
|---|---|
| Duloxetine 60mg/Day + Placebo for 18 Weeks(Phase 2) Participants who did not achieve remission at the end of Phase 1 entered Phase 2 and were randomized. 13 received 60mg duloxetine plus placebo for 18 additional weeks. | 13 |
| Duloxetine 120mg/Day for 18 Weeks (Phase 2) Participants who did not achieve remission at the end of Phase 1 entered Phase 2 and were randomized. 15 received 120mg duloxetine for 18 additional weeks. | 15 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Duloxetine 60mg/Day + Placebo for 18 Weeks(Phase 2) | Total | Duloxetine 120mg/Day for 18 Weeks (Phase 2) |
|---|---|---|---|
| Age, Customized Age Baseline | 36.6 Years STANDARD_DEVIATION 14.2 | 36 Years STANDARD_DEVIATION 12.6 | 35.5 Years STANDARD_DEVIATION 11.6 |
| Age of onset, mean age | 9.9 Years STANDARD_DEVIATION 3.3 | 12.0 Years STANDARD_DEVIATION 6.46 | 13.9 Years STANDARD_DEVIATION 8.1 |
| At least one concurrent mood or anxiety disorder Concurrent mood or anxiety disorder | 7 Participants | 8 Participants | 1 Participants |
| At least one concurrent mood or anxiety disorder No concurrent mood or anxiety disorders | 6 Participants | 20 Participants | 14 Participants |
| Clinical Global Impression-Improvement (CGI-I) | 3.25 CGI-I Score STANDARD_DEVIATION 0.97 | 3.31 CGI-I Score STANDARD_DEVIATION 1.09 | 3.36 CGI-I Score STANDARD_DEVIATION 1.22 |
| Clinical Global Impression-Severity (CGI-S) | 5.10 CGI-S Score STANDARD_DEVIATION 0.43 | 5.00 CGI-S Score STANDARD_DEVIATION 0.27 | 4.93 CGI-S Score STANDARD_DEVIATION 0.36 |
| Current comorbidity, Dysthymia Comorbid Dysthymia | 2 Participants | 2 Participants | 0 Participants |
| Current comorbidity, Dysthymia No Comorbid Dysthymia | 11 Participants | 26 Participants | 15 Participants |
| Current comorbidity, Generalized anxiety disorder (GAD) Comorbid GAD | 2 Participants | 2 Participants | 0 Participants |
| Current comorbidity, Generalized anxiety disorder (GAD) No Comorbid GAD | 11 Participants | 26 Participants | 15 Participants |
| Current comorbidity, Major depressive disorder (MDD) Comorbid MDD | 5 Participants | 5 Participants | 0 Participants |
| Current comorbidity, Major depressive disorder (MDD) No Comorbid MDD | 8 Participants | 23 Participants | 15 Participants |
| Current comorbidity, Panic Disorder (PD) Comorbid PD | 1 Participants | 1 Participants | 0 Participants |
| Current comorbidity, Panic Disorder (PD) No Comorbid PD | 12 Participants | 27 Participants | 15 Participants |
| Duration of illness, mean years (SD) | 27.6 Years STANDARD_DEVIATION 17 | 23.7 Years STANDARD_DEVIATION 14.9 | 20.1 Years STANDARD_DEVIATION 12.3 |
| Educational status, college graduate College Graduate | 10 Participants | 17 Participants | 7 Participants |
| Educational status, college graduate Not College Graduate | 3 Participants | 11 Participants | 8 Participants |
| Liebowitz Self-Rated Disability Scale (LSDSR) | 7.58 LSDSR Score STANDARD_DEVIATION 6.43 | 8.79 LSDSR Score STANDARD_DEVIATION 5.83 | 10.0 LSDSR Score STANDARD_DEVIATION 5.41 |
| Liebowitz Social Anxiety Scale (LSAS) | 75.2 LSAS Score STANDARD_DEVIATION 6.9 | 74.6 LSAS Score STANDARD_DEVIATION 4.52 | 74.1 LSAS Score STANDARD_DEVIATION 6.2 |
| Lifetime alcohol or substance abuse or dependence Lifetime Alcohol/substance abuse/dependence | 3 Participants | 6 Participants | 3 Participants |
| Lifetime alcohol or substance abuse or dependence No Lifetime Alcohol/substance abuse/dependence | 10 Participants | 22 Participants | 12 Participants |
| Lifetime depression Lifetime depression | 6 Participants | 10 Participants | 4 Participants |
| Lifetime depression No Lifetime depression | 7 Participants | 18 Participants | 11 Participants |
| Montgomery Asberg Depression Rating Scale (MADRS) | 8.08 MADRS Score STANDARD_DEVIATION 5 | 9.17 MADRS Score STANDARD_DEVIATION 6.6 | 10.3 MADRS Score STANDARD_DEVIATION 7.79 |
| Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) | 49.1 Q-LES-Q Score STANDARD_DEVIATION 8.83 | 47.5 Q-LES-Q Score STANDARD_DEVIATION 9.12 | 46.2 Q-LES-Q Score STANDARD_DEVIATION 9.47 |
| Race/Ethnicity, Customized Alaskan Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 9 Participants | 22 Participants | 13 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Sex/Gender, Customized Female | 7 Participants | 11 Participants | 4 Participants |
| Sex/Gender, Customized Male | 6 Participants | 17 Participants | 11 Participants |
| Sheehan Disability Scale (SDS) | 11.2 SDS Score STANDARD_DEVIATION 6.06 | 12.9 SDS Score STANDARD_DEVIATION 5.71 | 14.1 SDS Score STANDARD_DEVIATION 5.52 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 2 / 15 |
| serious Total, serious adverse events | 2 / 13 | 0 / 15 |
Outcome results
Primary
Anxiety Symptoms as Assessed by Liebowitz Social Anxiety Scale
The Liebowitz Social Anxiety Scale (LSAS; Liebowitz, 1987) is a 24-item scale that provides separate scores for fear and avoidance in social and performance situations with higher scores representing increased social anxiety. The LSAS contains three total scores: 1) total fear score (0-72), 2) total avoidance score(0-72), 3) and total overall score (0-144). Suggested interpretations: 55-65 Moderate social phobia, 65-80 Marked social phobia, 80-95 Severe social phobia, Greater than 95 - Very severe social phobia.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine 60mg/Day + Placebo for 18 Weeks (Phase 2) | Anxiety Symptoms as Assessed by Liebowitz Social Anxiety Scale | 67.9 Scores on a scale | Standard Error 7.6 |
| Duloxetine 120mg/Day for 18 Weeks (Phase 2) | Anxiety Symptoms as Assessed by Liebowitz Social Anxiety Scale | 53.7 Scores on a scale | Standard Error 7.9 |
p-value: <0.132t-test, 2 sided
Secondary
CGI-S
The Clinician Global Impression-Severity Scale (CGI-S) is a clinician-rated instrument used to assess global severity of symptoms (Guy, 1976). The CGI ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Baseline collected for Phase 1 at week 0 and for Phase 2 at week 6.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Duloxetine 60mg/Day + Placebo for 18 Weeks (Phase 2) | CGI-S | 4.42 Scores on a scale | Standard Error 0.48 |
| Duloxetine 120mg/Day for 18 Weeks (Phase 2) | CGI-S | 3.60 Scores on a scale | Standard Error 0.57 |
p-value: <0.292t-test, 2 sided