Social Phobia
Conditions
Keywords
Social Anxiety Disorder, Pharmacotherapy, Genetics, Treatment Refractory
Brief summary
This study will compare the effectiveness of either adding clonazepam or placebo to standard treatment or switching to venlafaxine in treating generalized social anxiety disorder in individuals who have not responded to treatment with sertraline.
Detailed description
Generalized social anxiety disorder (GSAD) is one of the most common psychiatric disorders, and often causes significant distress and dysfunction in affected individuals. Although currently available treatments for GSAD are effective, most individuals have residual symptoms after initial psychosocial or psychopharmacologic intervention. Further treatment is necessary for such individuals, but sufficient research has not been done to guide clinicians on what the safest and most effective next step may be. This study will compare the effectiveness of either combining clonazepam or placebo with sertraline or completely switching to venlafaxine in treating GSAD in individuals who have not responded to treatment with sertraline. This study will also examine predictors of treatment response, including factors such as age at disease onset, duration of illness, comorbidities, and genes that influence serotonin and catecholamine metabolism. Participants in this double-blind study will first partake in an initial 10-week phase in which they will be treated with sertraline. Participants who do not respond to sertraline treatment will proceed to phase two of the study, in which they will be randomly assigned to one of three treatment groups. One group will receive both sertraline and clonazepam, another group will receive both sertraline and placebo, and the third group will receive only venlafaxine. All treatments will continue for 12 weeks. Sertraline and venlafaxine are both FDA-approved for the treatment of GSAD. Clonazepam is widely used for the treatment of anxiety, but is not FDA-approved for the treatment of GSAD. All participants will attend weekly study visits at Weeks 1, 2, 4, 6, 8, and 10. Participants who continue into phase two will attend weekly study visits at Weeks 11-14, 16, 18, 20, and 22. Symptom remission rates and post-treatment social phobia severity will be assessed at Week 22.
Interventions
DRUGSertraline
DRUGVenlafaxine
DRUGPlacebo
DRUGClonazepam
Sponsors
National Institute of Mental Health (NIMH)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Primary psychiatric diagnosis of GSAD as defined by DSM-IV criteria and a score above 60 on the LSAS * Agrees to use an effective form of contraception throughout the study
Exclusion criteria
* Clinically significant abnormalities found upon physical examination, electrocardiogram, and laboratory tests * History of more than two unsuccessful, adequate treatment trials, indicated by a lack of response to over 10 weeks of any of the following: SSRIs (e.g., 40 mg of paroxetine or its equivalent per day); benzodiazepine (e.g. at least 2.5 mg of clonazepam per day) plus antidepressant (adequate dose as above); monoamine oxidase inhibitors (e.g., 60 mg of phenelzine or its equivalent per day); or a single failed trial of over 10 weeks of venlafaxine ( at least 150 mg per day) * Pregnant or breastfeeding * Simultaneous use of other psychotropic medications, with the exception of psychostimulants to treat ADHD; participants must discontinue regular benzodiazepine or antidepressant therapy at least two weeks (5 weeks for fluoxetine) prior to study entry; beta-blockers must be discontinued unless they are indicated medically (e.g., for hypertension) * DSM-IV diagnosis of any of the following: lifetime history of schizophrenia or any other psychosis, mental retardation, organic medical disorder, bipolar disorder, or obsessive compulsive disorder; eating disorder in the past 6 months; alcohol or substance abuse in the past 3 months or dependence within the past 6 months (entry of participants with major depression, dysthymia, panic disorder, generalized anxiety disorder, or post-traumatic stress disorder will be permitted if the social anxiety disorder is judged to be the predominant disorder) * Significant suicidal ideation as indicated by a score greater than 3 on the Montgomery-Asberg Depression Rating Scale or suicidal behaviors within 6 months prior to study entry * Significant personality dysfunction that could interfere with study participation * Serious medical illness or instability for which hospitalization may be likely during the study * Seizure disorders, with the exception of a childhood history of isolated, non-recurrent febrile seizures * Any concurrent psychotherapy initiated within 3 months of study entry, or ongoing psychotherapy of any duration directed specifically toward treatment of GSAD (prohibited psychotherapy includes cognitive behavioral therapy or psychodynamic therapy that focuses on exploring specific, dynamic causes of the phobic symptomatology and that provides management skills; general supportive therapy for more than 3 months is acceptable)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Remission (LSAS≤30) After 12 Weeks of Randomized Treatment During Phase II, Among Phase I Non-responders | Measured at Week 22 (Endpoint) | The Liebowitz Social Anxiety Scale (LSAS) is a 24-item scale assessing fear and avoidance in social and performance situations; it is widely used in studies of pharmacological treatment of Generalized Social Anxiety Disorder (GSAD). Scores on the LSAS range from 0 to 144, with higher scores indicating greater pathology. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-treatment Social Phobia Severity as Defined by Endpoint LSAS Scores | Change from Week 10 to Week 22 | The Liebowitz Social Anxiety Scale (LSAS) is a 24-item scale assessing fear and avoidance in social and performance situations; it is widely used in studies of pharmacological treatment of Generalized Social Anxiety Disorder (GSAD). We analyzed the overall change in LSAS (last Phase II LSAS minus Week 10 LSAS). Higher numbers reflect greater drops in social anxiety disorder severity. Scores on the LSAS range from 0 to 144, with higher scores indicating greater pathology. |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment for this study began in 2006 at the Massachusetts General Hospital, the University of California San Diego, and the Anxiety Disorders Clinic, McMaster University Medical Centre. Through approved recruitment methods, 397 patients with Generalized Social Anxiety Disorder (GSAD) were enrolled in Phase I of the study (open sertraline).
Pre-assignment details
Among the 397 patients enrolled in Phase I of the study, 295 patients entered Phase II. A total of 181 (61%) of the patients who began Phase II were non-responders at week 10 (LSAS\>50), and were therefore randomized to receive 12 weeks of treatment in one of three treatment arms (sertraline plus clonazepam, venlafaxine, or sertraline plus placebo).
Participants by arm
| Arm | Count |
|---|---|
| Sertraline and Clonazepam Participants will take both sertraline and clonazepam | 63 |
| Venlafaxine Participants will take venlafaxine only | 59 |
| Sertraline and Placebo Participants will take both sertraline and placebo | 59 |
| Total | 181 |
Baseline characteristics
| Characteristic | Sertraline and Clonazepam | Venlafaxine | Sertraline and Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 34.7 years STANDARD_DEVIATION 12.2 | 33.7 years STANDARD_DEVIATION 12 | 35.3 years STANDARD_DEVIATION 14.2 | 34.6 years STANDARD_DEVIATION 12.8 |
| Region of Enrollment Canada | 26 participants | 25 participants | 25 participants | 76 participants |
| Region of Enrollment United States | 37 participants | 34 participants | 34 participants | 105 participants |
| Sex: Female, Male Female | 25 Participants | 21 Participants | 20 Participants | 66 Participants |
| Sex: Female, Male Male | 38 Participants | 38 Participants | 39 Participants | 115 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 | 51 / 63 | 51 / 59 | 55 / 59 |
| serious Total, serious adverse events | 3 / 63 | 0 / 59 | 0 / 59 |
Outcome results
Primary
Rates of Remission (LSAS≤30) After 12 Weeks of Randomized Treatment During Phase II, Among Phase I Non-responders
The Liebowitz Social Anxiety Scale (LSAS) is a 24-item scale assessing fear and avoidance in social and performance situations; it is widely used in studies of pharmacological treatment of Generalized Social Anxiety Disorder (GSAD). Scores on the LSAS range from 0 to 144, with higher scores indicating greater pathology.
Time frame: Measured at Week 22 (Endpoint)
Population: The present analysis was conducted in the modified ITT population (n=181), with remission based on week 22 LSAS for study completers (n=154, and last Phase II LSAS for the 27 patients who terminated early.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sertraline and Clonazepam | Rates of Remission (LSAS≤30) After 12 Weeks of Randomized Treatment During Phase II, Among Phase I Non-responders | 17 participants |
| Venlafaxine | Rates of Remission (LSAS≤30) After 12 Weeks of Randomized Treatment During Phase II, Among Phase I Non-responders | 11 participants |
| Sertraline and Placebo | Rates of Remission (LSAS≤30) After 12 Weeks of Randomized Treatment During Phase II, Among Phase I Non-responders | 10 participants |
Secondary
Post-treatment Social Phobia Severity as Defined by Endpoint LSAS Scores
The Liebowitz Social Anxiety Scale (LSAS) is a 24-item scale assessing fear and avoidance in social and performance situations; it is widely used in studies of pharmacological treatment of Generalized Social Anxiety Disorder (GSAD). We analyzed the overall change in LSAS (last Phase II LSAS minus Week 10 LSAS). Higher numbers reflect greater drops in social anxiety disorder severity. Scores on the LSAS range from 0 to 144, with higher scores indicating greater pathology.
Time frame: Change from Week 10 to Week 22
Population: This analysis was conducted in Phase I non-responders, randomized to receive 12 weeks of continued sertraline plus the addition of clonazepam, switch to venlafaxine, or prolonged sertraline plus placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sertraline and Clonazepam | Post-treatment Social Phobia Severity as Defined by Endpoint LSAS Scores | 27 units on a scale | Standard Deviation 24.4 |
| Venlafaxine | Post-treatment Social Phobia Severity as Defined by Endpoint LSAS Scores | 18 units on a scale | Standard Deviation 19 |
| Sertraline and Placebo | Post-treatment Social Phobia Severity as Defined by Endpoint LSAS Scores | 16 units on a scale | Standard Deviation 23 |