Flushing in Social Anxiety Disorder on Cipralex
Condition: Social Anxiety Disorder
MeSH terms: Anxiety Disorders; Phobia, Social
Study type: Interventional
Phase: Phase 2

Summary: 
      To add to our understanding of the relationship between blushing, symptom severity and
      potential mechanisms that underlie blushing in patients with SP, we propose comparing SP
      patients' vascular responses to topical m-N pre and post treatment with S-citalopram or
      placebo.

      S-citalopram (an SSRI) has been widely used in the treatment of mood and anxiety disorders as
      it has shown efficacy in these patients (Lepola et al., 2003; Stahl et al., 2003; Burke et
      al., 2002; Davidson et al., 2002; Wade et al., 2002). In comparison to placebo, S-citalopram
      has been shown to be effective and well tolerated in those with short and long term SP (Lader
      et al 2004; Montgomery et al., 2003; Kasper et al., 2002). As indicated, responses to the
      blushing exposure will be assessed prior to and following treatment with S-citalopram or
      placebo and at one month following the intervention.

      Levels of prostaglandin will be compared between groups and will also be correlated with
      symptom severity in the clinical groups. Effective psychological interventions that reduced
      the fear of blushing in individuals with social phobia did not lead to a reduction in actual
      blushing during a social test (Mulkens et al., 2001). As such, it is expected that the
      patients' perception of amount of blushing will change following treatment. In addition, we
      are undertaking an investigation as to whether nican topical administration will change
      following treatment to match the pattern seen in healthy controls.

      The objectives are to evaluate the efficacy of S-citalopram 10 to 20 mg once daily (QD) in
      the treatment of social phobia and to determine if treatment outcome is related changes in
      intensity of the vasodilatory response to 10 mM topical m-N. This is a randomized,
      double-blind flexible-dose study evaluating the efficacy, safety and tolerability of
      S-citalopram 10 to 20 mg and placebo in outpatient subjects diagnosed with SP. At the
      screening visit those who are eligible will enter a randomized trial with S-citalopram 10 to
      20 mg and placebo. The study will begin with a single week of S-citalopram 10 mg.
      Subsequently, capsules will be administered in a flexible dose fashion and patients will be
      followed up weekly (biweekly after week 6) and at the clinician's discretion. After the first
      week the patients' dosage will be increased up to a maximum of 20 mg daily. This dose will
      remain fixed after 8 weeks of treatment until week 16.
    

Detailed description: 
      Objectives

      The objectives are to evaluate the efficacy of S-citalopram 10 to 20 mg once daily (QD) in
      the treatment of social phobia and to determine if treatment outcome is related changes in
      intensity of the vasodilatory response to 10 mM topical m-N.

      Study Population

      Out-patients (n = 36) with a primary diagnosis of Social Phobia using DSM-IV criteria
      (300.02), with or without other comorbid secondary illnesses, who meet all other
      inclusion/exclusion criteria are eligible to enter the study. We have chosen to assign 36
      completed subjects as the number of desired completers. Given a drop out rate of 20%, 44
      subjects will be enrolled in the study.

      Study Design

      This is a randomized, double-blind flexible-dose study evaluating the efficacy, safety and
      tolerability of S-citalopram 10 to 20 mg and placebo in outpatient subjects diagnosed with
      SP. At the screening visit those who are eligible will enter a randomized trial with
      S-citalopram 10 to 20 mg and placebo. The study will begin with a single week of S-citalopram
      10mg. Subsequently, capsules will be administered in a flexible dose fashion and patients
      will be followed up weekly (biweekly after week 6) and at the clinicians discretion. After
      the first week the patients' dosage will be increased up to a maximum of 20 mg daily. This
      dose will remain fixed after 8 weeks of treatment until week 16.

      Voluntary discontinuation by a subject

      Subjects are free to discontinue their participation in the study at any time, without
      prejudice to further treatment. Subjects who discontinue from the study should always be
      asked about the reason(s) for their discontinuation and the presence of any adverse events.
      If possible, they should be seen and assessed by an investigator. Adverse events will be
      followed up.

      Safety Evaluation:

      Once treatment phase is initiated and 30 days following the conclusion of the trial, subjects
      will be questioned on any adverse events related to administration of S-citalopram. At the
      final visit, 30 days after the conclusion of the trial, patients will be given a full
      physical examination. Adverse experiences will be documented in response to a non-leading
      question such as, "Have you felt different in any way since starting the new treatment or
      since the last visit?" In addition, all adverse experiences observed by the investigator or
      volunteered spontaneously by the patient will be recorded. Any serious adverse events (SAE)
      will be reported to H. Lundbeck A/S contact person within 24 hours of becoming aware of them.

      Serious Adverse Events meets at least one of the following indicators:

        1. Death

        2. Life threatening

        3. In patient hospitalization

        4. Persistent or significant disability/ incapacity

        5. Congenital anomaly/birth defect

        6. Judged medically important

      Efficacy Evaluation:

      Primary efficacy parameter

      The primary objective is as follows:

      In individuals with SP, changes in intensity of the vasodilatory response to 10 mM topical
      m-N will be measured in association with symptomatic improvement following treatment with
      S-citalopram 10 to 20 mg. The end point of the study period is Week 16.

      Secondary efficacy parameters

      The secondary objectives are as follows and the end point of the study period is Week 16:

        1. Mean change from baseline on the Liebowitz Social Anxiety Scale (LSAS); Hamilton Anxiety
           Scale (HAM-A), Social Phobia Inventory (SPIN); Beck Anxiety Inventory (BAI); Social
           Phobia Scale (SPS) at final visit; and the Social Interaction Anxiety Scale (SIAS)

        2. Mean change from baseline on fear of blushing scales: Blushing, Trembling, and Sweating
           Questionnaire (BTS-Q) and Propensity Scale (BPS).

        3. Decreased levels of prostaglandin D2 will be observed in association with the findings
           of decreased m-N -induced flushing in the SP population. Any significant differences in
           levels of prostaglandin D2 and its metabolite between the three groups (treatment group
           and the controls) will disappear with symptom improvement in the SP group.

        4. Potential changes in peripheral serotonin synthesis from tryptophan will be altered such
           that changes in levels of plasma serotonin will be correlated with outcome and flushing
           response in SP subject who received treatment.

        5. Mean change from baseline on the Sheehan Disability Scale (work, social life and family
           life domains), Euroquol (quality of life) and the Medical Outcomes Study Short-Form-36
           (SF-36), ), Penn State Worry Questionnaire (PSWQ)

      Trial Design:

      This is a randomized, double-blind flexible-dose study evaluating the efficacy, safety and
      tolerability of S-citalopram 10 to 20 mg and placebo in outpatient subjects diagnosed with
      SP.

      After providing written informed consent at the screening visit, the patient will undergo all
      tests indicated to determine suitability for the study. Patients meeting all
      inclusion/exclusion criteria will then be assigned to receive S-citalopram (N = 18) or
      placebo (N = 18). The initial dose of S-citalopram will be 10mg. After week one, patients
      will be managed on a dose of 10mg daily to a maximum of 20mg. The dose may be adjusted for
      the first 8 weeks and then kept stable for duration of the rest of the study. Patients will
      be seen weekly from week one to 6 and biweekly until week 16, and if necessary, telephone
      contact will be initiated by the Investigator or study coordinator between visits to assess
      the patient's response to therapy.

      Procedure for Assessing Blushing/Vasodilation:

      Prior to application of each m-N patch, a 5 mm diameter circle of relatively hairless,
      unblemished skin will be masked off with hypoallergenic medical tape. This area will be found
      on both the subjects' inner forearm and face (center of cheekbone - below the outside corner
      of the eye). Initially, a five-minute baseline laser Doppler measurement will be taken.
      Subsequently, the 10 mM m-N patch will be applied over the skin area on the forearm or face
      for one minute and then removed. This is followed by a 20-minute period during which blood
      flow will be measured continuously over both the face and arm.

      Vasodilatation will be measured by using a Moor Instruments moorLAB laser Doppler
      spectroscope adjusted to measure changes in cutaneous blood flow. The Laser Doppler flow
      meter takes real time measurements of local tissue blood flow by reflecting light off a
      moving object such as a red blood cell. Each measurement will then be assigned an arbitrary
      unit (Flux) which is a parameter based on the summed intensity of reflections recorded by the
      instrument (Moor Instruments Limited, 1998). Flux will be sampled 40 times per second and
      transferred to a personal computer for analysis.

      Subsequently, blood flow (flux) data will be averaged into 30-second bins and analyses will
      be undertaken using non-linear curve fitting using the software program Prism (Graphpad
      software). The flux at any time t [F(t)] will be fitted to a curve with parameters F(0), the
      baseline flux, F, the maximal plateau change in flux, µ, the maximal rate of change, and L,
      the lag time between applying the test patch and vasodilatation occurring (Equation 1). Runs
      which do not produce a significant reaction (this being defined as at least one block of 5
      consecutive 30 second time periods being significantly (Student's t-test; P < 0.05) above
      baseline blood flow) will be assigned a F value of zero; the µ and L parameters can not be
      calculated in these circumstances).

      Approximate half maximal dose (EC50) values will be calculated using non-linear curve fitting
      to a standard sigmoidal dose response curve using the median F values derived from each dose
      of m-N.
    

Intervention name(s): Cipralex; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10-20mg; one per day; Matched to Cipralex
Other intervention name(s): Escitalopram
Intervention MeSH terms: Escitalopram
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment