Drug Treatment Validation of Functional Magnetic Resonance Imaging in Generalized Anxiety Disorder

• To evaluate the effects of an anxiolytic drug versus placebo on eye blink startle response at rest and during emotional stimuli (anxiety potentiated startle, APS) as well as on clinical scales. [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]
• To correlate the fMRI measurements with the clinical/behavioral measurements of efficacy. [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]

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.

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.

• Drug: 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).
  Other Name: Xanax
• Drug: Placebo
  Placebo, bid, p.o. for 28 +/- 2 days.

• Experimental: alprazolam
  Alprazolam, an FDA-approved drug, will be administered to 24 patients with generalized anxiety disorder.
  Intervention: Drug: Alprazolam (Xanax)
• Placebo Comparator: placebo
  A placebo comparator will be administered to 12 patients with generalized anxiety disorder
  Intervention: Drug: Placebo

• Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB. Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry. 2005 Mar;62(3):282-8.
• Salmeron BJ, Stein EA. Pharmacological applications of magnetic resonance imaging. Psychopharmacol Bull. 2002 Winter;36(1):102-29. Review.
• Simmons A, Strigo I, Matthews SC, Paulus MP, Stein MB. Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects. Biol Psychiatry. 2006 Aug 15;60(4):402-9.
• Baas JM, Grillon C, Bocker KB, Brack AA, III Morgan CA, Kenemans JL, Verbaten MN. Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl). 2002 May;161(3):233-47.
• Grillon C, Baas JM, Pine DS, Lissek S, Lawley M, Ellis V, Levine J. The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry. 2006 Oct 1;60(7):760-6. Epub 2006 Apr 21.

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 ECG), especially no findings (including concomitant medications) that would constitute contraindications for treatment with alprazolam
3. DSM-IV criteria for GAD (exception: at least 3 months of symptoms)
4. HAM-A at screening >/= 20
5. 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 FSH level greater than 40 mIU/mL unless the subject is receiving HRT), 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. BMI > 32.5 kg/m2
14. Contraindication to magnetic resonance imaging based on a standard fMRI screening forms
15. Concurrent participation in an 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®)