Neurobiological Mechanisms in Panic Disorder
Condition: Panic Disorder
MeSH terms: Panic Disorder
Study type: Observational

Summary: 
      This study will examine brain and noradrenaline function in panic disorder. Noradrenaline is
      a brain chemical that is involved in the regulation of emotion, anxiety, sleep, stress
      hormones such as cortisol, and other body functions that are disturbed in panic disorder.

      Healthy normal volunteers and patients with panic disorder between 18 and 60 years of age may
      be eligible for this study. Candidates are screened with psychiatric and medical histories, a
      physical examination, blood and urine tests, and an electrocardiogram.

      Participants undergo the following tests and procedures:

        -  Blood draw to obtain DNA for genetic studies of panic disorder - particularly of a gene
           that helps control noradrenaline activity - and to grow cell lines that can be frozen
           and used for future research on the disorder.

        -  Magnetic resonance imaging: MRI uses a magnetic field and radio waves to produce images
           of body tissues and organs. For this procedure, the subject lies on a table that is
           moved into the scanner (a narrow cylinder), and wears earplugs to muffle loud knocking
           and thumping sounds that occur during the scanning process. The procedure lasts about 60
           minutes, during which the patient is asked to lie still for 10 to 15 minutes at a time.

        -  Yohimbine injection with PET scanning: Catheters (plastic tubes) are placed in two
           veins, one to administer yohimbine, a drug that increases noradrenaline activity in the
           body for about 60 minutes, and one to draw blood samples. Yohimbine often causes
           temporary trembling, goosebumps, and clammy palms, and may cause emotions such as
           elation, anxiety, panic attacks, or depression. During yohimbine administration,
           subjects undergo positron emission tomography (PET) scanning. PET uses small amounts of
           a radioactive chemical called [fluoro-18]-fluorodeoxyglucose that "labels" active areas
           of the brain, showing patterns of glucose (sugar) metabolism. For the procedure, the
           subject lies on the scanner bed, with a special mask fitted to his or her head and
           attached to the bed to help keep the head still. A brief "transmission" scan is done
           just before the radioactive tracer is injected in order to calibrate the scanner. After
           the tracer is injected through the catheter, pictures are taken for about an hour, while
           the subject lies still on the scanner bed.

        -  Saline injection with PET scanning: The procedure is the same as that described above,
           except a saline solution is administered as placebo instead of yohimbine.
    

Detailed description: 
      A considerable body of preclinical and clinical evidence suggests that dysregulated activity
      of noradrenergic systems in the brain is involved in the development of mood disturbance,
      anxiety, and fear. Neuroanatomical and neurophysiological studies of the noradrenergic system
      provide a basis for relating increased activity of this system to the behavioral expression
      of fear and anxiety and the somatic symptoms and cardiovascular changes that accompany severe
      anxiety states. Previously, extensive research has been done on the role of noradrenergic
      mechanisms in panic disorder (PD), and it has been suggested that in at least a subgroup of
      PD patients an abnormality of noradrenergic mechanisms may exist. Studies in patients with PD
      using the alpha2-adrenoreceptor (AR) antagonist yohimbine showed that a subgroup of PD
      patients exhibit abnormalities in the regulation of noradrenergic function. Yohimbine, which
      activates noradrenergic neurons, has been shown to produce greater increases in anxiety,
      somatic symptoms, blood pressure and plasma levels of the noradrenergic metabolite MHPG in
      some patients with PD relative to healthy controls. The effect of yohimbine on brain regions
      hypothesized to be involved in the pathogenesis of PD has not been determined in PD patients
      using modern neuroimaging techniques. The anxiogenic effects of yohimbine do not occur in all
      PD patients, although the neurobiological basis for this differential response to yohimbine
      has not been identified.

      This research project proposes to address these two unresolved questions. The effects of
      yohimbine on regional cerebral glucose metabolism will be determined in PD patients and
      healthy controls. In addition, preliminary data will be obtained as to whether the behavioral
      and cerebral metabolic responses to yohimbine relate to functional polymorphisms of the COMT
      gene which affect catecholamine metabolism.

      It is predicted that yohimbine will produce decreases in cerebral metabolism in the
      prefrontal cortex, orbitofrontal cortex, and anterior cingulate. Healthy controls will
      exhibit an inverse direction of change in these brain regions. These findings would be
      similar to those we have previously observed in PTSD patients and may reflect an altered
      dose-response effect of yohimbine in PD and PTSD relative to controls since preclinical
      pharmacological studies of stress have shown that high levels of norepinephrine release in
      the brain decrease brain metabolism whereas lower levels increase brain metabolism. In terms
      of polymorphisms of the COMT and other catecholamine systems-related gene polymorphisms, it
      is predicted that the low-activity COMT (met allele) alleles will be associated with greater
      behavioral and cerebral metabolic responses to yohimbine.
    

Keywords: Panic Disorder; Norepinephrine; Yohimbine; Genes; Pathophysiology; Noradrenergic Mechanisms; PET Imaging; PD; Healthy Volunteer; HV