Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers
Condition: Mood Disorder; Anxiety Disorders
MeSH terms: Anxiety Disorders; Mood Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      There is growing evidence that neuropeptides act as neuronal messengers in the brain and have
      diverse functions that may include the regulation of mood and behavior. For example,
      neuropeptide Y (NPY) is thought to play a role in the adaptive stress response. The
      therapeutic application of neuropeptides for psychiatric disorders has been limited by
      difficult and unreliable penetration of the blood-brain barrier (BBB). However, recent data
      suggest that intranasal administration may provide a means of effectively delivering some of
      these neuropeptides to the brain. Thus far it is unclear if this is the case for NPY. The
      aims of this project are:

        1. To evaluate, in 15 healthy male volunteers aged 25-45, the effect of intranasal NPY
           administration (0, 50 and 100 nmol) on its levels in cerebrospinal fluid (CSF), measured
           by means of lumbar puncture using an intraspinal catheter between L4 and L5, and in
           plasma, measured using an intravenous catheter in the forearm. One of the three
           treatments will be administered to each participant in a double-blind fashion. The 0
           nmol condition will serve as the placebo control.

        2. To test the effect of intranasal NPY administration on mood and anxiety.
    

Detailed description: 
      There is growing evidence that neuropeptides, including neuropeptide Y (NPY), act as neuronal
      messengers in the brain and have diverse neurobehavioral functions. Their therapeutic
      application for psychiatric disorders has been limited, however, by difficult and unreliable
      penetration of the blood-brain barrier (BBB). The BBB has prevented the use of many
      therapeutic agents for treating central nervous system (CNS) disorders. Several molecules
      have successfully been administered through intranasal delivery, however, thanks to the
      unique connection that the nerves involved in sensing odors and chemicals provide between the
      CNS and its environment.

      NPY, the most abundant peptide in the mammalian brain, is co-localized with norepinephrine in
      sympathetic nerve fibers and has been of longstanding interest to our research group (Morgan
      et al., 2002; Morgan et al., 2003; Morgan et al., 2001; Morgan et al., 2000; Rasmusson et
      al., 2000; Rasmusson et al., 1998) because of its potential role in modulating mood and
      anxiety. NPY has been implicated as factor in the adaptive stress response (Thorsell et al.,
      1999), and has been shown to impact the consolidation of fear-related memories after shock
      (Flood et al., 1989). Clinically, lower plasma NPY levels have been correlated with greater
      psychological distress, increased symptoms of dissociation, and poorer performance among
      active duty military personnel. Acute stress in humans has been found to elicit NPY release,
      in a manner parallel to the changes in cortisol and norepinephrine that are usually seen,
      with a blunting of the plasma NPY response in response to yohimbine (Morgan et al., 2002).
      Baseline NPY levels in combat veterans with PTSD are reduced compared to healthy
      non-traumatized individuals (Rasmusson et al., 2000). Another study found that repeated
      exposure to traumatic stress, rather than the presence of PTSD or PTSD-type symptoms, is
      associated with a reduction in baseline plasma NPY (Morgan et al., 2003). A recent report
      found deceased CSF concentrations of NPY in patients with treatment resistant unipolar major
      depression (Heilig et al 2004). In summary, there has been suggestion from studies in
      patients with anxiety and mood disorders as well as healthy volunteers of an abnormal
      regulation of this peptide.

      In this study, we will evaluate intranasal administration of NPY in healthy male volunteers
      ages 25-45 using a specialized delivery device. Pending the initial feasibility and
      tolerability in healthy volunteers, future protocols will examine the effect of intranasal
      NPY administration in patients with disorders such as PTSD, major depression, panic disorder,
      and social anxiety disorder.
    

Intervention name(s): Low dose NPY; High dose NPY; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 50nmol, administered intranasally; 100nmol administered intranasally; placebo comparator (0nmol)) administered intranasally
Other intervention name(s): Neuropeptide Y; Neuropeptide Y
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Mood Disorder; Anxiety Disorders