- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00748956
Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers (NPY)
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:
- 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.
- To test the effect of intranasal NPY administration on mood and anxiety.
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
New York
-
New York, New York, United States, 10029
- Mount Sinai School of Medicine
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Men aged 25-45.
- No history of Axis I disorder as defined in the DSM-IV other than past nicotine abuse or dependence or adjustment disorder.
Exclusion Criteria:
- Nicotine or caffeine abuse or dependence within the preceding 3 months.
- History or complaint of nasal disorders or allergies.
- Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic.
- Significant obesity (BMI > 30), scoliosis, spinal stenosis or a history of lumbosacral laminectomy.
- Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG.
- Current use of any medications that have effects on CNS function.
- Prior sinonasal surgery, or significant nasal polyps as determined by nasal endoscopy.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Low dose NPY
Low dose, Receive 50 nmol dose of NPY
|
50nmol, administered intranasally
Other Names:
|
EXPERIMENTAL: High dose NPY
High Dose, Receive 100 nmol dose of NPY
|
100nmol administered intranasally
Other Names:
|
PLACEBO_COMPARATOR: Placebo
Placebo comparator
|
placebo comparator (0nmol)) administered intranasally
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Levels of NPY in CSF
Time Frame: on study day 2
|
Levels of Neuropeptide Y in the cerebrospinal fluid
|
on study day 2
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Systematic Assessment of Treatment-Emergent Effects (SAFTEE)
Time Frame: on study day 2
|
Number of participants with serious adverse events
|
on study day 2
|
Appetite Scale
Time Frame: on study day 2
|
measure in 2 hours post intranasal administration
|
on study day 2
|
Post-sleep Questionnaire
Time Frame: on study day 2
|
measure in the morning
|
on study day 2
|
Quick Inventory of Depressive Symptoms (QIDS)
Time Frame: on study day 2
|
measure in 2 hours post intranasal administration
|
on study day 2
|
Profile of Mood States (POMS)
Time Frame: on study day 2
|
measure in 2 hours post intranasal administration and on the next morning
|
on study day 2
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Dennis Charney, MD, Icahn School of Medicine at Mount Sinai
Publications and helpful links
General Publications
- Morgan CA 3rd, Rasmusson AM, Winters B, Hauger RL, Morgan J, Hazlett G, Southwick S. Trauma exposure rather than posttraumatic stress disorder is associated with reduced baseline plasma neuropeptide-Y levels. Biol Psychiatry. 2003 Nov 15;54(10):1087-91. doi: 10.1016/s0006-3223(03)00433-5.
- Morgan CA 3rd, Wang S, Southwick SM, Rasmusson A, Hazlett G, Hauger RL, Charney DS. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biol Psychiatry. 2000 May 15;47(10):902-9. doi: 10.1016/s0006-3223(99)00239-5.
- Rasmusson AM, Hauger RL, Morgan CA, Bremner JD, Charney DS, Southwick SM. Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol Psychiatry. 2000 Mar 15;47(6):526-39. doi: 10.1016/s0006-3223(99)00185-7.
- Rasmusson AM, Southwick SM, Hauger RL, Charney DS. Plasma neuropeptide Y (NPY) increases in humans in response to the alpha 2 antagonist yohimbine. Neuropsychopharmacology. 1998 Jul;19(1):95-8. doi: 10.1016/S0893-133X(97)00199-1.
- Thorsell A, Carlsson K, Ekman R, Heilig M. Behavioral and endocrine adaptation, and up-regulation of NPY expression in rat amygdala following repeated restraint stress. Neuroreport. 1999 Sep 29;10(14):3003-7. doi: 10.1097/00001756-199909290-00024.
- Flood JF, Baker ML, Hernandez EN, Morley JE. Modulation of memory processing by neuropeptide Y varies with brain injection site. Brain Res. 1989 Nov 27;503(1):73-82. doi: 10.1016/0006-8993(89)91706-x.
- Heilig M. The NPY system in stress, anxiety and depression. Neuropeptides. 2004 Aug;38(4):213-24. doi: 10.1016/j.npep.2004.05.002.
- Eaton K, Sallee FR, Sah R. Relevance of neuropeptide Y (NPY) in psychiatry. Curr Top Med Chem. 2007;7(17):1645-59. doi: 10.2174/156802607782341037.
- Nikisch G, Agren H, Eap CB, Czernik A, Baumann P, Mathe AA. Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram. Int J Neuropsychopharmacol. 2005 Sep;8(3):403-10. doi: 10.1017/S1461145705005158. Epub 2005 Mar 23.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- GCO 05-0986
- PT050986
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