NPY: Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers

• Sponsor: Dennis Charney (Other)
• Overall Status: Completed
• CT.gov ID: NCT00748956
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 3
• Duration (Months): 24
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Mood Disorder; Anxiety Disorders	Drug: Low dose NPY; Drug: High dose NPY; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low dose NPY Low dose, Receive 50 nmol dose of NPY	Drug: Low dose NPY; 50nmol, administered intranasally; Other Names: Neuropeptide Y
Experimental: High dose NPY High Dose, Receive 100 nmol dose of NPY	Drug: High dose NPY; 100nmol administered intranasally; Other Names: Neuropeptide Y
Placebo Comparator: Placebo Placebo comparator	Drug: Placebo; placebo comparator (0nmol)) administered intranasally

Outcome Measures

Primary Outcome Measures

1. Levels of NPY in CSF [on study day 2]

   Levels of Neuropeptide Y in the cerebrospinal fluid

Secondary Outcome Measures

1. Systematic Assessment of Treatment-Emergent Effects (SAFTEE) [on study day 2]

   Number of participants with serious adverse events

2. Appetite Scale [on study day 2]

   measure in 2 hours post intranasal administration

3. Post-sleep Questionnaire [on study day 2]

   measure in the morning

4. Quick Inventory of Depressive Symptoms (QIDS) [on study day 2]

   measure in 2 hours post intranasal administration

5. Profile of Mood States (POMS) [on study day 2]

   measure in 2 hours post intranasal administration and on the next morning

Eligibility Criteria

Criteria

• Ages Eligible for Study: 25 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mount Sinai School of Medicine	New York	New York	United States	10029

Sponsors and Collaborators

• Dennis Charney

Investigators

• Principal Investigator: Adriana Feder, MD, Icahn School of Medicine at Mount Sinai
• Principal Investigator: Dennis Charney, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Publications

• Eaton K, Sallee FR, Sah R. Relevance of neuropeptide Y (NPY) in psychiatry. Curr Top Med Chem. 2007;7(17):1645-59. Review.
• 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.
• Heilig M. The NPY system in stress, anxiety and depression. Neuropeptides. 2004 Aug;38(4):213-24. Review.
• 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.
• 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.
• Nikisch G, Agren H, Eap CB, Czernik A, Baumann P, Mathé 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. Epub 2005 Mar 23.
• 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.
• 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.
• 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.

• Responsible Party: Dennis Charney, Dean, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT00748956
• Other Study ID Numbers: GCO 05-0986; PT050986
• First Posted: Sep 9, 2008
• Last Update Posted: Aug 1, 2017
• Last Verified: Jul 1, 2017

• Keywords provided by Dennis Charney, Dean, Icahn School of Medicine at Mount Sinai: Mood Disorder; Anxiety Disorders
• Additional relevant MeSH terms: Disease; Anxiety Disorders; Mood Disorders

Study Results

Participant Flow

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Period Title: Overall Study
STARTED	0	5	5
COMPLETED	0	5	5
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo	Total
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally	Total of all reporting groups
Overall Participants	0	5	5	10
Age (Count of Participants)
<=18 years	0 NaN	0 0%	0 0%
Between 18 and 65 years	5 Infinity	5 100%	10 200%
>=65 years	0 NaN	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 NaN	0 0%	0 0%
Male	5 Infinity	5 100%	10 200%

Outcome Measures

1. Primary Outcome

Title	Levels of NPY in CSF
Description	Levels of Neuropeptide Y in the cerebrospinal fluid
Time Frame	on study day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Measure Participants	0	5	5
Mean (Standard Deviation) [pg/mL]	329.4 (119.9)	351.0 (41.6)

2. Secondary Outcome

Title	Systematic Assessment of Treatment-Emergent Effects (SAFTEE)
Description	Number of participants with serious adverse events
Time Frame	on study day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Measure Participants	0	5	5
Count of Participants [Participants]	0 NaN	0 0%	0 0%

3. Secondary Outcome

Title	Appetite Scale
Description	measure in 2 hours post intranasal administration
Time Frame	on study day 2

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Measure Participants	0	0	0

4. Secondary Outcome

Title	Post-sleep Questionnaire
Description	measure in the morning
Time Frame	on study day 2

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Measure Participants	0	0	0

5. Secondary Outcome

Title	Quick Inventory of Depressive Symptoms (QIDS)
Description	measure in 2 hours post intranasal administration
Time Frame	on study day 2

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Measure Participants	0	0	0

6. Secondary Outcome

Title	Profile of Mood States (POMS)
Description	measure in 2 hours post intranasal administration and on the next morning
Time Frame	on study day 2

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Low Dose NPY	High Dose NPY	Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally	High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally	Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
Measure Participants	0	0	0

Adverse Events

Arm/Group Title	Low Dose NPY		High Dose NPY		Placebo
Arm/Group Description	Low dose, Receive 50 nmol dose of NPY Low dose NPY: 50nmol, administered intranasally		High Dose, Receive 100 nmol dose of NPY High dose NPY: 100nmol administered intranasally		Placebo comparator Placebo: placebo comparator (0nmol)) administered intranasally
All Cause Mortality
	Low Dose NPY		High Dose NPY		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Low Dose NPY		High Dose NPY		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		1/5 (20%)		1/5 (20%)
Nervous system disorders
Headache and Nausea	0/0 (NaN)		0/5 (0%)		1/5 (20%)
Headache	0/0 (NaN)		1/5 (20%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Low Dose NPY		High Dose NPY		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/5 (0%)		0/5 (0%)

Limitations/Caveats

Small sample size

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.