Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers

Anxiety Disorders Clinical Trial

— NPY  

Official title:

Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00748956
• Other study ID #: GCO-05-0986
• Secondary ID: PT050986
• Status: Completed
• Phase: Phase 2
• First received: September 8, 2008
• Last updated: December 10, 2012
• Start date: January 2010
• Est. completion date: January 2012

Study information

• Verified date: December 2012
• Source: Icahn School of Medicine at Mount Sinai
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: January 2012
• Est. primary completion date: December 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 25 Years to 45 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Anxiety Disorders
• Disease
• Mood Disorder
• Mood Disorders

Intervention

Drug:
• Low dose NPY
50nmol, administered intranasally
• High dose NPY
100nmol administered intranasally
• Placebo
placebo comparator (0nmol)) administered intranasally

Locations

Country	Name	City	State
United States	Mount Sinai School of Medicine	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Dennis Charney

Country where clinical trial is conducted

United States, 

References & Publications (9)

Eaton K, Sallee FR, Sah R. Relevance of neuropeptide Y (NPY) in psychiatry. Curr Top Med Chem. 2007;7(17):1645-59. Review. — View Citation

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. — View Citation

Heilig M. The NPY system in stress, anxiety and depression. Neuropeptides. 2004 Aug;38(4):213-24. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Levels of NPY in CSF and plasma	samples collected at 10 min and 20 minute intervals in 2 hours post intranasal administration	on study day 2	No
Secondary	Systematic Assessment of Treatment-Emergent Effects (SAFTEE)	measure in 2 hours post intranasal administration	on study day 2	Yes
Secondary	Appetite Scale	measure in 2 hours post intranasal administration	on study day 2	No
Secondary	Post-sleep questionnaire	measure in the morning	on study day 2	No
Secondary	Quick Inventory of Depressive Symptoms (QIDS)	measure in 2 hours post intranasal administration	on study day 2	No
Secondary	Profile of Mood States (POMS)	measure in 2 hours post intranasal administration and on the next morning	on study day 2	No