Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers

NCT ID: NCT00748956

Last Updated: 2017-08-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-01-31
• Study Completion Date: 2012-01-31

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.

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.

Conditions

Mood Disorder; Anxiety Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

Low dose NPY

Low dose, Receive 50 nmol dose of NPY

Group Type: EXPERIMENTAL

Low dose NPY

Intervention Type: DRUG

50nmol, administered intranasally

High dose NPY

High Dose, Receive 100 nmol dose of NPY

Group Type: EXPERIMENTAL

High dose NPY

Intervention Type: DRUG

100nmol administered intranasally

Placebo

Placebo comparator

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

placebo comparator (0nmol)) administered intranasally

Interventions

Low dose NPY

50nmol, administered intranasally

Intervention Type: DRUG

High dose NPY

100nmol administered intranasally

Intervention Type: DRUG

Placebo

placebo comparator (0nmol)) administered intranasally

Intervention Type: DRUG

Other Intervention Names

Neuropeptide Y; Neuropeptide Y

Eligibility Criteria

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.

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Dennis Charney

OTHER

Sponsor Role: lead

Responsible Party

Dennis Charney

Dean

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Adriana Feder, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Dennis Charney, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

Mount Sinai School of Medicine

New York, New York, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 14625151 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10807963 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10715359 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9608581 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10549813 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 2611661 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15337373 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17979774 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15784158 (View on PubMed)

Other Identifiers

PT050986

Identifier Type: -

Identifier Source: secondary_id

GCO 05-0986

Identifier Type: -

Identifier Source: org_study_id