Intranasal Administration of Neuropeptide Y in Healthy Male Volunteers

Phase 2

Completed

Conditions: Anxiety Disorders
Mood Disorder

Interventions: Drug: High dose NPY
Drug: Placebo
Drug: Low dose NPY

Registration Number: NCT00748956

Lead Sponsor: Dennis Charney

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 10

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

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High dose NPY	High dose NPY	High Dose, Receive 100 nmol dose of NPY
Placebo	Placebo	Placebo comparator
Low dose NPY	Low dose NPY	Low dose, Receive 50 nmol dose of NPY

Primary Outcome Measures

Name	Time	Method
Levels of NPY in CSF	on study day 2	Levels of Neuropeptide Y in the cerebrospinal fluid

Secondary Outcome Measures

Name	Time	Method
Quick Inventory of Depressive Symptoms (QIDS)	on study day 2	measure in 2 hours post intranasal administration
Profile of Mood States (POMS)	on study day 2	measure in 2 hours post intranasal administration and on the next morning
Appetite Scale	on study day 2	measure in 2 hours post intranasal administration
Post-sleep Questionnaire	on study day 2	measure in the morning
Systematic Assessment of Treatment-Emergent Effects (SAFTEE)	on study day 2	Number of participants with serious adverse events