A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder

Abstract Background Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder. Methods Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes. Results Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score. Conclusions Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).

[1]  D. Charney,et al.  Neuropeptide Y, resilience, and PTSD therapeutics , 2017, Neuroscience Letters.

[2]  E. Sabban,et al.  Potential of neuropeptide Y for preventing or treating post-traumatic stress disorder , 2016, Neuropeptides.

[3]  F. Reichmann,et al.  Neuropeptide Y: A stressful review , 2016, Neuropeptides.

[4]  C. Marmar,et al.  Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical Trials. , 2015, JAMA.

[5]  L. Simms,et al.  Confirmatory factor analyses of DSM-5 posttraumatic stress disorder symptoms in psychiatric samples differing in Criterion A status. , 2015, Journal of anxiety disorders.

[6]  Xinfeng Liu,et al.  Intranasal delivery: circumventing the iron curtain to treat neurological disorders , 2015, Expert opinion on drug delivery.

[7]  J. Zohar,et al.  Diurnal Fluctuations in HPA and Neuropeptide Y-ergic Systems Underlie Differences in Vulnerability to Traumatic Stress Responses at Different Zeitgeber Times , 2015, Neuropsychopharmacology.

[8]  M. Lauková,et al.  Early intervention with intranasal NPY prevents single prolonged stress-triggered impairments in hypothalamus and ventral hippocampus in male rats. , 2014, Endocrinology.

[9]  P. Horn,et al.  Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder , 2014, Psychoneuroendocrinology.

[10]  L. Pucillo,et al.  Intranasal neuropeptide Y reverses anxiety and depressive-like behavior impaired by single prolonged stress PTSD model , 2014, European Neuropsychopharmacology.

[11]  C. Nievergelt,et al.  Characterization of cerebrospinal fluid (CSF) and plasma NPY levels in normal volunteers over a 24-h timeframe , 2013, Psychoneuroendocrinology.

[12]  G. Griebel,et al.  50 years of hurdles and hope in anxiolytic drug discovery , 2013, Nature Reviews Drug Discovery.

[13]  T. Geracioti,et al.  Neuropeptide Y and posttraumatic stress disorder , 2013, Molecular Psychiatry.

[14]  M. Lauková,et al.  Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats , 2013, Neuroscience.

[15]  E. Nestler,et al.  Neurobiology of resilience , 2012, Nature Neuroscience.

[16]  A. Misra,et al.  Drug delivery systems from nose to brain. , 2012, Current pharmaceutical biotechnology.

[17]  T. Montine,et al.  Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment A Pilot Clinical Trial , 2011 .

[18]  D. Charney,et al.  Central functions of neuropeptide Y in mood and anxiety disorders , 2011, Expert opinion on therapeutic targets.

[19]  P. Horn,et al.  Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder , 2009, Biological Psychiatry.

[20]  J. Lee,et al.  Dose Escalation Methods in Phase I Cancer Clinical Trials , 2009, Journal of the National Cancer Institute.

[21]  Ahmad R. Hariri,et al.  Genetic variation in human NPY expression affects stress response and emotion , 2008, Nature.

[22]  M. Śmiałowska,et al.  The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y , 2007, Neuropsychopharmacology.

[23]  R. Yehuda,et al.  Plasma Neuropeptide Y Concentrations in Combat Exposed Veterans: Relationship to Trauma Exposure, Recovery from PTSD, and Coping , 2006, Biological Psychiatry.

[24]  A. Steiger,et al.  Neuropeptide Y (NPY) shortens sleep latency but does not suppress ACTH and cortisol in depressed patients and normal controls , 2006, Psychoneuroendocrinology.

[25]  D. York,et al.  Effects of Altered Amygdalar Neuropeptide Y Expression on Anxiety-Related Behaviors , 2005, Neuropsychopharmacology.

[26]  Olga V. Demler,et al.  Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[27]  R. G. Thorne,et al.  Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration , 2004, Neuroscience.

[28]  J. Born,et al.  Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man , 2004, Physiology & Behavior.

[29]  M. Heilig.  The NPY system in stress, anxiety and depression , 2004, Neuropeptides.

[30]  D. Charney,et al.  Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. , 2004, The American journal of psychiatry.

[31]  J. Born,et al.  NPY attenuates positive cortical DC-potential shift upon food intake in man , 2003, Psychoneuroendocrinology.

[32]  Jan Born,et al.  Sniffing neuropeptides: a transnasal approach to the human brain , 2002, Nature Neuroscience.

[33]  J. Harro,et al.  The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y , 2002, Neuroscience & Biobehavioral Reviews.

[34]  H. Pincus,et al.  The DSM-IV Text Revision: rationale and potential impact on clinical practice. , 2002, Psychiatric services.

[35]  R. Quirion,et al.  Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Steiger,et al.  Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men , 2000, Neuropharmacology.

[37]  A. Bannon,et al.  Behavioral characterization of neuropeptide Y knockout mice , 2000, Brain Research.

[38]  C. A. Morgan,et al.  Plasma neuropeptide-Y concentrations in humans exposed to military survival training , 2000, Biological Psychiatry.

[39]  C. A. Morgan,et al.  Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD , 2000, Biological Psychiatry.

[40]  L. Edvinsson,et al.  Functional effects of neuropeptide Y receptors on blood flow and nitric oxide levels in the human nose. , 1999, American journal of respiratory and critical care medicine.

[41]  Lacroix Js,et al.  Attenuation of allergen-evoked nasal responses by local pretreatment with exogenous neuropeptide Y in atopic patients , 1996 .

[42]  S. Goodman,et al.  Some practical improvements in the continual reassessment method for phase I studies. , 1995, Statistics in medicine.

[43]  A. Beck,et al.  Further evidence for the validity of the beck anxiety inventory with psychiatric outpatients , 1993 .

[44]  Stephen Senn,et al.  Cross-over trials in clinical research , 1993 .

[45]  M. Kaliner,et al.  Neuropeptide Y is a vasoconstrictor in human nasal mucosa. , 1992, Journal of applied physiology.

[46]  S. Orr,et al.  Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. , 1987, Archives of general psychiatry.

[47]  T. Crow,et al.  Neuropeptide Y distribution in human brain , 1983, Nature.

[48]  J. Zohar,et al.  The Neuropeptide Y (NPY)-ergic System is Associated with Behavioral Resilience to Stress Exposure in an Animal Model of Post-Traumatic Stress Disorder , 2012, Neuropsychopharmacology.

[49]  Daniel S. Weiss,et al.  The Impact of Event Scale: Revised , 2007 .

[50]  J. Davidson,et al.  Clinician‐administered PTSD scale: A review of the first ten years of research , 2001, Depression and anxiety.

[51]  B. Mosimann,et al.  Attenuation of allergen-evoked nasal responses by local pretreatment with exogenous neuropeptide Y in atopic patients. , 1996, The Journal of allergy and clinical immunology.

[52]  C. Spielberger,et al.  Manual for the State-Trait Anxiety Inventory , 1970 .