Review | Published:

The promise and pitfalls of intranasally administering psychopharmacological agents for the treatment of psychiatric disorders

Molecular Psychiatry volume 21, pages 2938 (2016) | Download Citation

Abstract

Accumulating research demonstrates the potential of intranasal delivery of psychopharmacological agents to treat a range of psychiatric disorders and symptoms. It is believed that intranasal administration offers both direct and indirect pathways to deliver psychopharmacological agents to the central nervous system. This administration route provides a unique opportunity to repurpose both old drugs for new uses and improve currently approved drugs that are indicated for other administration routes. Despite this promise, however, the physiology of intranasal delivery and related assumptions behind the bypassing of the blood brain barrier is seldom considered in detail in clinical trials and translational research. In this review, we describe the current state of the art in intranasal psychopharmacological agent delivery research and current challenges using this administration route, and discuss important aspects of nose-to-brain delivery that may improve the efficacy of these new therapies in future research. We also highlight current gaps in the literature and suggest how research can directly examine the assumptions of nose-to-brain delivery of psychopharmacological agents in humans.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , , , et al. Grand challenges in global mental health. Nature 2011; 475: 27–30.

  2. 2.

    , , , , , et al. The Global Economic Burden of Non-communicable Diseases. Geneva: World Economic Forum 2011.

  3. 3.

    . Is pharma running out of brainy ideas. Science 2010; 329: 502–504.

  4. 4.

    . Novartis to shut brain research facility. Nature 2011; 480: 161–162.

  5. 5.

    , , , , , et al. Innovative solutions to novel drug development in mental health. Neurosci Biobehav Rev 2013; 37: 2438–2444.

  6. 6.

    , , . Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 2007; 6: 521–532.

  7. 7.

    . Revolution stalled. Sci Transl Med 2012; 4: 155cm111–155cm111.

  8. 8.

    , . New uses for old drugs. Nature 2007; 448: 645–646.

  9. 9.

    , , . The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22: 151–185.

  10. 10.

    , , , . Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev 2015; 49: 182–192.

  11. 11.

    , , , . Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004; 127: 481–496.

  12. 12.

    , , , . Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995; 692: 278–282.

  13. 13.

    , , , . Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol 1986; 251: 260–280.

  14. 14.

    , , , . Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope 2006; 116: 466–472.

  15. 15.

    . CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998; 70: 1781–1792.

  16. 16.

    , , , , , . Absorption of water-soluble compounds with different molecular weights and [Asu1.7]-eel calcitonin from various mucosal administration sites. J Control Release 2001; 76: 363–374.

  17. 17.

    , , , , , et al. Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 2013; 38: 612–625.

  18. 18.

    , , , , . Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study. Pharmacotherapy 2008; 28: 875–882.

  19. 19.

    , , . Intranasal delivery of proteins and peptides in the treatment of neurodegenerative diseases. AAPS J 2015; 17: 780–787.

  20. 20.

    , . The blood-brain barrier and nasal drug delivery to the central nervous system. Am J Rhinol Allergy 2015; 29: 124–127.

  21. 21.

    , , . Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother 2015; 49: 808–817.

  22. 22.

    , , . Intranasal delivery: circumventing the iron curtain to treat neurological disorders. Expert Opin Drug Deliv 2015; 12: 1717–1725.

  23. 23.

    . Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry 2015; 76: e628–e631.

  24. 24.

    . The mode of infection in epidemic poliomyelitis. J Am Med Assoc 1912; 59: 1371–1372.

  25. 25.

    , , . The relation to the blood of the virus of epidemic poliomyelitis. J Exp Med 1914; 19: 223–233.

  26. 26.

    , . Infection with neurotropic yellow fever virus following instillation into the nares and conjunctival sac. J Pathol Bacteriol 1935; 40: 55–64.

  27. 27.

    , . Studies on herpetic infection in mice: II. The pathways of invasion of the central nervous system after intranasal instillation of virus in suckling mice. J Exp Med 1943; 78: 315.

  28. 28.

    , , . Mouse hepatitis virus and herpes simplex virus move along different CNS pathways. In: Laude H, Vautherot J-F (eds). Coronaviruses, vol. 342. Springer, New York, 1993, pp 313–318.

  29. 29.

    , , . Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J Drug Target 1998; 5: 415–441.

  30. 30.

    , , , . Pharmaceutical aspects of intranasal delivery of vaccines using particulate systems. J Pharm Sci 2009; 98: 812–843.

  31. 31.

    , , . Uptake of nickel into the brain via olfactory neurons in rats. Toxicol Lett 1997; 91: 153–162.

  32. 32.

    , , , , . Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimers Dis 1998; 1: 35–44.

  33. 33.

    , , , , , . Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol 2004; 151: 66–77.

  34. 34.

    . Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin-horseradish peroxidase applied to the nasal epithelium. Brain Res Bull 1985; 15: 129–142.

  35. 35.

    , . Cranial nerve I: olfactory nerve, chapter 7. In: Goetz CG (ed) Textbook of Clinical Neurology (3rd edn). W.B. Saunders: Philadelphia, 2007 pp 99–112.

  36. 36.

    . Sensory systems: the coupling between brain and environment. The Long Evolution of Brains and Minds. Springer, Dordrecht, The Netherlands, 2013, pp 165–192.

  37. 37.

    , . Management of smell dysfunction. Curr Allergy Asthma Rep 2012; 12: 154–162.

  38. 38.

    . The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 2008; 63: 7–15.

  39. 39.

    , , . Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. Glia 2005; 52: 245–251.

  40. 40.

    , . Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol (Berl) 1971; 19: 145–154.

  41. 41.

    , , . Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2009; 99: 1654–1673.

  42. 42.

    , , , , , . Epithelial and endothelial barriers in the olfactory region of the nasal cavity of the rat. Histochem Cell Biol 2008; 130: 127–140.

  43. 43.

    , , , , . Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 2000; 17: 737–742.

  44. 44.

    , , , , . A new approach to fertility regulation by interfering with neuroendocrine pathways. In: Anand Kumar TC (ed). Neuroendocrine Regulation of Fertility. Karger: Basel, 1976; 314–322.

  45. 45.

    , , , , , . Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS. J Drug Target 2010; 18: 179–190.

  46. 46.

    , , . Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J Pharm Sci 1999; 88: 754–758.

  47. 47.

    , , , , , . Pharmacokinetics of buccal and intranasal lorazepam in healthy adult volunteers. Eur J Clin Pharmacol 2012; 68: 155–159.

  48. 48.

    , , , , , . Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm 2008; 358: 285–291.

  49. 49.

    , , . Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth 1981; 53: 805–810.

  50. 50.

    , , , , , et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987; 64: 190–194.

  51. 51.

    , . Experimental methods for studying drug uptake in the head and brain. Curr Drug Metab 2000; 1: 333–356.

  52. 52.

    , . Lipophilic character and biological activity of drugs II: the parabolic case. J Pharm Sci 1973; 62: 1–21.

  53. 53.

    , . Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res Bull 1985; 15: 287–292.

  54. 54.

    , , , , . Investigation of an F-18 oxytocin receptor selective ligand via PET imaging. Bioorg Med Chem Lett 2013; 23: 5415–5420.

  55. 55.

    , , , , . Carbon-11N-methyl alkylation of L-368,899 and in vivo PET imaging investigations for neural oxytocin receptors. Bioorg Med Chem Lett 2013; 23: 902–906.

  56. 56.

    , . Understanding the oral mucosal absorption and resulting clinical pharmacokinetics of asenapine. AAPS PharmSciTech 2012; 13: 1110–1115.

  57. 57.

    . The relevance to humans of animal models for inhalation studies of cancer in the nose and upper airways. Qual Assur 1993; 2: 213–231.

  58. 58.

    , , , , . Long-term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care 1987; 10: 573–578.

  59. 59.

    , , , , , et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2015; 41: 483–493.

  60. 60.

    , , , , , et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry 2015; 56: 444–452.

  61. 61.

    , , , , , et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76: 970–976.

  62. 62.

    , , , , , et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain 2004; 108: 17–27.

  63. 63.

    , , , , , et al. Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med 2005; 29: 265–271.

  64. 64.

    , . Visualization of in vivo olfactory uptake and transfer using fluorescein dextran. J Drug Target 2002; 10: 379–386.

  65. 65.

    , . Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat. Exp Brain Res 1986; 63: 461–473.

  66. 66.

    , , , , . Delivery of galanin-like peptide to the brain: targeting with intranasal delivery and cyclodextrins. J Pharmacol Exp Ther 2008; 325: 513–519.

  67. 67.

    , , , , , et al. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 2011; 14: 3–16.

  68. 68.

    , . Solid-state chemical stability of proteins and peptides. J Pharm Sci 1999; 88: 489–500.

  69. 69.

    . Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents. Mol Imaging Biol 2003; 5: 376–389.

  70. 70.

    . Drug and gene delivery to the brain: the vascular route. Neuron 2002; 36: 555–558.

  71. 71.

    , , , . Bioavailability of leuprolide acetate following nasal and inhalation delivery to rats and healthy humans. Pharm Res 1992; 9: 244–249.

  72. 72.

    . The upper airways. I. Nasal physiology and defense of the lungs. Am Rev Respir Dis 1977; 115: 97–129.

  73. 73.

    . Cell and Tissue Biology: A Textbook of Histology. Lippincott Williams & Wilkins, 1988.

  74. 74.

    . Osteolytic sinusitis and pneumomediastinum: deceptive otolaryngologic complications of cocaine abuse. Laryngoscope 1986; 96: 206–210.

  75. 75.

    . The nose and paranasal sinuses physiology and anatomy. Adv Drug Deliv Rev 2001; 51: 5–19.

  76. 76.

    , . The nasal valve: a review of the anatomy, imaging, and physiology. Am J Rhinol 2004; 18: 143–150.

  77. 77.

    , . Maximum nasal inspiratory flow and nasal resistance. Ann Otol Rhinol Laryngol 1970; 79: 481–488.

  78. 78.

    , , . The assessment of topical nasal drug distribution. Clin Otolaryngol Allied Sci 2004; 29: 201–205.

  79. 79.

    . On the physiology of the nasal respiration. Acta Otolaryngol (Stockh) 1940; 28: 15–59.

  80. 80.

    . Le nez comme voie respiratoire. Presse Otolaryng Belge 1903; 2: 481–496.

  81. 81.

    , . Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Deliv Rev 1998; 29: 3–12.

  82. 82.

    , , , . Influence of anatomy and head position on intranasal drug deposition. Eur Arch Otorhinolaryngol 2006; 263: 827–832.

  83. 83.

    , , . Accessing the brain: the nose may know the way. J Cereb Blood Flow Metab 2013; 33: 793–794.

  84. 84.

    , , , , , et al. Low dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized 4-way crossover trial with nasal cavity dimension assessment. Transl Psychiatry 2015; 5: 1–9.

  85. 85.

    , , . Sensitivity of three loci on the tongue and soft palate to four basic tastes in smokers and non-smokers. Acta Otolaryngol (Stockh) 2002; 122: 74–82.

  86. 86.

    , . An endoscopic photographic comparison of nasal drug delivery by aqueous spray. Clin Otolaryngol Allied Sci 1998; 23: 560–563.

  87. 87.

    , , , . Increased brain radioactivity by intranasal 32 P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int J Nanomed 2012; 7: 1373.

  88. 88.

    . Brain delivery of small interfering ribonucleic acid and drugs through intranasal administration with nano-sized polymer micelles. Medl Devices (Auckl) 2015; 8: 57.

  89. 89.

    , , , , , et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012; 69: 29–38.

  90. 90.

    , . Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats. Anesth Analg 2011; 113: 641.

  91. 91.

    , . Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump. J Aerosol Med Pulm Drug Deliv 2012; 25: 280–289.

  92. 92.

    , . The role of oxytocin in parturition. BJOG 2003; 110: 46–51.

  93. 93.

    , , , , . Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor. Science 1982; 215: 1396–1398.

  94. 94.

    , , , , , et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007; 61: 498–503.

  95. 95.

    , , , , , et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 2003; 28: 193–198.

  96. 96.

    , , , , , . Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci USA 1996; 93: 11699–11704.

  97. 97.

    , , , , . Oxytocin enhances onset of lactation among mothers delivering prematurely. BMJ 1981; 283: 340–342.

  98. 98.

    . Brain–fluid barriers: relevance for theoretical controversies regarding vasopressin and oxytocin memory research. Adv Pharmacol 2004; 50: 531–592.

  99. 99.

    , , , , . The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat. J Pharm Pharmacol 1987; 39: 357–362.

  100. 100.

    , . Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 2012; 35: 649–659.

  101. 101.

    , , , , . Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology 2013; 38: 1985–1993.

  102. 102.

    , , , , , et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep 2013; 3: 3440.

  103. 103.

    , . Oxytocin mediates acquisition of maternally associated odor preferences in preweanling rat pups. Behav Neurosci 1996; 110: 583.

  104. 104.

    , , . Low doses of oxytocin facilitate social recognition in rats. Psychopharmacology (Berl) 1992; 106: 71–74.

  105. 105.

    , , , , , et al. Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 2014; 78: 194–202.

  106. 106.

    , , , , , et al. Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain. Biol Psychiatry 2013; 74: 172–179.

  107. 107.

    , , , , , et al. Oxytocin facilitates protective responses to aversive social stimuli in males. Proc Natl Acad Sci USA 2012; 109: 18144–18149.

  108. 108.

    , , , , , . Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord 2014; 44: 521–531.

  109. 109.

    , , , , , et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 67: 692–694.

  110. 110.

    , , , , , et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012; 3: 16.

  111. 111.

    , , , , , . Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 2010; 107: 4389–4394.

  112. 112.

    , , , . Attachment style moderates the effects of oxytocin on social behaviors and cognitions during social rejection applying a research domain criteria framework to social anxiety. Clin Psychol Sci 2014; 2: 740–747.

  113. 113.

    , , , , , et al. A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. Schizophr Res 2015.

  114. 114.

    , , , , , et al. Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: results from a randomized double blind placebo controlled pilot study. Schizophr Res 2013; 145: 110–115.

  115. 115.

    , , , , , et al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res 2013; 147: 393–397.

  116. 116.

    , , , . Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study. Psychopharmacology (Berl) 2013; 228: 623–631.

  117. 117.

    , , , , , et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology 2013; 38: 2831–2843.

  118. 118.

    , , , , , et al. Effect of long-term intranasal oxytocin on sexual dysfunction in premenopausal and postmenopausal women: a randomized trial. Fertil Steril 2015; 104: 715–723.

  119. 119.

    , , , , , et al. A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome. Am J Med Genet A 2014; 164: 2232–2239.

  120. 120.

    , , , , , et al. A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis. Schizophr Bull 2014; 41: 483–493.

  121. 121.

    , . Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry 2013; 3: e258.

  122. 122.

    , , , , , et al. Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci 2015; 40: E1.

  123. 123.

    . The neurobiology of social cognition. Curr Opin Neurobiol 2001; 11: 231–239.

  124. 124.

    , , , , , et al. Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men. Psychoneuroendocrinology 2012; 37: 447–461.

  125. 125.

    , , , , , et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry 2014.

  126. 126.

    , , , , . Immunohistochemical localization of oxytocin receptors in human brain. Neuroscience 2013; 253: 155–164.

  127. 127.

    , , , , . CSF and blood oxytocin concentration changes following intranasal delivery in macaque. PLoS One 2014; 9: e103677.

  128. 128.

    , , , , . Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci USA 2012; 109: 959–964.

  129. 129.

    , , , . Cerebrospinal fluid and plasma concentrations of oxytocin and vasopressin during parturition and vaginocervical stimulation in the sheep. Brain Res Bull 1991; 26: 803–807.

  130. 130.

    , . Intranasal oxytocin: myths and delusions. Biol Psychiatry 2015.

  131. 131.

    , . Intranasal oxytocin mechanisms can be better understood but its effects on social cognition and behavior are not to be sniffed at. Biol Psychiatry 2015 in press.

  132. 132.

    . Intranasal drug delivery for children with acute illness. Curr Drug Ther 2006; 1: 127–130.

  133. 133.

    . Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J 2004; 21: 275.

  134. 134.

    . KetamineMedical Toxicology of Drug Abuse. John Wiley & Sons, Inc, 2012 pp 110–119.

  135. 135.

    , , , , , et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos 2003; 24: 37–43.

  136. 136.

    , , , , . Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 1996; 77: 203–207.

  137. 137.

    , , . Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012; 62: 63–77.

  138. 138.

    , , , , , et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2014; 170: 1134–1142.

  139. 139.

    , , , , , et al. Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect. Psychol Med 2010; 40: 1443–1451.

  140. 140.

    , , , , , et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry 2012; 72: 331–338.

  141. 141.

    , , , , . Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000; 55: 139–141.

  142. 142.

    , . Nasal drug delivery in EMS: reducing needlestick risk. JEMS 2003; 28: 52–63.

  143. 143.

    , , , , , . Intranasal administration of naloxone by paramedics. Prehosp Emerg Care 2002; 6: 54–58.

  144. 144.

    , , , , , et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–962.

  145. 145.

    , , , , . Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques. Psychoneuroendocrinology 2014; 45: 49–57.

  146. 146.

    , , , . Oxytocin, brain physiology, and functional connectivity: a review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 2013; 38: 962–974.

  147. 147.

    , , , . A role for autonomic cardiac control in the effects of oxytocin on social behavior and psychiatric illness. Front Neurosci 2013; 7: 48.

  148. 148.

    , , , , , . Nasal oxytocin for social deficits in childhood autism: A randomized controlled trial. J Autism Dev Disord 2014; 44: 521–531.

  149. 149.

    , , , , , et al. Oxytocin facilitates the extinction of conditioned fear in humans. Biol Psychiatry 2014; 78: 194–202.

  150. 150.

    , , . Oxytocin enhances the encoding of positive social memories in humans. Biol Psychiatry 2008; 64: 256–258.

  151. 151.

    , , , , . A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 2009; 34: 917–923.

  152. 152.

    , , , , , et al. A randomized, double‐blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. Bipolar Disord 2012; 14: 697–706.

Download references

Author information

Affiliations

  1. NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, University of Oslo, and Oslo University Hospital, Oslo, Norway

    • D S Quintana
    • , L T Westlye
    •  & O A Andreassen
  2. Brain and Mind Center, Central Clinical School, University of Sydney, Sydney, NSW, Australia

    • A J Guastella
  3. Department of Psychology, University of Oslo, Oslo, Norway

    • L T Westlye

Authors

  1. Search for D S Quintana in:

  2. Search for A J Guastella in:

  3. Search for L T Westlye in:

  4. Search for O A Andreassen in:

Competing interests

Daniel S Quintana, Lars T Westlye and Ole A Andreassen are investigators in a project studying oxytocin’s effects after intranasal delivery partnered by OptiNose AS (Oslo, Norway) and funded by a BIA grant (219483) from the Research Council of Norway. Adam J Guastella is an investigator in a project investigating oxytocin’s effects partnered by OptiNose AS and funded by a Linkage Grant from the Australian Research Council (LP150101307). The funders and partner had no influence in the ideas contained in the manuscript and no role in the writing of the manuscript.

Corresponding author

Correspondence to D S Quintana.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/mp.2015.166

Further reading