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Potential of Oxytocin in the Treatment of Schizophrenia

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Abstract

Schizophrenia is a heterogeneous, debilitating disorder characterized by three distinct sets of clinical features: positive symptoms, negative symptoms, and cognitive deficits. Extant antipsychotic drugs have been most successful at treating the positive symptoms of patients with schizophrenia but have minimal therapeutic effects on negative symptoms and cognitive deficits, which are the symptoms that best predict the poor prognosis of these patients. Therefore, there has been a major effort towards identifying compounds that alleviate these symptoms. Oxytocin (OT) is a nonapeptide that regulates peripheral reproductive-relevant functions, and also acts as a neurotransmitter in the brain. Converging evidence from both preclinical and clinical research suggests that OT may have therapeutic efficacy for the positive symptoms, negative symptoms, and cognitive deficits of schizophrenia. In the majority of the small, randomized, placebo-controlled clinical trials conducted to date, OT has shown particular promise in its potential to treat the intractable negative symptoms and social cognitive deficits exhibited by most of the patients with this debilitating disorder. In this leading article, we summarize the clinical evidence relevant to (1) endogenous OT and schizophrenia, and (2) the putative therapeutic effects of OT on each of the three clinical domains.

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References

  1. Young J, Geyer M. Developing treatments for cognitive deficits in schizophrenia: the challenge of translation. J Psychopharmacol. 2015;29(2):178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Feifel D, Shilling PD. Modeling schizophrenia in animals. In: Conn MP, editor. Animal models for the study of human disease. New York: Elsevier; 2013. p. 727–48.

    Chapter  Google Scholar 

  3. Nordstrom AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry. 1993;33(4):227–35.

    Article  CAS  PubMed  Google Scholar 

  4. Weinberger DR, Gallhofer B. Cognitive function in schizophrenia. Int Clin Psychopharmacol. 1997;12(Suppl 4):S29–36.

    Article  PubMed  Google Scholar 

  5. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry. 2012;17(12):1206–27.

    Article  CAS  PubMed  Google Scholar 

  6. Minassian A, Young JW. Evaluation of the clinical efficacy of asenapine in schizophrenia. Expert Opin Pharmacother. 2010;11(12):2107–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kuroki T, Nagao N, Nakahara T. Neuropharmacology of second-generation antipsychotic drugs: a validity of the serotonin-dopamine hypothesis. Prog Brain Res. 2008;172:199–212.

    Article  CAS  PubMed  Google Scholar 

  8. Krakowski MI, Czobor P, Nolan KA. Atypical antipsychotics, neurocognitive deficits, and aggression in schizophrenic patients. J Clin Psychopharmacol. 2008;28(5):485–93.

    Article  PubMed  Google Scholar 

  9. McGurk SR, Lee MA, Jayathilake K, Meltzer HY. Cognitive effects of olanzapine treatment in schizophrenia. Med Gen Med. 2004;6(2):27.

    Google Scholar 

  10. Carpenter WT, Koenig JI. The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology. 2008;33(9):2061–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32(2):214–9.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Sarnyai Z, Kovacs GL. Oxytocin in learning and addiction: from early discoveries to the present. Pharmacol Biochem Behav. 2014;119:3–9.

    Article  CAS  PubMed  Google Scholar 

  13. Sumiyoshi T, Kunugi H, Nakagome K. Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia. Front Neurosci. 2014;8:395.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dolen G, Darvishzadeh A, Huang KW, Malenka RC. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature. 2013;501(7466):179–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Skuse DH, Gallagher L. Genetic influences on social cognition. Pediatr Res. 2011;69(5 Pt 2):85R–91R.

    Article  PubMed  Google Scholar 

  16. Rosenfeld AJ, Lieberman JA, Jarskog LF. Oxytocin, dopamine, and the amygdala: a neurofunctional model of social cognitive deficits in schizophrenia. Schizophr Bull. 2011;37(5):1077–87.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Donaldson ZR, Young LJ. Oxytocin, vasopressin, and the neurogenetics of sociality. Science. 2008;322(5903):900–4.

    Article  CAS  PubMed  Google Scholar 

  18. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81(2):629–83.

    CAS  PubMed  Google Scholar 

  19. Sogolow SR. An historical review of the use of oxytocin prior to delivery. Obstet Gynecol Surv. 1966;21(2):155–72.

    Article  CAS  PubMed  Google Scholar 

  20. Uvnas-Moberg K, Eriksson M. Breastfeeding: physiological, endocrine and behavioural adaptations caused by oxytocin and local neurogenic activity in the nipple and mammary gland. Acta Paediatr. 1996;85(5):525–30.

    Article  CAS  PubMed  Google Scholar 

  21. Landgraf R, Neumann ID. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol. 2004;25(3–4):150–76.

    Article  CAS  PubMed  Google Scholar 

  22. Meister B. Gene expression and chemical diversity in hypothalamic neurosecretory neurons. Mol Neurobiol. 1993;7(2):87–110.

    Article  CAS  PubMed  Google Scholar 

  23. Stoop R. Neuromodulation by oxytocin and vasopressin. Neuron. 2012;76(1):142–59.

    Article  CAS  PubMed  Google Scholar 

  24. Horn AM, Robinson IC, Fink G. Oxytocin and vasopressin in rat hypophysial portal blood: experimental studies in normal and Brattleboro rats. J Endocrinol. 1985;104(2):211–24.

    Article  CAS  PubMed  Google Scholar 

  25. Macdonald K, Feifel D. Oxytocin in schizophrenia: a review of evidence for its therapeutic effects. Acta Neuropsychiatr. 2012;24(3):130–46.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Veening JG, de Jong T, Barendregt HP. Oxytocin-messages via the cerebrospinal fluid: behavioral effects; a review. Physiol Behav. 2010;101(2):193–210.

    Article  CAS  PubMed  Google Scholar 

  27. Loup F, Tribollet E, Dubois-Dauphin M, Dreifuss JJ. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study. Brain Res. 1991;555(2):220–32.

    Article  CAS  PubMed  Google Scholar 

  28. Loup F, Tribollet E, Dubois-Dauphin M, Pizzolato G, Dreifuss JJ. Localization of oxytocin binding sites in the human brainstem and upper spinal cord: an autoradiographic study. Brain Res. 1989;500(1–2):223–30.

    Article  CAS  PubMed  Google Scholar 

  29. Tribollet E, Dubois-Dauphin M, Dreifuss JJ, Barberis C, Jard S. Oxytocin receptors in the central nervous system. Distribution, development, and species differences. Ann N Y Acad Sci. 1992;652:29–38.

    Article  CAS  PubMed  Google Scholar 

  30. Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, et al. Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol. 2012;24(4):609–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, Capurro V, et al. Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry. 2011;69(9):875–82.

    Article  CAS  PubMed  Google Scholar 

  32. Schorscher-Petcu A, Sotocinal S, Ciura S, Dupre A, Ritchie J, Sorge RE, et al. Oxytocin-induced analgesia and scratching are mediated by the vasopressin-1A receptor in the mouse. J Neurosci. 2010;30(24):8274–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Song Z, McCann KE, McNeill JK 4th, Larkin TE 2nd, Huhman KL, Albers HE. Oxytocin induces social communication by activating arginine-vasopressin V1a receptors and not oxytocin receptors. Psychoneuroendocrinology. 2014;50C:14–9.

    Article  CAS  Google Scholar 

  34. Insel TR, Young L, Wang Z. Molecular aspects of monogamy. Ann N Y Acad Sci. 1997;807:302–16.

    Article  CAS  PubMed  Google Scholar 

  35. Shahrokh DK, Zhang TY, Diorio J, Gratton A, Meaney MJ. Oxytocin-dopamine interactions mediate variations in maternal behavior in the rat. Endocrinology. 2010;151(5):2276–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baskerville TA, Allard J, Wayman C, Douglas AJ. Dopamine-oxytocin interactions in penile erection. Eur J Neurosci. 2009;30(11):2151–64.

    Article  CAS  PubMed  Google Scholar 

  37. Succu S, Sanna F, Melis T, Boi A, Argiolas A, Melis MR. Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: involvement of central oxytocin. Neuropharmacology. 2007;52(3):1034–43.

    Article  CAS  PubMed  Google Scholar 

  38. Caldwell HK, Stephens SL, Young WS 3rd. Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice. Mol Psychiatry. 2009;14(2):190–6.

    Article  CAS  PubMed  Google Scholar 

  39. Hrabovszky E, Liposits Z. Novel aspects of glutamatergic signalling in the neuroendocrine system. J Neuroendocrinol. 2008;20(6):743–51.

    Article  CAS  PubMed  Google Scholar 

  40. Ninan I. Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex. J Neurochem. 2011;119(2):324–31.

    Article  CAS  PubMed  Google Scholar 

  41. Emiliano AB, Cruz T, Pannoni V, Fudge JL. The interface of oxytocin-labeled cells and serotonin transporter-containing fibers in the primate hypothalamus: a substrate for SSRIs therapeutic effects? Neuropsychopharmacology. 2007;32(5):977–88.

    Article  CAS  PubMed  Google Scholar 

  42. Feifel D, Reza T. Oxytocin modulates psychotomimetic-induced deficits in sensorimotor gating. Psychopharmacology. 1999;141(1):93–8.

    Article  CAS  PubMed  Google Scholar 

  43. Feifel D, Shilling PD, Macdonald K. A review of oxytocin’s effects on the positive, negative, and cognitive domains of schizophrenia. Biol Psychiatry. 2016;79:222–33.

    Article  CAS  PubMed  Google Scholar 

  44. Bartholomeusz CF, Ganella EP, Labuschagne I, Bousman C, Pantelis C. Effects of oxytocin and genetic variants on brain and behaviour: implications for treatment in schizophrenia. Schizophr Res. 2015. doi:10.1016/j.schres.2015.06.007.

    Google Scholar 

  45. Kagerbauer SM, Martin J, Schuster T, Blobner M, Kochs EF, Landgraf R. Plasma oxytocin and vasopressin do not predict neuropeptide concentrations in human cerebrospinal fluid. J Neuroendocrinol. 2013;25(7):668–73.

    Article  CAS  PubMed  Google Scholar 

  46. Takagi T, Tanizawa O, Otsuki Y, Sugita N, Haruta M, Yamaji K. Oxytocin in the cerebrospinal fluid and plasma of pregnant and nonpregnant subjects. Horm Metab Res. 1985;17(6):308–10.

    Article  CAS  PubMed  Google Scholar 

  47. Carson DS, Berquist SW, Trujillo TH, Garner JP, Hannah SL, Hyde SA, et al. Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children. Mol Psychiatry. 2015;20(9):1085–90.

    Article  CAS  PubMed  Google Scholar 

  48. Veenema AH, Neumann ID. Central vasopressin and oxytocin release: regulation of complex social behaviours. Prog Brain Res. 2008;170:261–76.

    Article  CAS  PubMed  Google Scholar 

  49. Rubin LH, Carter CS, Drogos L, Pournajafi-Nazarloo H, Sweeney JA, Maki PM. Peripheral oxytocin is associated with reduced symptom severity in schizophrenia. Schizophr Res. 2010;124(1–3):13–21.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Rubin LH, Carter CS, Bishop JR, Pournajafi-Nazarloo H, Drogos LL, Hill SK, et al. Reduced levels of vasopressin and reduced behavioral modulation of oxytocin in psychotic disorders. Schizophr Bull. 2014;40(6):1374–84.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Souza RP, de Luca V, Meltzer HY, Lieberman JA, Kennedy JL. Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes. Int J Neuropsychopharmacol. 2010;13(6):793–8.

    Article  CAS  PubMed  Google Scholar 

  52. Jobst A, Dehning S, Ruf S, Notz T, Buchheim A, Henning-Fast K, et al. Oxytocin and vasopressin levels are decreased in the plasma of male schizophrenia patients. Acta Neuropsychiatr. 2014;26(6):347–55.

    Article  PubMed  Google Scholar 

  53. Sasayama D, Hattori K, Teraishi T, Hori H, Ota M, Yoshida S, et al. Negative correlation between cerebrospinal fluid oxytocin levels and negative symptoms of male patients with schizophrenia. Schizophr Res. 2012;139(1–3):201–6.

    Article  PubMed  Google Scholar 

  54. Strauss GP, Keller WR, Koenig JI, Gold JM, Ossenfort KL, Buchanan RW. Plasma oxytocin levels predict olfactory identification and negative symptoms in individuals with schizophrenia. Schizophr Res. 2015;162(1–3):57–61.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Keri S, Kiss I, Kelemen O. Sharing secrets: oxytocin and trust in schizophrenia. Soc Neurosci. 2009;4(4):287–93.

    Article  PubMed  Google Scholar 

  56. Teltsh O, Kanyas-Sarner K, Rigbi A, Greenbaum L, Lerer B, Kohn Y. Oxytocin and vasopressin genes are significantly associated with schizophrenia in a large Arab-Israeli pedigree. Int J Neuropsychopharmacol. 2012;15(3):309–19.

    Article  CAS  PubMed  Google Scholar 

  57. Montag C, Brockmann EM, Bayerl M, Rujescu D, Muller DJ, Gallinat J. Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia: a case-control study. World J Biol Psychiatry. 2013;14(7):500–8.

    Article  PubMed  Google Scholar 

  58. Haram M, Tesli M, Bettella F, Djurovic S, Andreassen OA, Melle I. Association between genetic variation in the oxytocin receptor gene and emotional withdrawal, but not between oxytocin pathway genes and diagnosis in psychotic disorders. Front Hum Neurosci. 2015;9:9.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Chang WH, Lee IH, Chen KC, Chi MH, Chiu NT, Yao WJ, et al. Oxytocin receptor gene rs53576 polymorphism modulates oxytocin-dopamine interaction and neuroticism traits—a SPECT study. Psychoneuroendocrinology. 2014;47:212–20.

    Article  CAS  PubMed  Google Scholar 

  60. Wang J, Qin W, Liu B, Wang D, Zhang Y, Jiang T, et al. Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects. Neuroimage. 2013;81:199–204.

    Article  CAS  PubMed  Google Scholar 

  61. Wang J, Qin W, Liu B, Zhou Y, Wang D, Zhang Y, et al. Neural mechanisms of oxytocin receptor gene mediating anxiety-related temperament. Brain Struct Funct. 2014;219(5):1543–54.

    Article  CAS  PubMed  Google Scholar 

  62. Goldman M, Marlow-O’Connor M, Torres I, Carter CS. Diminished plasma oxytocin in schizophrenic patients with neuroendocrine dysfunction and emotional deficits. Schizophr Res. 2008;98(1–3):247–55.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Rubin LH, Carter CS, Drogos L, Jamadar R, Pournajafi-Nazarloo H, Sweeney JA, et al. Sex-specific associations between peripheral oxytocin and emotion perception in schizophrenia. Schizophr Res. 2011;130(1–3):266–70.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Brown EC, Tas C, Kuzu D, Esen-Danaci A, Roelofs K, Brune M. Social approach and avoidance behaviour for negative emotions is modulated by endogenous oxytocin and paranoia in schizophrenia. Psychiatry Res. 2014;219(3):436–42.

    Article  CAS  PubMed  Google Scholar 

  65. Strauss GP, Keller WR, Koenig JI, Sullivan SK, Gold JM, Buchanan RW. Endogenous oxytocin levels are associated with the perception of emotion in dynamic body expressions in schizophrenia. Schizophr Res. 2015;162(1–3):52–6.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Strauss GP, Keller WR, Koenig JI, Gold JM, Frost KH, Buchanan RW. Plasma oxytocin levels predict social cue recognition in individuals with schizophrenia. Schizophr Res. 2015. doi:10.1016/j.schres.2015.01.034.

    Google Scholar 

  67. Frost K, Keller W, Buchanan R, Gold J, Koenig J, Ossenfort K, et al. C-14Plasma oxytocin levels are associated with impaired social cognition and neurocognition in schizophrenia. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol. 2014;29(6):577–8.

    Article  Google Scholar 

  68. Rubin LH, Carter CS, Bishop JR, Pournajafi-Nazarloo H, Harris MS, Hill SK, et al. Peripheral vasopressin but not oxytocin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis. Schizophr Res. 2013;146(1–3):138–43.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Davis MC, Horan WP, Nurmi EL, Rizzo S, Li W, Sugar CA, et al. Associations between oxytocin receptor genotypes and social cognitive performance in individuals with schizophrenia. Schizophr Res. 2014;159(2–3):353–7.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Damiano CR, Aloi J, Dunlap K, Burrus CJ, Mosner MG, Kozink RV, et al. Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards. Mol Autism. 2014;5(1):7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Montag C, Brockmann EM, Lehmann A, Muller DJ, Rujescu D, Gallinat J. Association between oxytocin receptor gene polymorphisms and self-rated ‘empathic concern’ in schizophrenia. PLoS One. 2012;7(12):e51882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tost H, Kolachana B, Verchinski BA, Bilek E, Goldman AL, Mattay VS, et al. Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults. Biol Psychiatry. 2011;70(9):e37–9 (author reply e41–2).

    Article  CAS  PubMed  Google Scholar 

  73. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005;435(7042):673–6.

    Article  CAS  PubMed  Google Scholar 

  74. Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron. 2008;58(4):639–50.

    Article  CAS  PubMed  Google Scholar 

  75. Feifel D, Macdonald K, Nguyen A, Cobb P, Warlan H, Galangue B, et al. Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry. 2010;68(7):678–80.

    Article  CAS  PubMed  Google Scholar 

  76. Feifel D, Macdonald K, Cobb P, Minassian A. Adjunctive intranasal oxytocin improves verbal memory in people with schizophrenia. Schizophr Res. 2012;139(1–3):207–10.

    Article  PubMed  Google Scholar 

  77. Michalopoulou PG, Averbeck BB, Kalpakidou AK, Evans S, Bobin T, Kapur S, et al. The effects of a single dose of oxytocin on working memory in schizophrenia. Schizophr Res. 2015;162(1–3):62–3.

    Article  PubMed  Google Scholar 

  78. Pedersen CA, Gibson CM, Rau SW, Salimi K, Smedley KL, Casey RL, et al. Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia. Schizophr Res. 2011;132(1):50–3.

    Article  PubMed  Google Scholar 

  79. Modabbernia A, Rezaei F, Salehi B, Jafarinia M, Ashrafi M, Tabrizi M, et al. Intranasal oxytocin as an adjunct to risperidone in patients with schizophrenia: an 8-week, randomized, double-blind, placebo-controlled study. CNS Drugs. 2013;27(1):57–65.

    Article  CAS  PubMed  Google Scholar 

  80. Lee MR, Wehring HJ, McMahon RP, Linthicum J, Cascella N, Liu F, 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(1–3):110–5.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gibson CM, Penn DL, Smedley KL, Leserman J, Elliott T, Pedersen CA. A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia. Schizophr Res. 2014;156(2–3):261–5.

    Article  PubMed  Google Scholar 

  82. Singewald N, Schmuckermair C, Whittle N, Holmes A, Ressler KJ. Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther. 2014. doi:10.1016/j.pharmthera.2014.12.004.

    PubMed  PubMed Central  Google Scholar 

  83. Cacciotti-Saija C, Langdon R, Ward PB, Hickie IB, Scott EM, Naismith SL, 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. doi:10.1093/schbul/sbu094.

    PubMed  PubMed Central  Google Scholar 

  84. Davis MC, Green MF, Lee J, Horan WP, Senturk D, Clarke AD, et al. Oxytocin-augmented social cognitive skills training in schizophrenia. Neuropsychopharmacology. 2014. doi:10.1038/npp.2014.68.

    Google Scholar 

  85. Averbeck BB, Bobin T, Evans S, Shergill SS. Emotion recognition and oxytocin in patients with schizophrenia. Psychol Med. 2012;42(2):259–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Goldman MB, Gomes AM, Carter CS, Lee R. Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia. Psychopharmacology. 2011;216(1):101–10.

    Article  CAS  PubMed  Google Scholar 

  87. Fischer-Shofty M, Brune M, Ebert A, Shefet D, Levkovitz Y, Shamay-Tsoory SG. Improving social perception in schizophrenia: the role of oxytocin. Schizophr Res. 2013;146(1–3):357–62.

    Article  CAS  PubMed  Google Scholar 

  88. Davis MC, Lee J, Horan WP, Clarke AD, McGee MR, Green MF, et al. Effects of single dose intranasal oxytocin on social cognition in schizophrenia. Schizophr Res. 2013;147(2–3):393–7.

    Article  PubMed  Google Scholar 

  89. Woolley JD, Chuang B, Lam O, Lai W, O’Donovan A, Rankin KP, et al. Oxytocin administration enhances controlled social cognition in patients with schizophrenia. Psychoneuroendocrinology. 2014;47:116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Guastella AJ, Ward PB, Hickie IB, Shahrestani S, Hodge MA, Scott EM, et al. A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia. Schizophr Res. 2015;168(3):628–33.

    Article  Google Scholar 

  91. Evans SL, Dal Monte O, Noble P, Averbeck BB. Intranasal oxytocin effects on social cognition: a critique. Brain Res. 2014;1580:69–77.

    Article  CAS  PubMed  Google Scholar 

  92. Shin NY, Park HY, Jung WH, Park JW, Yun JY, Jang JH, et al. Effects of oxytocin on neural response to facial expressions in patients with schizophrenia. Neuropsychopharmacology. 2015;40(8):1919–27.

    Article  CAS  PubMed  Google Scholar 

  93. Wigton R, Radua J, Allen P, Averbeck B, Meyer-Lindenberg A, McGuire P, et al. Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. J Psychiatry Neurosci. 2015;40(1):E1–22.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Striepens N, Kendrick KM, Hanking V, Landgraf R, Wullner U, Maier W, et al. Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans. Sci Rep. 2013;3:3440.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Chang SW, Barter JW, Ebitz RB, Watson KK, Platt ML. Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta). Proc Natl Acad Sci USA. 2012;109(3):959–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Neumann ID, Maloumby R, Beiderbeck DI, Lukas M, Landgraf R. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology. 2013;38(10):1985–93.

    Article  CAS  PubMed  Google Scholar 

  97. Vaccari C, Lolait SJ, Ostrowski NL. Comparative distribution of vasopressin V1b and oxytocin receptor messenger ribonucleic acids in brain. Endocrinology. 1998;139(12):5015–33.

    CAS  PubMed  Google Scholar 

  98. Bales KL, Solomon M, Jacob S, Crawley JN, Silverman JL, Larke RH, et al. Long-term exposure to intranasal oxytocin in a mouse autism model. Transl Psychiatry. 2014;4:e480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bales KL, Perkeybile AM, Conley OG, Lee MH, Guoynes CD, Downing GM, et al. Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles. Biol Psychiatry. 2013;74(3):180–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Huang H, Michetti C, Busnelli M, Manago F, Sannino S, Scheggia D, et al. Chronic and acute intranasal oxytocin produce divergent social effects in mice. Neuropsychopharmacology. 2014;39(5):1102–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rault JL, Carter CS, Garner JP, Marchant-Forde JN, Richert BT, Lay DC Jr. Repeated intranasal oxytocin administration in early life dysregulates the HPA axis and alters social behavior. Physiol Behav. 2013;112–113:40–8.

    Article  PubMed  CAS  Google Scholar 

  102. Boers M. Add-on or step-up trials for new drug development in rheumatoid arthritis: a new standard? Arthritis Rheum. 2003;48(6):1481–3.

    Article  PubMed  Google Scholar 

  103. Ottolenghi L, Bertele V, Garattini S. Limits of add-on trials: antirheumatic drugs. Eur J Clin Pharmacol. 2009;65(1):33–41.

    Article  PubMed  Google Scholar 

  104. Hirota T, Schwartz S, Correll CU. Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. J Am Acad Child Adolesc Psychiatry. 2014;53(2):153–73.

    Article  PubMed  Google Scholar 

  105. Feifel D. The use of placebo-controlled clinical trials for the approval of psychiatric drugs: Part II-ethical considerations related to the individual participant. Psychiatry (Edgmont). 2009;6(12):19–25.

    PubMed  PubMed Central  Google Scholar 

  106. MacDonald K, Feifel D. Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. Front Neurosci. 2013;7:35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Figueira ML, Ouakinin S. Gender-related endocrinological dysfunction and mental disorders. Curr Opin Psychiatry. 2010;23(4):369–72.

    Article  PubMed  Google Scholar 

  108. Mendrek A, Stip E. Sexual dimorphism in schizophrenia: is there a need for gender-based protocols? Expert Rev Neurother. 2011;11(7):951–9.

    Article  CAS  PubMed  Google Scholar 

  109. Champagne F, Diorio J, Sharma S, Meaney MJ. Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors. Proc Natl Acad Sci USA. 2001;98(22):12736–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Patisaul HB, Scordalakes EM, Young LJ, Rissman EF. Oxytocin, but not oxytocin receptor, is regulated by oestrogen receptor beta in the female mouse hypothalamus. J Neuroendocrinol. 2003;15(8):787–93.

    Article  CAS  PubMed  Google Scholar 

  111. Murakami G, Hunter RG, Fontaine C, Ribeiro A, Pfaff D. Relationships among estrogen receptor, oxytocin and vasopressin gene expression and social interaction in male mice. Eur J Neurosci. 2011;34(3):469–77.

    Article  CAS  PubMed  Google Scholar 

  112. Popeski N, Amir S, Diorio J, Woodside B. Prolactin and oxytocin interaction in the paraventricular and supraoptic nuclei: effects on oxytocin mRNA and nitric oxide synthase. J Neuroendocrinol. 2003;15(7):687–96.

    Article  CAS  PubMed  Google Scholar 

  113. Uvnas-Moberg K, Alster P, Svensson TH. Amperozide and clozapine but not haloperidol or raclopride increase the secretion of oxytocin in rats. Psychopharmacology. 1992;109(4):473–6.

    Article  CAS  PubMed  Google Scholar 

  114. Kiss A, Bundzikova J, Pirnik Z, Mikkelsen JD. Different antipsychotics elicit different effects on magnocellular oxytocinergic and vasopressinergic neurons as revealed by Fos immunohistochemistry. J Neurosci Res. 2010;88(3):677–85.

    CAS  PubMed  Google Scholar 

  115. Gordon I, Zagoory-Sharon O, Leckman JF, Feldman R. Oxytocin and the development of parenting in humans. Biol Psychiatry. 2010;68(4):377–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Holt-Lunstad J, Birmingham W, Light KC. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrinology. 2011;36(8):1249–56.

    Article  CAS  PubMed  Google Scholar 

  117. Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M, et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology. 2010;35(1):83–93.

    Article  CAS  PubMed  Google Scholar 

  118. Bartz JA, Zaki J, Bolger N, Ochsner KN. Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci. 2011;15(7):301–9.

    CAS  PubMed  Google Scholar 

  119. Macdonald KS. Sex, receptors, and attachment: a review of individual factors influencing response to oxytocin. Front Neurosci. 2012;6:194.

    PubMed  PubMed Central  Google Scholar 

  120. Walss-Bass C, Fernandes JM, Roberts DL, Service H, Velligan D. Differential correlations between plasma oxytocin and social cognitive capacity and bias in schizophrenia. Schizophr Res. 2013;147(2-3):387–92.

    Article  PubMed  Google Scholar 

  121. Linkowski P, Geenen V, Kerkhofs M, Mendlewicz J, Legros JJ. Cerebrospinal fluid neurophysins in affective illness and in schizophrenia. Eur Arch Psychiatry Neurol Sci. 1984;234(3):162–5.

    Article  CAS  PubMed  Google Scholar 

  122. Beckmann H, Lang RE, Gattaz WF. Vasopressin–oxytocin in cerebrospinal fluid of schizophrenic patients and normal controls. Psychoneuroendocrinology. 1985;10(2):187–91 (pii: 0306-4530(85)90056-3).

    Article  CAS  PubMed  Google Scholar 

  123. Legros JJ, Gazzotti C, Carvelli T, Franchimont P, Timsit-Berthier M, von Frenckell R, et al. Apomorphine stimulation of vasopressin- and oxytocin-neurophysins. Evidence for increased oxytocinergic and decreased vasopressinergic function in schizophrenics. Psychoneuroendocrinology. 1992;17(6):611–7.

    Article  CAS  PubMed  Google Scholar 

  124. Mai JK, Berger K, Sofroniew MV. Morphometric evaluation of neurophysin-immunoreactivity in the human brain: pronounced inter-individual variability and evidence for altered staining patterns in schizophrenia. J Hirnforsch. 1993;34(2):133–54.

    CAS  PubMed  Google Scholar 

  125. Glovinsky D, Kalogeras KT, Kirch DG, Suddath R, Wyatt RJ. Cerebrospinal fluid oxytocin concentration in schizophrenic patients does not differ from control subjects and is not changed by neuroleptic medication. Schizophr Res. 1994;11(3):273–6.

    Article  CAS  PubMed  Google Scholar 

  126. Souza RP, Ismail P, Meltzer HY, Kennedy JL. Variants in the oxytocin gene and risk for schizophrenia. Schizophr Res. 2010;121(1–3):279–80.

    Article  PubMed  Google Scholar 

  127. Watanabe Y, Kaneko N, Nunokawa A, Shibuya M, Egawa J, Someya T. Oxytocin receptor (OXTR) gene and risk of schizophrenia: case-control and family-based analyses and meta-analysis in a Japanese population. Psychiatry Clin Neurosci. 2012;66(7):622.

    Article  PubMed  Google Scholar 

  128. Fischer-Shofty M, Shamay-Tsoory SG, Levkovitz Y. Characterization of the effects of oxytocin on fear recognition in patients with schizophrenia and in healthy controls. Front Neurosci. 2013;7:127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. de Macedo LRH, Zuardi AW, Machado-de-Sousa JP, Chagas MH, Hallak JE. Oxytocin does not improve performance of patients with schizophrenia and healthy volunteers in a facial emotion matching task. Psychiatry Res. 2014;220(1–2):125–8.

    Article  CAS  Google Scholar 

  130. Bujanow W. Hormones in the treatment of psychoses. Br Med J. 1972;4(5835):298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bujanow W. Letter: is oxytocin an anti-schizophrenic hormone? Can Psychiatr Assoc J. 1974;19(3):323.

    CAS  PubMed  Google Scholar 

  132. Bakharev VD, Tikhomirov SM, Lozhkina TK. Psychotropic properties of oxytocin. Probl Endokrinol (Mosk). 1984;30(2):37–41.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Paul D. Shilling

  2. Department of Psychiatry, University of California, San Diego Medical Center, 200 West Arbor Drive, San Diego, CA, 92103-8218, USA

    David Feifel

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  1. Paul D. Shilling
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  2. David Feifel
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Correspondence to David Feifel.

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DF is named inventor of a patent filing by UCSD involving the use of oxytocin. PDS reports no biomedical financial interests or potential conflicts of interest.

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DF and PDS are partially funded by NIMH (RO1 MH103421-01A1).

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Shilling, P.D., Feifel, D. Potential of Oxytocin in the Treatment of Schizophrenia. CNS Drugs 30, 193–208 (2016). https://doi.org/10.1007/s40263-016-0315-x

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