Introduction: In recent years, several studies were conducted to explore the potential augmenting effect of oxytocin for the treatment of individuals with severe mental illness. Nonetheless, studies exploring its effects in routine inpatient settings using high-quality randomized controlled trials are scarce. The current study assessed the effect of oxytocin administration on treatment process and outcome among psychiatric inpatients, while employing a rigorous experimental methodology. Methods: A double-blind, placebo-controlled, randomized trial was conducted at a public psychiatric hospital in Israel. Patients (N = 87, 71.3% female participants) were administered intranasal oxytocin/placebo twice daily for 4 weeks, as add-on to usual care. Patients were assessed for severity of anxiety and depression symptoms and their working alliance with their therapist after each therapy session, and treatment outcome was assessed weekly. Multilevel modeling was performed to assess the linear change from pre- to post-treatment. Results: Patients receiving OT demonstrated significantly larger symptomatic improvements (B = −0.01, t [437] = −2.36, p = 0.01). Larger gains were also observed for depression (B = −0.14, p < 0.001 in the OT group, B = −0.06, p = 0.02 in the placebo group) and general distress (B = −0.57, p < 0.001 in the OT group, B = −0.29, p = 0.02 in the placebo group). No significant effect was observed for anxiety, the working alliance, or attachment. Discussion: Oxytocin has the potential to improve treatment outcome among inpatients. Nonetheless, additional controlled research is needed to further assess its effects on therapy process, as well as to account for therapeutic, pharmacological, and neuronal intervening factors.

1.
Hertenstein E, Trinca E, Schneider CL, Wunderlin M, Fehér K, Riemann D, et al. Augmentation of psychotherapy with neurobiological methods: current state and future directions. Neuropsychobiology. 2021 Apr;80(6):437–53.
2.
Peled-Avron L, Abu-Akel A, Shamay-Tsoory S. Exogenous effects of oxytocin in five psychiatric disorders: a systematic review, meta-analyses and a personalized approach through the lens of the social salience hypothesis. Neurosci Biobehav Rev. 2020 Jul;114:70–95.
3.
Scantamburlo G, Hansenne M, Geenen V, Legros JJ, Ansseau M. Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: an open trial. Eur Psychiatry. 2015 Jan;30(1):65–8.
4.
Parker KJ, Oztan O, Libove RA, Sumiyoshi RD, Jackson LP, Karhson DS, et al. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci U S A. 2017 Jul;114(30):8119–24.
5.
De Coster L, Lin L, Mathalon DH, Woolley JD. Neural and behavioral effects of oxytocin administration during theory of mind in schizophrenia and controls: a randomized control trial. Neuropsychopharmacology. 2019 May;44(11):1925–31.
6.
Olff M, Langeland W, Witteveen A, Denys D. A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder. CNS Spectr. 2010 Aug;15(8):522–30.
7.
Xu L, Becker B, Kendrick KM. Oxytocin facilitates social learning by promoting conformity to trusted individuals. Front Neurosci. 2019 Feb;13:56.
8.
Crits-Christoph P, Rieger A, Gaines A, Gibbons MBC. Trust and respect in the patient-clinician relationship: preliminary development of a new scale. BMC Psychol. 2019;7(1):91–8.
9.
Flückiger C, Del Re AC, Wampold BE, Horvath AO. The alliance in adult psychotherapy: a meta-analytic synthesis. Psychotherapy. 2018 May;55(4):316–40.
10.
Levy KN, Kivity Y, Johnson BN, Gooch CV. Adult attachment as a predictor and moderator of psychotherapy outcome: a meta-analysis. J Clin Psychol. 2018 Sep;74(11):1996–2013.
11.
Bernaerts S, Prinsen J, Berra E, Bosmans G, Steyaert J, Alaerts K. Long-term oxytocin administration enhances the experience of attachment. Psychoneuroendocrinology. 2017 Apr;78:1–9.
12.
Flanagan JC, Sippel LM, Wahlquist A, Moran-Santa Maria MM, Back SE. Augmenting prolonged exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial. J Psychiatr Res. 2018 Mar;98:64–9.
13.
Stauffer CS, Musinipally V, Suen A, Lynch KL, Shapiro B, Woolley JD. A two-week pilot study of intranasal oxytocin for cocaine-dependent individuals receiving methadone maintenance treatment for opioid use disorder. Addict Res Theor. 2016 Mar;24(6):490–8.
14.
MacDonald K, MacDonald TM, Brüne M, Lamb K, Wilson MP, Golshan S, et al. Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology. 2013 Dec;38(12):2831–43.
15.
Walum H, Waldman ID, Young LJ. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatry. 2016 Feb;79(3):251–7.
16.
Horta M, Kaylor K, Feifel D, Ebner NC. Chronic oxytocin administration as a tool for investigation and treatment: a cross-disciplinary systematic review. Neurosci Biobehav Rev. 2020 Jan;108:1–23.
17.
Elliott ML, Romer A, Knodt AR, Hariri AR. A connectome-wide functional signature of transdiagnostic risk for mental illness. Biol Psychiatry. 2018 Sep;84(6):452–9.
18.
Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: the scale for suicide ideation. J Consult Clin Psychol. 1979;47(2):343–52.
19.
Bakermans-Kranenburg MJ, Van Ijzendoorn MH. Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry. 2013 May;3(5):e258.
20.
MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ. A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology. 2011 Sep;36(8):1114–26.
21.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56–62.
22.
Spielberger CD, Gorsuch RL, Lushene RE. Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press; 1983.
23.
Lambert MJ, Burlingame GM, Umphress V, Hansen NB, Vermeersch DA, Clouse GC, et al. The reliability and validity of the outcome questionnaire. Clin Psychol Psychother. 1996 Dec;3(4):249–58.
24.
Lutz W, Tholen S, Schürch E, Berking M. Reliabilität von kurzformen gängiger psychometrischer instrumente zur evaluation des therapeutischen fortschritts in psychotherapie und psychiatrie. Diagnostica. 2006 Jan;52(1):11–25.
25.
Falkenström F, Hatcher RL, Skjulsvik T, Larsson MH, Holmqvist R. Development and validation of a 6-item working alliance questionnaire for repeated administrations during psychotherapy. Psychol Assess. 2015 Mar;27(1):169–83.
26.
Brennan KA, Clark CL, Shaver PR. Self-report measurement of adult attachment: an integrative overview. In: Simpson JA, Rholes WS, editors. Attachment theory and close relationships. New York, NY: Guilford Press; 1998. p. 46–76.
27.
Faul F, Erdfelder E, Lang AG, Buchner AG. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175–91.
28.
Verbeke G, Molenberghs G. Linear mixed models in practice: a SAS-oriented approach. New York, NY: Springer; 1997. p. 160–72.
29.
Pinheiro J, Bates D, DebRoy S, Sarkar D. nlme: linear and nonlinear mixed effects models. R package version 3.1-122; 2016.
30.
Frijling JL. Preventing PTSD with oxytocin: effects of oxytocin administration on fear neurocircuitry and PTSD symptom development in recently trauma-exposed individuals. Eur J Psychotraumatol. 2017 Feb;8(1):1302652.
31.
Baron-Cohen KL, Feldman R, Fearon P, Fonagy P. Intranasal oxytocin administration improves mood in new mothers with moderate low mood but not in mothers with elevated symptoms of postnatal depression: a randomised controlled trial. J Affect Disord. 2020Mar;300:358–65.
32.
Kahn JH, Schneider WJ. It’s the destination and it’s the journey: using multilevel modeling to assess patterns of change in psychotherapy. J Clin Psychol. 2013 Jan;69(6):543–70.
33.
Cardoso C, Kingdon D, Ellenbogen MA. A meta-analytic review of the impact of intranasal oxytocin administration on cortisol concentrations during laboratory tasks: moderation by method and mental health. Psychoneuroendocrinology. 2014 Nov;49:161–70.
34.
Wirth MM, Gaffey AE, Martinez BS. Effects of intranasal oxytocin on steroid hormones in men and women. Neuropsychobiology. 2015 Sep;71(4):202–11.
35.
Stanić D, Plećaš-Solarović B, Mirković D, Jovanović P, Dronjak S, Marković B, et al. Oxytocin in corticosterone-induced chronic stress model: focus on adrenal gland function. Psychoneuroendocrinology. 2017 Jun;80:137–46.
36.
Labuschagne I, Phan KL, Wood A, Angstadt M, Chua P, Heinrichs M, et al. Oxytocin attenuates amygdala reactivity to fear in generalized social anxiety disorder. Neuropsychopharmacology. 2010 Aug;35(12):2403–13.
37.
Giovanna G, Damiani S, Fusar-Poli L, Rocchetti M, Brondino N, de Cagna F, et al. Intranasal oxytocin as a potential therapeutic strategy in post-traumatic stress disorder: a systematic review. Psychoneuroendocrinology. 2020 May;115:104605.
38.
Sun Q, Holmqvist Larsson M, Falkenström F. Separating the effects of improvements and deteriorations in mechanisms on outcome using the asymmetric effects model. J Couns Psychol. 2021 Aug;68(6):696–704.
39.
Acheson DT, Feifel D, Kamenski M, Mckinney R, Risbrough VB. Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response. Depress Anxiety. 2015 Mar;32(6):400–7.
40.
Grossman-Giron A, Tzur Bitan D, Zilcha-Mano S, Nitzan U, Mendlovic S, Maoz H. Case report: oxytocin and its association with psychotherapy process and outcome. Front Psychiatry. 2021 Sep;12:691055.
41.
Zhang K, Fan Y, Yu R, Tian Y, Liu J, Gong P. Intranasal oxytocin administration but not peripheral oxytocin regulates behaviors of attachment insecurity: a meta-analysis. Psychoneuroendocrinology. 2021 Oct;132:105369.
42.
Engel S, Klusmann H, Ditzen B, Knaevelsrud C, Schumacher S. Menstrual cycle-related fluctuations in oxytocin concentrations: a systematic review and meta-analysis. Front Neuroendocrinol. 2019 Jan;52:144–55.
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