Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes

Koch, Saskia B.J.; van Zuiden, Mirjam; Nawijn, Laura; Frijling, Jessie L.; Veltman, Dick J.; Olff, Miranda

doi:10.1016/j.psyneuen.2013.11.018

Cited by 124Posttraumatic Stress Disorder ResearchNeuroendocrine regulation and behaviorStress Responses and Cortisol

Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes

Koch, Saskia B.J., van Zuiden, Mirjam, Nawijn, Laura, Frijling, Jessie L., Veltman, Dick J., Olff, Miranda·2014·Psychoneuroendocrinology

DOI 10.1016/j.psyneuen.2013.11.018

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Abstract

About ten percent of people experiencing a traumatic event will subsequently develop post-traumatic stress disorder (PTSD). PTSD is characterized by an exaggerated fear response which fails to extinguish over time and cannot be inhibited in safe contexts. The neurobiological correlates of PTSD involve enhanced salience processing (i.e. amygdala, dorsal anterior cingulate cortex (dACC) and anterior insula (AI) hyperactivity), and reduced top-down inhibitory control over this fear response (i.e. dorsal and ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between the vmPFC, hippocampus and amygdala). Therefore, dampening the exaggerated fear response (i.e. by reducing amygdala hyperactivity) and enhancing top-down inhibitory control (i.e. by promoting prefrontal control over the amygdala) during psychotherapy is an important target for medication-enhanced psychotherapy (MEP) in PTSD patients. Since the neuropeptide oxytocin (OT) has been found to act on these two processes, we propose that OT is a promising pharmacological agent to boost treatment response in PTSD. Human fMRI studies indicate that intranasal OT attenuates amygdala (hyper)activity and enhances connectivity of the amygdala with the vmPFC and hippocampus, resulting in increased top-down control over the fear response. In addition, intranasal OT was found to attenuate amygdala-brainstem connectivity and to change activity and connectivity in nodes of the salience network (i.e. AI and dACC). Furthermore, OT administration may modulate hypothalamus-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) function and may enhance social behaviour, which could be beneficial in the therapeutic alliance. We also discuss contextual and interindividual factors (e.g. gender and social context) which may influence the effectiveness of OT in MEP. In all, we propose that intranasal OT given prior to each psychotherapy session may be an effective additive treatment to boost treatment response in PTSD.

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These findings suggest that oxytocin has potential as an adjunctive therapy for extinction-based PTSD treatments such as PE.
“These findings suggest that oxytocin has potential as an adjunctive therapy for extinction-based PTSD treatments such as PE (Koch et al., 2014; Olff et al., 2010).”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Koch et al., 2014
Prevailing hypotheses suggest that oxytocin may uniquely help mitigate barriers to engaging in behavioral treatments that specifically target avoidance, which would thereby allow patients who might otherwise be unable to tolerate PE to engage effectively, complete the treatment, obtain an adequate therapeutic dose, and experience long-term remission of PTSD.
“Prevailing hypotheses suggest that oxytocin may uniquely help mitigate barriers to engaging in behavioral treatments that specifically target avoidance (Preckel et al., 2014), which would thereby allow patients who might otherwise be unable to tolerate PE to engage effectively, complete the treatment, obtain an adequate therapeutic dose, and experience long-term remission of PTSD (Frijling et al.,”
From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Koch et al., 2014
Oxytocin has been suggested as a promising pharmacological agent to enhance treatment response in PTSD.
“OT has been suggested as a promising pharmacological agent to enhance treatment response in PTSD (Koch et al, 2014;Olff et al, 2010).”
From Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients (2016) · cites this paper as Koch et al, 2014
Oxytocin has been proposed as an effective novel drug treatment for PTSD.
“oxytocin has been repeatedly proposed as an effective novel drug treatment for PTSD [3, 58]”
From Intranasal oxytocin reduces provoked symptoms in female patients with posttraumatic stress disorder despite exerting sympathomimetic and positive chronotropic effects in a randomized controlled trial (2017) · cites this paper as [3]

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Oxytocin buffers cortisol responses to stress in individuals with impaired emotion regulation abilities
Quirin, M., Kuhl, J., & Düsing, R. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.12.005 · Cited by 204 · see citing works
Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex
Sripada, C. S., Phan, K. L., Labuschagne, I., Welsh, R., Nathan, P. J., & Wood, A. G. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145712000533 · Cited by 197 · see citing works
Oxytocin increases amygdala reactivity to threatening scenes in females
Lischke, A., Gamer, M., Berger, C., Grossmann, A., Hauenstein, K., Heinrichs, M., Herpertz, S. C., & Domes, G. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.01.011 · Cited by 194 · cited 2× · see citing works
“Several human neuroimaging studies have shown that OT administration in healthy females resulted in enhanced, rather than attenuated, amygdala reactivity towards threatening scenes (Lischke et al., 2012) and fearful faces (Bertsch et al.”
Background
Oxytocin increases anxiety to unpredictable threat
Grillon, C., Krimsky, M., Charney, D. R., Vytal, K., Ernst, M., & Cornwell, B. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.156 · Cited by 192 · cited 2× · see citing works
“electric shocks) was increased after OTadministration compared to AVP and placebo administration (Grillon et al., 2012).”
BackgroundResult
No Laughing Matter: Intranasal Oxytocin Administration Changes Functional Brain Connectivity during Exposure to Infant Laughter
Riem, M. M. E., van IJzendoorn, M. H., Tops, M., Boksem, M. A. S., Rombouts, S. A. R. B., & Bakermans-Kranenburg, M. J. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.313 · Cited by 191 · see citing works
Oxytocin plasma concentrations after single intranasal oxytocin administration–a study in healthy men
Gossen, A., Hahn, A., Westphal, L., Prinz, S., Schultz, R. T., Gründer, G., & Spreckelmeyer, K. N. (2012) · Neuropeptides · doi:10.1016/j.npep.2012.07.001 · Cited by 189 · see citing works
Intranasal oxytocin attenuates the cortisol response to physical stress: a dose-response study
Cardoso, C., Ellenbogen, M. A., Orlando, M. A., Bacon, S. L., & Joober, R. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.07.013 · Cited by 187 · see citing works
Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders
MacDonald, K., & Feifel, D. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00035 · Cited by 181 · see citing works
Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: A systematic review
Quidé, Y., Witteveen, A. B., El‐Hage, W., Veltman, D. J., & Olff, M. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.09.004 · Cited by 174 · see citing works
Self-citation
Effective psychotherapies for posttraumatic stress disorder: a review and critique.
Cloître, M. (2009) · PubMed · Cited by 171 · see citing works
Exaggerated Activation of Dorsal Anterior Cingulate Cortex During Cognitive Interference: A Monozygotic Twin Study of Posttraumatic Stress Disorder
Shin, L. M., Bush, G., Milad, M. R., Lasko, N. B., Brohawn, K. H., Hughes, K. C., Macklin, M. L., Gold, A. L., Karpf, R. D., Orr, S. P., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.09121812 · Cited by 170 · see citing works
Sex differences in vasopressin and oxytocin innervation of the brain
DEVRIES, G. (2008) · Progress in Brain Research · doi:10.1016/s0079-6123(08)00402-0 · Cited by 169 · see citing works
Pre-trauma individual differences in extinction learning predict posttraumatic stress
Lommen, M. J. J., Engelhard, I. M., Sijbrandij, M., van den Hout, M. A., & Hermans, D. (2013) · Behaviour Research and Therapy · doi:10.1016/j.brat.2012.11.004 · Cited by 167 · see citing works
Oxytocin causes a sustained decrease in plasma levels of corticosterone in rats
Petersson, M., Hulting, A., & Uvnäs‐Moberg, K. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00159-7 · Cited by 156 · see citing works
Anxiolytic-like effect of oxytocin in the simulated public speaking test
de Oliveira, D. C., Zuardi, A. W., Graeff, F. G., Queiroz, R. H., & Crippa, J. A. (2012) · Journal of Psychopharmacology · doi:10.1177/0269881111400642 · Cited by 154 · see citing works
Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder
Pitman, R. K., Orr, S. P., & Lasko, N. B. (1993) · Psychiatry Research · doi:10.1016/0165-1781(93)90035-f · Cited by 150 · see citing works
Reduced neural activation during an inhibition task is associated with impaired fear inhibition in a traumatized civilian sample
Jovanovic, T., Ely, T., Fani, N., Glover, E. M., Gutman, D., Tone, E. B., Norrholm, S. D., Bradley, B., & Ressler, K. J. (2013) · Cortex · doi:10.1016/j.cortex.2012.08.011 · Cited by 146 · see citing works
A heartfelt response: oxytocin effects on response to social stress in men and women
Kubzansky, L. D., Mendes, W. B., Appleton, A. A., Block, J., & Adler, G. K. (2012) · Biological Psychology · doi:10.1016/j.biopsycho.2012.02.010 · Cited by 142 · see citing works
The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample
Acheson, D., Feifel, D., de Wilde, S., Mckinney, R., Lohr, J., & Risbrough, V. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3099-4 · Cited by 141 · see citing works
Oxytocin and psychotherapy: a pilot study of its physiological, behavioral and subjective effects in males with depression
MacDonald, K., MacDonald, T. M., Brüne, M., Lamb, K., Wilson, M. P., Golshan, S., & Feifel, D. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.05.014 · Cited by 140 · see citing works
Medial frontal hyperactivity to sad faces in generalized social anxiety disorder and modulation by oxytocin
Labuschagne, I., Phan, K. L., WOOD, A. G., Angstadt, M., Chua, P. M.-L., Heinrichs, M., Stout, J. C., & Nathan, P. J. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001489 · Cited by 139 · see citing works
Elevated salivary levels of oxytocin persist more than 7 h after intranasal administration
van IJzendoorn, M. H., Bhandari, R., van der Veen, R., Grewen, K. M., & Bakermans-Kranenburg, M. J. (2012) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00174 · Cited by 137 · see citing works
Amygdala Volume in Combat-Exposed Veterans With and Without Posttraumatic Stress Disorder: A Cross-sectional Study
Kuo, J. R., Kaloupek, D. G., & Woodward, S. H. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2012.73 · Cited by 136 · see citing works
White Matter Integrity in Highly Traumatized Adults With and Without Post-Traumatic Stress Disorder
Fani, N., King, T. Z., Jovanovic, T., Glover, E. M., Bradley, B., Choi, K., Ely, T., Gutman, D. A., & Ressler, K. J. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.146 · Cited by 135 · see citing works
A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder
Olff, M., Langeland, W., Witteveen, A., & Denys, D. (2010) · CNS Spectrums · doi:10.1017/s109285290000047x · Cited by 135 · see citing works
Self-citation
Amygdala Volume in Adults with Posttraumatic Stress Disorder: A Meta-Analysis
Woon, F. L., & Hedges, D. W. (2009) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/jnp.2009.21.1.5 · Cited by 120 · see citing works
Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner
Toth, I., Neumann, I. D., & Slattery, D. A. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2702-4 · Cited by 107 · see citing works
Intranasal Oxytocin as an Adjunct to Risperidone in Patients with Schizophrenia
Modabbernia, A., Rezaei, F., Salehi, B., Jafarinia, M., Ashrafi, M., Tabrizi, M. H., Hosseini, S. M. R., Tajdini, M., Ghaleiha, A., & Akhondzadeh, S. (2012) · CNS Drugs · doi:10.1007/s40263-012-0022-1 · Cited by 107 · see citing works
Increased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative words
Thomaes, K., Dorrepaal, E., Draijer, N., de Ruiter, M. B., Elzinga, B. M., Sjoerds, Z., van Balkom, A. J., Smit, J. H., & Veltman, D. J. (2013) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsr084 · Cited by 103 · see citing works
Self-citation
Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses
Cohen, H., Kaplan, Z., Kozlovsky, N., Gidron, Y., Matar, M. A., & Zohar, J. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02003.x · Cited by 94 · see citing works
Early Altered Resting-State Functional Connectivity Predicts the Severity of Post-Traumatic Stress Disorder Symptoms in Acutely Traumatized Subjects
Zhou, Y., Wang, Z., Qin, L.-D., Wan, J.-Q., Sun, Y.-W., Su, S.-S., Ding, W.-N., & Xu, J.-R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046833 · Cited by 89 · see citing works
Learning About Oxytocin: Pharmacologic and Behavioral Issues
Chini, B., Leonzino, M., Braida, D., & Sala, M. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.08.029 · Cited by 87 · see citing works
An fMRI study of unconditioned responses in post-traumatic stress disorder
Linnman, C., Zeffiro, T. A., Pitman, R. K., & Milad, M. R. (2011) · Biology of Mood & Anxiety Disorders · doi:10.1186/2045-5380-1-8 · Cited by 80 · see citing works
The Promise and Perils of Oxytocin
Miller, G. (2013) · Science · doi:10.1126/science.339.6117.267 · Cited by 76 · cited 1× · see citing works
“longterm consequences of OT administration, difference in effects between acute and chronic OT administration and whether intranasal OT does enter the brain) (Macdonald and Feifel, 2013; Miller, 2013).”
Background
Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory
Blundell, J. J., Blaiss, C. A., Lagace, D. C., Eisch, A. J., & Powell, C. M. (2011) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2011.02.006 · Cited by 76 · see citing works
Hippocampal but not amygdalar volume affects contextual fear conditioning in humans
Pohlack, S. T., Nees, F., Liebscher, C., Cacciaglia, R., Diener, S. J., Ridder, S., Woermann, F. G., & Flor, H. (2011) · Human Brain Mapping · doi:10.1002/hbm.21224 · Cited by 69 · see citing works
Social anxiety modulates amygdala activation during social conditioning
Pejic, T., Hermann, A., Vaitl, D., & Stark, R. M. (2011) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsr095 · Cited by 61 · see citing works
Different Regional Gray Matter Loss in Recent Onset PTSD and Non PTSD after a Single Prolonged Trauma Exposure
Chen, Y., Fu, K., Chen, F., Tang, L., Zhang, J., Huan, Y., Cui, J., Mu, Y., Qi, S., Xiong, L., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048298 · Cited by 59 · see citing works
DecreasedN‐acetyl‐aspartate levels in anterior cingulate and hippocampus in subjects with post‐traumatic stress disorder: a proton magnetic resonance spectroscopy study
Ham, B., Chey, J., Yoon, S. J., Sung, Y., Jeong, D., Kim, S. J., Sim, M., Choi, N., Choi, I., Renshaw, P. F., et al. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05253.x · Cited by 55 · see citing works
Pharmacological Innovations for Posttraumatic Stress Disorder and Medication- Enhanced Psychotherapy
Dunlop, B. W., Mansson, E. E., & Gerardi, M. A. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212803530899 · Cited by 48 · see citing works
Amygdala response to negative images in postpartumvsnulliparous women and intranasal oxytocin
Rupp, H. A., James, T. W., Ketterson, E. D., Sengelaub, D. R., Ditzen, B., & Heiman, J. R. (2012) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nss100 · Cited by 44 · see citing works
More vulnerability of left than right hippocampal damage in right-handed patients with post-traumatic stress disorder
Shu, X., Li, X., Liu, W. D., Chen, F.-Y., Zhu, C., Sun, X.-H., Wang, X., Liu, Z.-C., & Zhao, H. (2012) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2012.04.009 · Cited by 38 · see citing works
P.3.026 Intranasal oxytocin in patients with post traumatic stress disorder: a single dose, pilot double blind crossover study
Yatzkar, U., & Klein, E. (2010) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(10)70098-5 · Cited by 32 · see citing works

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Treating PTSD: A Review of Evidence-Based Psychotherapy Interventions
Watkins, L. E., Sprang, K. R., & Rothbaum, B. O. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00258 · Cited by 563 · see citing works
Reward functioning in PTSD: a systematic review exploring the mechanisms underlying anhedonia
Nawijn, L., van Zuiden, M., Frijling, J. L., Koch, S. B. J., Veltman, D. J., & Olff, M. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.01.019 · Cited by 250 · see citing works
Self-citation
Restoring large-scale brain networks in PTSD and related disorders: a proposal for neuroscientifically-informed treatment interventions
Lanius, R. A., Frewen, P. A., Tursich, M., Jetly, R., & McKinnon, M. C. (2015) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v6.27313 · Cited by 246 · see citing works
Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms
Inserra, A., De Gregorio, D., & Gobbi, G. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000056 · Cited by 232 · see citing works
Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain
Puglia, M. H., Lillard, T. S., Morris, J. P., & Connelly, J. J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1422096112 · Cited by 216 · see citing works
Single-Prolonged Stress: A Review of Two Decades of Progress in a Rodent Model of Post-traumatic Stress Disorder
Lisieski, M. J., Eagle, A. L., Conti, A. C., Liberzon, I., & Perrine, S. A. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00196 · Cited by 224 · see citing works
Posttraumatic Stress Disorder: Overview of Evidence-Based Assessment and Treatment
Lancaster, C. L., Teeters, J. B., Gros, D., & Back, S. E. (2016) · Journal of Clinical Medicine · doi:10.3390/jcm5110105 · Cited by 225 · see citing works
Treatment of Posttraumatic Stress Disorder: A State-of-the-art Review
Burback, L., Brémault‐Phillips, S., Nijdam, M. J., McFARLANE, A. C., & Vermetten, E. H. G. J. M. (2023) · Current Neuropharmacology · doi:10.2174/1570159x21666230428091433 · Cited by 232 · see citing works
The role of oxytocin in male and female reproductive behavior
Veening, J. G., A, T. R. D. J., Waldinger, M. D., Korte, S. M., & Olivier, B. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.07.045 · Cited by 156 · see citing works
PTSD: from neurobiology to pharmacological treatments
Kelmendi, B., Adams, T., Yarnell, S. C., Southwick, S., Abdallah, C., & Krystal, J. (2016) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v7.31858 · Cited by 136 · see citing works
Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder
Koch, S. B. J., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.1 · Cited by 132 · see citing works
Self-citation
Oxytocin, vasopressin, and the motivational forces that drive social behaviors
Caldwell, H. K., & Albers, H. E. (2015) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2015_390 · Cited by 129 · see citing works
Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial
Flanagan, J. C., Sippel, L. M., Wahlquist, A., Moran-Santa Maria, M. M., & Back, S. E. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.12.014 · Cited by 117 · see citing works
Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial
Quintana, D. S., Westlye, L. T., Alnæs, D., Rustan, Ø. G., Kaufmann, T., Smerud, K. T., Mahmoud, R. A., Djupesland, P. G., & Andreassen, O. A. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.04.010 · Cited by 102 · see citing works
Oxytocin and stress-related disorders: neurobiological mechanisms and treatment opportunities
Sippel, L. M., Allington, C. E., Pietrzak, R. H., Harpaz-Rotem, I., Mayes, L. C., & Olff, M. (2017) · Chronic Stress · doi:10.1177/2470547016687996 · Cited by 99 · see citing works
Self-citation
Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients
Koch, S. B., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.299 · Cited by 98 · see citing works
Self-citation
Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders
Lotan, A., Fencková, M., Bralten, J., O’Leary, A., Dixson, L., Williams, R. W., & van der Voet, M. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00331 · Cited by 87 · see citing works
Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces.
Luo, L., Becker, B., Geng, Y., Zhao, Z., Gao, S., Zhao, W., Yao, S., Zheng, X., Ma, X., Gao, Z., et al. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2017.08.079 · Cited by 79 · see citing works
Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear
Sparta, D. R., Smithuis, J., Stamatakis, A. M., Jennings, J. H., Kantak, P. A., Ung, R. L., & Stuber, G. D. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00129 · Cited by 75 · see citing works
Posttraumatic Stress Disorder and Anxiety-Related Conditions
Williamson, J. B., Jaffee, M. S., & Jorge, R. E. (2021) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001054 · Cited by 68 · see citing works
Oxytocin modulates amygdala reactivity to masked fearful eyes
Kanat, M., Heinrichs, M., Mader, I., van Elst, L. T., & Domes, G. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.111 · Cited by 65 · see citing works
Injection of oxytocin into paraventricular nucleus reverses depressive-like behaviors in the postpartum depression rat model
Wang, T., Shi, C., Li, X., Zhang, P., Liu, B., Wang, H., Wang, Y., Yang, Y., Wu, Y., Li, H., et al. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.09.012 · Cited by 62 · see citing works
Oxytocin facilitates adaptive fear and attenuates anxiety responses in animal models and human studies—potential interaction with the corticotropin-releasing factor (CRF) system in the bed nucleus of the stria terminalis (BNST)
Janeček, M., & Dabrowska, J. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2889-8 · Cited by 61 · see citing works
What's Love Got to do with it: Role of oxytocin in trauma, attachment and resilience
Sharma, S. R., Gonda, X., Dome, P., & Tarazi, F. I. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107602 · Cited by 61 · see citing works
Intranasal oxytocin enhances neural processing of monetary reward and loss in post-traumatic stress disorder and traumatized controls
Nawijn, L., van Zuiden, M., Koch, S. B. J., Frijling, J. L., Veltman, D. J., & Olff, M. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.01.020 · Cited by 59 · see citing works
Self-citation
Epigenetic variability in the human oxytocin receptor (OXTR) gene: A possible pathway from early life experiences to psychopathologies
Kraaijenvanger, E. J., He, Y., Spencer, H., Smith, A. K., Bos, P. A., & Boks, M. P. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.11.016 · Cited by 57 · see citing works
Controllability modulates the neural response to predictable but not unpredictable threat in humans
Wood, K. H., Wheelock, M. D., Shumen, J. R., Bowen, K. H., Hoef, L. V., & Knight, D. C. (2015) · NeuroImage · doi:10.1016/j.neuroimage.2015.06.086 · Cited by 57 · see citing works
Oxytocin receptor gene polymorphisms, attachment, and PTSD: Results from the National Health and Resilience in Veterans Study
Sippel, L. M., Han, S., Watkins, L. E., Harpaz‐Rotem, I., Southwick, S. M., Krystal, J. H., Olff, M., Sherva, R., Farrer, L. A., Kranzler, H. R., et al. (2017) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2017.07.008 · Cited by 57 · see citing works
Self-citation
Intranasal oxytocin reduces provoked symptoms in female patients with posttraumatic stress disorder despite exerting sympathomimetic and positive chronotropic effects in a randomized controlled trial
Sack, M., Spieler, D., Wizelman, L., Epple, G., Stich, J., Zaba, M., & Schmidt, U. (2017) · BMC Medicine · doi:10.1186/s12916-017-0801-0 · Cited by 57 · see citing works
On the Control of Social Approach–Avoidance Behavior: Neural and Endocrine Mechanisms
Kaldewaij, R., Koch, S. B. J., Volman, I., Toni, I., & Karin Roelofs, A. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_446 · Cited by 55 · see citing works
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How Do Stress Exposure and Stress Regulation Relate to Borderline Personality Disorder?
Bourvis, N., Aouidad, A., Cabelguen, C., Cohen, D., & Xavier, J. (2017) · Frontiers in Psychology · doi:10.3389/fpsyg.2017.02054 · Cited by 48 · see citing works
The role of oxytocin in relationships between dogs and humans and potential applications for the treatment of separation anxiety in dogs
Thielke, L. E., & Udell, M. A. R. (2015) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12235 · Cited by 55 · see citing works
Mineralocorticoid receptor function and cognition in health and disease
Wingenfeld, K., & Otte, C. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.09.010 · Cited by 53 · see citing works
Intranasally Delivered Wnt3a Improves Functional Recovery after Traumatic Brain Injury by Modulating Autophagic, Apoptotic, and Regenerative Pathways in the Mouse Brain
Zhang, J. Y., Lee, J. H., Gu, X., Wei, Z. Z., Harris, M., Yu, S. P., & Wei, L. (2017) · Journal of Neurotrauma · doi:10.1089/neu.2016.4871 · Cited by 49 · see citing works
Long-term mental health outcomes after unintentional burns sustained during childhood: a retrospective cohort study
Duke, J. M., Randall, S. M., Palanivelu, V. T., McGarry, S., Boyd, J., Rea, S. M., & Wood, F. M. (2018) · Burns & Trauma · doi:10.1186/s41038-018-0134-z · Cited by 49 · see citing works
Brain circuits that regulate social behavior
Li, H., Zhao, Z., Jiang, S., & Wu, H. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03037-6 · Cited by 57 · see citing works
Military Veterans and Their PTSD Service Dogs: Associations Between Training Methods, PTSD Severity, Dog Behavior, and the Human-Animal Bond
LaFollette, M. R., Rodriguez, K. E., Ogata, N., & O’Haire, M. E. (2019) · Frontiers in Veterinary Science · doi:10.3389/fvets.2019.00023 · Cited by 48 · see citing works
Social support, oxytocin, and PTSD
Olff, M., Koch, S. B. J., Nawijn, L., Frijling, J. L., Van Zuiden, M., & Veltman, D. J. (2014) · European Journal of Psychotraumatology · doi:10.3402/ejpt.v5.26513 · Cited by 46 · see citing works
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Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics
Schindler, E., Wallace, R., Sloshower, J., & D'Souza, D. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00177 · Cited by 42 · see citing works
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Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder
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Augmenting Treatment for Posttraumatic Stress Disorder and Co-Occurring Conditions with Oxytocin
Flanagan, J. C., & Mitchell, J. (2019) · Current Treatment Options in Psychiatry · doi:10.1007/s40501-019-00171-1 · Cited by 10 · see citing works

Authors: Koch, S. B. J., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M.
Affiliations: Amsterdam UMC Location University of Amsterdam (NL)
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
Corresponding author: Koch, Saskia B.J.
ORCID: Koch, Saskia B.J.
Nawijn, Laura
Frijling, Jessie L.
Veltman, Dick J.
Olff, Miranda
Venue: Psychoneuroendocrinology
Publisher: Elsevier BV
Published: 2014-02
Volume: 40
Pages: 242-256
ISSN: 0306-4530 (ISSN-L)
DOI: 10.1016/j.psyneuen.2013.11.018
OpenAlex: W1977778322
Cited by: 123
References: 114
Citations by year: 2026: 5 · 2025: 7 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 9 · 2018: 19 · 2017: 15 · 2016: 9 · 2015: 16 · 2014: 8
FWCI: 1.61
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Psychoneuroendocrinology (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Topics: Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: intranasal oxytocin, post-traumatic stress disorder, salience processing, fear inhibition, amygdala hyperactivity, salience network, anterior insula, dorsal anterior cingulate cortex, hypothalamic-pituitary-adrenal axis, autonomic nervous system, social behavior, therapeutic relationship, gender differences, treatment response
MeSH terms: Adaptation, Psychological, Administration, Intranasal, Animals, Combined Modality Therapy, Fear, Humans, Mental Processes, Oxytocin, Psychotherapy, Stress Disorders, Post-Traumatic

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Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes

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