ISTSS Logo
 
Home > Public Resources > Trauma Blog > 2016 - October > Biological Perspectives: Can a Few Sprays of Oxytocin Improve Treatment for Posttraumatic Stress Dis

Biological Perspectives: Can a Few Sprays of Oxytocin Improve Treatment for Posttraumatic Stress Disorder?

October 24, 2016

Intranasal oxytocin may be a safe and effective pharmacological mechanism for improving effectiveness of trauma-focused psychotherapies—but caution is warranted.

The hormone oxytocin is well known for its effects on social and reproductive processes. Intranasal oxytocin (IN OT) has made a splash in the media and scientific community because of its potential for treating autism, schizophrenia, social anxiety and posttraumatic stress disorder (PTSD). While sometimes lauded as a panacea, IN OT is not without its critics (Leng & Ludwig, 2016), and for good reasons. Questions about its pharmokinetic properties (MacDonald & Feifel, 2013), the effectiveness of intranasal administration for crossing the blood-brain barrier (Guastella et al., 2013), the reproducibility of effects (Lane, Luminet, Nave, & Mikolajczak, 2016), and potential moderators of effects (Bartz, Zaki, Bolger, & Ochsner, 2011), as well as the lack of research on long-term administration and varying dosages, suggest we should proceed with cautious optimism.   

OT is a nonapeptide hormone produced by the hypothalamus and released by the pituitary gland to several brain areas, including the amygdala, hippocampus, insula, and striatum (Meyer-Lindenber, Domes, Kirsch, & Heinrichs, 2011). These brain areas are implicated in threat and reward processing—both of great relevance to PTSD (Nawijn, van Zuiden, Frijling, Koch, Veltman, & Olff, 2015; Patel, Spreng, Shin, & Girard, 2012). In addition to improving social cognition (Graustella & MacLeod, 2012) and increasing prosocial behavior (Striepens, Kendrick, Maier, & Hurlemann, 2011), IN OT reduces neural activity in brain regions that mediate negative affect experiences (e.g., anterior cingulate cortex, anterior insula, midbrain, orbitofrontal cortex, and thalamus) and autonomic fear (amygdala; Huber, Veinante, & Stoop, 2005), while increasing activity in prefrontal cortical areas that mediate emotion regulation and fear inhibition (Ma, Shamay-Tsoory, Han, & Zink, 2016), and connectivity of these areas to the amygdala (Sripada et al., 2013). IN OT also facilitates fear extinction (Acheson et al., 2013), the proposed mechanism of exposure-based therapies.

IN OT is therefore a promising pharmacological agent for the treatment of PTSD (Koch et al., 2014). IN OT could serve multiple functions that enhance outcomes for trauma-focused psychotherapies, including reducing exaggerated fear, facilitating fear extinction, increasing reward salience of social cues, and promoting therapeutic alliance (Olff, Langeland, Witteveen, & Denys, 2010). While no published studies of IN OT-enhanced psychotherapy for PTSD yet exist, single-dose studies with PTSD samples are promising.

In a pilot study, IN OT decreased state anxiety and PTSD symptoms, improved mood, and increased desire for social interaction (Yatzkar & Klein, 2010). Trend-level reductions in physiological responses to combat imagery were observed in Vietnam-era veterans (Pitman, Orr, & Lasko, 1993). fMRI studies in a sample of police officers have shown that IN OT dampened amygdala activity to emotional faces (Koch et al., 2016a), normalized amygdala functional connectivity (Koch et al., 2016b), and increased striatal, dorsal anterior cingulate, and insula responses to monetary reward (Nawijn et al., 2016).

Despite the proliferation of studies, our understanding of the therapeutic value of IN OT remains limited in ways that are meaningful to the application of IN OT to PTSD. As is often the case with novel therapeutics, IN OT does not affect all individuals in the same way. IN OT enhances processing of salient social cues, and salience is determined by intraindividual and contextual variables (Shamay-Tsoory & Abu-Akel, 2016).

For example, effects of IN OT are dampened or even reversed in individuals who report early life stress or childhood adverse events (e.g., Grimm et al., 2014), perhaps due to preexisting negative social information processing biases that are enhanced under IN OT (Taft, Schumm, Marshall, Panuzio, & Holtzworth-Munroe, 2008). Additional studies of the effects of IN OT on threat perception in PTSD samples are very much needed, especially given evidence that IN OT increases anxiety to unpredictable threat (Grillon et al., 2013).

IN OT may even have distinct effects at different stages of information processing—for example, evidence from an fMRI-fear conditioning study suggests that IN OT may first enhance threat perception before reducing fear to levels lower than those observed under placebo (Eckstein et al., 2014). Effects of IN OT also vary as a function of psychiatric symptoms, including symptoms highly comorbid with PTSD; for example, IN OT had anxiogenic effects in individuals with major depressive disorder (MacDonald et al., 2013) and decreased trust and cooperation among individuals with borderline personality disorder (Bartz et al., 2011).

Finally, based on evidence that IN OT is associated with negative behaviors like gloating (Shamay-Tsoory, 2009) and aggression (Ne’eman, Perach-Barzilay, Fischer-Shofty, Atias, & Shamay-Tsoory, 2016), IN OT may increase not only prosocial approach behaviors but also “antisocial” approach behaviors (Kemp & Guastella, 2011).

Finally, though women are at greater risk of PTSD than men, most studies of the effects of IN OT on PTSD-relevant processes have been conducted in men. Evidence for sex-specific effects of IN OT is mixed (MacDonald et al., 2013; Wigton et al., 2015), and studies that have found sex differences are inconclusive.

For example, one study found sex-specific patterns of functional connectivity in PTSD patients that were normalized with one-dose IN OT administration in both men and women (Koch et al., 2016b). However, a study of a three-week course of daily IN OT showed significant decreases in anxiety scores in men but increases in anxiety among women (Feifel, MacDonald, McKinney, Heisserer, & Serrano, 2011). Given that hormone levels, menstrual phase, and hormonal contraceptive status may impact OT levels (Scheele, Plota, Stoffel-Wagner, Maier, & Hurlemann, 2016), psychiatric symptoms (Nillni et al., 2015), and evidence for sex-specific responses to stress (Taylor, 2006), researchers must make concerted efforts to include women in these studies to measure or monitor these factors, and to test for sex differences in order to make accurate conclusions about the potential therapeutic role of IN OT for women with PTSD.

At this point, research shows that IN OT acts upon a number of processes highly relevant to PTSD, and preliminary data appear promising. However, IN OT does not have uniform effects on all individuals, and conclusions are limited by the reliance on single-dose studies. The potential for sexually dimorphic neural and behavioral effects of IN OT necessitate examination of IN OT in both men and women.

Conclusions about generalizability of effects also necessitate study of IN OT in other samples in whom PTSD is highly prevalent (e.g., military veterans, individuals with history of childhood maltreatment). Consideration of additional moderating variables relevant to PTSD (e.g., psychiatric comorbidities) will promote development of personalized treatment approaches that enhance desired cognitive-affective processes without facilitating maladaptive behaviors. There are a number of active IN OT trials in PTSD samples (clinicaltrials.gov), so we can expect increased clarity about the impact of IN OT on PTSD in the future.

About the Author

Lauren M. Sippel, PhD, is a research psychologist at the National Center for PTSD – Clinical Neurosciences Division and Yale University School of Medicine Department of Psychiatry.

References

Acheson, D., Feifel, D., de Wilde, S., Mckinney, R., Lohr, J., & Risbrough, V. (2013). The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology, 229(1), 199-208. doi: 10.1007/s00213-013-3099-4

Bartz, J., Simeon, D., Hamilton, H., Kim, S., Crystal, S., Braun, A., & Hollander, E. (2011). Oxytocin can hinder trust and cooperation in borderline personality disorder. Social Cognitive and Affective Neuroscience, 6(5), 556-563. doi: 10.1093/scan/nsq085

Bartz, J. A., Zaki, J., Bolger, N., & Ochsner, K. N. (2011). Social effects of oxytocin in humans: context and person matter. Trends in Cognitive Sciences, 15(7), 301-309. doi: 10.1016/j.tics.2011.05.002

DeWall, C. N., Gillath, O., Pressman, S. D., Black, L. L., Bartz, J.A., Moskovitz, J., & Stetler, D. A. (2014). When the love hormone leads to violence: Oxytocin increases intimate partner violence inclinations among high trait aggressive people. Social Psychological & Personality Science, 5, 691– 697. doi: 10.1177/1948550613516876

Dunlop, B. W., Mansson, E., & Gerardi, M. (2012). Pharmacological innovations for posttraumatic stress disorder and medication-enhanced psychotherapy. Current Pharmaceutical Design, 18(35), 5645-5658. doi: 10.2174/138161212803530899

Eckstein, M., Becker, B., Scheele, D., Scholz, C., Preckel, K., Schlaepfer, T. E. Hurlemann, R. (2015). Oxytocin facilitates the extinction of conditioned fear in humans. Biological Psychiatry, 78, 194-202.  doi:http://dx.doi.org/10.1016/j.biopsych.2014.10.015

Feifel, D., MacDonald, K., McKinney, R., Heisserer, N., & Serrano, V. (2011). A randomized, placebo-controlled investigation of intranasal oxytocin in patients with anxiety. Neuropsychopharmacology, 36, S324-S449.

Graustella, A. J., & MacLeod, C. (2012). A critical review of the influence of oxytocin nasal spray on social cognition in humans: Evidence and future directions. Hormones and Behavior, 61(3), 410-418. doi: 10.1016/j.yhbeh.2012.01.002

Grillon, C., Krimsky, M., Charney, D. R., Vytal, K., Ernst, M., & Cornwell, B. (2013). Oxytocin increases anxiety to unpredictable threat. Molecular Psychiatry, 18(9), 958-960. doi: 10.1038/mp.2012.156

Grimm, S., Pestke, K., Feeser, M., Aust, S., Weigand, A., Wang, J. & Bajbouj, M. (2014). Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress. Social Cognitive and Affective Neuroscience, 9(11), 1828-1835. doi: 10.1093/scan/nsu020

Guastella, A. J., Hickie, I. B., McGuinness, M. M., Otis, M., Woods, E. A., Disinger, H. M., & Banati, R. B. (2013). Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology, 38(5), 612-625. doi: 10.1016/j.psyneuen.2012.11.019

Huber, D., Veinante, P., & Stoop, R. (2005). Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science, 308(5719), 245-248. doi: 10.1126/science.1105636

Kemp, A. H., & Guastella, A. J. (2011). The role of oxytocin in human affect: A novel hypothesis. Current Directions in Psychological Science, 20(4), 222-231. doi: 10.1177/0963721411417547

Koch, S. B., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2014). Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: Salience processing and fear inhibition processes. Psychoneuroendocrinology, 40, 242-256. doi: 10.1016/j.psyneuen.2013.11.018

Koch, S.B., van Zuiden, M., Nawijn, L., Frijling, J.L., Veltman, D.J., Olff, M. (2016a). Intranasal oxytocin administration dampens amygdala reactivity towards emotional faces in male and female PTSD patients. Neuropsychopharmacology, 41(6), 1495-1504. doi: 10.1038/npp.2015.299

Koch, S. B., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2016b). Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacology, 41, 2041-2051. doi: 10.1038/npp.2016.1

Lane, A., Luminet, O., Nave, G., & Mikolajczak, M. (2016). Is there a publication bias in behavioural intranasal oxytocin research on humans? Opening the file drawer of one laboratory. Journal of Neuroendocrinology, 28(4). doi: 10.1111/jne.12384

Leng, G., & Ludwig, M. (2016). Intranasal oxytocin: Myths and delusions. Biological Psychiatry, 79(3), 243-250.
doi: 10.1016/j.biopsych.2015.05.003

Ma, Y., Shamay-Tsoory, S., Han, S., & Zink, C. F. (2016). Oxytocin and social adaptation: Insights from neuroimaging studies of healthy and clinical populations. Trends in Cognitive Sciences, 20(2), 133-145. doi: 10.1016/j.tics.2015.10.009

Macdonald, K., & Feifel, D. (2013). Helping oxytocin deliver: Considerations in the development of oxytocin-based therapeutics for brain disorders. Frontiers in Neuroscience, 7(35). doi: 10.3389/fnins.2013.00035

Macdonald, K. S. (2013). Sex, receptors, and attachment: A review of individual factors influencing response to oxytocin. Frontiers in Neuroscience, 6(194), 34-41. doi: 10.3389/fnins.2012.00194

MacDonald, K., MacDonald, T. M., BrĂ¼ne, M., Lamb, K., Wilson, M. P., Golshan, S., & Feifel, D. (2013). Oxytocin and psychotherapy: A pilot study of its physiological, behavioral and subjective effects in males with depression. Psychoneuroendocrinology, 38(12), 2831-2843. doi: 10.1016/j.psyneuen.2013.05.014

Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011). Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine. Nature Reviews Neuroscience, 12(9), 524-538. doi: 10.1038/nrn3044

Nawijn, L., van Zuiden, M., Frijling, J. L., Koch, S. B., Veltman, D. J., & Olff, M. (2015). Reward functioning in PTSD: A systematic review exploring the mechanisms underlying anhedonia. Neuroscience & Biobehavioral Reviews, 51, 189-204. doi: 10.1016/j.neubiorev.2015.01.019

Nawijn, L., van Zuiden, M., Koch, S. B., Frijling, J. L., Veltman, D. J., & Olff, M. (2016). Intranasal oxytocin enhances neural processing of monetary reward and loss in post-traumatic stress disorder and traumatized controls. Psychoneuroendocrinology, 66, 228-237. doi: 10.1016/j.psyneuen.2016.01.020

Ne'eman, R., Perach-Barzilay, N., Fischer-Shofty, M., Atias, A., & Shamay-Tsoory, S. G. (2016). Intranasal administration of oxytocin increases human aggressive behavior. Hormones and Behavior, 80, 125-131. doi: 10.1016/j.yhbeh.2016.01.015

Nillni, Y. I., Pineles, S. L., Patton, S. C., Rouse, M. H., Sawyer, A. T., & Rasmusson, A. M. (2015). Menstrual cycle effects on psychological symptoms in women with PTSD. Journal of Traumatic Stress, 28(1), 1-7. doi: 10.1002/jts.21984

Olff, M., Langeland, W., Witteveen, A., & Denys, D. (2010). A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder. CNS Spectrums, 15(08), 522-530. doi: 10.1017/S109285290000047X

Patel, R., Spreng, R. N., Shin, L. M., & Girard, T. A. (2012). Neurocircuitry models of posttraumatic stress disorder and beyond: A meta-analysis of functional neuroimaging studies. Neuroscience & Biobehavioral Reviews, 36(9), 2130-2142. doi: 10.1016/j.neubiorev.2012.06.003

Pitman, R. K., Orr, S. P., & Lasko, N. B. (1993). Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder. Psychiatry Research, 48(2), 107-117. doi: 10.1016/0165-1781(93)90035-F

Scheele, D., Plota, J., Stoffel-Wagner, B., Maier, W., & Hurlemann, R. (2016). Hormonal contraceptives suppress oxytocin-induced brain reward responses to the partner’s face. Social Cognitive and Affective Neuroscience, 11(5), 767-774. doi: 10.1093/scan/nsv157

Shamay-Tsoory, S. G., & Abu-Akel, A. (2016). The social salience hypothesis of oxytocin. Biological Psychiatry, 79(3), 194-202. doi: 10.1016/j.biopsych.2015.07.020

Shamay-Tsoory, S. G., Fischer, M., Dvash, J., Harari, H., Perach-Bloom, N., & Levkovitz, Y. (2009). Intranasal
administration of oxytocin increases envy and schadenfreude (gloating). Biological Psychiatry, 66(9), 864-870. doi: 10.1016/j.biopsych.2009.06.009

Sripada, C. S., Phan, K. L., Labuschagne, I., Welsh, R., Nathan, P. J., & Wood, A. G. (2013). Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. International Journal of Neuropsychopharmacology, 16(2), 255-260. doi: 10.1017/S1461145712000533

Striepens, N., Kendrick, K. M., Maier, W., & Hurlemann, R. (2011). Prosocial effects of oxytocin and clinical evidence for its therapeutic potential. Frontiers in Neuroendocrinology, 32(4), 426-450. doi: 10.1016/j.yfrne.2011.07.001

Taft, C.T., Schumm, J.A., Marshall, A.D., Panuzio, J., & Holtzworth-Munroe, A. (2008). Family-of-origin maltreatment, posttraumatic stress disorder symptoms, social information processing deficits, and relationship abuse perpetration. Journal of Abnormal Psychology, 117, 637-646. doi: http://dx.doi.org/10.1037/0021-843X.117.3.637

Taylor, S. E. (2006). Tend and befriend: Biobehavioral bases of affiliation under stress. Current Directions in Psychological Science, 15, 273–277. doi: 10.1111/j.1467-8721.2006.00451.x

Wigton, R., Radua, J., Allen, P., Averbeck, B., Meyer-Lindenberg, A., McGuire, P., Fusar-Poli, P. (2015). Neurophysiological effects of acute oxytocin administration: Systematic review and meta-analysis of placebo-controlled imaging studies. Journal of Psychiatry & Neuroscience, 40(1), E1-E22. doi: 10.1503/jpn.130289

Yatzkar, U., & Klein, E. (2010). P. 3.026 Intranasal oxytocin in patients with posttraumatic stress disorder: A single dose, pilot double blind crossover study. European Neuropsychopharmacology, 20, S84. doi: 10.1016/S0924-977X(10)70098-5