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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.


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