Intranasal oxytocin as a potential therapeutic strategy in post-traumatic stress disorder: A systematic review

Highlights

• IN-OT modulates activity in cognitive, emotion and reward brain areas in PTSD.

• Clinical evidences of efficacy for single IN-OT administrations are limited.

• Repeated IN-OT administrations and agumentation to psychotherapy may improve efficacy.

Abstract

Treatment options for Posttraumatic Stress Disorder (PTSD) are limited in terms of available drugs and the success of psychotherapeutic interventions. Oxytocin is a peptide involved in the modulation of social cognition, emotional skills and the reward system, all deficient in PTSD, and thus it has been suggested as a promising pharmacological target. In this systematic review, the potential effects of intranasal OT (INOT) administration on core symptoms in PTSD patients are discussed, as well as neurobiological correlates in functional imaging supporting its clinical evidence. The fourteen studies included in the present review provide tentative evidence that INOT could be a safe pharmacological intervention, although the results were mixed and insufficient to quantify the effectiveness of this intervention. Specifically, the primary outcome measures differed consistently between studies, and the sample sizes were usually small. Considering the neurobiological and clinical evidences, tentative hypotheses can be made on the possible role of INOT in facilitating socially- and goal-oriented cognition and behaviour, thus promoting a better therapeutic alliance and treatment outcome. Such strategies need to be further supported by literature. For instance, only one study to date has directly investigated the use of INOT as an augmentation strategy for psychotherapy (namely, Prolonged Exposure therapy) and for a limited time, nevertheless providing promising results for the efficacy and the medium-term tolerability of this drug after multiple administrations.

Introduction

Posttraumatic stress disorder (PTSD) can be conceptualized as the development of characteristic symptoms following direct or indirect exposure to traumatic events (e.g. actual or threatened death, serious injuries or sexual violence). Its clinical presentation is heterogeneous, including fear-based re-experiencing of traumatic events (with major emotional and behavioural consequences), involuntary and intrusive distressing memories, anhedonic or dysphoric mood states and impaired cognition, and severe dissociative symptoms (American Psychiatric Association, 2013) Patients suffering from PTSD are at a higher risk for self-harm, destructive behaviour and suicide (Panagioti et al., 2015), thus requiring intensive assistance. Initial treatment options for PTSD were primarily focused on non-pharmacological psychotherapeutic interventions (Friedman et al., 1988). Due to the lack of strong evidence supporting pharmacological augmentation with antidepressants (Hetrick 2010, Lee 2016), trauma-focused psychotherapy alone is still the preferred first line of intervention (ACPMH 2007). The field of pharmacology thus actively strives in the attempt to find safe and effective alternatives to selective serotonin reuptake inhibitors for PTSD.

Oxytocin (OT) is a hypothalamic neuropeptide primarily synthesized in the paraventricular and supraoptic nuclei (Leng et al., 2015). OT is renowned for its role in facilitating trust and attachment between individuals (Brondino et al., 2017) as well as its involvement in animal and human social behaviours such as mother-infant bonding (Feldman et al., 2007; Levine et al., 2007; Rocchetti et al., 2014), theory of mind (Feeser et al., 2015; Radke and de Bruijn, 2015) and empathic abilities (Bartz et al., 2010). Independent lines of research confirmed the relationship between OT and the systems involved in emotional regulation: on one hand, blood levels of OT are reduced in subjects suffering PTSD and emotional traumas (Donadon et al., 2018), on the other the administration of intranasal OT (INOT) has been shown to improve aspects of social cognition such as emotion recognition (Guastella et al., 2010; Lischke et al., 2012), interpersonal trust and prosocial, affiliative behaviour (MacDonald et al., 2010).

The crucial role played by OT in modulating human social dynamics reflects the wide range of neurophysiological processes and behaviours it contributes to regulate (Stoop et al., 2012). For instance, there is consensus that OT modulates anxiety, aggression, and the stress/fear response to social stimuli (Labuschagne et al., 2010; Hashimoto et al., 2012), even though its effectiveness as therapeutic agent for anxiety and depression remains controversial (De Cagna et al., 2019). A similar debate arose when OT was suggested as a potential treatment for PTSD. A preliminary study by Pitman et al. (1993) evaluated the effect of both OT and vasopressin on the heart rate, skin conductivity and electromyographic responses of Vietnam veterans suffering from PTSD. Despite OT not showing any clear effect on the outcome assessments, the data raised the possibility that the peptide might have therapeutic potential in PTSD (Pitman et al., 1993).

Subsequent fMRI-based studies showed consistent structural alterations in the brain of people suffering from PTSD, such as significantly smaller volumes of hippocampus, anterior cingulate cortex and amygdala (Karl et al., 2006). Functional alterations became also evident, including hyperactive middle and dorsal anterior cingulate cortex and amygdala, hypoactive ventromedial prefrontal cortex and inferior frontal gyrus (Hayes et al., 2012), increased activity of the salience network (Patel et al., 2012) and reduced top-down inhibitory control of the pre-frontal cortex (PFC) over the amygdala (Hayes et al., 2012). Enhancing the inhibitory control of the PFC over the amygdala as well as directly decreasing its hyperactivation was then suggested to be a promising target for the treatment of PTSD patients (Dunlop et al., 2012). Intriguingly, OT has an active role in promoting both the enhancement of the ventro-medial PFC-amygdala coupling (Sripada et al., 2013) and the decrease of amygdala activity (Domes et al., 2007).

On such insight and following findings, targeted studies were carried out investigating the effect of synthetic INOT on many aspects of PTSD treatment. These findings highlighted a crucial role of INOT in regulating many aspects that appear to be important in regulating the efficacy of psychotherapy in PTSD patients, a major treatment option that nevertheless yields poor results in about a third of subjects (Bradley et al., 2005).

However, to the best of our knowledge, there are no up-to-date reviews summarizing the results so far obtained with a systematic approach. With the present work, we aimed at systematically reviewing all randomized controlled trials (RCTs), evaluating the effect of INOT in individuals affected by PTSD. In detail, we collected data regarding to biological, imaging, and clinical domains, considering as most promising the evidences reproduced 1) in more than a study or 2) coherently in more than one domain.