Intranasal Oxytocin as Enhancer of Psychotherapy Outcomes in Severe Mental Illness: A Randomized Controlled Study

1. Introduction 1.1 Oxytocin (OT) OT is a nine-amino acid neuropeptide synthesized in the magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, and released by the pituitary gland (Meyer-Lindenberg, Domes, Kirsch, & Heinrichs, 2011). OT has both peripheral and central effects, and serves as a neurotransmitter, a neuromodulator and a hormone (see reviews in de Bono, 2003; Skuse & Gallagher, 2009). Peripherally, it is released from the posterior pituitary into the bloodstream where it functions as a hormone and influences bodily functions, such as regulating uterine contractions during labor and lactation (Keverne & Kendrick, 1992). Centrally, through direct axonal release from the PVN, OT acts as a neurotransmitter projecting to various critical brain structures rich with OT receptors such as the hippocampus, amygdala, striatum, and nucleus accumbens (Landgraf & Neumann, 2004;Macdonald & Macdonald, 2010; Ross & Young, 2009). As a neuromodulator, OT creates general volume diffusion, as it is released from all parts of the neuronal membrane into the extracellular space, affecting many regions of the brain (Landgraf & Neumann, 2004; Leng, Meddle, & Douglas, 2008; Ludwig & Leng, 2006).

1.2. Oxytocin and Social Behavior Perhaps one of the most well-known associations of OT is with social behavior. Often referred to as the "social bonding" hormone, OT has been consistently found to be involved in the formation and management of social bonds and in the promotion of affiliative prosocial behavior (Theodoridou, Rowe, Penton-Voak, & Rogers, 2009). Several studies have shown that OT administration increases cooperation, generosity and trust in others. For example, Mikolajczak et al. (2010) investigated the role of OT in interpersonal trust, by evaluating participants' willingness to take social risks compared to nonsocial risks. They found that participants who received IN-OT showed higher levels of trust, and expressed willingness to take risks during social (but not general) interactions, as compared to the placebo group. Similarly, Zak et al. (2007) infused participants with IN-OT or placebo before engaging in a blinded money gifting generosity game, in which there had to make a one-shot decision on how to split a sum of money with a stranger. Their findings indicated that participants in the IN-OT group were 80% more generous than those given a placebo (Zak et al., 2007). In an attempt to assess the neural correlatives of the OT-trust association, Baumgartner, Heinrichs, Vonlanthen, Fischbacher, & Fehr, (2008) assessed participants willingness to trust others even in light of a possible betrayal. They found that participants who had received IN-OT continued to show trusting behavior, even though their trust had been betrayed, as opposed to participants in the placebo group. During this task, they found reduced neural activation in the amygdala and caudate nucleus among participants receiving IN-OT, brain areas which are known to be involved in fear processing (amygdala) and behavioral adaptation (caudate nucleus) in situations with unknown outcome contingencies (Baumgartner, Heinrichs, Vonlanthen, Fischbacher, & Fehr, 2008).

Several studies have put forth the hypothesis that OT is responsible primarily to pro-social behavior. For example, Guastella, et al., (2008) presented participants with happy, angry, or neutral human faces after receiving IN-OT\placebo, and then tested their memory of these faces. They found that participants administered with OT were more likely to remember previously seen happy faces compared with angry and neutral human faces. These findings have indicated that OT has specific influence aimed encoding and recalling positive social information (Guastella, et al., 2008). In another double-blind, placebo-controlled study, Domes et al., (2007) evaluated male volunteers' ability to infer the affective mental state of others using the Reading the Mind in the Eyes Test (RMET) after IN-OT\placebo. They found that IN-OT significantly improved performance on the RMET compared with placebo, suggesting that OT facilitate the interpretation of subtle social cues from eye regions (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007). These, as well the previous studies on the effect of OT on trust and generosity, have set grounds for the hypothesis suggesting OT is responsible for pro-social behavior.

Although many studies have demonstrated an association between OT and pro-social behavior, other studies have found some contradicting findings which called the pro-social hypothesis into question. These studies have seemed to demonstrate that OT, under specific contexts, might actually induce a negative effect on social behavior. For example, Shamay-Tsoory et al., (2009) found that OT administration increased feelings of envy in a simulated money game when the other player gained more money, and feelings of gloating during the experience of success. Eckstein et al., (2014) exposed participants to social stress following IN-OT\placebo administration, and found that participants in the OT group reported increased perceived social stress, as well as increased activity in the precuneus and cingulate cortex, areas which are known to be sensitive to signals of social stress. Striepens et al., (2012) found that IN-OT enhanced the impact of negative social stimuli on the induction of startle response, and induced the subsequent memory toward negative rather than neutral items. Using fMRI analysis, the authors also demonstrated that despite reducing amygdala activity, IN-OT have increased the impact of aversive social information by increasing neural responses in the insular cortex - which play a role in emotional modulation of memory.

A proposed theoretical framework that has been suggested to reconcile these seemingly conflicting studies is "The social salience hypothesis" (Shamay-Tsoory & Abu-Akel, 2016). According to this hypothesis, OT may increase the salience of safety signals, attenuate stress and promote social approach in positive supportive contexts, yet increase the salience of threat signals, diminish social approach and increase anxiety in unpredictable threatening situations. In other words, this hypothesis suggests that OT affects human behavior in an adaptive and context-dependent manner (Andari, Hurlemann, & Young, 2017). It has been suggested that the underlying mechanism which associates OT with modulation of salience throughout different contexts is through the role of OT in attentional processes. OT receptors are found in visual associative areas in humans (Freeman and Young 2016) and in regions involved in attention such as the diagonal band of Broca (Freeman et al. 2014). Moreover, IN-OT has been found to increases visual fixation towards communicative areas of the face such as the eye regions (Guastella et al. 2008), and has also been found to improve the capacity to read subtle non-verbal cues from eye regions, through which individuals understand the intentions and behaviors of social partners (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007). These findings have put forth the idea that OT operates through the induction of attentional shifts towards important social information, and thereby increase the salience of socially relevant cues.