Oxytocin (OT) is produced in the hypothalamus, and is secreted into the blood through the posterior pituitary. OT acts in concert with the related neuropeptide vasopressin (VP), also produced by the hypothalamus and secreted by the posterior pituitary into the circulation, to regulate peripheral functions such as myometrium contraction and lactation (attributed to OT) and vasoconstriction and regulation of blood pressure (attributed to VP). Additionally, OT and VP have important neurotransmitter functions centrally in the brain that ultimately regulate social behavior, cognition, and sociality in humans and other mammalian species. These two peptides have a common origin, with VP being phylogenetically older.
Both OT and VP have receptors and associated pathways that have genetic variations between species and within the same species, and further may be epigenetically modulated, underscoring the importance of environmental factors in the development of social cognition. Generally, OT is linked to formation of pair bonding whereas VP is linked to aggression. Both OT and VP are necessary for sexual and paternal behaviors, and pair bonding. In particular, OT is the so-called love hormone that participates in the facilitation of birth, lactation, maternal behavior, trust, empathy, social bonds, and cognition. Early in development OT is associated with the development of the nervous system and the neocortex. Its actions may be influenced by a variety of internal and external factors. For example, the OT receptor promoter is
influenced by other hormonal signaling, such as thyroid and estrogen hormone receptors. OT is necessary for the attachment that promotes human sociality, for the extended periods of nurture necessary for rearing a child, for human intellectual development, and for the sense of psychological safety within family or a social group. OT dynamically modulates the autonomic nervous system, has effects on the vagal system, anti-inflammatory and anti-oxidant effects, that link social behavior to physical and emotional health in humans.
In this article we will describe several psychiatric conditions that from a psychoanalytical perspective are characterized with disturbances in empathy, relatedness, and attachment, and from biological psychiatry and neurobiological perspectives, with decreased OT levels. As such, these conditions may be treated both with psychotherapy and biological treatment aimed to directly modulate the level of OT.
Empathy as a psychoanalytic concept is the ability to understand other people’s point of view, feelings, and thoughts, and plays an important role in facilitating prosocial behaviors. It can be subdivided into cognitive empathy, being able to understand, and affective (emotional) empathy, being able to feel what others are feeling. There is also somatic empathy, which is a physical reaction likely based on the mirror neuron system. There are many clinical studies in different human populations showing OT enhances empathy. More specifically, OT has been found to enhance emotional empathy (EE). This effect was independent of culture and sex, and was dependent on amygdala activity and interactions with other key empathy regions such as the insula. The effect of OT on EE is modulated by the trait autism. It is of note that since the effects of OT are linked to VP, there are indications the ratio between OT and VP may influence stress and therefore play a role in empathy, relatedness, and attachment.
Attachment can be described as a specific neurobiological system resulting in the infant connecting to the primary caregiver in a way that creates an inner working model of relationships that continues throughout life and is very important to the future mental and physical health of the infant. The term “attachment” is based on the feelings-based bond between the infant and the primary caregiver. Secure attachment has been connected to affective and bodily self-regulation, insight and empathy. The neurobiological changes associated with the formation of attachment affect the emotional responses, reward and perception difficulties, that are recognized to play a role in psychiatric conditions such as borderline personality disorder, major depressive disorder, and autism spectrum disorders. The neurobiological mechanisms associated with attachment are tightly linked to the neuroendocrine systems that play a main role in reproduction and survival, the neuropeptides OT and VP. Variations in the human infants’ attachment behavior are associated with single nucleotide polymorphisms (SNP’s) in the OT receptor (OTR) gene suggesting a genetic component to the infant-mother attachment. Developmental exposure to social experiences and to OT and VP can modulate the nervous system, resetting the thresholds for sociality, emotion regulation, and aggression. OT is associated with decreased stress in securely attached individuals (Rebecca Thwing Emeny et al, 2015, Psychoneuroendocrinology).
OT has been found to enhance emotional empathy (EE). This effect was independent of culture and sex….
As attachment theory is integrated into adult psychotherapy, psychotherapists can tailor interventions to fit the attachment needs of their patients. Knowledge on the neurobiological roles of OT and VP in attachment, and conditions associated with lower levels of OT, allow for the administration of OT in psychiatric disorders such as major depression, PTSD, and borderline personality disorder, as an adjunct to the psychotherapeutic approaches. For such therapeutic purposes in the brain, OT has been administered as an intranasal aerosol spray (as opposed to the intravenous route for delivery induction) and it is assumed to be delivered through the intranasal mucosa into the cerebrospinal fluid. The uptake, however, may be variable and the intranasal delivery methods are being optimized.
OT is involved in the physiological events related to reproduction, such as uterine contraction and lactation. These physiologic effects are mechanistically and temporally linked to regulating attachment behavior between mother and offspring, and markers of the OTergic system have been linked to parental behavior and parent-infant bonding. High endogenous OT levels peripartum have been associated with increased mother-infant bonding, and higher plasma and
salivary OT levels in parents were positively associated with the parent-child social engagement, as well as paternal and maternal sensitivity. These early experiences and interactions of the child seem to influence his/her OT system later as an adult. In fact, numerous findings have shown how the early stages of parent-infant bonding influence not just the affiliation/attachment style and social cognition later in life, but also the response to exogenous administration of OT. For example, higher plasma OT levels were reported following mother-infant physical interactions among mothers reporting secure attachment patterns with their own mothers compared to those with insecure attachment patterns.
In another study investigating the effect of OT on attachment representations, more securely attached individuals remembered their mothers as more caring in childhood, while more anxiously attached individuals actually remembered their mothers as less close following OT vs. placebo. Another study showed how intranasal OT increased trust in healthy males who scored high on attachment avoidance but did not have any effects on individuals scoring high on attachment anxiety.
OT levels have also been demonstrated to increase prosocial behavior in women who reported experiencing low levels of maternal love withdrawal as a disciplinary measure versus those who had experienced high levels of maternal love withdrawal. In conclusion, the importance of parental bonding for the development of social bonding suggests the relevance of OT in both structuring enduring bonds and structuring adaptive responses to stressors.
The psychoanalytic concept of interpersonal relatedness is closely associated with the concept of attachment, attachment theory, and personality development. The polarity of attachment and separation is fundamental to personality development along two developmental lines—interpersonal relatedness and self-definition. This underlies the development of psychopathology such as the dependent (infantile) or hysterical personality disorders preoccupied with issues of interpersonal relatedness and the paranoid, obsessive-compulsive and depressive personality disorders in which issues of self-definition are prominent. A higher level of relatedness may be expressed as higher mutual cooperation, in mutual understanding of others’ perspective, and in expression of mutually attuned reciprocity. Relatedness and mutually attuned reciprocity are often found to be disturbed and lacking in autism spectrum disorders (ASD) and borderline personality disorder (BPD).
Despite a general impact of OT on sociality, its action is more complicated and the emerging research has raised doubt whether the effects of OT uniformly promote the formation of bonds and adaptive stress response. There is mounting evidence that social effects of exogenous OT are dependent upon both context and person variables (Rene Hurlemann and Dirk Scheele, 2016). As mentioned earlier, attachment style influences response to exogenous OT. Other individual factors such as sex, hormonal status, and childhood traumatic experiences can influence the effect of OT on social behavior. For example, OT administration did not necessarily dampen the physiological stress response, but this effect was dependent on the interpretation of salience cues. When the social cues are interpreted as safe, OT may promote prosociality, but when the social cues are interpreted as uncertain (because of real threats or perceived threats, such as in traumatized/sensitized individuals or people with severe attachment anxiety or BPD), OT may promote agonistic behavior.
In an evolutionary perspective, the formation of pair bonds has as a goal to maximize survival and procreation, and involves affiliative behaviors as well as agonistic behaviors toward potentially threatening situations. Moreover, OT seems to improve sensitivity to salience cues, increasing reactivity to perceived positive and negative cues in social context. For example, OT improves the buffering effect of social support on stress responsiveness (Markus Heinrichs et al, 2003), but also facilitates the sensation of psychosocial stress in the absence of social support (Monika Eckstein et al, 2014).
Sex-specific OT effects have been found in various domains ranging from social approach/avoidance behavior to moral decision making (Dirk Scheele et al, 2014). Interestingly, the action of OT is not restricted to the downstream level
of emotional responses, but alters higher representations of attitudes by exerting a modulatory influence on cortical areas and their reciprocal interplay with hormonal systems (Rene Hurlemann, 2017).
In healthy women, OT increases amygdala responses to fearful faces but on the flipside, OT reduces amygdala responses to infant crying (Madelon Riem et al, 2011), and higher doses of OT dampen amygdala responses to fearful faces in both male and female patients with PTSD (Saskia Koch et al, 2016). The effect of OT may vary depending on the dose administered. However, further studies need to be conducted to investigate long-term effects of exogenous OT.
Major depressive episodes with peripartum onset affect a relevant proportion of women and pose important challenges in terms of the mother–infant relationship and the child’s consequent cognitive, emotional, and behavioral development. Despite currently being treated in much the same manner as non-peripartum depression, factors unique to pregnancy and the postpartum period complicate its treatment with selective serotonin reuptake inhibitors (SSRI’s).
The characteristic difficulties in breastfeeding reported during postpartum depression have raised attention toward OT as possible mediator of this condition. Consistently, some data describe the relationship between OT, the hypothalamo-pituitary (HPA) axis responses and mood during lactation suggesting the role of OT as an antide-pressant and anxiolytic. These roles are in concert with the roles of OT in stress regulation, anxiety, and relatedness. Moreover, given its role in regulating maternal behavior, OT has been proposed as a potential treatment for this kind of depression. Peripheral high OT levels during pregnancy and postpartum predict enhanced maternal behavior; similarly, interactions with infants stimulate OT release in mothers but only in a subgroup of mothers with secure attachment.
Other studies have examined the role of exogenous intranasal OT administration in mothers, showing increase in incentive salience of an unknown infant’s laughter and decreased negative emotional arousal in front of an unknown infant’s cry. However, evidence is growing showing how women’s OT functions may be modified by their early caregiving experience and style of attachment (Marian Bakermans-Kranenburg, 2012). Further studies may be implemented to explore the complex context and person-dependent nature of OT effects and identify the subgroup of patients who may benefit from exogenous OT.
ASD are a group of varied conditions with deficits in the social-communication domain and the occurrence of restricted and repetitive behaviors (the so-called core symptoms). It has proven very difficult to find pharmacological treatments for the core symptoms of ASD. In ASD there may be different degrees of deficits in empathy. It has been found that empathy in young children at risk for autism depends on the early parent-child interactions and the polymorphisms in the OT receptor (OTR), underscoring the role of attachment and genetics. It has been proposed that an OTR gene variant may increase the social salience of interaction processes for specific allele carriers. OT has shown to effectively target the core symptoms of ASD, both the social-communication deficits and the restricted and repetitive behaviors. OT has shown some beneficial effects on empathy in ASD. Single doses of OT and multiple administrations in ASD have shown benefits in improving the social deficits with underlying biological mechanisms. (Takamitsu Watanabe et al, Brain, 2015) showed
six-week intranasal administration of OT in a randomized, double-blind, placebo-controlled crossover clinical trial of adults with high-functioning ASD improved the social reciprocity, as determined using the Autism Diagnostic Observation Scale (ADOS).
Furthermore, this OT treatment enhanced the social cognition task-independent resting state functional connectivity within areas of the prefrontal cortex (between the anterior cingulate cortex and the dorsomedial prefrontal cortex) that is impaired in ASD, as measured by functional magnetic resonance imaging (fMRI), and significantly mitigated behavioral and neural responses that were impaired during a social judgment task such as judgment tendency, eye gaze effect, anterior cingulate activity, and dorso-medial prefrontal activity. However, the effect sizes of OT treatment observed after a single or six-week administration were not different, underscoring the importance of selecting optimal treatment regimens with OT. Interestingly, it has been proposed that multiple doses of OT may lead to downregulation of the effects through a negative feedback loop.
It should be noted that sex-specific differences have been found by some investigators (Chunliang Feng et al, 2015) in the effects of OT and VP on human social behavior (cooperation). In one clinical study, sex differences have been observed for the effects of OT on the neural responses to reciprocated cooperation in humans in that 24 IU intranasal OT treatment increased the response of the caudate/putamen regions in males (as measured by fMRI) and decreased the response in the same regions in females. Therefore, this OT treatment may increase the reward or salience of positive social interactions among men and decrease their reward or salience among women. Similar sex differences have been observed for 20 IU VP within the bilateral insula and right supramarginal gyrus. These studies caution the uniform use of OT (and VP) for conditions such as depression or autism to men and women alike.
… the concept that OT is a pro-social hormone is too simplistic and other factors such as attachment style, exposure to trauma, and psychiatric disorders must be considered when determining its roles.
Paradoxically, in some studies OT treatment has been found to increase human aggressive behavior, suggesting OT may act to increase the salience of social stimuli rather than to directly promote prosocial behavior. It has been proposed that when OT levels are high, their biological effects on behavior may be due to stimulation primarily of the VP receptors and downregulation of the OT receptors, and therefore promote mobilization of potentially defensive responses and increase aggression instead of decreasing anxiety and promoting positive sociality. These issues have to be considered in the administration of OT for therapeutic purposes, by itself or in addition to psychotherapeutic approaches.
OT is implicated in borderline personality disorder (BPD), although its role in the pathophysiology of the disorder is not yet well understood. BPD is characterized by affect dysregulation, impulsivity, deficits in social cognition, and interpersonal dysfunction due to difficulties in establishing positive and stable interpersonal relationships. Several studies report the plasma OT levels are lower in BPD individuals. However, one study finds serum OT levels are not lower in female individuals with BPD but are higher in females with BPD who are in romantic relationships. This means the concept that OT is a pro-social hormone is too simplistic and other factors such as attachment style, exposure to trauma, and psychiatric disorders must be considered when determining its roles. This is something we outlined earlier—the peptide OT has modulatory functions, dependent on many other genetic and environmental factors. Studies show intranasal administration of OT in BPD leads to increased empathy, trust, better social synchrony, and change in the
relationships with abusive individuals, and therefore support the use of OT as an adjunct to psychotherapy, although further studies are warranted. However, there are findings in humans that intranasal OT in BPD may induce paradoxical reactions such as worsened interpersonal anxiety, reduced trust, and reduced cooperative behavior. It was found the divergent effects of OT were driven by the anxiously attached and rejection-sensitive participants (Jennifer Bartz et al, 2011) In this respect, it will be beneficial to further understand the interactions of OT with VP, testosterone, dopamine, and serotonin, which are also important in stress responsivity and social reward.
Since the neuropeptide OT influences social behavior, understanding its biological role can be very useful in the psychotherapeutic management of conditions in which there are disturbances in empathy, relatedness, and attachment. The role of OT in these conditions is complex and not yet completely understood, as it may be modulated by the closely related neuropeptide VP, opioid peptides, and the dopaminergic system. Importantly, effects may be specific of the individual, modulatory, and very complex because they are dependent on the current physiological, behavioral, and neuroendocrine state of the organism and environmental conditions. Genetics is important in the role of OT and responsiveness to exogenous OT administration since certain OT receptor polymorphisms have been found to play a greater role in social behavior than others. For example, in anorexia nervosa, which is associated with lower levels of OT, a specific polymorphism may alter neural responses to social stimuli and disrupt the engagement and disengagement of the default mode network. While clinical trials support the usefulness of OT in psychiatric conditions that may benefit from psychotherapy such as autism spectrum disorders, borderline personality disorder, major depression, and anorexia nervosa, more clinical trials are needed to determine the optimal treatment regimens, dose, and relationship to genetics. The effects of OT may be sex-specific due to interactions of the oxytonergic system with estrogen receptors in the brain. In summary, the clinical use of OT as a therapeutic agent in combination with psychotherapy is a fascinating and exciting area of research and therapy that calls for further investigation.
Editor’s Note:
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