Oxytocin is known for its role in childbirth and breastfeeding and it has also been shown to have a wider application in the development and regulation of social behaviour in many species.
There has been increasing interest in its potential use to help people overcome social difficulties as this can be one of the most difficult symptoms to treat in many psychiatric conditions such as schizophrenia, autism, anxiety and depression.
Research into the use of oxytocin almost always uses nasal spray application but little is known about how well this method delivers the required dose and reaches different areas of the brain.
Published in Nature Communications, the study is the first to compare different routes and administrations of synthetic oxytocin in terms of how they affect regional blood flow in the human brain, a surrogate measure of neuronal activation, as measured using fMRI scans.
Researchers compared three different methods in a sample of 17 male participants: injection of oxytocin into the blood; administration of oxytocin with a standard nasal spray; and administration with a nebuliser.
The nebuliser, a special nasal delivery device which administered a fine spray of oxytocin in a pulsatile fashion, was investigated as it is thought it can better reach important parts of the nasal cavity.
The results showed that, compared to when no oxytocin is delivered, both the intravenous and the nasal route of administering oxytocin reduced regional blood flow to the amygdala which is a key brain area involved in processing of social information, emotion and social anxiety.
Researchers also showed that the nasal route targeted other specific brain areas and that the patterns of regional blood flow differed depending on whether oxytocin was delivered through a standard spray or the nebuliser.
Senior author, Yannis Paloyelis from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) King’s College London said: ‘Our results show that a one-size-fits-all approach to administrating oxytocin is not the best approach and, to a certain extent, it may be possible to target where in the brain it takes effect.
The results showed that, compared to when no oxytocin is delivered, both the intravenous and the nasal route of administering oxytocin reduced regional blood flow to the amygdala which is a key brain area involved in processing of social information, emotion and social anxiety.
‘This has important implications for the potential application of oxytocin to patients as it suggests that, for some disorders, one route or mode of administration may be superior to others.
For example, clinical applications aiming to target the frontal gyrus, insula or parts of the basal ganglia may achieve better results using the nasal route.
Nevertheless applications that increase the amount of synthetic oxytocin in the blood, such as intravenous administration, could still have an application, as they can achieve localised effects in, for example, the amygdala or the anterior cingulate cortex and allow precise control over the administered dose. This could be very useful for future clinical trials.’
The researchers highlighted that the research might also be relevant for a range of compounds used in the treatment of neuropsychiatric and other disorders, for example nasal administration has been identified as an important route for delivery of insulin and ketamine. More research is needed to provide a more detailed insight into which brain areas are better targeted by nasal delivery and how this can be better optimised.
Loneliness is a crucial determent factor for common mental disorders and depression [1,2]. In major depressive disorder (MDD) patients, their depression severity is associated with degrees of loneliness [3].
Furthermore, loneliness could be an important risk factor for suicide among depression [4]. Loneliness is also associated with poor prognosis in late-life depression [5]. The presence of loneliness is associated with a flattening of the diurnal cortisol rhythm [6].
The negative association between loneliness and perceived social support is well-documented [7–9]. Higher loneliness or lower perceived social support at baselines are both significant predictors of depression remission [9], while loneliness might be a better predictor of depression than social support [10].
Compared the direct effects of loneliness on depression, the effects of social support is indirect and it plays a mediating role between loneliness and depression [11,12].
Evidence suggests that the influence of perceived social support on health is mediated by the neuropeptide oxytocin [13,14].
Oxytocin increases trust, regulates stress, facilitates emotion recognition, increases prosocial behavior, and attenuates loneliness [2,15]. Oxytocin modulates the emotional functions of the amygdala and hypothalamus [16,17].
On behavioral level, oxytocin facilitates expression of the levels of sociality, prosocial behavior, and stress regulation thorugh the effects on hypothalamic-pituitary-adrenal (HPA) axis [13,18,19].
Anxiety and depression are part of the adverse consequences of HPA axis dysfunction [20]. Increased morning cortisol [21], cortisol awakening response and average daily cortisol had been reported in depressed individuals [22].
Both higher serum oxytocin level and better social interaction are associated with reduced activity in the HPA axis. Studies also suggest that the alleviating effect of social support is mediated by oxytocin [14,23,24].
The negative correlations between oxytocin level and the core symptoms of depression have been reported [25]. Furthermore, oxytocin levels in depressed female were associatied with depression and anxiety symptoms severity [26]. Its enhancing effect on social affiliation may play a crucial role in both pathophysiology and therapeutic effect in MDD [27].
Despite that oxytocin-based social buffering effect of stress is observed in both animal [28] and human studies [13], the effect has not been examined in patients with depression.
Assuming that lack of social support could be a risk factor for the poor outcome among patients with MDD, in the current study we aimed to examine the buffer effect of oxytocin, in the link between lack of social support with loneliness, as well as poor HPA-axis activity in MDD patients.
Well-established statistical models were employed [29], to test that whether there is significant interaction between the serum oxytocin level and social support on the loneliness and HPA-axis activity in MDD patients.
DISCUSSION
In a female-predominant sample of patients with MDD, we observed an interaction effect between serum oxytocin level and social support, which was significantly associated with lower subjective loneliness.
Follow-up analyses further revealed a negative association between social support and loneliness which only observed in the high oxytocin level subgroup. Similarly, social support–oxytocin interaction was also negatively associated with serum cortisol level, a biological marker of stress.
Our first regression model (model 1) replicated previous observations that greater social support is associated with lower loneliness in a healthy population [36] and in elder depressive patients [11].
Prior research has observed the association between greater loneliness and poorer social support and depression; however, limited studies have investigated the concurrent association between social support and loneliness in adult depressive patients [37].
In line with our hypothesis, we found a negative association between social support and loneliness in model 2 and model 3, and our results further suggested that oxytocin might facilitate the effect of social support in terms of buffering loneliness, even after adjusting for age (model 2), sex, and level of depression (model 3).
Our results echoed findings of an oxytocin-based social buffering of stress cues in animal [28] and human studies [13]. The results suggested that social support may alleviate loneliness only in the existence of adequate oxytocin level in depressive patients.
As hypothesized, we observed a negative correlation between the social support–oxytocin level interaction and the serum cortisol level in model 2 and model 3, similar to that seen with loneliness.
The negative correlation between social support and cortisol level was stronger in the high oxytocin level group (r = −0.41) than in the low oxytocin level group (r = −0.11), supporting the hypothesis of an oxytocin-based social buffering effect on stress regulation in depressive patients.
This result suggests an oxytocin-based buffering effect to the current stress level, as to stress responsiveness observed by Heinrichs et al. [24], which employed intranasal oxytocin administration in a healthy male population.
Interestingly, we did not find a significant correlation between oxytocin and loneliness in MDD patients. The negative correlation with loneliness exists at the social support–oxytocin interaction level rather than the main effect of oxytocin may reflect a context-related prosocial effect of oxytocin.
The interaction of oxytocin and social support had more prominent effects to suppress the stress-induced cortisol response and anxiety than social support or oxytocin alone [24]. In contrast, a negative or null effect was observed while the administration of oxytocin was in a negative or non-social context [38–40]. In sum, the effects of oxytocin are social environment dependent [13] and vary in different level of social support.
The exact role of oxytocin in MDD is a complex question. Depressed female is more likely to display a dysregulated pattern of peripheral oxytocin release than controls [26], and has a reduced plasma oxytocin level [41,42].
Furthermore, a negative correlation between oxytocin and the severity of depressive symptoms was identified [25]. In summary, the level of oxytocin seems to be lower in individuals with more severe depressive symptoms, particularly in females.
Given that depression severity is associated with degrees of loneliness [3], we expected that depression severity may moderate the association between the social support, oxytocin level and loneliness.
However, in our sample, the severity of depression did not affect the alleviating effect of social support and its interaction effect with oxytocin on loneliness. Similarly, our results suggest that the synergistic effect of social support and oxytocin level on the HPA axis may be relatively independent to the severity of depression. These results imply a similar buffering effect of social support on loneliness and HPA axis activities in MDD patients and in healthy populations [6,11,43].
There were some limitations of the current study. First, the correlational analyses we applied limited the extent to which causal inferences may be made. Second, the sample size was limited, and the results may not be able to be generalized to other populations. Third, much of the variability in loneliness owing to objective social relationships, personality traits, or environmental interactions was not accounted for.
We replicated the buffering effect of social support on loneliness and HPA axis activity, and identified a facilitating factor, higher serum oxytocin level, that had synergistic effect with social support to alleviate the loneliness in drug-naïve female patients with depression.
Those depressive patients with lower level of oxytocin and socially unsupported were likely to experience higher level of loneliness and HPA axis hyperactivity. These findings will inform a new direction of study into the neurobiology of oxytocin that may significantly influence the effect of social support, and may indicate a more effective route for bio-psycho-social intervention and prevention in major depression.
Source:
King’s College London
