Oxytocin is a neuropeptide that is synthesised in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. It is released into the brain via distributed oxytocinergic pathways and oxytocin receptors are located in various socially relevant and stress-sensitive brain regions [1]. This neuropeptide can facilitate maternal-infant attachment and pair-bond formation in a variety of mammals [2–4], as well as decrease anxiety and stress [5] when centrally administered [6]. Oxytocin is also released in response to acute psychogenic stressors in mammals [6, 7].

Clinically, oxytocin has been shown to facilitate improved social communication behaviour in humans (e.g., eye contact, nonverbal positive behaviour and self-disclosure). In an investigation involving healthy controls, oxytocin compared with placebo reduced couple conflict (improved social communication) and reduced cortisol concentrations [8]. Multiple investigations have also demonstrated the therapeutic application of oxytocin for anxiety symptoms. For example, oxytocin has been shown to enhance the buffering effect of social support on stress responsiveness [9]. Oxytocin or placebo was administered to healthy controls prior to exposure to the Trier Social Stress Test (TSST) in the presence of participants’ best friend or no social support [9]. Compared to placebo, those administered oxytocin in the context of social support experienced increased calmness and decreased anxiety during the TSST, and showed the lowest salivary free cortisol concentrations [9]. In addition, in patients with social anxiety disorder, oxytocin compared to placebo was associated with improved positive evaluations of appearance and speech performance as exposure treatment sessions progressed [10]. These findings suggest that oxytocin can reduce symptoms of anxiety which is likely, due in part, to attenuating the activity of the HPA axis [8]. Although oxytocin can reduce anxiety and attenuate activity of the hypothalamo-pituitary adrenal (HPA) axis, [5, 11] the precise mechanisms by which this occurs are not yet well defined.

These findings suggest the possibility that oxytocin may be of clinical relevance to disorders associated with psychosocial impairment, anxiety and dysregulation of the HPA axis. Individuals with major depressive disorder (MDD) often experience difficulties in interpersonal relationships, and social isolation. Furthermore, up to 60% of patients with MDD experience elevated activity of the HPA-axis [12]. Dysregulation of the HPA system is reportedly the most prominent endocrine change seen in MDD and normalizing the HPA axis is one target of recent treatment developments [13–15].

Several lines of evidence support that the oxytocin system is altered in MDD. For example, a small sample of patients with MDD (n = 3) showed a 23% increase in oxytocin neurons in the PON of the hypothalamus compared with matched healthy controls [16]. It was concluded that this increase may be linked to increased HPA axis activity, commonly reported in patients with MDD [16]. Increased staining for oxytocin neurons has since been demonstrated in other research [17]. Potential differences in oxytocin, cortisol and arginine vasopressin concentrations in patients with MDD (n = 11) compared with matched healthy controls (n = 19) have also been investigated [18]. Results revealed increased oxytocin concentrations in individuals with MDD compared to healthy controls, whereas no differences were observed in cortisol or arginine vasopressin concentrations [18]. Elevated oxytocin concentrations found in MDD is also consistent with evidence that oxytocin mRNA levels are increased in depressed patients (e.g., [16, 18]).

The potential clinical relevance of oxytocin to MDD has also been investigated. Plasma oxytocin concentrations have been linked to the temperament dimension of reward dependence (according to Temperament and Character Inventory, TCI) in patients with MDD [19]. In other research, although an association between performance on neuropsychological testing and elevated basal cortisol concentrations was demonstrated in MDD, no association was found between performance and plasma concentrations of oxytocin [20]. Significant correlations have also been shown between oxytocin concentrations and depressive symptoms in several studies involving individuals with a diagnosis of: obsessive compulsive disorder [21], fibromyalgia [22] and MDD [23, 24].

A relationship between oxytocin and treatment outcomes has also been investigated in MDD. In one study involving patients with MDD or bipolar disorder, oxytocin concentrations were not influenced by treatment (involving either an SSRI, tricyclic antidepressant or electroconvulsive therapy) [25]. These findings are in agreement with previous results demonstrating no difference in cerebrospinal fluid oxytocin concentrations in medicated, symptomatic individuals with MDD compared to healthy controls [26]. Patients included in the study were taking heterogeneous treatments, however, (10 patients were treated with a tricyclic antidepressant, two with a monoamine oxidase inhibitor, two with lithium carbonate and one with an antipsychotic [26]) which may have influenced the outcomes.

Preclinical evidence indicates that oxytocin can influence activity of the serotonin system, which may relate to the antidepressant effects of SSRIs [27]. In a recent study in mice, widespread expression of oxytocin receptor containing cells were shown to be co-localised with tryptophan hydroxylase-positive neurones in the raphe nuclei [28]. Furthermore, intra-raphe infusion of oxytocin increased serotonin release within the median raphe, a response that was inhibited by serotonin 2A/2C receptor antagonists. It was speculated thus that the increased serotonergic activity induced by oxytocin may underlie its anxiolytic effects [28]. Given the use and effectiveness of SSRI’s in MDD, these findings may also relate to their antidepressant-like effects [27].

Further, evidence supports that the serotonin and oxytocin systems may interact in the hypothalamus [29]. In macaques, neuroanatomic evidence shows that the distribution of serotonin transporter fibres follows the distribution of oxytocin cells in the hypothalamus in the parvicellular, magnocellular, dorsal, and posterior subdivisions of the paraventricular nuclei. In the supraoptic nuclei, serotonin transporter fibers and oxytocin cells overlap in the ventromedial subdivision and in the ‘capsular’ part of the dorsolateral supraoptic nuclei [29]. Again, it has been concluded that these findings provide neuroanatomical support that SSRIs’ therapeutic effects may be mediated in part, through components of the oxytocin system [29].

Although a number of pharmacological agents are available to treat depression, at least 30-40% of patients do not respond to these [30, 31]. Therefore, there is a major emphasis in psychiatry to uncover the underlying aetiology of mood disorders, to be able to develop more effective treatments [27]. In this respect, oxytocin may be of therapeutic benefit in patients with MDD. The primary aim of this study was to gain further understanding of the role of oxytocin in the pathophysiology of MDD. Using an open label treatment design we examined whether there is a relationship between oxytocin concentrations and symptoms of MDD and their resolution following (SSRI Treatment. In a secondary aim, we intended to investigate whether there is a clinically relevant relationship between oxytocin and cortisol in relation to symptoms of MDD and their resolution.