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There is substantial recent interest in the role of oxytocin in social and affiliative behaviors— animal models of depression have suggested a link between oxytocin and mood. We reviewed literature to date for evidence of a potential relationship between peripheral oxytocin concentration and depressive symptoms in humans. Pubmed® and PsychINFO® were searched for biomedical and social sciences literature from 1960 – May 19, 2015 for empirical articles in English involving human subjects focused on the relationship between peripheral oxytocin concentration and depressive symptoms, excluding articles on the oxytocin receptor gene, or involving exogenous (i.e. intranasal) administration of oxytocin. Eight studies meeting criteria were identified and formally reviewed. Studies of pregnant women suggested an inverse relationship between oxytocin level and depressive symptom severity. Findings in non-pregnant women were broadly consistent with the role of oxytocin release in response to stress supported by animal studies. The relationship between oxytocin and depression in men appeared to be in the opposite direction, possibly reflecting the influence of gonadal hormones on oxytocinergic functioning found in other mammalian species. Overall, small sample sizes, heterogeneity in study designs, and other methodological limitations may account for inconsistent findings. Future research utilizing reliable oxytocin measurement protocols including measurements across time, larger sample sizes, and sample homogeneity with respect to multiple possible confounders (age, gender, race and ethnicity, ovarian status among women, and psychosocial context) are needed to elucidate the role of oxytocin in the pathogenesis of depression, and could guide the design of novel pharmacologic agents.
Depression is a common and debilitating illness that adversely affects functioning, quality of life, and the course of other medical illnesses.1 Nearly 8% of persons 12 years of age or older (6% of males and 10% of females) report current depression.2 Despite the increasing number of pharmacologic therapies for depression, only 60 – 70% of patients will respond to first-line monotherapy, and more than one third are considered treatment-resistant.3 One reason for treatment resistance may be the inherent heterogeneity that exists in the clinical presentation of depression.4 For example, different subtypes of depression (melancholic, atypical, hostile, and anxious depression, double depression, bipolar depression, and depression with comorbid personality disorders) may actually involve different biological substrates.5 While the development of most pharmacologic approaches to depression have primarily centered on the monoamine hypothesis of depression,6 hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation represents another important area of inquiry, 7 particularly as a substantial proportion of individuals do not respond to currently available antidepressants.3
The neuropeptide hormone, oxytocin, is produced in the hypothalamus and released from the posterior pituitary gland in response to cervical and uterine distension during childbirth, stimulation of nipples during lactation, and a variety of types of social interactions.8-10 Animal studies first raised the possibility of a relationship between oxytocin and mood when immobility in mice in the forced swim test could be diminished through intracerebrovascular administration of oxytocin, and systemic administration of oxytocin was as effective as the antidepressant, imipramine, in reducing immobility11. Demonstration of the role of oxytocin in social and affiliative behaviors in animals and humans led to further interest in the role of oxytocinergic function in the pathogenesis of depression.12-15
In light of the problem of treatment resistance, and the apparent influence of oxytocin in animal studies, elucidating the role oxytocinergic functioning in the pathogenesis of depression in humans can guide the design of novel pharmacologic and behavioral treatments.15 As such, this review was guided by the question, what is the relationship between oxytocin concentration and depressive symptoms in humans?
To search the literature, we utilized PubMed® and PsychINFO® using the key word ‘oxytocin,’ combined with each of the following terms: ‘depression,’ ‘mood,’ and ‘depressive.’ We restricted the search to articles written or translated into English from December 1960 to May 19, 2015 with a main focus on the relationship between endogenous oxytocin levels and depressive symptoms. While studies involving the exogenous (i.e. intranasal) administration of oxytocin are of substantial importance, the focus of this review was on endogenous oxytocin release, as reflected by peripheral measurements. We refer readers to the excellent review by McQuaid et al., 2014 for a summary of studies on exogenously administered oxytocin.15 The search was initiated on January 6, 2015, and completed on May 19, 2015. Titles and abstracts from the 139 potentially-relevant citations were examined and limited to original journal articles in English involving human subjects (figure). Studies on the oxytocin receptor (OXTR) gene, intranasal or other exogenous administration of oxytocin, and studies that did not measure depressive symptoms, or were not primarily focused on the relationship between oxytocin and depression or depressive symptoms were excluded. Fourteen remaining articles were ascertained in full and reviewed in detail. References were hand-searched for additional relevant articles (n = 3). The seventeen articles remaining were then examined for the use of multivariable analysis to control for confounding factors. Nine studies were excluded, resulting in a remaining 8 studies constituting the formal review. As shown in the table, we further detail other parameters of study quality that may affect findings including: (a) the method used for diagnosing depression (self-report questionnaires versus interview-based assessments); and (b) the method of assaying oxytocin levels, including whether assays were performed after extraction.
The 8 studies formally reviewed were conducted in 5 countries worldwide: the United States (n = 3), Canada (n = 1), Switzerland (n = 1), Turkey (n = 2), and Australia (n = 1), and varied substantially with regard to sample size (N = 34 to 287 subjects), racial and ethnic composition of participants, and measures used to diagnose depression or measure depressive symptoms (table). Five studies included exclusively women,16-20 three of which involved only pregnant women,16,17,19 and three studies involved mixed-gendered samples.21-23 The table summarizes study characteristics and findings from these reviewed studies.
An inverse relationship between plasma oxytocin concentration and depressive symptoms was found in all 3 studies of perinatal women. Skrundz and colleagues (2011) were the first to explore the link between oxytocin and risk for postpartum depression in a sample of 73 middle-class German-speaking Swiss, non-smoking, non-depressed, non-obese, healthy women with singleton pregnancies.19 Lower plasma oxytocin concentration measured in the 30th to 34th weeks of pregnancy predicted a positive screen for depression (score of 10 or higher) at two weeks postpartum using the German version of the Edinburgh Postpartum Depression Scale (EPDS).24 The other two studies of perinatal women found similar inverse relationships between plasma oxytocin concentration and depressive symptoms. While Eapen and colleagues (2014) did not show a longitudinal relationship between pregnancy oxytocin and postpartum depressive symptoms in a fairly educated sample of 127 racially and ethnically diverse pregnant women (52% Caucasian, 23% Asian, 10% Indian, 8% Arabic) in Australia, lower oxytocin concentration at 3 months postpartum was associated with greater depressive symptoms at that time, measured by the EPDS.25 Zelkowitz et al (2014) found that under conditions of high psychosocial stress as measured by the Antenatal Risk Questionnaire,26 higher oxytocin levels in pregnancy were correlated with lower depressive symptoms in pregnancy, and at 8 weeks postpartum. In summary, the 3 reviewed studies of pregnant and postpartum women suggested inverse relationships between plasma oxytocin concentration and depressive symptoms.
Studies of non-pregnant women suggested non-linear relationships. In a study of plasma oxytocin release following an affiliation-focused task and a stress-focused task in 17 depressed non-medicated women and 17 non-depressed women, Cyranowski and colleagues (2008) found that, compared to controls, depressed women displayed greater variability in pulsatile oxytocin release during both tasks, and higher oxytocin levels during the affiliation task. Moreover, oxytocin levels in depressed women were directly associated with severity of depressive symptoms measured by the Beck Depression Inventory.27 The other study of oxytocin and depression in non-pregnant women examined the relationship between oxytocin levels and depressive symptoms over a 10-week period in an ethnic minority (African-American or Caribbean) sample of Human Immunodeficiency Virus (HIV) -positive women participating in a larger study on the influence of stress on health outcomes in women living with HIV.20 Interestingly, a curvilinear relationship was found; very high and very low plasma oxytocin levels were predictive of an increase in depressive symptoms measured by the BDI over the 10 week period. Taken together, in non-pregnant women, both extremes of oxytocin levels (high and low), in addition to greater variability in oxytocin levels, were associated with greater depressive symptoms.
Ozsoy and colleagues (2009) found lower oxytocin levels in 40 depressed patients (30 women, 10 men) relative to controls, though the difference appeared to be driven by lower oxytocin in females only; levels among depressed and non-depressed males did not differ. The two remaining mixed-gendered studies examined bipolar depression and psychotic depression, respectively. Turan and colleagues (2013) compared plasma oxytocin levels among 21 patients with bipolar depression, 22 patients with acute mania, 24 bipolar patients in remission, and 24 healthy controls. Bipolar patients in any phase of illness exhibited higher oxytocin levels than controls, and there was no difference in oxytocin levels among any of the bipolar groups, leading authors to postulate that oxytocin may be a marker of bipolar illness. Yuen and colleagues (2014) compared plasma oxytocin levels among adults with psychotic depression (10 women, 4 men), non-psychotic depression (12 women, 4 men), and 19 healthy controls healthy controls (11 women, 8 men). Oxytocin levels did not differ between psychotic and non-psychotic depression groups when both genders were compared together. However, depressed females had lower oxytocin levels than healthy females, while depressed men showed a trend toward higher oxytocin levels compared to healthy men (difference not statistically significant).
While animal models have suggested that oxytocin attenuates depression-like behavior 10, 28-31 raising the possibility of an oxytocinergic pharmacologic intervention in humans, the relationship between plasma oxytocin concentration and depressive symptoms in humans appears more complicated and more difficult to study directly, as suggested by the studies reviewed. We discuss findings in the context of hypothesized actions of oxytocin based on literature to date, and suggest directions for future work.
Elevations in peripheral oxytocin have been previously proposed to represent a biomarker of stress and social separation in females.29 Grippo et al., (2007) showed that female prairie voles exposed to extended periods of social isolation displayed an increased number or oxytocin-immuno-reactive cells in the paraventircular nucleus of the hypothalamus. 30 Moreover, in several mammalian species, oxytocin appears to exert a tonic inhibitory influence over the HPA axis, thereby attenuating rises in cortisol in response to stress.30-32 Interpreted within the context of these animal studies, the inverse relationships observed between oxytocin levels and depressive symptoms among pregnant16,17,19 and non-pregnant women20,21 could reflect a failure of the oxytocin system to effectively adjust to stress. However, it is also possible that both high and low extremes of oxytocin levels could be observed in women experiencing depressive symptoms, such as documented in the Cyranowski (2008) study. Thus, it is unclear whether depressive symptoms precedes a change in oxytocin levels, or whether oxytocin levels reflect adaptations made in response to depression.
What could account for this inter-individual variability in oxytocinergic function? There is evidence to suggest that common variations in the OXTR gene are associated with different degrees of stress reactivity,33 or interact with social support to reduce stress in humans.34 Future research that combines the study of oxytocin responses longitudinally with genotyping at OXTR could elucidate how variations in OXTR may mediate differences in oxytocinergic functioning in women.
Yuen and colleagues (2014) showed that depressed females had lower oxytocin levels than healthy females, but depressed males showed a trend in the opposite direction. This could reflect the complex interplay between oxytocin and gonadal hormones documented in other mammalian species—oxytocin synthesis is partially estrogen dependent in mice 35 and oxytocin release and the oxytocin receptor respond to changes in ovarian status across the female menstrual cycle. 36 Future studies that examine men and women separately and take ovarian status into account is advisable.
Turan and colleagues (2013) found that plasma oxytocin concentration was higher among bipolar disorder patients in any phase (depressed, euthymic, manic) relative to healthy controls, while most studies of unipolar depressed patients suggested an inverse relationship between oxytocin levels and depressive symptoms. In individuals with bipolar disorder, abnormal sensitivity in reward-related neural circuitry involving dopamine may account for observed excesses in motivation during life events involving rewards and goal attainment. On the other hand, individuals with unipolar depression show decreased reward responsivity and reward-related neural activation.37 Strong reciprocal interactions likely exist between oxytocin and dopamine systems as oxytocin receptor density has been found to be high in the mesocorticolimbic dopamine pathway including the prefrontal cortex and the nucleus accumbens among prairie voles.38 Thus, mood dysregulation marked by either excessive or diminished social-affiliative behaviors may be future targets of pharmacologic agents designed to alter oxytocin levels.
Results need to be considered in the context of several methodological issues. First, the relationship between peripherally measured oxytocin (plasma, salivary) and central levels of oxytocin (cerebrospinal fluid) is unclear.39 Next, diurnal variations in plasma oxytocin concentrations40 and the possibility of variation in oxytocin function by ethnicity41 complicates comparisons across studies. Finally, measurements of oxytocin made on unextracted samples could result in the tagging and detection of other molecules in addition to oxytocin42 leading to an overestimation of oxytocin levels. As there is increased attention paid to oxytocin in the lay press,43 clinicians and healthcare providers might be prepared to address questions from patients and inform them about the preliminary nature of findings to date, based on information from this review.
While studies employing animal models of depression have supported a clear role of oxytocin in relation to depressive symptoms, studies in humans are inadequate to support translation to the clinical setting at this time. Future investigations should utilize samples large enough to test for gender differences (or separate the study of men and women), employ serial measurements of oxytocin, consider ovarian status among women (premenopausal versus menopausal and phase of menstrual cycle), use reliable and reproducible techniques for assaying oxytocin, utilize consistent socio-environmental contexts and racially and ethnically homogeneous samples, and examine homogenous subtypes of depression (chronic versus acute, unipolar versus bipolar) to most accurately clarify the role of oxytocin in the pathogenesis of depression in humans.
This work was supported by a grant from the Evergreen Invitational Women’s Health Grants Initiative of the Northwestern Memorial Foundation (PI: Massey, 9/12/13 Agreement Date) and grant K23 DA037913 from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (PI: Massey). The Evergreen Invitational, Northwestern Memorial Foundation, and NIDA had no role in the study design, collection, analysis or interpretation of data, writing the manuscript, or the decision to submit the paper for publication.
Disclosures: Authors Massey, Backes, and Schuette have no conflicts of interest or financial disclosures to report.