Postprandial oxytocin secretion is associated with severity of anxiety and depressive symptoms in anorexia nervosa

Abstract

Objective

Anorexia nervosa, a psychiatric disorder characterized by self-induced starvation, is associated with endocrine dysfunction and comorbid anxiety and depression. Animal data suggest that oxytocin may have anxiolytic and antidepressant effects. We have reported increased postprandial oxytocin levels in women with active anorexia nervosa (AN), and decreased levels in weight-recovered women with anorexia nervosa (ANWR) compared to healthy controls (HC). A meal may represent a significant source of stress in patients with disordered eating. We therefore investigated the association between post-prandial oxytocin secretion and symptoms of anxiety and depression in anorexia nervosa.

Method

We performed a cross-sectional study of 35 women (13 AN, 9 ANWR and 13 HC). Serum oxytocin and cortisol and plasma leptin levels were measured fasting and 30, 60, and 120min after a standardized mixed meal. The area under the curve (AUC), and for oxytocin, postprandial nadir and peak levels were determined. Anxiety and depressive symptoms were assessed using the Spielberger State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory II (BDI-II).

Results

In women with anorexia nervosa, oxytocin AUC and post-prandial nadir and peak levels were positively associated with STAI scores. Oxytocin AUC and nadir levels were positively associated with BDI-II scores. After controlling for cortisol AUC, most relationships remained significant. After controlling for leptin AUC, all of the relationships remained significant. Oxytocin secretion explained up to 51% of the variance in STAI trait and 24% of BDI-II scores.

Conclusions

Abnormal post-prandial oxytocin secretion in women with anorexia nervosa is associated with increased symptoms of anxiety and depression. This may represent an adaptive response of oxytocin secretion to food-related symptoms of anxiety and depression.

Introduction

Anorexia nervosa is a psychiatric illness affecting predominantly young women, characterized by self-induced starvation, endocrine dysregulation, and comorbid psychiatric disease ¹. Anxiety and affective disorders are common in this population, with lifetime prevalences of up to 65 and 80%, respectively ², and the effect of these conditions on outcome of anorexia nervosa is empirically unclear. The nutritional effects of dieting and starvation complicate the assessment of anxiety and depressive disorders in anorexia nervosa and treatment is initially focused on nutritional rehabilitation.

Oxytocin is an anorexigenic (i.e., reduces food intake) peptide hormone produced in the hypothalamus and secreted peripherally via the posterior pituitary, and centrally in brain regions that include the limbic system. We have reported abnormal oxytocin secretion in anorexia nervosa, associated with symptom severity^{3, 4}. Nocturnal oxytocin levels were lower in women with active anorexia nervosa (AN) than healthy controls³. In response to a meal, however, oxytocin secretion was higher in AN and lower in weight-recovered anorectics (ANWR) than controls, and associated with disordered eating psychopathology⁴. Using a food-related fMRI paradigm, we demonstrated that AN and ANWR had fasting and post-prandial hypoactivation of the amygdala, a brain region involved in emotion, compared to healthy women, and post-prandial oxytocin secretion mediated a significant portion of this difference in AN^{4, 5}. Animal data indicate that oxytocin has anxiolytic and antidepressant properties^6-10. Oxytocin administration reduces symptoms in rodent models of anxiety and depression, and serotoninergic neurons may mediate these effects¹¹. Data on the relationship between oxytocin secretion and psychiatric symptoms in humans is lacking.

We therefore investigated the relationship between abnormal oxytocin secretion in anorexia nervosa and psychiatric symptoms. In the analyses, we controlled for secretion of appetite-regulating hormones, leptin and cortisol, which have been linked to anxiety and depression. Levels of leptin, a fat-derived anorexigenic hormone, are low in AN and associated with increased anxiety and depressive symptoms, independent of body fat¹². Cortisol, an orexigenic (i.e., increases food intake) adrenal hormone secreted in response to stress, is increased in AN and has also been implicated in anxiety and depressive symptoms in this population¹³.

Method

Subjects

We studied 35 women, 18-28 years old: 13 AN, 9 ANWR and 13 normal-weight healthy women (HC) recruited from the community.

Subjects were excluded for active drug or alcohol abuse, use of hormones or medications affecting hormone levels (including estrogen) within eight weeks, use of depot medroxyprogesterone within six months, diabetes mellitus, gastrointestinal surgery, pregnancy/breastfeeding within eight weeks, or hematocrit<30%.

AN met diagnostic criteria as assessed by the Structured Clinical Interview for DSM Disorders-IV (SCID), including intense fear of gaining weight, body image disturbance, weight<85% of ideal body weight (IBW)¹⁴, and amenorrhea ≥3 months¹⁵. AN met criteria for restricting-subtype and had no more than one binge and one purge episode per month in the prior three months. Subjects with a history of psychosis by SCID were excluded.

ANWR were 90-110% IBW with regular menstrual cycles and stable weight for ≥6 months. ANWR met a diagnosis of past AN, by DSM-IV criteria other than amenorrhea, as assessed by SCID. ANWR had not exercised >10 hrs/wk or run >25 mi/wk in the prior three months.

HC were 90-110% IBW with regular menstrual cycles. HC had no history of amenorrhea and no history of a psychiatric disorder (including an eating disorder) as assessed by SCID. HC were excluded if they had exercised >10 hrs/wk or ran >25 mi/wk in the prior three months.

Procedures

This study was approved by the Partners Human Research Committee. Written informed consent was obtained prior to procedures. Subjects were seen at the Massachusetts General Hospital Clinical Research Center and Athinoula A. Martinos Imaging Center. Subject characteristics, psychiatric scores and levels of oxytocin, cortisol and leptin have been reported^{4, 5}. However, the relationship between oxytocin secretion and severity of anxiety and depressive symptoms has not been described.

At the screening visit, height, weight and elbow breadth were measured, blood was drawn, and a history (including exercise patterns and alcohol intake) and physical exam were performed. %IBW and BMI were calculated. Frame size was determined by comparing elbow breadth to race-specific norms derived from the US Health and Nutritional Examination Survey-I¹⁶. The Mood Episode, Psychotic and Associated Symptoms, Mood Disorder, Anxiety, Somatoform, Substance Abuse and Disordered Eating modules of the SCID were administered¹⁵.

At the main visit, %IBW and BMI were reevaluated. A brief medical history was performed. ANWR and HC were studied during the follicular phase of the menstrual cycle, the time when estradiol levels are lowest, and therefore most similar to the amenorrheic women with anorexia nervosa. Subjects were asked to fast for 12 hours. Given the role of oxytocin, cortisol and leptin in appetite regulation, we measured levels fasting and in response to food. Subjects were given a 400kcal mixed breakfast meal standardized for nutrient content (approximately 20% calories from protein, 20% fat, and 60% carbohydrates) at 9AM and asked to eat the entire meal over 15 minutes. Upon completion, bionutrition staff weighed the meal to determine exact caloric intake. Blood was drawn serially for hormones: fasting immediately pre-meal, and 30, 60, and 120min post-meal. The BDI-II and STAI were self-administered. STAI state was assessed pre- and post-meal.

Biochemical analysis

Samples were stored at −80° C. Serum oxytocin levels were measured following extraction using an enzyme immunosassay kit (Assay Designs; Ann Arbor, MI) as previously described⁴. The intra-assay CV is less than 6.0%. The inter-assay CV for the extracted, then assayed specimens was 16.5%; the lower limit of detection was 7.0 pg/ml. Serum cortisol levels were measured using a chemiluminescent immunoassay (Beckman-Coulter; Fullerton, CA). The inter-assay CV was 6.4-7.9%; sensitivity was 0.4 mcg/dl. Plasma leptin levels were measured using a radioimmunoassay (LINCO Research; St. Charles, MO). The intra-assay CV was 3.4-8.3%; sensitivity was 0.5 ng/mL. AUC was calculated using the trapezoidal method.

Anxiety and depressive symptom assessment

The STAI is a well-validated, reliable instrument for assessing anxiety symptoms. The State scale assesses how subjects feel “right now, at this moment,” and the Trait scale assesses how they feel “generally”. Based on normative data, >46 on the State Scale and >45 on the Trait Scale (1 SD>mean), were considered abnormal^{17, 18}. The BDI-II is a validated, reliable questionnaire for assessing symptoms of depression. The BDI-II assesses the severity of depression over the prior two weeks, using DSM-IV criteria. The reference range is: 0-13 minimal, 14-19 mild, 20-28 moderate, and 29-63 severe symptoms¹⁹.

Data analysis

JMP Statistical Discoveries (version 9.0; SAS Institute, Inc., Cary, NC) was used for statistical analyses. Hormones were not normally distributed and were therefore log-transformed prior to analyses. Clinical characteristics, hormone levels, and psychiatric scores were compared using overall Analysis of Variance; variables that were significantly different were then compared by Fisher’s Least Significant Difference Test. Linear regression analyses were used to investigate associations between oxytocin levels and psychiatric symptoms. Multivariate least-square analyses were constructed to control for cortisol and leptin levels. Stepwise regression analyses were performed to further investigate determinants of psychiatric symptoms (forward direction, p<0.1 to enter and leave). Statistical significance was defined as a two-tailed p-value ≤ 0.05. Data are reported as mean ± SEM.

Results

Subjects

Table 1 presents subject characteristics. Mean age was 22.2±0.4 years, and did not differ between groups. Weight, BMI and %IBW were low in AN, but did not differ between ANWR and HC, as per design. For AN, mean %IBW was 80.6±1.3 and time since diagnosis was 52.7±11.2 months. ANWR had a mean %IBW of 98.3±3.8 and reported weight stability for at least 12 months and regular menstrual cycles for at least 14 months. ANWR had recovered weight and menses a mean of 44.4±12.0 and 47±17.4 months prior to the study, respectively. Comorbid Axis 1 diagnoses in AN included: three subjects with current Generalized Anxiety Disorder, one with current Attention Deficit Hyperactivity Disorder (ADHD) – NOS, one with current Generalized Anxiety Disorder and history of Bipolar 1, ADHD-NOS, and Post Traumatic Stress Disorder, two with a history of Major Depressive Disorder, and one with a history of Depressive Disorder – NOS. Comorbid Axis 1 diagnoses in ANWR included one subject with a past history of Major Depressive Disorder and Social Phobia and two with a past history of Major Depressive Disorder. Five AN were taking psychotropic medications: two were taking venlafaxine, one was taking fluoxetine, one was taking a low dose of amphetamine/dextroamphetamine (5 mg 24 hours prior to the scan), and one was taking escitalopram and aripiprazole. One ANWR was taking a psychotropic medication: fluoxetine. Subjects in each group reported similar mean hours of sleep and hours since last per os intake. No subjects consumed alcohol within 24 hours or caffeine within 12 hours of the study. No subjects smoked cigarettes on the morning of the study. Three AN, one ANWR and three HC failed to consume the entire meal. Caloric content consumed at the meal did not differ between groups.

Table 1.

Subject characteristics and hormone levels

				p-value			Overall
	AN	ANWR	HC	AN vs. ANWR	AN vs. HC	ANWR vs. HC	ANOVA
Subject characteristics
Age (years)	21.7±0.7	23.2±0.8	22.0±0.4	-	-	-	NS
Weight (kg)	48.2±1.1	58.4±2.0	62.0±1.7	<0.0001	<0.0001	NS	<0.0001
Body mass index (kg/m2)	17.7±0.3	22.1±0.7	22.5±0.4	<0.0001	<0.0001	NS	<0.0001
% Ideal body weight	80.6±1.3	98.3±3.8	97.2±1.7	<0.0001	<0.0001	NS	<0.0001
Hours exercise/wk	7.8±1.7	3.8±0.8	4.1±0.7	-	-	-	0.054
No. alcoholic drinks/wk	0.8±0.4	2.8±0.7	3.1±0.8	0.038	0.011	NS	0.023
Hrs. of sleep previous night	6.0±0.3	6.7±0.5	6.1±0.3	-		-	NS
Hrs. since last po intake	13.9±0.4	13.9±0.2	14.1±0.2	-		-	NS
Calories consumed at breakfast	378.5±16.2	408.5±6.4	405.8±2.0	-		-	NS
Protein (g)	18.3±0.7	19.4±0.6	19.4±0.2	-		-	NS
Fat (g)	9.4±0.8	10.4±0.6	10.6±0.3	-		-	NS
Carbohydrates (g)	58.2±2.0	62.1±1.4	61.5±0.5	-		-	NS
Hormone Levels
Oxytocin
T 0 Fasting	15.8±1.1	8.1±0.6	16.4±2.3	0.0003	NS	0.0006	0.0005
T 30	17.6±2.5	9.3±1.1	15.4±1.9	0.004	NS	0.024	0.012
T 60	16.6±2.3	9.0±1.0	12.3±1.9	0.003	0.049	NS	0.009
T 120	19.1±3.7	7.7±0.4	12.0±1.2	<0.0001	0.009	0.018	<0.0001
Area under the curve	2086±195	1040±96	1621±125	<0.0001	0.041	0.002	<0.0001
Post-prandial nadir	13.5±1.1	7.7±0.4	9.0±0.7	<0.0001	0.0002	NS	<0.0001
Post-prandial peak	23.4±4.0	9.9±3.2	18.9±1.8	0.0001	NS	0.001	0.0004
Cortisol
T 0 Fasting	15.9±1.4	12.7±1.1	11.7±1.1	NS	0.014	NS	0.042
T 30	15.1±1.6	11.3±1.0	11.7±0.8	-	-	-	0.089
T 60	13.3±1.5	11.5±0.7	10.9±0.8	-	-	-	NS
T 120	12.9±1.3	11.1±0.8	8.8±0.7	NS	0.006	0.067	0.019
Area under the curve	1679±159	1383±83	1280±73	-	-	-	0.084
Leptin
T 0 Fasting	3.2±0.4	9.3±1.4	10.9±1.3	<0.0001	<0.0001	NS	<0.0001
T 30	2.9±0.4	8.4±1.3	9.7±1.2	<0.0001	<0.0001	NS	<0.0001
T 60	2.9±0.4	8.7±1.3	10.3±1.2	<0.0001	<0.0001	NS	<0.0001
T 120	2.8±0.4	8.3±1.3	9.5±1.1	<0.0001	<0.0001	NS	<0.0001
Area under the curve	347±48	1034±159	1203±140	<0.0001	<0.0001	NS	<0.0001

Mean±S.E.M.

Significant p-values are shown in bold

Hormones

Table 1 and Figure 1 present hormone levels. Oxytocin, cortisol and leptin levels at specific timepoints and AUC were previously reported⁴. Mean fasting levels of oxytocin were comparable in AN and HC, but lower in ANWR. Mean oxytocin levels were higher in AN than HC at 60 and 120 min, and lower in ANWR than HC at 30 and 120 min and AN at all timepoints. Mean oxytocin AUC was highest in AN, intermediate in HC, and lowest in ANWR. The change in oxytocin levels at 30, 60 and 120 min from baseline did not significantly differ between groups. To explore oxytocin secretory dynamics more fully here, we analyzed differences in nadir and peak oxytocin levels. The mean postprandial nadir oxytocin level was higher in AN than ANWR or HC. The mean postprandial peak oxytocin level did not differ between AN and HC, but was lower in ANWR than AN or HC. To take into account possible effects of antidepressant medications, we then excluded subjects on antidepressants, and the results were similar. Mean leptin levels at every timepoint and AUC were lower in AN than ANWR or HC. Mean cortisol levels at 0 and 120 min and AUC were higher in AN than HC. The mean cortisol AUC differences between AN, ANWR, and HC did not reach statistical significance. In AN and ANWR, there were negative relationships between leptin AUC and oxytocin AUC (r=−0.42, p=0.053), nadir (r=−0.44, p=0.042) and peak (r=−0.35, p=0.11); relationships between cortisol AUC and oxytocin secretion were positive but nonsignificant.

Figure 1. Oxytocin levels fasting and after a mixed meal.

Oxytocin levels were high in AN compared to HC at 60 and 120 min after the meal and low in ANWR compared to HC fasting and 30 and 120 min after the meal. Diamonds, AN; triangles, HC; squares, ANWR. *, p<0.05 compared to HC.

Psychiatric symptoms

Anxiety state pre- and post-meal, anxiety trait, and depressive symptoms were higher in AN than ANWR and HC (Table 2). 62% of AN, 22% of ANWR, and no HC had clinically significant STAI trait scores. 46% of AN, 33% of ANWR, and 8% of HC had an increase in anxiety symptoms following the meal. 62% of AN, 11% of ANWR, and no HC had more than minimal depressive symptoms.

Table 2.

Symptoms of anxiety and depression

				p-value			Overall
	AN	ANWR	HC	AN vs. ANWR	AN vs. HC	ANWR vs. HC	ANOVA
State-Trait Anxiety Index
Trait score	53.2±3.7	33.7±3.7	28.0±1.5	<0.0001	<0.0001	NS	<0.0001
Pre-meal state score	48.8±2.3	30.0±3.5	25.9±1.3	<0.0001	<0.0001	NS	<0.0001
Post-meal state score	50.0±3.4	28.6±2.4	24.6±1.2	<0.0001	<0.0001	NS	<0.0001
Beck Depression Inventory-II	16.8±3.3	6.3±1.9	0.8±0.4	0.004	<0.0001	NS	0.0004

Mean±S.E.M.

Significant p-values are shown in bold

Oxytocin and anxiety symptoms in anorexia nervosa

We investigated the relationship between oxytocin secretion -- as defined by oxytocin AUC, postprandial nadir, and postprandial peak -- and the severity of psychiatric symptoms in subjects with anorexia nervosa - AN and ANWR (Table 3, Figure 2). Oxytocin AUC, nadir and peak levels were positively associated with anxiety trait, and pre- and post-meal anxiety state scores; these relationships remained significant after controlling for cortisol AUC and leptin AUC. The results were similar when we excluded subjects taking antidepressants. We entered oxytocin AUC, cortisol AUC and leptin AUC into a stepwise regression. Oxytocin AUC explained 51% of the variance in STAI trait scores. When oxytocin nadir was substituted for oxytocin AUC, oxytocin accounted for 46% of the variance in STAI trait scores. When oxytocin peak was used as the measure of oxytocin secretion, oxytocin explained 45% of the variance of STAI trait scores. The effects of cortisol AUC and leptin AUC were not significant in any of these models.

Table 3.

Relationship between oxytocin secretion and psychiatric symptoms in AN and ANWR

	Oxytocin AUC		Oxytocin Nadir		Oxytocin Peak
	r	p	r	p	r	p
State-Trait Anxiety Index
Trait score	0.72	0.0002*,a	0.68	0.0005*,a	0.67	0.0007*,a
Pre-meal state score	0.63	0.002*,a	0.63	0.002*,a	0.58	0.005*,a
Post-meal state score	0.66	0.0008*,a	0.74	<0.0001*,a	0.58	0.004*,a
Beck Depression Inventory-2	0.44	0.043 *	0.49	0.021*, a	0.40	0.069*

^*p<0.05 after controlling for cortisol AUC

^ap<0.05 after controlling for leptin AUC

Significant p-values are shown in bold

Figure 2. Relationship between oxytocin secretion and symptoms of anxiety and depression in AN and ANWR.

Oxytocin AUC was significantly associated with (A) STAI trait (r=0.72, p=0.0002) and (B) BDI-II (r=0.44, p=0.043) scores.

Oxytocin in anorectics with anxiety symptoms

Figure 3 shows oxytocin levels in AN and ANWR with and without anxiety symptoms. Ten of the 22 women had elevated STAI trait scores, indicating significant baseline anxiety symptoms. Mean oxytocin AUC (2135±235 vs. 1260±158, p=0.002), nadir (12.8±1.2 vs. 9.8±1.2 pg/ml, p=0.042), and peak oxytocin levels (25.2±4.9 vs. 11.8±1.7 pg/ml, p=0.002) were higher in subjects with elevated STAI trait scores (i.e., clinically-relevant anxiety symptoms) than those with normal scores (i.e., no anxiety symptoms), independent of cortisol AUC and leptin AUC.

Figure 3. Oxytocin secretion in AN and ANWR subjects with and without anxiety and depressive symptoms.

Mean oxytocin AUC was high in active and weight-recovered women with (A) anxiety (black) and (B) more than minimal depressive (striped) symptoms compared to those without (white). *, p=0.002 vs. those without symptoms.

Oxytocin and depressive symptoms in anorexia nervosa

Table 3 shows the associations between oxytocin secretion and depressive symptoms. Oxytocin AUC and severity of depressive symptoms were positively correlated, independent of cortisol AUC. There was also a significant positive relationship between oxytocin nadir levels and severity of depressive symptoms. After controlling for cortisol AUC and leptin AUC, this relationship remained significant. These results were similar when subjects on antidepressants were excluded from the analysis. In a stepwise regression model including oxytocin AUC, cortisol AUC and leptin AUC, oxytocin explained 19% of the variance in BDI-II scores. When oxytocin nadir and peak were substituted for oxytocin AUC, oxytocin accounted for 24% and 16% of the variance in BDI-II scores, respectively. The effects of cortisol AUC and leptin AUC were not significant in these models. Peak oxytocin levels were positively associated with the degree of suicidal ideation, as assessed by the BDI-II, independent of cortisol AUC. In a stepwise regression model that included peak oxytocin, cortisol AUC and leptin AUC, oxytocin accounted for 20% of the variance in suicidal ideation, while cortisol AUC and leptin AUC did not have significant effects.

Oxytocin in anorectics with depressive symptoms

Figure 3 shows oxytocin levels in AN and ANWR with and without symptoms of depression. Nine of the 22 subjects had more than minimal symptoms of depression, based on BDI-II scores. Subjects with more than minimal symptoms of depression had higher oxytocin AUC (2014±199 vs. 1218±117, p=0.002) than those who did not; this difference remained significant after controlling for cortisol AUC and leptin AUC. Subjects with more than minimal symptoms of depression also had higher nadir oxytocin levels (13.3± 1.6 vs. 9.7± 0.9 pg/ml, p=0.041) compared to those who did not; this difference remained significant after controlling for cortisol AUC and became a trend after controlling for leptin AUC. Peak oxytocin levels were also higher in subjects with more than minimal symptoms of depression compared to those without (23.9±5.1 vs. 13.7±2.6 pg/ml, p=0.018); this remained significant after controlling for cortisol AUC and leptin AUC.

Discussion

This is the first report linking altered secretion of oxytocin to anxiety and depressive symptoms in anorexia nervosa. Oxytocin secretion in response to a food-related paradigm, whether assessed using AUC, peak or nadir levels, was strongly associated with anxiety and depressive symptoms in women with active and weight-recovered anorexia nervosa. In stepwise regression models that included other hormones with effects on mood and behavior, up to 51% of anxiety and 24% of depressive symptom variance was attributable to oxytocin secretion. Post-prandial oxytocin levels were higher in women with elevated symptoms of anxiety and depression than those without symptoms. The higher post-prandial oxytocin levels in AN may represent a response to the stress of food. Although women with active or weight-recovered anorexia nervosa seem to have an altered setpoint for oxytocin secretion compared to healthy controls, the endogenous oxytocin secretion in women with anorexia nervosa is directly related to the severity of anxiety and depressive symptoms and may reflect a physiologic response geared toward reduction of these symptoms.

Oxytocin knockout mice display increased anxiety-like behaviors and corticosterone response to stress ^{20, 21}. Oxytocin administration reduces anxiety-like behaviors and blunts the hypothalamic-pituitary-adrenal stress response in animal models of anxiety²²,⁶, ²³, ²⁰, ⁸. In mice, administration of an oxytocin antagonist blocks the anxiolytic effects of oxytocin²⁰, ⁸. Several human studies have shown that oxytocin administration reduces anxiety related to psychosocial stress²⁴, ²⁵. Although the exact mechanisms of oxytocin-mediated anxiolysis have not been defined, key pathways and brain regions have been identified. In vitro data indicate that oxytocin, similar to benzodiazepines, promotes inhibitory neurotransmission in the central amygdala, suggesting that oxytocin in this limbic region may dampen anxiety²⁶. Interestingly, generalized anxiety disorder patients display heightened fMRI amygdala activation, and administration of oxytocin in these patients results in normalization of amygdala activation in response to viewing fearful faces²⁷. Consistent with these data, we previously reported lower pre- and post-prandial amygdalar activation using a food-related fMRI paradigm in AN than controls, associated with differences in oxytocin secretion⁴. There is also evidence that oxytocin may modulate anxiety through activation of neurons that release serotonin. Serotonergic neurons in the raphe nuclei of mice express oxytocin receptors; oxytocin administration increases serotonin release and inhibits anxiety-like behaviors¹¹. Furthermore, administration of a serotonin 2A/2C antagonist blocks the anxiolytic effects of oxytocin, indicating that serotoninergic neurons mediate oxytocin effects on anxiety. We demonstrated a positive correlation between oxytocin secretion and anxiety symptoms, independent of cortisol or leptin – hormones implicated in anxiety in anorexia nervosa. In stepwise regression models that included cortisol and leptin, oxytocin secretion accounted for more than 50% of the variability in anxiety trait scores. Our findings support the preclinical literature linking oxytocin to anxiety symptoms. Although we cannot infer causality, a possible explanation is that anxiety in women with anorexia nervosa induces increased oxytocin secretion in an effort to reduce these symptoms.

Arletti et al. first showed that oxytocin had an antidepressant effect similar or better than the tricyclic antidepressant imipramine in mouse models of depression⁹. In male mice, mating has an antidepressant effect. The typical antidepressant effects of mating are absent in male oxytocin receptor knockout mice, and an oxytocin receptor antagonist blocks the expected antidepressant effects of mating in wild-type mice¹⁰. We found that post-prandial oxytocin secretion was associated with the severity of depressive symptoms, independent of cortisol; and in a stepwise regression model that included cortisol and leptin, post-prandial oxytocin secretion accounted for one-quarter of the variability in depressive symptoms. Furthermore, subjects who had more than minimal symptoms of depression had higher post-prandial oxytocin secretion. Post-prandial oxytocin secretion was also positively associated with the degree of suicidality. In a stepwise regression model that included cortisol and leptin, post-prandial oxytocin secretion accounted for 20% of the variance in suicidal ideation.

Limitations of this study include its cross-sectional design and small sample size. Although we do not know the relationship between oxytocin secretion in the brain and serum, the robust associations between peripheral oxytocin secretion and psychiatric symptoms suggest that they are linked. Methods for the quantitative measurement of oxytocin in peripheral blood are not standardized and results are method-specific. We selected the commercially available Assay Designs ELISA with extraction, a method that is useful in examining relative differences in oxytocin levels ³⁰. Finally, although we cannot rule out the possibility that social interactions during the study visit affected oxytocin levels, procedures and exposure to research staff were similar across groups.

In summary, we found that increased post-prandial oxytocin secretion is associated with severity of anxiety and depressive symptoms in anorexia nervosa. This supports preclinical data linking oxytocin pathways to anxiety and depressive symptoms, and raises the question of whether abnormal post-prandial oxytocin dynamics in part represent a response to food-induced stress in these patients. Further research will be important to investigate this. Studies administering centrally-acting oxytocin or oxytocin agonists will also be critical in determining whether modulation of this pathway may be useful in the treatment of anxiety and/or depression.