Evidence of Dysregulated Peripheral Oxytocin ReleaseAmong Depressed Women

Jill M. Cyranowski, Ph.D.Western Psychiatric Institute and ClinicUniversity of Pittsburgh Medical School

Oxytocin:Females, Affiliation and Stress

Mammalian neuropeptide Synthesized in hypothalamus, released both centrally and peripherally Associated with female reproductive function Uterine contractions, milk let-down Regulated by female reproductive hormones Facilitates affiliative behaviors Animal models of maternal caregiving and

pair-bonding Released centrally and peripherally with stress Anxiolytic effects within animal models

Women’s BiobehavioralResponses to Stress

Fight-or-Flight response Majority of supportive animal (and human) research conducted with males Tend-and-Befriend response (Taylor et al., 2000) Evolutionarily adaptive for females? Females more likely to affiliate with others when under stress Based on oxytocin-mediated attachment / caregiving system

Pubertal intensification in affiliative need

Female gendersocialization

Hormonal changes at puberty

(role of oxytocin)

Insecure parental attachments

Anxious/inhibited temperament

Low instrumental coping skills

Difficult adolescent transition

Anxiety

Stress:Negative Life

Events(esp. life events with

interpersonal consequences)

DepressogenicDiathesis

• high affiliative focus• low attachment security• high anxiety• low instrumentality

Depression

From Cyranowski et al. (2000),Archives of General Psychiatry

Timing of the Gender Gap in Depression Gender gap in MDD emerges at puberty OT role in female reproduction Anxious Depression in Women Gender gap in MDD appears to be differentially associated with anxious depression OT modulates anxiety and stress responses Interpersonal Stress Sensitivity Post-pubertal women display increased risk of depression with interpersonal life stress OT women’s “tend and befriend” stress response Increase threat of relationship gaps or loss? Elevated OT as indicator of social distress?

What we know about depression in women

Postmortum human brain tissue Increased OT expressing neurons in PVN of depressed patients (Purba et al., 1996)

Plasma levels in Depression Mixed findings: though high levels of patient

heterogeneity in terms of gender, age, reproductive status, medication status, and methods of plasma sampling Short half-life of OT in plasma

Oxytocin, Stress and Depression

Oxytocin Dysregulation and

Depression in Women

Study Sample

Inclusion Criteria Females, aged 20-40 Normal menstrual cycling; intact uterus Exclusion Criteria Pregnant, lactating, < than 6 mo post-partum Significant or unstable medical illness Taking hormone replacement Taking antidepressant medications Currently-Depressed Women SCID-IV criteria for current MDD episode HRSD > 14 at initial assessment Never-Depressed Women No current or lifetime history of mood disorder

Lab Procedures

Lab protocol run at WPIC CNRC Sessions scheduled during follicular phase

of menstrual cycle Testing sessions began at 2 pm Participants asked to abstain from eating, caffeine, smoking after 12:30 pm of test day

Lab set-up Catheterization, BP monitor, EKG leds 25 minute habituation period

25 m

Habituation

20 minute

RestingBaseline

Blood draws q5 minutes Catheter Placed

1 2 3 4 5 6 7 8 9 10 11 12

10 min

TASK# 1

30 minute

RestingRecovery

20 min Rest

Period

20 minute

RestingBaseline 10 min

TASK# 2

30 minute

RestingRecovery

1 2 3 4 5 6 7 8 9 10 11 12

Study Design: Biobehavioral MechanismsOf Depression in Women

Assessments

Plasma Oxytocin RIA of OT in plasma using previously published

methods (Amico et al., 1985) Minimum detectable concentration = .5 pg/mL,

inter- and intra-assay coefficients of variation < 10% Sensitive, specific to 9-amino acid chain peptide Depression and Anxiety Clinician rated: HRSD-17 Self-report: BDI, BAI Interpersonal Function Short-form of Inventory of Interpersonal Problems (IIP; Horowitz et al., 1988, 1989)

Analysis Plan

Total Oxytocin Concentrations Integrated Area Under the Curve (AUC), using

trapezoidal approximation Utilized 2 (group) x 2 (task order) ANCOVA,

controlling for age, current OC use Oxytocin Concentration and Interpersonal Function Partial correlations, controlling for task order,

age, OC use Oxytocin Variability Evaluated within-task standard deviation (SD)

of oxytocin levels obtained each subject Logistic regression models comparing subjects

displaying high (SD > 1.5) versus low oxytocin SD

Never-Depressed Controls

N = 17

Depressed Participants

N = 17

Demographic Characteristics

Age (mean, SD) 27.0 (4.95) 31.0 (6.80)

% White (N, %) 14 (82.4%) 14 (82.4%)

% Married (N, %) 4 (23.5%) 5 (29.4%)

Current romantic partner (N, %) 13 (76.4%) 14 (82.3%)

College degree or higher (N, %) 14 (82.3%) 11 (64.7%)

Nulliparas (N, %) 16 (94.1%) 13 (76.5%)

Oral contraceptive use (N, %) 9 (52.9%) 6 (35.3%)

Clinical Characteristics

HRSD-17 (mean, SD) 3.88 (2.76) 17.0 (5.41)

BDI (mean, SD) 2.29 (2.71) 21.19 (7.93)

BAI (mean, SD) 2.82 (4.19) 17.47 (10.45)

Study Sample

Fig 4a: Guided Imagry Task - Controls

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Fig 4b: Guided Imagery Task - Depressed

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Individual OT Data: Affiliative Imagery Task

Cyranowski et al., 2008

Individual OT Data: Stress Task

Fig 4c: Stress Task - Controls

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Fig 4d: Stress Task - Depressed

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Cyranowski et al., 2008

Results: OT Concentrations For imagery task, group effect for OT concentration Depressed women displayed greater OT

concentration [F(1,26)=7.9, p=.01] Effect persisted after controlling for age & OC use Variable F df p

Age 5.60 (1,26) .028

OC Use 5.99 (1,26) .023

Group 4.43 (1,26) .047

Task Order 2.32 (1,26) .143

Group*Task Order 2.22 (1,26) .151

Cyranowski et al., 2008

Oxytocin Concentrations During Imagery

Figure 7: OT Concentration During Relationship Imagry

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Non-Depressed Women Depressed WomenStudy Group

Oxyto

cin

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ncen

trati

on

(p

g/m

l)

* Non-transformed oxytocin levels, adjusted for age and oral contraceptive use

Results: OT Variability

Depressed women more likely to display elevated OT variability For each task, approximately one quarter of

sample displayed elevated OT variability (SD > 1.5) % Displaying high OT variability, by Group

Imagery Task: Wald statistic = 3.51, df=1, p=.06Stress Task: Wald statistic = 4.46, df=1, p=.03

Imagery Task Stress Task

Depressed 6 (37.5%) 7 (41.2%)

Controls 1 (6.3%) 1 (5.9%)

Associations between OT ConcentrationAnd Psychiatric and Interpersonal Factors

Depression & Anxiety

Controlling for

Task Order

Controlling for Task Order,

Age, & OC Use

HRSD-17 r (p) .528 (.006) .646 (.001)

Beck Depression Inv r (p) .540 (.005) .638 (.001)

Beck Anxiety Inv r (p) .528 (.006) .611 (.002)

Inventory of Interpersonal Problems (IIP) Scales

Socially Avoidant r (p) .500 (.009) .576 (.003)

Hard to be Social r (p) .533 (.006) .628 (.001)

Nonassertive r (p) .438 (.028) .628 (.001)

Domineering r (p) .525 (.006) .567 (.004)

Depression and Peripheral OT: Conclusions

Depressed women more likely to display “dysregulated” pattern of peripheral OT release characterized by highly variable OT release Not all depressed women showed this pattern (only about 40%) Pattern characterized by pulsatile release and

extremely brief half-life Greater levels of dysregulation associated with greater symptoms of depression, anxiety, and interpersonal difficulties No evidence of task-induced OT release Cannot address central OT levels

Oxytocin, DepressionAnd the Social Modulation

Of Stress in Women

The Social Modulation of Stress

Do depressed and non-depressed women show differences in the social modulation of stress? If so, could this related to OT dysregulation?

The Social Modulation of Stress:Blood Pressure Response to Stress Task

Non-Depressed Women:Systolic BP During Stress Session

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Base 1 Base 2 SpeechPrep

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Relationship Taskbefore StressStress Task First

Depressed Women:Systolic BP During Stress Session

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Base 1 Base 2 SpeechPrep

SpeechTask

Recov 1 Recov 2 Recov 3

Relationship Taskbefore StressStress Task First

▪ Group X Task Order interaction effect, F(1,32)=7.31, p=.01

Cyranowski et al., under review

The Social Modulation of Stress:Cortisol Response to Stress Task

Non-Depressed Women:Cortisol During Stress

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Baseline Task Start Post-Task Recov 1 Recov 2 Recov 3

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Relationship Taskbefore StressStress Task First

Depressed Women:Cortisol During Stress

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Baseline Task Start Post-Task Recov 1 Recov 2 Recov 3

Relationship Taskbefore StressStress Task First

Comparing Depressed WomenWith vs Without Evidence of OT Dysregulation:

Cortisol Response to Stress Task

Non-Dysregulated Depressed Women:Cortisol During Stress

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Base Task Start Post Task Recov 1 Recov 2 Recov 3

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Oxytocin Dysregulated Depressed Women:Cortisol During Stress

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Relationship Taskbefore Stress

Stress Task First

Depression and Social Modulation of Stress

Depression has long been associated with elevated levels of social or interpersonal dysfunction, social isolation, and reduced social support

In some contexts, elevations in peripheral oxytocin levels or dysregulated patterns of oxytocin release may represent a biomarker of social distress or unmet affiliative need Other data to support this interpretation?

Depression and Oxytocin: Recent Data

Taylor et al (2006, in press) Elevated basal OT associated with relationship

gaps and difficulties, and elevated cortisol levels In press, Psychological Science findings

Grippo et al (2007 cites, 2009) Female praire voles exposed to chronic

social isolation display: Higher plasma OT

OT related brain differences Depressed and anxious behavioral profiles

Grippo et al (2007): Higher Peripheral OT Levels Following Isolation

Grippo et al: OT-Related Brain and Behavioral Changes

Behavioral changes following social isolation Decreased sucrose intake (anhedonia?) Immobility in forced swim test (helplessness?)

Brain changes following social isolation Significant increases in OT-immunoreactive cell density in the hypothalamic PVN of socially isolated female praire voles

Neuroendocrine responses in females may be especially sensitive to social isolation

Mean (+SEM) immobility time during a 5-min FST in paired or isolated prairie voles administered daily oxytocin (OT; 20 μg/50 μl/vole, SC) or vehicle (V; 50 μl/vole, SC)

Grippo et al: Depression Treatment Implications?

Collaborators and Support

Janet Amico, MD Ellen Frank, PhD Howard Seltman, MD, PhDHou-Ming Cai, MDTara Hofkens, BAHeather Spielvogle, MSW, John Scott, AM, Deb Stapf, BS, and Lynda Rose, BS

Grant SupportMH64144, MH30915Clinical Neuroscience Research Center (RR0000056) Pittsburgh Mind-Body Center (HL076852/076858)