Evidence of Dysregulated Peripheral Oxytocin Release Among Depressed Women Jill M. Cyranowski, Ph.D. Western Psychiatric Institute and Clinic University 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 Biobehavioral Responses 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 gender socialization 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) Depressogenic Diathesis 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  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 Resting Baseline Blood draws q5 minutes Catheter Placed min TASK # 1 30 minute Resting Recovery 20 min Rest Period 20 minute Resting Baseline 10 min TASK # 2 30 minute Resting Recovery Study Design: Biobehavioral Mechanisms Of Depression in Women

Assessments u 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 u 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%) % 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

Individual OT Data: Affiliative Imagery Task Cyranowski et al., 2008

Individual OT Data: Stress Task Cyranowski et al., 2008

Results: OT Concentrations u 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 VariableFdfp Age5.60(1,26).028 OC Use5.99(1,26).023 Group4.43(1,26).047 Task Order2.32(1,26).143 Group*Task Order2.22(1,26).151 Cyranowski et al., 2008

Oxytocin Concentrations During Imagery * Non-transformed oxytocin levels, adjusted for age and oral contraceptive use

Results: OT Variability u 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=.06 Stress Task: Wald statistic = 4.46, df=1, p=.03 Imagery TaskStress Task Depressed6 (37.5%)7 (41.2%) Controls1 (6.3%)1 (5.9%)

Associations between OT Concentration And Psychiatric and Interpersonal Factors Depression & Anxiety Controlling for Task Order Controlling for Task Order, Age, & OC Use HRSD-17r (p). 528 (.006).646 (.001) Beck Depression Invr (p).540 (.005).638 (.001) Beck Anxiety Invr (p).528 (.006).611 (.002) Inventory of Interpersonal Problems (IIP) Scales Socially Avoidantr (p).500 (.009).576 (.003) Hard to be Socialr (p).533 (.006).628 (.001) Nonassertiver (p).438 (.028).628 (.001) Domineeringr (p).525 (.006).567 (.004)

Depression and Peripheral OT: Conclusions u 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 u No evidence of task-induced OT release  Cannot address central OT levels

Oxytocin, Depression And the Social Modulation Of Stress in Women

The Social Modulation of Stress u 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 ▪ 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

Comparing Depressed Women With vs Without Evidence of OT Dysregulation: Cortisol Response to Stress Task

Depression and Social Modulation of Stress u 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 u Taylor et al (2006, in press)  Elevated basal OT associated with relationship gaps and difficulties, and elevated cortisol levels  In press, Psychological Science findings uGrippo 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 u Behavioral changes following social isolation  Decreased sucrose intake (anhedonia?)  Immobility in forced swim test (helplessness?) u Brain changes following social isolation  Significant increases in OT-immunoreactive cell density in the hypothalamic PVN of socially isolated female praire voles u 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, PhD Hou-Ming Cai, MD Tara Hofkens, BA Heather Spielvogle, MSW, John Scott, AM, Deb Stapf, BS, and Lynda Rose, BS Grant Support MH64144, MH30915 Clinical Neuroscience Research Center (RR ) Pittsburgh Mind-Body Center (HL076852/076858)