Rethinking obesity interventions Polycystic Ovary Syndrome as a

Rethinking obesity interventions: Polycystic Ovary Syndrome as a Model Physical Illness Dana L Rofey Ph. D University of Pittsburgh Department of Psychiatry, Pediatrics, and Psychology Obesity Journal Club February 26, 2015 Western Psychiatric Institute & Clinic

Overview n Brief background and rationale n Results of past and current studies n Future directions n Clinical implications

Definition of obesity CDC BMI %ile Underweight < 5 th Healthy 5 th-85 th At Risk for Overweight Obese International Obesity Task Force BMI <18. 5 WHO BMI >2 SDs above the growth standard median 85 th=95 th >95 th 18. 5 – 24. 9 25. 0 – 29. 9 30. 0 and Above >1 SD above the growth standard median >2 SDs above the growth standard median

Defining PCOS Diagnostic complexity of Polycystic Ovary Syndrome NIH 1990 Rotterdam 2003 - - Chronic anovulation Clinical and/or biochemical signs of hyperandrogenism (with exclusion of other etiologies, e. g. , congenital adrenal hyperplasia) Both criteria needed - AE-PCOS Society 2006 Oligo- and/or anovulation Clinical and/or biochemical signs of hyperandrogenism - Polycystic ovaries Two of three criteria needed - Clinical and/or biochemical signs of hyperandrogenism Ovarian dysfunction (oligo -anovulation and/or polycystic ovarian morphology) Both criteria needed

Etiology of PCOS n Two opposing theories: – Gonadotrophin over-stimulation of the ovaries – High insulin levels are stimulating ovarian androgen production

Diagnosis of PCOS Hormonal and Metabolic Features in adolescents with hyperandrogenism Free Testosterone Androstenedione Luteinizing Hormone (LH) Follicle-Stimulating Hormone (FSH) Insulin-like growth factor binding protein-1 (IGF-BP 1) Sex Hormone Binding Globulin (SHBG) (Warren-Ulanch et al. , 2006)

Treatment of PCOS n Medication management, depending on severity: – Oral contraceptive pills – Insulin sensitizer

Innovative Behavioral Intervention PCOS as a model illness PCOS Physiological Behavioral (obesity, sleep, metabolic) (eating, physical activity) Emotional (depression)

Viewing PCOS as a model physical illness n Behavioral intervention to target high rates of: – Obesity – Depression – Sleep disturbances n Behavioral intervention affects physiological outcomes

Co-occurrence in PCOS n Physiological – Obesity: ~75% – Sleep: 5 fold increased likelihood, compared to controls, to have obstructive sleep apnea – Metabolic: insulin resistance, hyperinsulinemia, beta-cell dysfunction

Co-occurrence in PCOS n Psychological – Depression: Severe presentation – Anxiety Disorder: Precipitating factor for depression – Binge Eating Disorder: Atypical presentation

Co-occurrence in PCOS n Behavioral – Caloric intake – Energy expenditure

Targeting inter-regulatory processes n Leveraging synergistic relationships n Focus on positive spirals n Window of opportunity during adolescence Rofey/Mc. Makin et al. , 2013

Aims of the current investigation n Aim 1: Behavioral – Change in weight – Increase in energy expenditure n Aim 2: Emotional – Change in depression n Aim 3: Physiological – Sleep – Metabolic parameters

Screening Process Step 1 Participants are screened for depression (≥ 10 on the CDI) ↓ Step 2 a Participants meet other inclusion criteria: PCOS (hyperandrogenism; oligoovulation; exclusion of other endocrine disorders) and are between the ages of 11 and 21 ↓ ↓ Step 2 b Participants complete a semi-structured clinical interview, K-SADS ↓ Step 2 c Participants meet DSM-IV criteria for minor/major depressive disorder ↓ Step 3 Participants sign the consent to participate in the intervention (11 sessions) Rofey/Szigethy et al. , 17 2009

Methods n Eighty-three adolescents with PCOS – – – n Ages 11 -21, M=15 85% Caucasian Mean BMI=38 11 sessions of one-on-one coaching within the community – Evidence-based treatment – Family-based component

Methods Weight Management Solution: Armband Feedback Device Answer-only cellular phone Total physical activity Caloric intake Number of steps Sleep duration/efficiency

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Results Paired T-Tests Documenting Behavioral, Emotional, and Physiological Parameters in Adolescents with PCOS Pre- and Post-Intervention (Baseline – 6 -months) ____________________________ Variables (N=83) Pre-Tx Post-Tx t Value Effect Mean (SD) Size ____________________________ Depressive Symptoms CDI 14. 1(8. 2) 9. 4(8. 6) 4. 45**. 81 Weight BMI z-score 2. 1(. 5) 2. 0(. 5) 4. 82** 1. 6 Sleep PSQ 2. 4(1. 5) 1. 5 (1. 6) 2. 87**. 4 ____________________________ Note: CDI – Children’s Depression Inventory; PSQ – Pediatric Sleep Questionnaire, Sleepiness; ** p =. 00.

Physiological findings n n n High rates of depression in adolescents with PCOS (45%) compared to obese (20%) and control (8%) youth. However, there was no relationship between depressive symptoms in adolescents with PCOS and free testosterone, rho=-. 02, p=. 46 or insulin resistance, rho= -. 06, p=. 37. In a larger obese sample, after controlling for race and BMI, there was a negative partial correlation between depression and insulin sensitivity (o. DI; r=-0. 49, p<. 001). Rofey et al. , 2012 Hannon/Rofey et al. , 2013

Psychological presentation n An exploratory factor analysis (maximum likelihood) of participants’ self-report on the CDI at baseline revealed three novel factors compared to the non-obese clinical and normative samples: 1. 2. 3. 4. 5. n Stigma Internalization Negative Self-Esteem (5 th in instrument samples) School Negative Mood (1 st in instrument samples) Results failed to replicate three of the original factors: 1) Interpersonal Problems, 2) Ineffectiveness and, 3) Anhedonia Black/Rofey et al. , 2014

EMA Results n Ecological Momentary Assessment Pilot Data – Compliance rate for armband: 74. 7±. 3% – Compliance rate for phone calls: 64. 2 ±. 3% – Higher BMIs were more likely to be compliant with EMA methods, rho=. 78, p<. 01. – No association between compliance rates for EMA and level of depressive symptoms. Rofey/Dahl et al. , 2012

EMA Results: A focus on physical activity n n n Sixty percent of adolescents averaged at least one daily physical activity bout lasting > 10 minutes, and 14% averaged a daily physical activity bout lasting > 30 minutes BMI was negatively correlated with physical activity bout duration ( p = 0. 04) Parental ratings of depression were predictive of youths’: – Total physical activity (β = -0. 46; p = 0. 01) – Bouts of physical activity > 10 minutes (β = -0. 35; p = 0. 05) n Physical activity was associated with increased positive affect post exercise, (F (1, 314) = 5. 01, p =. 026). n Sleep > 8 hours per night led to more steps taken the next day, r=. 52, p<. 01 Michael/Rofey et al. , 2014 / Rofey/Jakubowski et al. , 2014

If PCOS/obesity affects multiple systems, what does it do to the brain? Conceptual framework for next steps

Brain-obesity links Cognitive function n Gray matter volume n White matter integrity n n Impact of a weight management program, with varying degrees of diet and physical activity change, on brain health

Preliminary brain findings Youth who are obese perform more poorly than normal weight controls Right Hippocampus Volume (mm 2) 5000 Obese<Controls with regards to hippocampal volume 4000 3000 2000 1000 0 Control Overweight Type II Diabetes Obese<Controls with regards to white matter integrity Rofey, Arslanian, Verstynen/Erickson et al. , 2013

Cognitive Deficits n Executive functioning: Umbrella term including planning, execution, and ability to solve problems n Working memory: Actively holding multiple pieces of transitory information in the mind n Psychomotor speed: Coordination of a sensory or cognitive process and motor activity Hannon/Rofey et al. , 2013

Brain Morphology Results Preliminary results suggest that obesity is associated with reduced gray matter volume in the caudate and thalamus, with all other regions following a similar trend, compared to control youth.

Brain Morphology Results Using Diffusion Tensor Imaging (DTI) we found that obese adolescents had reduced integrity of the white matter projections into the caudate from the lateral frontal regions compared to the control group

Clinical implications n n Rule out PCOS, as well as other illnesses that affect multiple systems Assess not only for physiological, but also psychological and behavioral disturbances Provide broad, evidence-based programs (or refer to folks who can) Do not under-estimate how behavioral, cognitive, and psychological disturbances affect physical illness

Clinical Implications n n n Address weight issues Be empathetic and ask open-ended questions before delivering advice (e. g. , “what do you think about your health behaviors? ”) Implementation not information problem Explore barriers Refer, if necessary

Next steps n Dissemination and Implementation – Multi-site within Adolescent Medicine Clinics – Crossing interconnected processes – Utilizing existent providers to extend services n If obesity is associated with brain-based deficits, how do cognitive deficits (pre-intervention) affect weight management outcomes n If obesity persists, what else can we do for patients – Trauma – Interpersonal relationships/sexual practices

Thank you Mentors Liz Miller, MD, Ph. D Ronald Dahl, MD Silva Arslanian, MD Thank you Collaborators Kirk Erickson, Ph. D Robert Noll, Ph. D Eva Szigethy, MD, Ph. D Nermeen El Nokali, Ph. D Marguerite O’Hara, MA Ronette Blake, MS Jodi Krall, Ph. D Tamara Hannon, MD Kara Hughan, MD Barb Cardinal-Busse, CRNP Gina Sucato, MD Emily Filippelli, MBA Marsha Marcus, Ph. D Anne Marie Kuchera, RD, MA Jennifer Silk, Ph. D Aletha Akers, MD Selma Witchel, MD Neal Ryan, MD Chris Ryan, Ph. D Kay. Loni Olson, Angela Vincent, Kelly Rabenstein, Katherine Belendiuk, Britney Brinkman, Erica Stein, Glory Ojiere, Amy Gillio, Jenn Jones, Jill Matlock, Brittany Musselman, Meaghan Beckner, Rachel Metz, Megan Barna, Ashley Rowden, Brian Thoma, Dee Astute, Dana Schreiber, Sara Andrasy, Bryan Powell, Kat Belendiuk, Christina Wallace, Amanda Peterson, Deana Ekas, Jessica Black, Ikechukwu Onyewuenyi, Juliet Cameron, Clare Newlon, Sammy Dhaliwal, Meredith Dillon, Alyssa Spector, Bre. Anne Herline, Renae Sweeney, Deepika Singapogu 36 Weight Management & Wellness Center Polycystic Ovary Syndrome Center Adolescent Medicine Clinic

Questions Thank you for your time!