The VascularBipolar Link Heart Risk or Hearty Opportunity

The Vascular-Bipolar Link: Heart Risk or Hearty Opportunity? Benjamin I. Goldstein, MD, Ph. D, FRCPC Director, Centre for Youth Bipolar Disorder Sunnybrook Health Sciences Centre Professor Departments of Psychiatry & Pharmacology University of Toronto Faculty of Medicine Adjunct Professor, Department of Psychiatry, University of Pittsburgh

Financial Disclosures None.

Pre-Test: What Do These Pictures Represent? 1 Established Treatment 3 2 Up and Coming Treatments

Bipolar Disorder among Canadian Adolescents and Young Adults Female White Anxiety disorder Substance abuse Suicidality Received treatment Kozloff et al, J Affect Disord 2010 15 -18 yo 19 -24 yo 64. 9% 72. 7% 41. 8% 32. 1% 54. 6% 45. 8% 52. 3% 77. 7% 48. 6% 46. 0% 48. 6% 60. 3%

Heart-Bipolar: An Unplanned Journey Kupfer, JAMA 2005 “What does your t-shirt say? ”

Premature Onset of Heart Disease among Adults with Bipolar Disorder in the United States Age 17 years Goldstein et al, J Clin Psych 2015

“Not at all infrequently and in comparative youth arteriosclerosis is present” —Emil Kraepelin, 1921

Circulation Volume 132(10): 965 -986 September 8, 2015 Copyright © American Heart Association, Inc. All rights reserved.

Step 1: Risk Stratification by Disease Process Tier I: High Risk • • Diabetes mellitus, type 1 and type 2 Chronic kidney disease/end-stage renal disease/post kidney transplant Post heart transplant Kawasaki disease with current coronary artery aneurysms Tier II: Moderate Risk • • • Kawasaki disease with regressed coronary aneurysms Chronic inflammatory disease HIV Nephrotic syndrome Major depressive disorder or bipolar disorder (NEW) ≈0. 5% ≈10% Copyright © American Heart Association, Inc. All rights reserved.

Step 2: Assess Cardiovascular Risk Factors • Family history of early CVD in expanded 1 st degree pedigree (♂ ≤ 55 y; ♀ ≤ 65 y) • Fasting lipid profile* • Smoking history* • Blood pressure (BP), 3 separate occasions, interpreted for age/sex/height percentile • Height, weight, body mass index (BMI)* • Fasting glucose (FG) • Diet, physical activity/exercise history* *Increased prevalence among adolescents with bipolar disorder If ≥ 2 Risk Factors, move to Tier I Copyright © American Heart Association, Inc. All rights reserved.

Reasons for Excessive and Premature Cardiovascular Disease among People with Bipolar Disorder Behavior and Environment Pathophysiology • • Inflammation Oxidative stress Autonomic dysfunction Endothelial dysfunction • • • Early adversity/abuse Sleep disturbance Sedentary lifestyle Suboptimal nutrition Tobacco, alcohol, and substance use CVD Medication • Anti-depressants: weight gain (mild) • Second generation antipsychotics: weight gain (significant), dysglycemia, dyslipidemia

Primary Reasons that Medications Do Not Fully Explain the Bipolar-Cardiovascular Link 1. Medications may increase CVD risk factors, but increased risk of CVD is independent of CVD risk factors 2. Bipolar-CVD link described decades before the advent of medications 3. Most people in population studies had not received any treatment for mood disorders, let alone pharmacological treatment

Psychiatric Correlates of Cardiovascular Risk Factors in Bipolar Disorder • More suicide attempts • More manic and depressive episodes • More psychiatric hospitalization • Worse global symptom severity • Worse global functional impairment • What is the direction of this association? Goldstein et al, 2017; Fagiolini et al, 2003; Ruzickova et al, 2003; Cassidy et al, 1999

Elevated Triglycerides are Associated with Reduced Executive Function BD: r=-0. 396, p=0. 020 HC: r=-0. 057, p=0. 744 Naiberg et al, Acta Psychiatrica Scand 2016

Greater BMI Correlates with Lower Frontal Cortical Thickness and Volumes BD HC Linear(BD) Linear(HC) OFC Volume 38000 33000 β=161. 54, η 2 p=0. 041, p=0. 182 28000 Group-BMI interaction P=0. 005 β=-269. 48, η 2 p=0. 195, p=0. 007 23000 18000 15 17 19 21 23 25 27 29 Body Mass Index Islam et al, J Psychiatry Neurosci 2017 31 33 35

Arteriole Venule

Retinal Photography: Window to Examine Brain Blood Vessels in Bipolar Disorder In adolescents with BD, but not healthy adolescents, retinal vessels associated with: • Blood pressure • Fingertip blood vessel function • Mood symptoms BD group: r=0. 458, p=0. 004 HC group: r =-0. 077, p=0. 649 Naiberg et al, J Affective Disord 2017

Lower Cerebrovascular Reactivity in White Matter among Adolescents with Bipolar Disorder Urback et al, Bipolar Disorders 2018

* *p=0. 005

• Increased baseline frontal CBF in two left medial frontal regions and bilateral middle cingulate • These findings were not related to volumetric frontal differences, BMI, mood, SGAs Mac. Intosh et al, J Affect Disord. 2017

Elevated Cerebral Blood Flow among Adolescents with Bipolar Disorder Mac. Intosh et al, J Affect Disord. 2017

How Do Heartbeats Affect the Brain? Cyclic pressure from heartbeats Healthy small blood vessels dampen pressure 120 Heartbeats reach even tiny vessels 80 80 Low, steady pressure in tiny vessels 40 40 Old (~80 yrs. ) Young (~20 yrs. ) Courtesy of Athena Theyer, MSc candidate and Brad Mac. Intosh, Ph. D rta Ar La te rg rie e s Ar Sm te a rie ll s Ar te rio le s Ca pi lla rie s Ve Ar Sm te a rie ll s Ar te rio le s Ca pi lla rie s Ar La te rg rie e s rta Ao nt Lef ric t le Ve nt Lef ric t le 0 0 Ao Pressure (mm. Hg) Arteries fail to dampen pressure O’Rourke and Hashimoto, JACC 2007

How Do Heartbeats Affect the Brain? f. MRI sorted by time f. MRI sorted by heartbeat R 2 = 0. 007 R 2 = 0. 793 Group (BD>HC) Session (Pre>Post) Group x Session Gray Matter . 01 . 002 . 11 White Matter . 004 . 009 . 16 Theyer et al, J Cereb Blood Flow Metab 2018; Goldstein et al, unpublished

Future Treatment Approaches Challenges Opportunities • Completely new medications • Existing medications can be are not anticipated in the near “repurposed” for the future treatment of bipolar disorder, such as nitrous oxide • Completely new therapies are not anticipated in the near future • Existing therapies can be used to address new targets, such as exercise

Next steps: Nitrous Oxide for Bipolar Disorder Readily available + Inexpensive + Generally safe + Ease of administration = Potential game-changer for bipolar depression

Next Steps: Aerobic Exercise for Bipolar Disorder MOOD NEUROCOGNITION • Low rates of aerobic exercise among youth with bipolar disorder • Multiple potential benefits on brain, mind, heart • Benefits are within reach for vast majority, regardless of weight loss HEART • Greatest benefits come to those who are most aerobically unfit Vancampfort et al, J Affect Disord 2013; Sylvia et al, J Affect Disord 2013; Ross et al, Circulation

Toward Exercise as Medicine for Adolescents with Bipolar Disorder (TEAM-BD) Aerobic fitness testing Measures of physical activity Weekly phone calls Exercise coaching Motivation enhancement sessions Psychoeducation Familyfocused counseling Exercise Intervention Peer support Additional Modules

“heart-bipolar”, a symbol of compassion, care, the role of blood vessels in bipolar disorder, integration, and stigma-reduction

Conclusions • Adolescents with bipolar disorder have increased cardiovascular risk from a convergence of factors • Cardiovascular risk factors among adolescents with bipolar disorder are associated with brain structure and function • Cerebrovascular function appears to be impaired among adolescents early in their course of bipolar disorder • The heart-bipolar link may offer clues toward novel biomarker and treatment approaches

Acknowledgments Patients, research participants, and their families Anonymous Donor Great Gulf Foundation Michael Albert Garron Foundation

Helena Brown, BA Mikaela Dimick, BSc Lisa Fiksenbaum, Ph. D Alana Friedlander, BSc Anahit Grigorian, MSc Alvi Islam, MSc Sudhir Karthikeyan, MSc Kody Kennedy, BSc Diana Khoubaeva, HBSc Megan Mio, BSc Rachel Mitchell, MD, MSc Danielle Omrin, MSW Najla Popel, BSc Jessica Roane, MSW Randa Shickh, MPK Alifa Siddiqui, BSc Ariel Silver, MSc Alysha Sultan, BSc Vanessa Timmins, MSW Wendy Yi Zou, BSc Simina Toma, MD, FRCPC Neal Westreich, MD, FRCPC sunnybrook. ca/youthbipolar