Considerations in Managing Major Depressive Disorder in Patients With Comorbid Cardiovascular Disease

Transcription

1 Considerations in Managing Major Depressive Disorder in Patients With Comorbid Cardiovascular Disease Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD. July 2017 MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

2 Sloan Manning, MD Medical Director Novant Health Urgent Care & Occupational Medicine Adjunct Associate Professor University of North Carolina School of Medicine Co-Director of the Mood Disorder Clinic Moses Cone Family Medicine Residency Program Madhukar Trivedi, MD Director of Mood Disorders Research Professor UT Southwestern Medical Center Betty Jo Hay Distinguished Chair in Mental Health Julie K. Hersh Chair for Depression Research and Clinical Care 2

3 This presentation was developed with the support of Otsuka Pharmaceutical Development & Commercialization, Inc., (OPDC) and Lundbeck, LLC Drs Manning and Trivedi are compensated contractors of OPDC 3

4 PsychU Virtual Forum: Rules of Engagement Otsuka Pharmaceutical Development & Commercialization, Inc., (OPDC) and Lundbeck, LLC have collaborated with OPEN MINDS to explore new ways of bringing and increasing awareness of serious mental illness OPDC/Lundbeck s interaction with OPEN MINDS is through PsychU, an online, non-branded portal dedicated to providing information and resources on important disease state and care delivery topics related to mental illness. A method that will be employed for the sharing of information is the hosting of virtual fora. Virtual fora conducted by OPDC/Lundbeck are based on the following parameters: When conducting medical dialogue, whether by presentation or debate, OPDC/Lundbeck and their paid consultants aim to provide the viewer with information that is accurate, not misleading, scientifically rigorous, and not a promotion of OPDC/Lundbeck products OPDC/Lundbeck and their paid consultants do not expect to be able to answer every question or comment during a PsychU Virtual Forum; however, they will do their best to address important topics and themes that arise OPDC/Lundbeck and their paid consultants are not able to provide clinical advice or answer questions related to specific patients conditions Otsuka and Lundbeck employees and contractors should not participate in this program (eg, submit questions or comments) unless they have received express approval to do so from Otsuka Legal Affairs. OPDC/Lundbeck operate in a highly regulated and scrutinized industry. Therefore, we may not be able to discuss every issue or topic that you are interested in, but we will do our best to communicate openly and directly. The lack of response to certain questions or comments should not be taken as an agreement with the view posed or an admission of any kind. 4

5 Key Objectives Describe the bidirectional association between major depressive disorder and cardiovascular disease Review pathophysiology that may underlie the complex relationship between cardiovascular disease and depression Discuss considerations for pharmacological treatment of depression that avoid exacerbation of cardiovascular symptoms Discuss nonpharmacological considerations for patients with depression and comorbid cardiovascular disease 5

6 Bidirectional Relationship Between Major Depressive Disorder (MDD) and Cardiovascular Disease (CVD) advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

7 Depression and Cardiovascular Disease: A Bidirectional, Multifaceted Relationship Depressi on Depression doubles the risk of developing new cardiovascular disease 1 and may be associated with greater cardiac Text complications 2 Depression is 3 times more frequent in patients after an acute MI than in the general community and may be associated with worse prognosis 3 MI, myocardial infarction. 1. Hare et al. Eur Heart J. 2014;35: Khawaja et al. Psychiatry 2009;6: Lichtman et al. Circulation. 2008;118:

8 Depression Is Highly Prevalent in Patients With Cardiovascular Disease After acute myocardial infarction, two-thirds of patients reported mild depression 1 Approximately 15% of patients with CVD had MDD (2 to 3 times higher than the general population) 1 40% of patients with severe chronic heart failure (NYHA class IV) were depressed 3 27% of patients undergoing coronary artery bypass graft surgery had depression afterwards 2 CVD, cardiovascular disease; MDD, major depressive disorder; NYHA, New York Heart Association. 1. Hare et al. Eur Heart J. 2014;35: Khawaja et al. Psychiatry 2009;6: Rutledge et al. J Am Coll Cardiol 2006;48:

9 Patients With Major Depressive Disorder Demonstrated Reduced Cardiac Resilience Decreased heart rate variability (HRV) Marker of autonomic inflexibility, inability to respond to change, and ill health 1 May be a trait marker for depression 2 May link cardiovascular disease, depression, and sudden cardiac death 2 Patients with depression with comorbid cardiovascular disease displayed lower HRV than patients who were not depressed 1 Unmedicated patients with major depressive disorder and no cardiovascular disease displayed lower HRV than healthy, age-matched controls 1 Low HRV predicts Future adverse cardiovascular events 2 Inflammatory-mediated atherosclerosis 1 Death after myocardial infarction 2 1. Kemp et al. PLOS One. 2012;7:e Brunoni et al. Int J Neuropsychopharmacol. 2013;16:

10 Depression and Cardiovascular Disease Comorbidity Is Associated With Poor Outcomes After myocardial infarction, patients with depression had More medical comorbidities and cardiac complications 1 3-fold increase in mortality 2 41% higher 1-year health costs 1 Negative outcomes associated with comorbidity 1,2 Patients with acute coronary syndrome and history of depression reported 1 Triple the physical limitations Almost triple the risk of diminished health-related quality of life Twice the rate of angina Patients with chronic heart disease and depression reported 1 Depression as the most important correlate of diminished quality of life More days in bed due to illness More ambulatory and emergency room visits Increased functional disability 1. Davidson. ISRN Cardiology. 2012;2012: Hare et al. Eur Heart J. 2014;35:

11 Depression Is a Predictor of Mortality in Patients With Established Coronary Heart Disease In patients with established CHD, depression was predictive of all-cause mortality and cardiac-related mortality 1 Studies analyzed Van Melle et al, 2004 Outcome(s) assessed All-cause mortality Cardiac mortality Cardiovascular events OR relative risk (95% CI) of CHD P value < < < Barth et al, 2004 All-cause mortality NR Nicholson et al, 2006 All-cause mortality < Meijer et al, 2011 Meijer et al, 2013 All-cause mortality Cardiac mortality Cardiovascular events All-cause mortality Cardiovascular events <0.001 <0.001 <0.001 <0.001 < Following a meta-analysis of 53 studies, an AHA expert panel recommended that depression be elevated to the status of a risk factor for poor prognosis in patients with ACS 2 ACS, acute coronary syndrome; AHA, American Heart Association; CHD, coronary heart disease; CI, confidence interval; NR, not reported; OR, odds ratio. 1. Carney and Freedland. Nat Rev Cardiol. 2017;14: Lichtman et al. Circulation. 2014;129:

12 Pathophysiology Underlying Major Depressive Disorder and Cardiovascular Disease advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

13 Psychosocial Factors May Negatively Affect Select Biological Mechanisms Mood state (eg, depression, anxiety) can lead to increased Inflammation Platelet function Autonomic nervous system dysregulation Hypothalamic pituitary adrenal axis dysregulation Acute stress (eg, traumatic life event) can lead to increased Sympathetic nervous system function Hypothalamic pituitary adrenal axis activity Blood pressure Heart rate Interleukin-6 level Chronic stress (eg, work stress, marital strain, life adversity) can lead to increased Sympathetic nervous system function Hypothalamic pituitary adrenal axis activity Ambulatory blood pressure Heart rate Inflammation Stoll et al. J Cardiovasc Dis Diagn. 2014;2:

14 Complex Relationship Between Depression and Cardiovascular Disease 1 Psychosocial stress can lead to chronic inflammation throughout the body, contributing to both depression 2 and cardiovascular disease 3 Depression Biological mechanisms influence both depression and cardiovascular disease 1 eg, inflammation, autonomic nervous system, platelet receptors, coagulopathic factors, endothelial function, neurohormonal factors, and genetic linkages such as serotonin transporter mechanism Cardiovascular disease Depression may lead to behavioral factors that facilitate development of cardiovascular disease 4 eg, weight gain, inactivity, poor nutrition Perceived loss (eg, perception of lost independence or physical health) can lead to a depressed state 1 1. Hare et al. European Heart Journal. 2014;35: Miller et al. Nat Rev Immunol. 2016;16: Puzianowska-Kuźnicka et al. Immun Ageing. 2016;13: Crichton et al. BMC Public Health. 2016;16:

15 Inflammation Plays a Key Role in Both Depression and Cardiovascular Disease Patients with depression display higher levels of the inflammatory cytokines IL-6 and TNF-α 1 Relative risk of recurrent myocardial infarction or coronary death is elevated in patients with higher baseline levels of C-reactive protein 2 IL Healthy controls MDD patients TNF-ɑ Healthy controls MDD patients CRP, C-reactive protein; IL-6, interleukin 6; MDD, major depressive disorder; TNF-α, tumor necrosis factor alpha. *P<0.05 vs <0.12 mg/dl CRP. 1. Kim et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31: Ridker et al. Circulation. 1998;98: Relative risk of MI or coronary death * <0.12 >0.66 Baseline CRP (mg/dl) 15

16 Microbiota-Gut-Brain Axis May Link Depression and Comorbidities 1,2 The gut microbiome is influenced by diet, may be associated with the pathogenesis of MDD and other conditions, and may contribute to drug metabolism and interindividual variability in treatment efficacy and side effects 2 MDD Obesity Type 2 diabetes Chronic fatigue syndrome IBS Excess inflammation Unhealthy diet Healthy diet Healthy CNS function Healthy levels of inflammatory cells Short-chain fatty acids Serotonin Dysbiosis (microbial imbalance in the gastrointestinal tract) Eubiosis (Healthy balance of microflora in the gastrointestinal tract) CNS, central nervous system; IBS, irritable bowel syndrome MDD, major depressive disorder. 1. Slyepchenko et al. Psychother Psychosom. 2017;86: Rogers et al. Molecular Psychiatry. 2016;21:

17 Considerations for Management of Depression in Patients With Comorbid Cardiovascular Disease advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

18 Routine Depression Screening Is Recommended for Patients With Coronary Heart Disease The AHA and APA suggest screening for depressive symptoms in patients with CHD to identify patients who may require further assessment and treatment 1. Screen with PHQ-2 2. Screen with PHQ-9 If yes to either question If necessary, evaluate for acute suicidality and respond accordingly Minimal symptoms, short duration Mild to moderate, uncomplicated Major depression Provide support and education follow-up If symptoms persist or worsen Refer for clinical evaluation by mental health specialist Determine appropriate treatment and carefully monitor for adherence, drug efficacy, and safety AHA, American Heart Association; APA, American Psychiatric Association; CHD, coronary heart disease; PHQ, Patient Health Questionnaire. Lichtman et al. Circulation. 2008;118:

19 Optimal Treatment for Depression May Involve a Combination of Approaches Although antidepressants are the cornerstone of treatment for depression, a combination of treatments may yield optimal outcomes Pharmacotherapy Antidepressants Atypical antipsychotics Lithium Thyroid medication L-methylfolate Psychostimulants Sedative-hypnotic medications Psychotherapy CBT Individual therapy Group therapy Problem-solving therapy Other Electroconvulsive therapy TMS VNS Light therapy Promotion of healthy behaviors Sleep hygiene Decreased caffeine, tobacco, and alcohol Increased exercise Weight loss Meditation CBT, cognitive-behavioral therapy; TMS, transcranial magnetic stimulation; VNS, vagus nerve stimulation. American Psychiatric Association. Practice Guidelines for the Treatment of Patients With Major Depressive Disorder. 3rd ed

20 Antidepressants Have Been Associated With Weight Gain and Metabolic Abnormalities Weight gain is a common side effect of acute and long-term antidepressant use 1 TCAs and MAOIs are more likely to cause weight gain than SSRIs Antidepressant use may be associated with 2 Metabolic syndrome Metabolic syndrome components * 2.01* 1.99* Metabolic syndrome HDL, high-density lipoprotein MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. *P<0.01 vs patients not using antidepressants. P< Fava. J Clin Psychiatry. 2006;61(Suppl11): Crichton et al. BMC Public Health. 2016;16:502. Odds ratio Odds of metabolic syndrome and individual syndrome components in patients with depression (Maine-Syracuse Longitudinal Study) 2 Elevated glucose No antidepressant use Hypertension 1.66 Low HDL cholesterol Antidepressant use 20

21 Cardiovascular Side Effects of Antidepressants Examples of cardiovascular side effects of antidepressants 1,2 Lengthening of cardiac myocyte action potentials Increases in heart rate Increases in blood pressure Orthostatic hypertension Arrhythmias Tachycardia Hypertensive crisis Tricyclic antidepressants and monoamine oxidase inhibitors are contraindicated in many patients with comorbid cardiac conditions because they may cause cardiotoxic side effects 3 Determining optimal therapy for patients with chronic heart failure may be challenging. For example, when the QTc interval is borderline, the physician may choose to examine the potential for improved quality of life against potential arrhythmic risk 1 1. Hare et al. Eur Heart J. 2014:35: American Psychiatric Association. Practice Guidelines for the Treatment of Patients With Major Depressive Disorder. 3rd ed Lichtman et al. Circulation. 2008;118:

22 SSRI Treatment Can Improve Global Functioning in Patients With MDD and Are Generally Safe in the Cardiac Setting CGI-I responders, % Treatment with an SSRI significantly improved CGI-I score vs placebo in patients with recurrent depression with recent MI or unstable angina (SADHART trial) * SSRI 51 Patients with any recurrent MDD Placebo 78 78* 45 Patients with severe MDD No significant difference between groups in measures of cardiovascular safety LVEF Heart rate Blood pressure PR interval QRS duration QTc interval Measure of autonomic balance Ventricular tachycardia Laboratory indices CGI-I, Clinical Global Impression Improvement scale; LVEF, left ventricular ejection function; MDD, major depressive disorder; MI, myocardial infarction; PR interval, time from the onset of the P wave to the start of the QRS complex; QRS complex, the portion of the electrocardiogram comprising the Q, R, and S waves, together representing ventricular depolarization; QTc interval, corrected measure of the time between the start of the Q wave and the end of the T wave; SSRI, selective serotonin reuptake inhibitor. *P<0.01 vs placebo. 1. Glassman et al. JAMA; 2002;288:

23 Inflammation May Influence Effectiveness of Antidepressant Treatment CRP levels have been differentially related to antidepressant treatment outcomes in patients with MDD 1 Remission rate 1 Reduction in disease severity over time 1 SSRI n=51 NDRI + SSRI n=55 Remission during acute phase of CO-MED, % CRP< 1mg/L CRP 1mg/L QIDS-SR score, mean * * * SSRI CRP <1 mg/l SSRI CRP 1 mg/l NDRI + SSRI CRP <1 mg/l NDRI + SSRI CRP 1 mg/l * Week Data are consistent with a previous assessment of patients with depression 2 in which Patients with CRP <1 mg/l had greater reduction in depression severity with an SSRI (compared with a TCA) Patients with CRP 1 mg/l had better response to a TCA (compared with an SSRI) CO-MED, Combining Medications to Enhance Depressions Outcome; CRP, C-reactive protein; MDD, major depressive disorder; NDRI, norepinephrinedopamine reuptake inhibitor; QIDS-SR, Quick Inventory of Depressive Symptomatology Self-Report; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. *P 0.05 for SSRI CRP <1 vs 1 mg/l. 1. Jha et al. Psychoneuroendocrinology. 2017;78: Uher et al. Am J Psychiatry. 2014;171:

24 Adjunctive Treatment Options in Patients With Inadequate Response to Antidepressive Treatment Adjunctive atypical antipsychotics may improve rate of remission Studies analyzed* Shelton et al Shelton et al Corya et al Thase et al. I 2007 Thase et al. II 2007 Mahmoud et al Keitner et al Reeves et al Khullar et al Mattingly et al McIntyre et al Earley et al El-Khalili et al Berman et al Berman et al Marcus et al Odds ratio, 95% CI Individual patient characteristics and relative risk of side effects should inform optimal treatment choice Favors placebo Favors atypical antipsychotics CI, confidence interval. *Meta-analysis of 16 trials in patients with treatment-resistant major depressive disorder (N=3484 patients). Nelson and Papakostas. Am J Psychiatry. 2009;166:

25 Nonpharmacological Considerations for Depression and Cardiovascular Disease advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

26 Many Guidelines Recommend Nonpharmacological Interventions for MDD and CV Risk Reduction In addition to recommending pharmacological therapy, treatment guidelines for MDD 1 and reduction of CV risk 2 promote healthy behaviors Healthy weight Physical activity Good nutrition Psychosocial interventions Cessation of smoking or substance use Establish a therapeutic alliance CV, cardiovascular; MDD, major depressive disorder. 1. American Psychiatric Association. Practice Guidelines for the Treatment of Patients With Major Depressive Disorder. 3rd ed Eckel et al. J Am Coll Cardiol. 2014;63:

27 Weight Management May Help Optimize MDD Treatment and Reduce Cardiovascular Risk Patients with MDD and elevated BMI demonstrated a reduced rate of response with antidepressants 1 Patients with >50% reduction in HAM-D score after 5 weeks, % Normal weight (BMI 25) 46.5 Overweight (BMI >25 and 30) 17.4 Obese (BMI >30) For all patients, including those with mental illness, as little as 5% weight loss may significantly decrease risk factors of cardiometabolic disease, including 2 Glucose Glycemic control Triglycerides HDL cholesterol Blood pressure BMI, body mass index; HAM-D, Hamilton Rating Scale for Depression; HDL, high-density lipoprotein; MDD, major depressive disorder. 1. Kloiber et al. Biol Psychiatry. 2007;62: Wing et al. Diabetes Care. 2011;34:

28 Physical Activity May Improve Depression and Cardiovascular Health Patients with inadequate response to SSRI who added exercise demonstrated improved rates of remission after 12 weeks 1 50 In patients with recent AMI, exercise reduced rate of mortality and subsequent nonfatal AMI over 4 years Patients, % * Patients, % Low add-on exercise 4 kcal/kg/wk (n=61) High add-on exercise 16 kcal/kg/wk (n=61) AMI, acute myocardial infarction; SSRI, selective serotonin reuptake inhibitor. *P<0.05 vs low add-on exercise. 1. Trivedi et al. J Clin Psychiatry. 2011;72: Blumenthal et al. Med Sci Sports Exerc. 2004;36: Mortality (all cause) Patients reporting regular exercise Subsequent AMI (nonfatal) Patients reporting no regular exercise 28

29 Interventions That Decrease Psychosocial Stress May Improve Life Expectancy In female patients hospitalized for coronary disease,* adding a psychosocial intervention to treatment regimen was associated with a reduction in all-cause mortality Cumulative all-cause mortality, % Women receiving usual care (n=125) Women receiving usual care and psychosocial intervention (n=112) Year after hospitalization *Women (N=237) were consecutively hospitalized at a university hospital in Stockholm, Sweden, for acute myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention. Patients were not screened at enrollment for depression. Intervention provided education about the heart, achieving a healthy lifestyle, improving mastery of marital stress, coping with illness, counteracting anxiety and depression, improving social relationships, and relaxation. Orth-Gomer et al. Circ Cardiovasc Qual Outcomes. 2009;2: % 7.1% ~3-fold protective effect of adding intervention 29

30 Healthy Lifestyle Modifications May Improve Overall Wellness Intensive lifestyle modifications* improved cardiovascular risk factors, as well as ratings of depression, physical health, and mental health, over a 1-year period 50 Body mass index LDL cholesterol (mg/dl) Total cholesterol (mg/dl) Depression scale (CES-D) Physical health composite Mental health composite 36.8 Change from baseline, % Patients with cardiovascular disease (N=35) Patients with elevated risk factors (N=37) LDL, low-density lipoprotein; CES-D, Center for Epidemiologic Studies Depression Scale. *Program includes eating a low-fat vegetarian diet, participating in 1 hour of stress management per day, performing 3 hours of aerobic exercise each week, and attending weekly group support sessions for 1 year. Participants must have a diagnosis of cardiovascular disease or two or more cardiovascular risk factors and were not screened for depression before enrollment. Ellsworth et al. Prev Cardiol. 2004;7:

31 Summary Major depressive disorder (MDD) and cardiovascular disease are highly comorbid and share a complex, multifactorial, and bidirectional relationship Psychosocial, biological, and behavioral mechanisms may underlie the shared pathophysiology between MDD and cardiovascular disease Individual patient characteristics and possible adverse effects are factors in treatment choice for patients with comorbid MDD and cardiovascular disease Nonpharmacological strategies, such as increasing physical activity, may confer benefit in patients with comorbid MDD and cardiovascular disease 31

32 Discussion advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

33 Thank You advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.