Daniel Suzuki, MD Adjunct Clinical Associate Professor of Psychiatry, USC Keck School of Medicine Clinical Adjunct Professor/Faculty, Graduate School of Psychology, Fuller Theological Seminary Medical Director, Las Encinas Hospital, Pasadena, CA
Financial relationships with commercial interests listed below are not relevant to the CME activity: Takeda Lundbeck Alkermes Allergan
1. Explain the link between depression and cardiovascular disease (CVD) and diabetes 2. Recognize signs and symptoms of depression 3. Discuss treatment options for depression in context of comorbid cardiovascular disease and/or diabetes
Depression is the leading cause of disability worldwide reported by the World Health Organization 1 Lifetime prevalence rate in the US is 16% 2 Suicide is among the top 10 leading causes of all deaths in the US 3 1. World Health Organization, Fact Sheet, 2016 2. JAMA. 2003; 289 (23): 3095-3105 3. National Vital Statistics Reports, Vol.65, No. 2, Feb 16, 2016, CDC
In cardiac patients, MDD prevalence estimated to be as high as 40% 1 Depression is an independent risk factor of CVD 2 Depression doubles the risk of coronary artery disease (CAD) 3 1. Celano, C.M., & Huffman. J.C. Cardiology in Review, 2011;19(3):130-142. 2. M. Alvarenga, D. Byrne (eds.), Handbook of Psychocardiology, DOI 10.1007/978-981-4560-53- 5_9-1 3. Srinivasan, K. Indian Journal of Psychiatry. 2011;53(3), 192.
Meta analysis of 11 studies found relative risk of developing ischemic heart disease of 1.64 in those with MDD vs healthy controls 1 American Heart Association study found screening positive for depression was associated with a 55% greater risk of cardiac events 2 1. Katon, W.J et al. J of General Internal Medicine, 2004; 19(12):1192-1199. 2. Elderon, L et al (2011). Circulation, Cardiovascular Quality and Outcomes, 2011; 4(5):533-540.
Depression developed after acute coronary syndrome (ACS) is associated with worse cardiac outcomes 1 MDD after an episode of unstable angina increases the risk of cardiac events during the following year with a 4-fold increase of cardiac death 2 Patients with MDD are at increased risk of cardiac death, particularly within the first 6 months 3 1. Zuidersima M et al. Psychotherapy and Psycho-somatics, 2001;80(4):227-237 2. Lesperance F et al. Archives of Internal Medicine, 2001;160(9): 1354-1360. 3. Ziegelstein RC et al. Archives of Internal Medicine, 2000;160(12): 1818-1823.
Behavioral factors Sympathetic nervous system Platelet function Inflammation
The link between depression and diabetes is bi-directional Type 2 DM has an increased risk of depression 1 Depression has a 60% increased risk of Type 2 DM 2 1. Nouwen A et al. Diabetologia 2010: 53: 2480-86. 2. Mezuk B. Eaton WW, Albrecht S, Golden SH. Diabetes Care 2008; 31: 2383-90.
Depression is link to prognostic variables including micro and macrovascular complications 1 Even in the context of good glucose control, depression is found to increase all cause mortality 2 1. De Groot M et al. Psychosomatic Medicine 2001;63(4):619-30. 2. Sullivan MD et al. Diabetes Care. 2012;35(8):1708-15.
Recommendations for Screening, Referral, and Treatment Conclusions: The opportunity to screen and treat depression in cardiac patients should not be missed, as effective depression treatment may improve health outcomes Patients with positive screening results should be evaluated by a professional qualified in the diagnosis and management of depression Patients with cardiac disease under treatment for depression should be carefully monitored Coordination of care between healthcare providers is essential Lichtman, JH. Circulation 2008;118:1768-1775
Depressed Mood Loss of interest or pleasure Diminished ability to think/concentrate or indecisiveness Significant change in weight or appetite Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or excessive guilt Suicidal ideation Cognitive Emotional Physical
Screening for depression in patients with coronary heart disease. *Meets diagnostic criteria for major depression, has a PHQ-9 score of 10 19, has had no more than 1 or 2 prior episodes of depression, and screens negative for bipolar disorder, suicidality, significant substance abuse, or other major psychiatric problems. Meets the diagnostic criteria for major depression and 1) has a PHQ-9 score 20; or 2) has had 3 or more prior depressive episodes; or 3) screens positive for bipolar disorder, suicidality, significant substance abuse, or other major psychiatric problem. If Yes to Q.9 suicidal, immediately evaluate for acute suicidality. Judith H. Lichtman et al. Circulation. 2008;118:1768-1775 Copyright American Heart Association, Inc. All rights reserved.
Moderate depression and above may need robust antidepressant treatment. Mild depression and below may only require counseling, relaxation and exercise.
*Bipolar Disorder Hirschfeld et al found 21% of those taking antidepressants in a primary care clinic screened positive for bipolar disorder Past history of mania Family history of bipolar disorder Past response to antidepressants Age of onset Quality of Depression *Substance Abuse *Assess for suicide risk Hirschfeld et al. J am Board Fam Pract 2005;18:233-239
A useful tool to screen for presence of mood disorder
Primary Care Companion J Clin Psychiatry 2008;10(2): 145-152
Response: defined in clinical trials as a 50% decrease from a baseline score on depression scales (e.g. PHQ-9 if baseline score 18 9) Remission: criteria for depression no longer met
In community practice, response to PHQ- 9 is a strong predictor of suicide attempt and suicide death over the following 2 years 1 Anxiety as an acute risk factors 2 Protective factors 1. Simon GE et al. J of Clin Psychiatry 2016;77(2):221 2. Busch k et al. Psychiatric Annals 2004;34(5):357
Acute Phase (6-12 weeks) Achieve Remission Choose initial treatment aimed at inducing major depressive episode remission Assess response and side effects About 4-8 weeks are needed before concluding partial or no response to intervention Continuation Phase (4-9 months) Preserve Remission Continue treatment, monitor for signs of relapse Assess side effects, adherence, and functional status Maintenance Phase Minimize Recurrence Continue for patients at risk (eg. >3 prior MDEs, presence of residual symptoms) Monitor at regular intervals
SADHART study 1 ENRICHD study 2 Meta-Review of pharmacological Tx of depression with comorbid DM 3 1. Serebruany VL et al. Circulation, 2003; 108(8):939-944. 2. Pizzi, C et al. The American Journal of Cardiology 2011; 107(7): 972-979. 3. Lancet Diabetes Endocrinol 2015; 3: 472-85.
Depressed patients receiving treatment with an SSRI had a 42% reduction in death or recurrent MI Sertraline and citalopram are the first line antidepressant drug for patients with CVD If patients had responded previously to another antidepressant, resume if not contraindicated
Contraindications: Tricyclic antidepressants and monoamine oxidase inhibitors are contraindicated Considerations: Weight gain and metabolic issues with some treatment Dual indications (psychiatric and medical) with duloxetine
1950s 1980s 1990s MAOI/ TCAs Miscellaneous SSRIs tranylcypromine phenelzine imipramine nortriptyline bupropion mirtazapine nefazodone trazodone fluoxetine sertraline paroxetine citalopram escitalopram 1990s 2000s SNRIs Antipsychotic Adjunct Other venlafaxine duloxetine desvenlafaxine aripiprazole quetiapine XR olanzapine+ fluoxetine brexpiprazole vilazodone vortioxetine Levomilnacipran ER
Optimize treatment to reduce depressive symptoms and improve cardiac prognosis and/or glycemic control Trials which used collaborative care approaches that target improvement of both general medical conditions and comorbid depression have been successful 1 1. Katon WJ et al. N Eng J Med 2010;363:2611
Prospective, randomized control trials N~3000 tx-seeking pts instead of volunteers Replicated real-world outpatients co-morbid medical, psychiatric conditions, substance abuse Average of moderately severe depression Ave ~3.3 general medical condition 2/3 at least 1 concurrent axis I psychiatric disorder All started with citalopram Rush et al. Am J Psychiatry 2006;163:1905-1917
Level 1 (2876) 32.9 Level 2 (1439) 30.6 Switch (789) 27.0 Augment (650) 35.0 Level 3 (377) 13.6 Switch (235) 10.3 Augment (142) 19.1 Level 4 (109) 14.7 By QIDS-SR 16 <5 at level exit
Prozac, Prozac Weekly, Sarafem (approved for PMDD) Usual dose: 20-40mg/day, 60mg for bulimia, OCD Titrate up by 10-20mg q4weeks Best matched for pts with hypersomnia, psychomotor retardation, apathy, & fatigue Most well-studied for bulimia nervosa Long t ½ (2-3 days, 14 days for metabolite) & active metabolite (norfluoxetine) Potent inhibitor of liver enzyme (2D6, 3A4)-many DDIs Common side effects: Activating (insomnia, headache, anxiety) 32
Zoloft Dosage: 50-200 mg/day; titrate up by 50 mg q2weeks (usual dose: 100-150 mg/day) Approved for OCD in children > 6 y.o. Must be given with food ( bioavailability by ~40%) Often well tolerated Common side effects: Mild S.E.--nausea, diarrhea, insomnia or sedation 33
Paxil, Paxil CR Usual Dose: 20-40 mg/day, titrate up by 10 mg q2weeks Preferred for pts w/ anxiety symptoms (most well studied in this population) No active metabolite Most case reports of 5HT withdrawal (additive w/ anticholinergic rebound) 12/05: increased risk of heart defects when used in 1 st trimester pregnancy (1.5-2% vs. 1%) Common side effects: anticholinergic (constipation, dry mouth, sedation), weight gain, sexual dysfunction 34
Citalopram (Celexa ) Dosage: 20-60 mg/day; titrate up by 10 mg q2weeks Often used in geriatrics population or for those w/ polypharmacy d/t low DDI Inconsistent therapeutic action at lower doses Often need titration to higher doses Common side effects: mild S.E. Very well tolerated. Escitalopram (Lexapro ) Dosage: 10-20 mg/day Active S-enantiomer 10 mg Lexapro = 20-40 mg Celexa Fewest drug interactions of the SSRIs 35
Wellbutrin, Wellbutrin SR, XL, Zyban Usual dose: 300 mg/day, titrate by 150 mg q 3-7days SR (twice daily): NTE 200 mg/dose, max/day: 400 mg XL (once daily): 450 mg/day max Common side effects: Activating (headache, insomnia, anxiety, agitation) NO sexual dysfunction Should not use in patients with seizure d/o, eating disorders, alcoholics d/t risk of seizure 36
Remeron, Remeron SolTab Usual dose: 15-30 mg/day, titrate by 15 mg q1-2 weeks. Max: 45 mg/day Multiple mechanism enhance efficacy Good especially for thin insomniacs (esp. elderly) Common side effects: sedation (higher at lower doses), appetite, weight gain, triglycerides, dizziness Minimal drug-drug interaction NO sexual dysfunction 37
Effexor, Effexor XR Act as a serotonin and norepinephrine reuptake inhibitor (SNRI) Also approved for GAD, SAD & PD Dosage: 75-375 mg/day Common side effects: nausea, headache, insomnia, blood pressure (dose related effect), sexual dysfunction
Cymbalta Acts as a serotonin and norepinephrine reuptake inhibitors (SNRI) FDA approved for MDD, diabetic peripheral neuropathy, & fibromyalgia Dosage: 40-60 mg/day, neuropathy/ fibromyalgia: 60-120mg/d Common side effects: nausea, dry mouth, constipation, sweating, sexual dysfunction
Viibryd The first and only SSRI and 5HT1A partial agonist No associated effects on blood pressure, heart rate, or EKG parameters Appears to have benefit with anxiety associated with major depression Dosage range: 10mg-40mg
Fetzima Potent and selective SNRI Has shown significant improvement in functional impairment Has been associated with increased heart rate, warnings to monitor prior to and periodically throughout treatment Dosage range: 20mg-120mg
Trintellix Multiple pharmacological activity including SERT and 5 serotonin subreceptors (classified MOA by WHO as other ) FDA registration trial with the elderly showing safety and efficacy at 5mg/day An FDA advisory committee has recommended it becomes the first antidepressant with an indication for improvement in cognitive functioning in major depression Dosage range: 5mg-20mg
Other biological interventions (TMS,ECT) Cognitive behavioral therapy (CBT) Psychoeducation Cardiac rehabilitation Collaborative Care Programs
Depression is a common comorbidity with cardiac disease and diabetes, resulting in worst clinical outcomes Cardiac and diabetic patients should be routinely screened for depression and suicidaility The PHQ-2 and PHQ-9 are established screening tools in the primary care setting Treatment should be monitored with remission as the goal Collaborative treatment is most effective with coordination of care between healthcare providers
Screening for depression in patients with coronary heart disease. *Meets diagnostic criteria for major depression, has a PHQ-9 score of 10 19, has had no more than 1 or 2 prior episodes of depression, and screens negative for bipolar disorder, suicidality, significant substance abuse, or other major psychiatric problems. Meets the diagnostic criteria for major depression and 1) has a PHQ-9 score 20; or 2) has had 3 or more prior depressive episodes; or 3) screens positive for bipolar disorder, suicidality, significant substance abuse, or other major psychiatric problem. If Yes to Q.9 suicidal, immediately evaluate for acute suicidality. Judith H. Lichtman et al. Circulation. 2008;118:1768-1775 Copyright American Heart Association, Inc. All rights reserved.
Depression is a common and modifiable risk factor for CVD and diabetes Screening and treatment of depression can have significant positive impact and course of these illness