Daniel Suzuki, MDAdjunct Clinical Associate Professor of Psychiatry, USC Keck School of MedicineClinical Adjunct Professor/Faculty, Graduate School of Psychology, Fuller Theological SeminaryMedical 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 Organization1

Lifetime prevalence rate in the US is 16%2

Suicide is among the top 10 leading causes of all deaths in the US3

1. World Health Organization, Fact Sheet, 20162. JAMA. 2003; 289 (23): 3095-31053. 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 CVD2

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_9-13. 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 controls1

American Heart Association study found screening positive for depression was associated with a 55% greater risk of cardiac events2

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 outcomes1

MDD after an episode of unstable angina increases the risk of cardiac events during the following year with a 4-fold increase of cardiac death2

Patients with MDD are at increased risk of cardiac death, particularly within the first 6 months3

1. Zuidersima M et al. Psychotherapy and Psycho-somatics, 2001;80(4):227-2372. 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 depression1

Depression has a 60% increased risk of Type 2 DM2

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 macrovascularcomplications1

Even in the context of good glucose control, depression is found to increase all cause mortality2

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

Emotional

PhysicalCognitive

• 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

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;118:1768-1775Copyright © 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 years1

Anxiety as an acute risk factors2

Protective factors

1. Simon GE et al. J of Clin Psychiatry 2016;77(2):2212. 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 study1

ENRICHD study2

Meta-Review of pharmacological Tx of depression with comorbid DM3

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

MAOI/

TCAs

tranylcyprominephenelzine

imipraminenortriptyline

Miscellaneous bupropionmirtazapinenefazodonetrazodone

SSRIs fluoxetinesertralineparoxetinecitalopramescitalopram

SNRIs venlafaxineduloxetinedesvenlafaxine

AntipsychoticAdjunct

aripiprazolequetiapine XRolanzapine+fluoxetinebrexpiprazole

Other vilazodonevortioxetineLevomilnacipranER

1950

s19

80s

1990

s

1990

s20

00s

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 successful1

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) 30.6Switch (789) 27.0Augment (650) 35.0

Level 3 (377) 13.6Switch (235) 10.3Augment (142) 19.1

Level 4 (109) 14.7By QIDS-SR16 <5 at level exit

32

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)

33

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

34

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 1st

trimester pregnancy (1.5-2% vs. 1%) Common side effects: anticholinergic (constipation, dry

mouth, sedation), weight gain, sexual dysfunction

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;118:1768-1775Copyright © 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