DEPRESSION AND COMORBIDITY: ROLE OF ESCITALOPRAM

Dr Ranjan Bhattacharyya. MD,DNB (Psychiatry).Asst Professor, Deptt of Psychiatry, MSDMCH.

DEPRESSION: THE IMPACT Depression is a mood disorder characterized by impaired

functioning at an emotional, physical, social and even occupational level.

Global Burden: Point prevalence 1.9% (men); 3.2% (women) 1

One year prevalence 5.8% (men); 9.5% (women) 1

Prediction 2020: 5.7% of total burden contributed by depression 1 Second leading cause of DALY (next to IHD) 1

Indians amongst the world’s most depressed 2

36% suffered from what is called Major Depressive Episode (MDE)

Depression common in high income group, women and average age of onset is 25.7 years.1. Grover S et al; An overview of Indian research in depression; Indian J Psychiatry. 2010 January;

52(Suppl1): S178–S1882. News report; Times of India Sinha K; July 27 2011, 01:48 am IST

MAJOR DEPRESSION: 5 OF 9 SX: Depressed mood Loss of interests/pleasure Change in sleep Change in appetite or weight Change in psychomotor activity Loss of energy Trouble concentrating Thoughts of worthlessness or guilt Thoughts about death or suicide

PNEUMONIC TO REMEMBER SX: "SIG: E CAPS" ( "prescribe energy capsules"): Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide + depressed mood

MAJOR DEPRESSION: DSM IV* CRITERIA FOR DIAGNOSIS: 5 of 9 symptoms One of the 5 must be either:

a depressed mood or

loss of interests/pleasure

Symptoms are present most of the day nearly every day for a minimum of two consecutive weeks

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision, American Psychiatric Association, Washington, DC 2000

DYSTHYMIC DISORDER Symptom list similar to Major

Depression Less stringent criteria

mild Present for at least two years. Symptom-free periods are possible

but may not exceed two months during the two-year timeframe

MINOR DEPRESSION Empirical data do not yet clearly

indicate where and how demarcation lines should be drawn among 'less-than major' depressions.

Varied Terminology used in research including 'minor,' 'subsyndromal,' 'subthreshold' depression

MINOR DEPRESSION: DSM-IV PROPOSED CRITERIA FOR DX:

Less than 5 of 9 symptoms of major depression (typically 2-4)

Sx present most of the day, nearly every day, for at least two weeks

At least one Sx being depressed mood or loss of interests/pleasure.

CO MORBIDITY

DefinitionAny distinct additional entity that has existed or may occur during the clinical course of a patient who has the index disease under study 1

Comorbidity can be classified as diagnostic, prognostic, cogent, non cogent, homotypic, heterotypic, concordant and disordant 2

1. Feinstein AR. Pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis. 1970;23(7):455–468.2. Ann Fam Med. 2009 July; 7(4): 357–363.

DEPRESSION AND COMORBID MEDICAL DISORDERS Cardiovascular

Myocardial infarction, angina, coronary artery disease, cardiac arrhythmias, congestive heart failure, mitral valve prolapse

Pulmonary Asthma, chronic obstructive pulmonary disease, pneumonia, pulmonary embolus,

pneumothorax Neurologic

HIV/AIDS dementia, Parkinson’s disease, Alzheimer’s disease, cerebrovascular accident, chronic pain, malignancies, epilepsy, encephalitis and encephalopathy

Endocrine Carcinoid syndrome, diabetes miletus, hypothyroid and hyperthyroid states,

hypoparathyroidism, pheochromocytoma Gastrointestinal

GERD, Irritable bowel syndrome Metabolic

Anemia, dehydration, electrolyte imbalance, hepatic failure, hypoxia, porphyria Miscellenous (Drug induced, drug withdrawal, rheumatoid arthritis, SLE)

PSYCHIATRIC COMORBIDITIES Anxiety disorders (particularly panic disorder,

obsessive-compulsive disorder, and posttraumatic stress disorder)

Cognitive disorders (specifically dementia) Eating disorders Somatoform disorders Personality disorders Sleep disorders (eg, obstructive sleep apnea) Substance use disorders (the combination of

substance use disorders with a primary psychiatric disorder is sometimes termed "dual diagnosis")

SCREENING: GOOD HISTORY A MUST! Suicide Risk Psychiatric co-morbidities Bipolar Disorder Family history Past history Substance Abuse Prescription Medications Occult medical illness

DEPRESSION AND DIABETES: COMORBIDITY FACTS

1684: T. Willis remarked that diabetes was the result of sadness or prolonged sorrow 1

Prevalence rate of depression is more than 3 times higher in type 1 diabetes patients and twice as high in type 2 diabetes patients compared to non diabetics 2

45% of all diabetes patients suffer with undiagnosed depression 3

Depression was associated with a 60% increase of type 2 diabetes 3

1. Leone T , C oast E , Narayanan S and de G raft AA; Diabetes and depression comorbidity and socioeconomic status in low and middle income countries (LMIC s): a mapping of the evidence; G lobalization and Health 2012, 8:39: 1 – 10

2. R oy T , Lloyd C E ; E pidemiology of depression and diabetes: A systematic review; J Affect Disord. 2012 O ct;142 Suppl:S8-S21

3. Eged LE , E llis C ; Diabetes and depression: G lobal perspectives; Diabetes R esearch and C linical Practice 87 (2010); 302 – 312.

DEPRESSION AND DIABETES: COMORBIDITY FACTS

1. Liu Y , Maier M, Hao Y , C hen Y , Q in Y , Huo R ; 2. Factors related to quality of life for patients with type 2 diabetes with or without depressive symptoms - results from a

community-based study in C hina. J C lin Nurs. 2012 Nov 8. doi: 10.1111/jocn.120106. C hoi SE , R eed PL; C ontributors to 3. Depressive Symptoms Among Korean Immigrants W ith T ype 2 Diabetes; Nurs R es. 2012 Nov 27 7. Fareeha F et al;

Depression and Diabetes in High-R isk U rban P opulation of P akistan; O pen Diabetes Journal; 2010, V ol. 3, p1-5. 8. G uruprasad,

4. K G , Niranjan, M R and Ashwin S; A Study of Association of Depressive Symptoms among the T ype 2 Diabetic O utpatients Presenting to a T ertiary C are Hospital; Indian Journal of Psychological Medicine; Jan-Mar2012, V ol. 34 Issue 1, p30-33.

5. 9. Mehdi J et al; Health R elated Q uality of Life in P atients with T ype 2 Diabetes Mellitus in Iran: A National Survey; PLoS O NE 7(8); August 2012, V olume 7, Issue 8 : e44526 10. R oshana M, Azidah AK, Husniati Y L; A Study on Depression among

6. P atient with T ype 2 Diabetes Mellitus in North-E astcoast Malaysia; International Journal of C ollaborative R esearch on Internal Medicine & Public Health (IJC R IMPH); Aug2012, V ol. 4 Issue 8, p1589-1600.

DEPRESSION AND DIABETES: PATHOPHYSIOLOGY

Depression and Insulin resistance Hormonal imbalance: Excess of cortisol and catecholamines in

depressed patients Increased inflammation and psychological stress: Increased

insulin resistance and β cell apoptosis Lifestyle changes: Depression influence lifestyles behaviors

such as dietary intake, exercise and medication adherence which are risk factors for diabetes development and progression

Suboptimal glycemic control Higher prevalence of diabetic complications: Including

retinopathy, nephropathy, neuropathy, macrovascular complications and sexual dysfunctions

High mortality ratesKan C et al; A systemic review and met analysis of the association between depression and insulin resistance; Diabetes Care 2013; 36: 480 - 89

DEPRESSION & DIABETES: INFLAMMATORY CHANGES

** Highly Significant (P<0.001)

Alvarez A et al; Endocrine and inflammatory profiles in type 2 DM with and without major depressive disorder; BMC research notes 2013, 6:61

DEPRESSION: IMPACT ON DIABETES Poor glycemic profile 1

Poor adherence to self care 1

Significantly greater diabetic complications 1

Increased disability, decreased work productivity and quality of life 1

Greater healthcare service utilization and costs 1

54% greater mortality rates as compared to non depressed 1

1. Egede LE , E llis C ; Diabetes and depression: G lobal perspectives; Diabetes R esearch and C linical Practice 87 (2010); 302 – 312.

DEPRESSION AND CARDIOVASCULAR DISEASES

Coexisting depression and cardiovascular diseases will lead the cause of disability worldwide by 2020 1, 2

Depression and Coronary Artery Diseases (CAD) 3 - 12

Depression increase the risk of recurrent cardiac events and death in patients with CAD by 3-4 folds

Increase platelet reactivity and inflammatory markers in depression linked to CAD, congestive heart failure (CHF), atherosclerosis , myocardial infarction (MI) and stroke

INTERHEART study: Depression for 2 or more week s was strongly associated with Acute MI

Depression is diagnosed in 20% of patients post Coronary Artery Bypass Graft (CABG); Depression symptoms prevalence 32% to 43%

Comorbid depression leads to frequent hospitalization at 6 months after CABG and recurrent angina during 5 year follow up

1. C oventry P A et al; C ollaborative Interventions for C irculation and Depression (C O INC IDE ): study protocol for a cluster randomized controlled trial of collaborative care for depression in people with diabetes and/or coronary heart disease; T rials 2012, 13:139 2. P oster No; P .3.E .038, R osenthal MH, Li D; E fficacy and tolerability of E scitalopram in patients intolerance to other SSR Is, presented at 23rd C ongress of the C ollegium, International Neuro – Psychopharmacolgicum, June 23 – 27, 2002, Montreal, C anada. 3. www.medpedia.com as accessed on 28/12/2012 4. Y usuf S, Hawken S, O unpuu S, et al; INTE R HE AR T Study Investigators. E ffect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTE R HE AR T study): case-control study. Lancet. 2004;364:937-952. 5. DiMatteo MR , Lepper HS, C roghan TW . Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med. 2000;160:2101-2107. 6. Bunde J, Martin R . Depression and prehospital delay in the context of myocardial infarction. Psychosom Med. 2006;68:51-57. 7. W ong C K, T ang E W , Herbison P , et al. Pre-existent depression in the 2 weeks before an acute coronary syndrome can be associated with delayed presentation of the heart attack. Q JM. 2008;101:137-144. 8. Scrutinio D, G iannuzzi P . C omorbidity in patients undergoing coronary artery bypass graft surgery: impact on outcome and implications for cardiac rehabilitation. E ur J C ardiovasc Prev R ehabil, 2008; 15: 379–385. 9. Hawkes AL, Nowak M, Bidstrup B, Speare R . O utcomes of coronary artery bypass graft. V asc Health R isk Manag, 2006; 2: 477––484. 10. T ully PJ, Baker R A, Knight JL. Anxiety and depression as risk factors for mortality after coronary artery bypass surgery. J Psychosom R es, 2008; 64: 285–290. 11. Saur C D, G ranger BB, Muhlbaier LH et al. Depressive symptoms and outcome of coronary artery bypass grafting. Am J C rit C are, 2001; 10: 4–10. 12. Borowicz L, R oyall R , G rega M, Selnes O , Lyketsos C , McKhann G . Depression and cardiac morbidity 5 years after coronary artery bypass surgery. Psychosomatics, 2002; 43: 464–471.

DEPRESSION AND CARDIOVASCULAR DISEASES Depression and MI 1, 2

Prevalence of depression post MI – 10 % to 20 % patients Risk of cardiac event doubles within 1 to 2 years after an MI in case

of untreated depression in CAD and post MI patients Depression and Heart Failure (HF) 1

19.3% to 33.6% patients with HF are diagnosed of clinical depression Depression in HF patients is associated with increased morbidity and

mortality, higher utility of healthcare resources and increased rates of hospitalization

CAD patients with depression are at more risk to develop HF Depression and Hypertension 3,4

Prevalence of depression in hypertensive patients was 48.6% Poor adherence to antihypertensive medications

1. Nieradko BF , Stepnowska M, Piotrowicz R ; E ffect of the dynamics of depression symptoms on outcomes after coronary artery bypass grafting; Kardiologia P olska 2012; 70, 6: 591–597.2. Laura T ; Depression in C ardiac P atients; U S Pharmacist. 2012;37(11):HS-12-HS-153. Bunde J, Martin R . Depression and prehospital delay in the context of myocardial infarction. Psychosom Med. 2006;68:51-57.4. Araghchian ; M.A. Seif R abie ; F . Zeraati; The Survey of Depression Frequency in Hypertensive P atients; Scientific Journal of Hamadan U niversity of Medical Sciences; Y ear: 2010 V olume: 16 - Issue: 4: 37 – 41

DEPRESSION AND NEUROLOGICAL DISORDERS

Neurological Disorder Prevalence of Depression 1

Parkinson Disease 20 – 45%Multiple sclerosis 25%Post - Stroke 30 – 50%Epilepsy 60%

1. Rickards H; J Neurol Neurosurg Psychiatry 2005;76(Suppl I):i48–i52.

MANAGEMENT OF COMORBID DEPRESSION IN CHRONIC DISEASES

Pharmacological agents in the management of Depression

Class of Drug Drugs Side effects/disadvantagesMonoamine oxidase (MAO) inhibitors

Phenelzine, tranylcypromine, moclobemide (MAO – A)

Interaction with food and beverages to lead to dangerous rise in blood pressure, as well as headache, nausea, vomiting, rapid heartbeat, psychotic symptoms, seizures, stroke and coma

Tricyclic Antidepressants

Imipramine, Clomiparmine, Amitriptyline, Desipramine, Nortriptyline, Amoxapine, Reboxetine

drowsiness, anxiety, dry mouth, constipation, urinary retention, difficulty urinating, cognitive and memory difficulties, weight gain, increased sweating, dizziness, increased heart beats , decreases sexual ability & desires, fatigue weakness, nausea

Class of Drug Drugs Side effects/disadvantagesSelective Serotonin Reuptake Inhibitors (SSRI)

Citalopram, Escitalopram, Fluoxetine, Sertaline, Paroxetine

Relatively safe and better acceptablility. Serotonin syndrome, sexual dysfunction, anorexia, insomnia.

Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)

Venlafaxine, Desvenlafaxine, Duloxetine

Nausea, dry mouth, dizziness, excessive sweating, tiredness, difficulty in urination, anixiety, constipation, insomnia, sexual dysfunctions , headache and anorexia.

Atypical Antidepressants

Trazodone, Mirtazapine, Agomelatine, Mianserin, Bupropion

MANAGEMENT OF COMORBID DEPRESSION IN CHRONIC DISEASES

ANTIDEPRESSANTS IN DIABETES (IMPORTANT CONSIDERATIONS) TCA associated with increased weight gain can be important in

development of insulin resistance

MAO inhibitors when given along with insulin and oral hypoglycemic agents can cause greater drop in blood sugar levels

Use of paroxetine and TCA such as amitriptyline and for more than 2 years in moderate to high dose is associated with 84% increased risk of diabetes

Fluoxetine is associated increased duration of action of sulfonylureas risking patients for side effects such as hypoglycemia

Higher rate of drug interactions with TCA, MAO inhibitors and SSRIs such as Fluoxetine, Fluvoxamine and Paroxetine

11. www.webmd.com as accessed on 8th December 2012. 12. Katon W J; The C omorbidity of Diabetes Mellitus and Depression; Am J Med. 2008 November ; 121(11 Suppl 2): S8–15. 13. www.medscape.com as accessed on 8th December 2012. 14. C ulpepper L; E scitalopram: A New SSR I for the T reatment of Depression in Primary C are; Primary C are C ompanion J C lin Psychiatry 2002; 4: 209 - 14

ANTIDEPRESSANTS IN CARDIOVASCULAR DISEASES (IMPORTANT CONSIDERATIONS) MAO inhibitors are associated with drug interactions and development of

hypertension

TCAs cause orthostatic hypotension and delayed cardiac conduction and can trigger ventricular arrhythmias

SSRIs attenuate platelet activation by depleting serotonin storage and have been shown to decrease platelet activity in patients with CAD

SSRI use was associated with reduced odds of MI suggesting greater MI protection with SSRIs

SSRIs with other complementary stress reducing interventions may improve depression with HF

SSRIs are associated with improved prognosis of post MI and HF patients

lassman AH, R oose SP , Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA. 1993; 269:2673-2675. 23. Sauer W H, Berlin JA, Kimmel SE ; E ffect of Antidepressants and Their R elative Affinity for the Serotonin T ransporter on the R isk of Myocardial Infarction; C irculation. 2003;108:32-36 24. W ozniak G , T oska A, Saridi M, Mouzas O ; Serotonin reuptake inhibitor antidepressants (SSR Is) against atherosclerosis; Med Sci Monit. 2011 Sep;17(9):R A205-14. 25. W oltz PC , C hapa DW , Friedmann E , Son H, Akintade B, Thomas SA; E ffects of interventions on depression in heart failure: a systematic review: Heart Lung. 2012 Sep-O ct; 41(5):469-83. 26. P araskevaidis I, P alios J, P arissis J, Filippatos G , Anastasiou-Nana M; T reating depression in coronary artery disease and chronic heart failure: what's new in using selective serotonin re-uptake inhibitors? C ardiovasc Hematol Agents Med C hem. 2012 Jun;10(2):109-15.

ESCITALOPRAM : THE DRUG OF CHOICE

Escitalopram has High selectivity and potency

Dose dependent inhibition of the human serotonin reuptake into presynaptic nerve terminal

Rapid onset antidepressant action

Cost effective dominating over other SSRIs and Venlafaxine

Garnock J; Escitalopram: A review of its use in the management of major depressive disorder in adults; CNS drugs.. 2010; 24 (9): 769 – 96

ESCITALOPRAM : THE DRUG OF CHOICE

Escitalopram has greater efficacy in relapse prevention

Predictable tolerability profile with mild to moderate and transient adverse events

Escitalopram has very low propensity for drug interactions

Escitalopram is only 55% bound to human plasma protein, which makes it least likely agent for drug – drug interactions by displacement of other highly protein bound drugs such as Sulfonylureas used in diabetes.

Garnock J; Escitalopram: A review of its use in the management of major depressive disorder in adults; CNS drugs.. 2010; 24 (9): 769 – 96

ESCITALOPRAM: ROLE IN DEPRESSION IN DIABETES

Amsterdam JD et al studied the safety and efficacy of Escitalopram in patients with comorbid depression and diabetes mellitus.

Duration of study: 16 weeks

Escitalopram caused significant reduction in mean HAM – D 17 score (p<0.001), CGI/S score (p=0.001) and CGI/C score (p=0.001)

Escitalopram produce non significant reduction in the fasting glucose, fructosamine and glycosylated Hb1Ac levels

HAM – D 17 (Hamilton depression rating 17 questionnaire); CGI/S – Clinical global impression severity scale; CGI/C – Clinical global impression changes scale

Neuropsychobiology 2006;54:208–214

ESCITALOPRAM: ROLE IN DEPRESSION IN DIABETES

Gehlawat P et al studied the effect of escitalopram in patients with diabetes and comorbid depression. They also studied the relationship of treament response for depression and glycemic control

Duration of study: 12 weeks

Significant reduction in HAM – D score from 3rd week onwards till the end of the study

There was a corresponding decline in mean fasting and post-prandial plasma glucose level at 6 and 12 weeks respectively and glycosylated hemoglobin level at 12 weeks was observed.

Gehlawat P; Asian Journal of Psychiatry Volume 6, Issue 5 , Pages 364-368, October 2013

ESCITALOPRAM: ROLE IN DEPRESSION IN DIABETES

Improved compliance and reduced health cost

In retrospective study by Wu EQ et al, treatment persistence and healthcare cost with escitalopram treatment was compared with citalopram.

RESULTS Patients with Escitalopram treatment were less likely to

discontinue the index drug or switch to other antidepressant Patients treated with escitalopram had significantly lower

health cost as compared to citalopram

Wu EQ et al; Treatment persistence & healthcare costs of adult MDD patients treated with escitalopram vs citalopram in medicaid population; Manag care 2012 Jan Vol. 21 pp 49-59

ESCITALOPRAM: ROLE IN CARDIOVASCULAR DISEASES

DECARD Trial (Depression in patients with Acute Coronary Syndrome) Hansen BH concluded that ….

Escitalopram significantly prevented the development of depression in post Acute coronary syndrome (ACS) (p<0.022)

Escitalopram treatment was safe and well tolerated by patients with recent ACS during the study duration of one year

Withdrawal rate due to adverse events was lower with escitalopram when compared to other antidepressants

TCAs showed risk for development of serious adverse cardiac events

Hansen BH et al; Rationale, design and methodology of a double-blind, randomized, placebo-controlled study of escitalopram in prevention of Depression in Acute Coronary Syndrome (DECARD). Trials. 2009 Apr 7;10:20

ESCITALOPRAM: ROLE IN CARDIOVASCULAR DISEASES

Bah TM et al 1 – Escitalopram lowered TNFα, IL1β and PGE2 levels which are elevated post MI

In a study by Flock A et al 2, Escitalopram showed a 23% decrease of ADP induced platelet aggregation (p=0.03) and a 15% reduction of collagen induced platelet aggregation

Excellent cardiovascular safety 3

C ardiac toxicity in citalopram overdoses appears to be related to QT prolongation caused by the active metabolite, didemethylcitalopram (DDC T), which is present in only minor amounts (<10%) in humans. E scitalopram metabolism revealed negligible amount of DDC T .

In a metaanalyis of five short term studies involving patients above 60yrs age treated with escitalopram , no laboratory abnormalities or changes from baseline in

vital signs or body weight, and no clinically notable changes in E C G values, signifying the excellent cardiovascular safety profile of escitalopram. C ardiac side effects are uncommon with escitalopram and are generally limited to slight bradycardia of little clinical significance.

1. Bah TM, Benderdour M, Kaloustian S, Karam R , R ousseau G , G odbout R .; E scitalopram reduces circulating pro-inflammatory cytokines and improves depressive behavior without affecting sleep in a rat model of post-cardiac infarct depression: Behav Brain R es. 2011 Nov 20;225(1):243-51

2. Flock A et al; Antiplatelet effects of antidepressant treatment: a randomized comparison between escitalopram and nortriptyline: Thromb R es. 2010 Aug; 126(2):e83-7.

3. :www.sajprevcardiology.com/vol9/vol9_3/behaviouralcardiology.htm as accessed on 20/13/13

FINAL OUT COME Depression foreseen as second leading cause of disability by 2020.

Depression is the common prevalent comorbid conditions with chronic disease

Presence of depression in diabetes impacts the treatment of diabetes as depressed diabetic patients have evidence of insulin resistance, poor treatment adherence, increased diabetes complications and poor quality of life

Treatment of depression with SSRIs safe in diabetic patients

Depression is a frequent comorbid condition in cardiovascular conditions and impacts the outcome of the disease

Treatment of depression in cardiovascular disease improves the disease prognosis and prevent recurrences

FINAL OUT COME Escitalopram is an approved SSRI for management of Major Depressive disorder

Rapid onset of action

Highly selective and potent

Effect on glycemic control minimum with better efficacy in treating comorbid depression

Effect on reducing Hb1Ac level, no effect on weight and less drug interactions make it a good choice of treating depression in diabetic patients

Escitalopram showed evidence of anti – inflammatory action, antiplatelet aggregation, no drug interactions and better cardiovascular safety with lower withdrawal rates, suggesting it as a safe and effective antidepressant in the management of depression with cardiovascular diseases