Depression and Comorbidity: Role of Escitalopram

1. Dr Ranjan Bhattacharyya. MD,DNB (Psychiatry). Asst Professor, Deptt of Psychiatry, MSDMCH. Depression and Comorbidity: Role of Escitalopram

2. 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. Depression: The Impact Grover S et al; An overview of Indian research in depression; Indian J Psychiatry. 2010 January; 52(Suppl1): S178–S188 News report; Times of India Sinha K; July 27 2011, 01:48 am IST

3. 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 Major Depression: 5 of 9 Sx:

4. "SIG: E CAPS" ( "prescribe energy capsules"): Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicide + depressed mood Pneumonic to remember Sx:

5. 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 Major Depression: DSM IV* Criteria for Diagnosis:

6. 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 Dysthymic disorder

7. 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

8. 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. Minor Depression: DSM-IV proposed criteria for Dx:

9. Definition Any 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 disordant2 Co morbidity Feinstein AR. Pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis. 1970;23(7):455–468. Ann Fam Med. 2009 July; 7(4): 357–363.

10. 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) Depression and Comorbid Medical Disorders

11. 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") Psychiatric comorbidities

12. Suicide Risk Psychiatric co-morbidities Bipolar Disorder Family history Past history Substance Abuse Prescription Medications Occult medical illness Screening: Good History a Must!

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

14. Depression and Diabetes: Comorbidity Facts Liu Y , Maier M, Hao Y , C hen Y , Q in Y , Huo R ; 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 linNurs. 2012 Nov 8. doi: 10.1111/jocn.120106. C hoi SE , R eed PL; C ontributors to 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, 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. 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 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.

15. 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 rates Depression and Diabetes: Pathophysiology Kan C et al; A systemic review and met analysis of the association between depression and insulin resistance; Diabetes Care 2013; 36: 480 - 89

16. ** Highly Significant (P<0.001) Depression & Diabetes: Inflammatory changes Alvarez A et al; Endocrine and inflammatory profiles in type 2 DM with and without major depressive disorder; BMC research notes 2013, 6:61

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

18. 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 Depression and Cardiovascular diseases 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 ardiovascPrev 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 iskManag, 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.

19. 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 Depression and Cardiovascular diseases 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. Laura T ; Depression in C ardiac P atients; U S Pharmacist. 2012;37(11):HS-12-HS-15 Bunde J, Martin R . Depression and prehospital delay in the context of myocardial infarction. Psychosom Med. 2006;68:51-57. 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

20. Depression and Neurological Disorders 1. Rickards H; J Neurol Neurosurg Psychiatry 2005;76(Suppl I):i48–i52.

21. Pharmacological agents in the management of Depression Management of Comorbid Depression in Chronic Diseases

22. Management of Comorbid Depression in Chronic Diseases

23. 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 Antidepressants in Diabetes (Important Considerations) 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

24. 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 Antidepressants in Cardiovascular Diseases (Important Considerations) 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 SciMonit. 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 ardiovascHematol Agents Med C hem. 2012 Jun;10(2):109-15.

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

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

27. 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 Escitalopram: Role in Depression in Diabetes Neuropsychobiology 2006;54:208–214

28. 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. Escitalopram: Role in Depression in Diabetes Gehlawat P; Asian Journal of Psychiatry Volume 6, Issue 5 , Pages 364-368, October 2013

29. 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 Escitalopram: Role in Depression in Diabetes Wu EQ et al; Treatment persistence & healthcare costs of adult MDD patients treated with escitalopramvscitalopram in medicaid population; Manag care 2012 Jan Vol. 21 pp 49-59

30. 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 Escitalopram: Role in Cardiovascular diseases 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

31. 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. Escitalopram: Role in Cardiovascular diseases 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 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. :www.sajprevcardiology.com/vol9/vol9_3/behaviouralcardiology.htm as accessed on 20/13/13

32. 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

33. 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 Final Out come