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
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.
 Indians
1.
2.
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
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
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 disordant
2
1.
2.
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.
DEPRESSION AND COMORBID MEDICAL DISORDERS

Cardiovascular


Pulmonary


GERD, Irritable bowel syndrome
Metabolic


Carcinoid syndrome, diabetes miletus, hypothyroid and hyperthyroid states,
hypoparathyroidism, pheochromocytoma
Gastrointestinal


HIV/AIDS dementia, Parkinson’s disease, Alzheimer’s disease, cerebrovascular
accident, chronic pain, malignancies, epilepsy, encephalitis and encephalopathy
Endocrine


Asthma, chronic obstructive pulmonary disease, pneumonia, pulmonary embolus,
pneumothorax
Neurologic


Myocardial infarction, angina, coronary artery disease, cardiac arrhythmias,
congestive heart failure, mitral valve prolapse
Anemia, dehydration, electrolyte imbalance, hepatic failure, hypoxia, porphyria
Miscellenous (Drug induced, drug withdrawal, rheumatoid arthritis, SLE)
PSYCHIATRIC COMORBIDITIES







Anxiety disorders (particularly panic disorder, obsessivecompulsive 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 rates
Kan 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



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


1.
2.
3.
4.
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
Prevalence of depression in hypertensive patients was 48.6%
Poor adherence to antihypertensive medications
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
DEPRESSION AND NEUROLOGICAL
DISORDERS
Neurological Disorder
Prevalence of Depression
Parkinson Disease
Multiple sclerosis
Post - Stroke
Epilepsy
20 – 45%
25%
30 – 50%
60%
1. Rickards H; J Neurol Neurosurg Psychiatry 2005;76(Suppl I):i48–i52.
1
MANAGEMENT OF COMORBID DEPRESSION IN
CHRONIC DISEASES

Pharmacological agents in the management of Depression
Class of Drug
Drugs
Side effects/disadvantages
Monoamine
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
MANAGEMENT OF COMORBID DEPRESSION IN
CHRONIC DISEASES
Class of Drug
Drugs
Side effects/disadvantages
Selective Serotonin Citalopram, Escitalopram,
Reuptake Inhibitors Fluoxetine, Sertaline,
(SSRI)
Paroxetine
Relatively safe and better acceptablility.
Serotonin syndrome, sexual dysfunction,
anorexia, insomnia.
Serotonin and
Venlafaxine, Desvenlafaxine,
Noradrenaline
Duloxetine
Reuptake Inhibitors
(SNRI)
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
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
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



1.
2.
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.
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
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