The document discusses the relationship between metabolic syndrome and cardiovascular disease, highlighting that the presence of metabolic syndrome doubles the risk of coronary heart disease. It also outlines the prevalence of depression among patients with coronary heart disease and the importance of managing both conditions effectively, including medication considerations and monitoring for potential complications. Additionally, it emphasizes the need for ECG monitoring when prescribing antipsychotics and the associated risks of QT interval prolongation.

1. Presented by : Mohammad Maddah –R3

2. Why?
u The metabolic syndrome is a cluster of interrelated
risk factors for the development of Cardiovascular
disease CVD
u Once the criteria of metabolic syndrome is there, the
prevalence of coronary heart disease (CHD) is
doubled.
u CHD Risk Increases with Increasing Number of Metabolic
Syndrome Risk Factors .

3. CHD Risk Increases with Increasing Number of
Metabolic Syndrome Risk Factors
Sattar et al, Circulation, 2003;108:414-419
Whyte et al, American Diabetes Association, 2001
Adapted from Ridker, Circulation 2003;107:393-397
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
6.5
7
one two three four
RelativeRisk

4. Cardiovascular risk factors
BMI = body mass index; TC = total cholesterol; DM = diabetes mellitus; HTN = hypertension.
Wilson PWF et al. Circulation. 1998;97:1837–1847.
0
2
4
6
8
10
12
14
HTNDMSmokingBMI >27 TC >220
Single Risk Factors
Multiple Risk
Factors
Oddsratios
Smoking
+ BMI
2
Smoking
+ BMI
+ TC >220
3
Smoking
+ BMI
+ TC >220
+ DM
4
Smoking
+ BMI
+ TC >220
+ DM + HTN
5The Framingham Study

5. u Which one of the following meds cause fatal myocarditis
and cardiomyopathy:
1. Ziprisdone
2. Risperidone
3. Clozapine
4. Sertraline
5. citalopram

6. u What is the average range of QTC in
female?
1. 440 msec.
2. 470 msec
3. 490 msec
4. 500 msec

7. Case
u A 62-year-old woman is brought to the emergency
department by paramedics for chest pain that has been
present for 5 hours. Medical history is notable for
DYSLIPEDIMIA . Medications include atorvastatin, and
aspirin.
u On physical examination, she appears comfortable. She
is afebrile, BP is 190/90 mm Hg, PR is 88/min and
respiration rate is 16/min. Cardiac examination shows
no murmurs, extra sounds, or rubs. The lungs are clear
and pulses are equal bilaterally. Neurologic examination
is normal.

8. u The electrocardiogram shows 2-mm ST-segment
elevation in leads I,V2, and V3.
u A coronary catheterization Iis done witin 1 hour.

9. u Current medications are aspirin, clopidogrel,
metoprolol, atorvastatin, and sublingual nitroglycerin.
u 4 weeks later patient started to be isolated , low mood
with frequent guilt feeling and death wishes
u according to the family she had these sx for the last 2
weeks.

10. u How will you appaoach this case?
HX,MSE,IX,File review,DD.
u What is your management?
u Will you start medications? Why?
u How will you follow up?

11. u In patients with CHD, the prevalence of major
depression is nearly 20% and the prevalence of minor
depression is approximately 27%.
u Francois Lesperance 25% of pt had an MI also gave hx of
MDD.
u 7% occurred in the year prior to the MI.
u 15% started after the MI.
u MDD rates higher around 6 months following MI and
gradually decrease around 1 year.

13. u Detailed hx and physical examination.
u Detailed meds HX
u rehabilitation programs include exercise
training, risk factor modification, education,
medical surveillance, vocational rehabilitation,
and psycholog- ical counseling

14. Approach
u Earlier prescription of antidepressants in
the hospital (in coordination with
cardiology) is recommended in the
following circumstances (Huffman et al.
2004).

15. u Depression with suicidal ideation .
u Development of sx during hospitalization.
u History of severe depression.
u Severe depression that inhibits
participation in rehabilitation or self-care

16. u CREATE
u SADHART
u ENRICHD
u MIND-IT

20. u In SADHART, the depression scale ratings did not
improve significantly in the total study population
with sertraline therapy compared with placebo [95].
However, the subset of patients who had a history of
major depression prior to their MI did have
significant improvements in depressive symptoms
with sertraline.

21. Clinical Management Only
n=142
Clinical Management + IPT
n=142
Citalopram
n=67
Placebo
n=75
284 Patients with CAD from 9 Canadian academic centers, meeting the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition criteria for major depression > 4 weeks duration and
had baseline 24-item Hamilton Depression Rating Scale (HAM-D) > 20
2X2 Factorial. Randomized. Controlled. Parallel-Group. Double-blinded.
Mean age 58.2 years, 25% women
! Primary Endpoint Change in 24-item HAM-D from baseline.
! Secondary Endpoint: Self-reported Beck Depression Inventory II (BDI-II)
score
12 weeks
R
R R
Citalopram
n=75
Placebo
n=67
Lespérance et al., JAMA 2007; 297(4): 367-79

22. u In CREATE, citalopram or placebo [ 89]. After 12
WK of therapy, the citalopram group had a
statistically significant greater decline in a
standard measurement of depression compared
with placebo.
u However, the United States FDA issued warnings
that citalopram causes dose-dependent QT
interval prolongation that can lead to arrhythmias,
and thus recommends avoiding citalopram in
patients with recent acute MI.

23. u compares psychotherapy (CBT) to treatment-as-
usual in patients with depression and/or
reduced social support following an MI.
u The intervention did not increase event free
survival.
u improved depression and social isolation.

25. u TCAs:
u Orthostasis, Type 1A antiarrhythmic
effects
u Generally safe in selected pts with
stable ht.disease
u Contraindicated after MI
u SSRIs:
u Safety shown for sertraline in SADHRT
and citalopram in CREATE
u Uncommonly cause bradycardia

26. u Mirtazapine: Safety shown in MIND-IT
u Stimulants: generally safe
u But there is a Black Box warning; PDR
says contraindicated in structural heart
disease.
u No ↑ CV risk in minors. N Engl J Med
2011; 365:1896
u No ↑ CV risk in adults? Am J Psychiatry
2012; 169:178
(small absolute↑ in VT, RR 1.8 but inverse dose
relationship

29. SSRIs and bleeding

30. SSRIs and bleeding
u Risk is increased still further in those also receiving
aspirin, NSAIDs or oral anticoagulants.
u Try to avoid SSRIs in patients receiving NSAIDs, aspirin or
oral anticoagulants or with history of cerebral or GI
bleeds.
u If SSRI use cannot be avoided, monitor closely and
prescribe gastroprotective proton pump inhibitors.

31. u ECG monitoring is essential for all
patients prescribed antipsychotics. An
estimate of QTC interval should be made
on admission to in-patient units (note that
this is recom- mended in the NICE
schizophrenia guideline13) and at least
yearly thereafter.

32. u Measure QTC in all patients prescribed antipsychotics.
u On admission :if previous abnormality or known
additional risk factor, at annual physical health .
u Consider measuring QTc within a week of achieving a
therapeutic dose of a newly pre- scribed antipsychotic
that is associated with a moderate or high risk of QTc
prolonga- tion or of newly prescribed combined
antipsychotics.

33. u In general, a QTc of 440 ms is considered the aver- age
upper limit of normal.
u • An interval of 500 ms or more is a signal to change the
treatment method (Glassman 2002).
u antipsychotics block cardiac potassium channels and are
linked to prolongation of the cardiac QT interval .
u 440msec for men, 470msec for women.
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35. u Hypotension: avoid low-potency agents and
clozapine (due to α1-adrenergic blockade)
u All antipsychotics may ↑ QT
u Higher risk with pimozide, thioridazine, mesoridazine,
droperidol, and ziprasidone
u Lowest risk with aripiprazole and olanzapine
u Screen for already ↑QT, other QT prolonging drugs,
personal or family Hx of unexplained syncope or sudden
death

36. u Estimated rates of clozapine-associated
myocarditis range from 1/500 to 1/10,000 .
u Eighty-five percent of the cases develop
during the first 2 months of therapy.
u Usually a dilated cardiomyopathy .

37. u Benzodiazepines, buspirone—safe
u Mood stabilizers
u Lithium generally safe at nontoxic doses, but avoid in heart
failure
u Valproic acid generally safe
u Cholinesterase inhibitors
u May have vagotonic effects on the heart (e.g. bradycardia)
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40. u What is the average range of QTC in male?
1. 440 msec
2. 470 msec
3. 490 msec
4. 500 msec

41. u 35 YO male schizopherinic pt well managed
on amisulpride 600 mg once daily ECG showed
flatened T - wave with QTC 460 msec:
1. Reduce dose and refer to cardiologist.
2. Change to olanzpine.
3. No need for intervention.
4. Reassure the pt and repeat ECG later.

42. u 48 YO male 6 weeks post MI and recent
hemorrhigic stroke on aspirin presented with
Depressive SX :
1. Start on 20 mg of citalopram.
2. Start on lorazepam 1mg then taper down.
3. No need for intervention.
4. Reassurance as these SX will fade by time.
5. Start on mirtazapine 30 mg .

43. Case
u 39 YO female pt kc of schizopherenia well controlled
on halloperidol 5 mg twice daily, cogentin 2mg once
daily admitted on the medical ward as case of MI
recently.
u The medical team change the AP to quetiapine 200 mg
twice daily and the regimen of the MI meds including
aspirin,clodepigrol and metapronolol.
u 3 days later the patient started to be agitated thinks
that the nurses want to harm him and hearing voices
commanding him to leave the hospital.
u The medical team consult you regarding his agitation.

44. u How will you appaoach this case?
HX,MSE,IX,File review,DD.
u What is your management?
u When will you start treatment?

45. Summary
u ECG must be done in cardiac patient as baseline
and follow up when reaching theraputic dose or
introducing new agent to avoid sudden cardiac
death.
u Average QTC range for male: 440msec, female:
470mse.
u Safest ADs : sertraline,citalopram,mirtazapine and
bupropione.
u All benzodiazepine cosider safe.

46. Summary
u Avoid IV AP and always go with low effect of AP
like olanzapine and resperidone .
u Aripaprizole is the safest AP.
u In polypharmacy always look for drug drug
interactions.
u Consult cardiologist if the patint condition
unstable.
u Almost all SSRIs have antiplatelet effect and
interact with warfarin which increse bleeding
time.

47. CASE
u Mr. x 29 YO saudi male k/c of CHD and DM 2 presented
to your clinic with disorganised behavior and audiatory
hallucination for the past 9 months you diagnosed him
as schizophrenia .
u Regardless to the medication he is taking for CHD and
DM 2 .
u What’s the most important work up before starting AP?
u What is the best AP regarding his condition?

48. PREVELENCE
u 6.4 percent in adults WORLD WIDE
u Saudi Arabia 890,000 , 2,523,000 (WHO).
u KSA, adults: 17.6%.
u prevalence in mentally ill is two to three times higher
than that found in the general population .

49. Prevelence in KSA
Al-Qurashi, et al., (2011)
u Epidemiological study in 6024 individuals
u D.M. 34.1% in males & 27.6% in females.
u Mean age :- 55.3 yrs.
u BMI > 25 :-
In general :- 72.5 %
In diabetics :- 85.7 % (females > males)
(p. = < .0001)

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51. DIAGNOSTIC CRITERIA:
u Diabetes mellitus can be diagnose according WHO either
by one of the followings:
u Random blood sugar more than 200mgdl with
symptoms.
u Fasting blood sugar more than 126mgdl.
u HbA1c more than 6.5.
u OGTT 2hour more than 200mgdl.

52. METABOLIC SYNDROME
u Current Adult Treatment Panel III (ATP III) criteria the
metabolic syndrome as the presence of any 3 of the
following :
u Abdominal obesity, as a waist circumference in men >102
cm (40 in) and in women >88 cm (35 in.)
u Serum triglycerides ≥150 mg/dl (1.7 mmol/L) or drug
treatment for elevated triglycerides .
u Serum high-density lipoprotein (HDL) cholesterol <40 mg/
dl (1 mmol/L) in men and <50 mg/dl (1.3 mmol/L) in
women, or drug treatment for low HDL cholesterol (HDL-
C) .
u Blood pressure ≥130/85 mmHg or drug treatment for
elevated blood pressure.
u Fasting plasma glucose (FPG) ≥100 mg/dl (5.6 mmol/L), or
drug treatment for elevated blood glucose (9)

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55. CATIE Trial Design
1493
patients with
SCZ
Comorbidity
Other meds
Participants who discontinue
Phase 2 choose one of the
following open-label
treatments
• ARIPIPRAZOLE
• FLUPHENAZINE
DECANOATE
• PERPHENAZINE
• RISPERIDONE
• OLANZAPINE
• ZIPRASIDONE
• QUETIAPINE
• 2 of the antipsychotics
above
Phase 3Phase 1*
R
OLANZAPINE
QUETIAPINE
RISPERIDONE
ZIPRASIDONE
PERPHENAZINE
Double-blind, random
treatment assignment.
Phase 2
CLOZAPINE
(open-label)
OLANZAPINE,
QUETIAPINE or
RISPERIDONE
OLANZAPINE,
QUETIAPINE or
RISPERIDONE
ZIPRASIDONE
R
R
No one assigned to same
drug as in Phase 1
Participants who discontinue
Phase 1 choose either the
clozapine or the ziprasidone
randomization pathways
*Phase 1A: participants with TD do not get randomized to perphenazine; phase 1B: participants who fail perphenazine
will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before they are eligible for phase 2.
Stroup TS et al. Schizophr Bull. 2003;29:15-31.
• CLOZAPINE

56. CATIE ( Metabolic Results )
Drug Average
Weight
Gain
(lbs)
Weight
Gain
>7%
Fasting Blood
Sugar (mg/dl)
/HgbA1c (%)
Change
Olanzapine 9.4 30% 15.0/0.41
Quetiapine 1.1 16% 6.8/0.05
Risperidone 0.8 14% 6.7/0.08
Perphenazine -2.0 12% 5.2/0.10
Ziprasadone -1.6 7% 2.3/-0.10

57. Citrome et al,2005
> 50% of patients on
Olanzapine & Clozapine will
gain more than
10% of their body weight
within 14 weeks
Newcomer,2006
meta-analysis
Wt. Gain after
1 year
Drug
< 1kgAripiprazole &
Ziprasidone
2 - 3 kgQuetiapine &
Risperidone
> 6 kgOlanzapine
(< 12.5 mg)
> 10 kgOlanzapine
( >12.5 mg )

59. + = increased effect; - = no effect; D = discrepant results.
Drug Weight Gain Diabetes Risk Dyslipidemia
Clozapine + + + + +
Olanzapine + + + + +
Risperidone + + D D
Quetiapine + + D D
Aripiprazole +/- - -
ziprasidone +/- - -
American Diabetes Association, American Psychiatric Association, American Association of Clinical
Endocrinologists, North American Association for the Study of Obesity - Diabetes Care 27:596-601, 2004

60. Effect on glucose homstasis
and weight
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SSRIs

61. Effect on glucose homstasis
and weight
SNRIs
Mirtazpine and trazadone

62. Effect on glucose homstasis
and weight
Agomelatine

63. MCQ
u Mr. x 29 YO saudi male k/c of CHD and DM 2 presented
to your clinic with disorganised behavior and audiatory
hallucination for the past 9 months you diagnosed him
as schizophrenia . Regardless to the medication he is
taking for CHD and DM 2 .
u Best AP is:
1. Olanzapine.
2. Amisulpride.
3. Aripiprizole.
4. Clozapine.

64. summary
u All depressed patient should should be screened for
diabetes.
u Monitoring of metabolic syndrome is a must.
u SSRIs as 1st line : fluoxetine.
u ziprasidone and aripiprazole showing the least effect.
u clozapine and olanzapine shows the most effect.
u SNRIs ( deluxtine) use for diabetic neuropathy.
u avoid TCAs and MAOIs if possible due to their effects on
weight and glucose homeostasis .

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