 Depression in old age : highly prevalent in => hypertension => coronary artery disease => vascular dementia  In large sample of primary care patients, depression patients had more vascular disease.  What association between vascular factors with depression? Depression and cardiovascular disease

 Depression is an secondary reaction to multiple deficits associated with CVD.  Depression is a direct consequence of ischemic brain damage or vascular lesion.  Depression influences the development of CVD vascular risk factor,stroke recovery.  A state of co-existence Relationship between Depression & CVD

What is the relationship? Vascular risk factors Depression

Vascular diseaseDepression Can depression induce CVD?

Can depression induce CAD? Prospective studies of depression and CAD  12 cohort studies - relative risk ( )  Depression is an independent risk factor for later developing CAD and MI

Can depression induce stroke? Six prospective studies of depression and stroke

Can depression change BP? Five prospective studies of depression and BP

Depression -  CVD Prospective studies showed depression can be an independent risk factor for the development of coronary artery disease and stroke Raised cortisol levels : cholesterol, TG Unhealthy life style : smoking, compliance Platelet and clotting system change :PF4 Antidepressant cardiotoxicity

Vascular disease Depression Can vascular disease induce depression ?

Depression in coronary artery disease  Major dep (20%) vs control (12%) ; (OR : 2) (Hipisley-Cox et al, 1998)  Depression is a major independent predictor of poor outcome –cardiac mortality (OR: 3.64)(Frasure-Smith,1995)  Vigorous treatment needed in CAD  Others - DM : greater depression Hypertension : unclear low cholesterol : unclear

Antidepressant and CVD Serotonin role in vasculature  thrombostatic effect : bleeding tendency SSRI -> transporter 억제 -> PLT 저하  Vasocontrictive effect 5-HT2 large vessel

Serotonin and SSRI in PLT

Serotonergic affinity and MI

Clinical implication on SSRI use in CVD  SSRI Tx > risk of bleeding & vasospasm  Affinity for 5-HTT and Dose of SSRI  Drug interaction anticoagulants ; citalopram,sertraline NSAID ; COX-2 inhibitor combination  Non-SSRI ; nortriptyline, mirtazapine venlafaxine

Neuroprotective effect of fluoxetine on ischemia-induced neuronal cell death in the hippocampus -dose dependent changes-

Effect of fluoxetine on ischemia- induced BDNF expression in the hippocampal CA1 region

The effect of fluoxetine on ischemia- induced CAT, GPX or SOD1 expression in the hippocampal CA1 region

 Depression following stroke is common. (20-60%)  Lesion location vs psychological rx. => Lesion laterality (Robinson, 1982) => Frontal lobe & Basal ganglia Frontal subcortical circuit (Vataja, 2001) => time factor ; early onset :biologic factors late onset : psychologic factors Depression & Stroke

Prevelance of MD in stroke patients

Results of the acute phase & 2 month follow-up examination in stroke patients Acute phase (N=69) Mean (SD) 2 Month follow-up (N=69) Mean (SD) P-value BDI14.75(9.47)13.34(8.05)0.19 BAI**12.33(10.22)8.13(6.38)<0.01 SSS94.77(20.16)95.27(17.23)0.86 BI**84.84(10.55)96.44(10.74)<0.01

OR of PSD after left hemisphere stroke (Bhogal et al, 2004) (N=20)

 Absence of neurological symptom  Absence of prior stroke and TIA  Presence of brain parenchymal lesion of vascular origin confirmed by CT or MRI Silent Cerebral Infarct (SCI)

Prevalence of Silent Infarct

Silent Infarct in Korea

Risk factors of SCI Normal N=50 ( 56.2%) Hyperintensity 1 N=26 ( 29.2%) Hyperintensity 2 N=13 ( 14.6%) Total N=89 (100.0%) Age (year ± SD)* Sex Male Female Systolic BP ** (mmHg ± SD) Diastolic BP (mmHg ± SD) Hypertension Yes No Smoking Yes No Smoking amount (Pack-year) Alcohol drinking Yes No Drinking amount (gram/day ± SD) Drinking days (/week ± SD) BMI (kg/m2 ± SD) SDS score (± SD) BEPSI score (± SD) ± ( 52.0%) 24 ( 48.0%) ± ± ( 28.0%) 36 ( 72.0%) 19 (38.0 %) 31 (62.0%) 4.76 ± ( 52.0%) 24 ( 48.0%) ± ± ± ± ± ± ( 50.0%) ± ± ( 42.3%) 15 ( 57.7%) 10 (38.5%) 16 (61.5%) 7.45 ± ( 57.7%) 11 ( 42.3%) ± ± ± ± ± ± ( 38.5%) 8 ( 61.5%) ± ± ( 38.5 %) 8 ( 61.5%) 4 ( 30.8%) 9 ( 69.2%) 6.10 ± ( 38.5%) 8 ( 61.5%) 6.43 ± ± ± ± ± ± ( 49.4%) 45 ( 50.6%) ± ± ( 33.7%) 59 ( 66.3%) 33 ( 37.1%) 56 ( 62.9%) 5.72 ± ( 51.6%) 43 ( 48.4%) ± ± ± ± ± 2.54

Silent Infarct & Risk of Dementia

Silent Infarct & Risk of Dementia

Silent stroke (> 5 mm) 83% among 104 geriatric depression patients in Japan, late onset depression (Fujikawa, 1993) In white population (N=203) ; silent stoke – 23% (65 yr >) Silent Infarct & Depression

Age [Psychiatric symptoms] Major depression [Pre-stroke depression] Major depression [Post-stroke depression] Dementia Stroke Silent cerebral infarction Risk factors (hypertension, DM, etc.)

 Leukoencephalopathy ; frequent finding in geriatric depression  Arteriola ectasia ; enlargement of perivascular spaces  Arteriosclerotic changes perforating arteries, or demyelinations  Small infarct (5 mm >) periventricular, deep white matter subcortical gray matter best related with mood disorder Hyperintensities in MRI

Subcortical white matter or basal ganglia hyperintensities (silent cerebral infarct) => normal aging => greater severity of late onset depression => loss of interest (apathy) => psychomotor retardation => poor response to antidepressant => increased delirium Clinical correlations of neuroimaging changes

Correlates of depression in stroke patients Risk factor Depressive group N=48(69.6%) Control group N=21(30.4%) logistic regression model aOR 1) 95%CI Age group(yrs) 1) <65 ≥ (71.0) 26 (68.4 ) 9 (29.0) 12 (31.6) Sex 2) male female 30 (69.8) 18 (69.2) 13 (30.2) 8 (30.8) PVH (36.4) 3 (100) 21 (67.7) 20 (83.3) 7 (63.6) 0 (0.0) 10 (32.3) 4 (16.7) ** DWMH (42.9) 12 (80.0) 15 (78.9) 15 (71.4) 8 (57.1) 3 (20.0) 4 (21.1) 6 (28.6) * 5.83 * Barthel’s index >?90 <90 8(50.0) 37(75.5) 8(50.0) 12(24.5) * Psychiatric Investigation 1: 44-49, 2004

Correlates of quality of life in stroke patients Risk factor Low QOL group N=33(47.8%) Control QOL group N=36(52.2%) logistic regression model aOR 1) 95%CI PVH (27.3) 1 (33.3) 15 (48.4) 14 (58.3) 8 (72.7) 2 (66.7) 16 (51.6) 10 (41.7) DWMH (50.0) 4 (26.7) 12 (63.2) 10 (47.6) 7 (50.0) 11 (73.3) 7 (36.8) 11 (52.4) SGMH * 4 (30.8) 1 (9.1) 16 (57.1) 12 (70.6) 6 (69.2) 10 (90.9) 12 (42.9) 5 (29.4) ** P < 0.01, * P < 0.05 J. of the Neurological Sciences 224: 37-41, 2004

SCI (hyperintensity) Depression Dementia (o) ?

Poststroke depression Arteriosclerotic depression (Krishnan, 1995) Vascular depression (Alexopoulos, Krishnan 1997) => Clinical defined VD - vascular score => MRI defined VD - hyperintensity Emerging Concept of VD

A. Major depression B1. Clinical evidence stroke, TIA, focal neurologic sx B2. Neuroimaging findings white or gray matter hyperintensity B3. Cognitive impairment memory, execute function, attention retarded information processing Proposed criteria for vascular depression subtype (1)

Supporting findings 1) Depression onset after 50 or change in the course of depression 2) Marked loss of interest or pleasure 3) Psychomotor retardation 4) Lack of family history of mood dis. 5) Marked disability in daily living Proposed criteria for vascular depression subtype (2)

Anatomical Model for Depression

 Prevention of GD by reducing risk factors for CVD  Minimizing of progression of VD anti-hypertensive, anti-hypercholesterolemia, anti-platelet agent RIMA, SSRI, SNRI D2 agonist Nimodipine augmentation  New therapeutic agent Implication in the treatments of vascular depression

 Pshchosocial factor in the etiology ; exclude the contribution of genetic, nonvascular biological, and psychosocial factors  Need of subtyping in VD PSD (type I), subcortical white matter lesion (II), multiple silent infact or combination (III)  Exclusion criteria : dementia, parkinsonism, apathetic syndrome Some limitation in the concept of vascular depression