Download Due to our conception of depression in AD?

Depression in AD and other dementias
Knut Engedal, Professor of Geriatric Psychiatry.
Norwegian Centre of Ageing and Health
Oslo University Hospital, Ullevaal, Oslo, Norway
Significant BPSD in demented NH patients (NPI)
%
Selbaek, Kirkevold, Engedal. Int J Geriatr Psychiatry, 2007; 23(9): 843-9
Major and Minor depression in AD referred
to specialist practices
Ballard et al, 1996 (n=124)
Lyketsos et al, 1997 (n=109)
Starkstein et al, 2005 (n=670)
Major
25 %
22 %
26 %
Minor
27.4 %
27 %
26 %
Early onset cases
Rosness et al, 2009
10 %
56 %
(submitted)
(n=221)
Depression – 1 •year follow-up of 546 NH patients (Cornell 7+)
12 months
Yes
Baseline
No
Yes
52 (9.5/44.8%)
Persistence
64 (11.7 %)
116 (21,2 %)
Prevalence at
baseline
No
64 (11,7 %)
Incidence
382
430
116 (21.2 %)
Prevalence at
12 months
430
546
Barca, Engedal, Laks, Selbaek. J Affective Disorders, 2009, Epub
Incidence and persistency of depression in AD
Incidence
 6 -12 months
6-18 %
Persistency
 6-12 months
30-50%
Lyketsos CG and Olin J. Biol Psychiatry 2002; 52: 243-52
Consequences of depression in AD
 Greater impairment in quality of life (Gonzales-Salvador et al, 2002)
 Greater impairment in ADL (Lyketsos et al, 1997, Starkstein et al, 2005, Lenze
et al. 2005 and several more studies)
 Earlier entry into residential care (Steele et al 1990)
 Increase in mortality, especially in early phase of dementia (Hoch et
al, 1993; Engedal 1996, Suh et al, 2004, Barca et al, 2009)
 Greater burden on carers (Gonzales- Salvador, 2002, Rosness, 2009)
Why high persistence rate and poor prognosis?
Due to treatment factors
 Not treated
 Treated with drugs with too low dosages?
 Drugs not effective?
Due to our conception of depression in AD?
 Diagnostic criteria
 Typical symptoms
 Heterogeneity
 Psychological or biological factors
 Similarities and interaction between depression and AD
Cochrane Database
 Seven studies were included:
 Fuchs 1993, Lyketsos 2003, Nyth 1992, Petracca 1996, Petracca 2001,
Reifler 1989 and Roth 1996.
 Results and conclusions:
 Weak evidence for effect.
 Significant fewer patients with side-effects in the placebo group.
 Lack of large scale good studies
Bains J et al. Issue 4, 2002
Why high persistence rate and poor prognosis?
Due to treatments
 Not treated
 Treated with drugs with too low dosages?
 Drugs not effective?
Due to our conception of depression in AD?
 Typical symptoms
 Heterogeneity
 Psychological or biological factors
 Similarities and interaction between depression and AD
Depression in AD
Different from that seen in non-demented subjects
More common ?
(motivational)
overlap with AD
symptoms?
Less common ?
(mood symptoms)
Lack of motivation
Anhedonia
Anxiety
Irritability
Agitation
Delusions
Hallucinations
Depressed mood
Guilt
Hopelessness
Suicidal behaviour
Rosenberg and Lyketsos
Depressive symptoms in AD patients compared to
depressed non demented patients – Different?
AD patients with depression (n=92) did not differ from
depressed patients (n=47) without dementia
Chemerinski et al,. Am J Psychiatry 2001; 158: 68-72
Depression in dementia (n=902) –Cornell scale symptoms
depressed mood less common?
Depressive symptoms by severity of dementia
%
Barca, Selbaek, Laks and Engedal, Int J Geriatr Psychiatry 2008; 23(10): 1058-65
Major vs minor depression in dementia
Loss of interest
Anxiety
Depressed mood
Irritability
Lack of mood reactivity
Agitation
Retardation
Lack of energy
RDC_ Major
depression
RDC_ Minor
depression
100 %
93.5 %
90.3 %
90.6 %
74.2 %
71 %
61.3 %
45.2 %
50 %
61.8 %
100 %
64.7 %
47.1 %
50.0 %
29.4 %
26.5 %
Ballard et al. J Affective Disorders 1996
‘Sad mood’ in Major and Minor depression by AD severity
Major depression
n=177
Mild dementia
Moderate dementia
Severe dementia
91%
90%
94%
Minor depression
n=177
75%
76%
44%
Starkstein et al, 2005; 162: 2086-93
Why high persistence rate and poor prognosis?
Due to treatments
 Not treated
 Treated with drugs with too low dosages?
 Drugs not effective?
Due to our conception of depression in AD?
 Typical symptoms
 Heterogeneity
 Various risk factors
 Psychological or biological factors
 Similarities and interaction between depression and AD
Risk factors of depression in AD
 Depression earlier in life
 18%
 30%
 26% in EO
(Agbayewa et al, JAGS 1986; 34: 561-84.
(Rovner et al, AJGP 1989; 146: 350-39)
(Rosness et al, IJGP 2009)
 Family history of depression (first degree)
 Poor physical health
 Female gender
 Marital Status
 ADL impairment/Dependency?
Cornell score by CDR and physical health
Mean Cornell sum in 902 patients in NH of whom 80 % have dementia
Physical Health
CDR
Good
Fairly Good
Poor/Very Poor
No dementia
2.3
3.1
5.7
Mild dementia
3.5
4.1
5.9
Moderate dementia
2.7
4.5
6.1
Severe dementia
3.8
6.3
7.7
Barca, Selbaek, Laks, Engedal. Int J Geriatr Psychiatry, 2009, 4:
Aetiology of depression in AD -mechanisms
Psychological explanation?
 High prevalence of depression in mild stage of dementia due to
insight of functional loss (ADL impairments, word finding
problems, social stress)
Biological explanation?
 High prevalence of depression in severe stage of dementia due to
structural damages
 Both?, than a bi-modal distribution
Severity of AD and depression - A systematic review
Associations between severity of AD and depressive symptoms
 19 studies
 No association
Associations between severity of AD and a depressive disorder
 7 studies
 No association
Verkaik, R. Int J Geriatr Psychiatry, 2007; 222: 1063-86
mild
moderate
severe
Depressive symptoms by dementia severity
Mean scores of Cornell sub scales (factor analysis) by CDR group, n=902
CDR 1
CDR 2
CDR 3
P value1
Cornell Sum 3.87
4.84
5.21
6.69
<0.001
Mood
1.53
1.83
1.66
1.98
0.326
Physical
0.48
0.68
0.69
1.33
<0.001
Cyclic
0.45
0.45
0.64
0.79
<0.001
Retardation
0.33
0.38
0.36
0.88
<0.001
Behavioural
0.57
0.73
0.93
1.40
<0.001
Scores
CDR<1
Barca, Selbaek, Laks, Engedal, Int J Geriatr Psychiatry 2008 ; 23: 1058-65
Aetiology of depression in AD -mechanisms
Psychological explanation?
 High prevalence of depression in mild stage of dementia due to insight of
functional loss (ADL impairments, word finding problems, social stress)
Biological explanation?
 High prevalence of depression in severe stage of dementia due to
structural damages
 Selective loss of noradrenergic neurons in loecus cerulus
 Selective loss of dopamiergic neurons in substantia nigra
 Selective loss of serotonergic neurons in dorsale raphe
 Damages of amygdala
Cell loss in AD brains and MD (in lifetime)
• Zweig et al, 1988




(n=25)
Zubenko et al, 1988
(n=14/37)
Förstl et al. 1992
(n= 14/52)
Hoogendijk et al, 1999 (n= 12/26)
Hendricksen et al, 2004(n = 7/14)
LC = Locus coeruleus (Noradrenergic)
SN = Substantia nigra (Dopamin)
DR = Dorsale raphe (Serotonin)
LC
Yes
Yes
Yes
No
-
SN
DR
Yes
No
-
No
Lewy bodies
Lewy bodies and MD in AD of mild to moderate degree
Score 1-2 = mostly brainstem
Score 3-6 = mostly limbic structures
Score 7-10= mostly neocortical structures (all positive cases also had LB in
amygdala)
Lopez et al. Neurology 2006; 67: 660-5.
Why high persistence rate and poor prognosis?
Due to treatments
 Not treated
 Treated with drugs with too low dosages?
 Drugs not effective?
Due to our conception of depression in dementia?
 Typical symptoms
 Heterogeneity
 Various risk factors
 Psychological or biological factors
 Similarities and interaction between depression and AD
Hippocampus atrophy
 Vascular factors
 Inflammatory processes
 AD pathology

Typical MTLA in AD
Reduced hippocampus volume in early and late
onset depression
Hickie et al. Br J Psychiatry 2005; 186: 197-202
Hippocampus atrophy in recurrent MD (n=10+10)
Sheline Y et al. Proc Natl Acad Sci 1996; 93: 3908-13
Hippocampus atrophy in recurrent MD
Sheline Y et al. Proc Natl Acad Sci 1996; 93: 3908-13
Depression, hippocampal volume and cognition in
elderly above 60 years of age
MD (DSM-IV; n=61) vs Controls (n=40)
Hippocampus volume, r
Hippocampus, volume, l
Whole brain volume
Salivary cortisol
Memory
Attention
Executive function
p< 0.04
p 0.23
p 0.75
p< 0.001
p< 0.001
p< 0.001
p< 0.001
Within the depressed subjects no correlation was found between
hippocampus volume and salivary cortisol level
O’Brien et al. Am J Psychiatry 2004; 161: 2081-90
Vascular factors
Cardiovascular factors and risk for depression
Almeida et al. Am J Geriatr Psychiatry 2007; 15: 506-13.
Risk factors for late onset depression
• Hypertension
• Diabetes
• Hyperhomocysteinemia
• Obesity
• Smoking
• Diet (omega 3 fatty acid)
• Lack of exercise
• Socioeconomic class
Risk factors for late onset AD
Very well established
 High age
 Genetic polymorphism (ApoE e4)
Established
 Hypertension
 Hypercholesterolemia
 Hyperhomocysteinemia
 Obesity
 Smoking
 Diet (3 omega fatty acid)
 Lack of exercise
 Lack of education/socioeconomic class
 Head injury
Late life depression and cytokines
Cytokines as chemical messengers between immune cells and
endothelial cells, playing a key role in mediating immune and
inflammatory responses which can lead to neurochemical (serotonin),
neuroendocrine (HPA axis) and behavioural effects (depression)
 The pro-inflammatory cytokines IL-6 (strongest), IL-1 beta, CRP
and TNF alpha are increased in depression (also in LO depression)
 The anti-inflammatory cytokines IL-4; IL-10 and IL-13 are
decreased in depressed patients, (uncertain in LO depression)
Craddock and Thomas . Essent Psychopharmacol 2006; 7(1): 42-52.
Plasma
cholesterol
Aging
Mitohondrial
dysfunction
APOE
Increased Ab
production
Ca++ homeostasis
Oxidative stress
Apoptosis
APP & presenilin
mutations
Tau protein
hyperphosphorylation
Synaptic damage
Neurodegeneration
Neurotransmitters’
deficits
Neuronal death
Micro- & astroglia
activation
Cognitive dysfunction
Inflammation
IL-6
(45 AD, 34 MCI patients and 28 Controls)
Bermejo et al. Immunology Letters 2008; 117: 198-202
TNF-alpha
Bermejo et al. Immunology Letters 2008; 117: 198-202
Inflammation in Depression and dementia/AD
Depression
Dementia/AD
Pro-inflammatory cytokines
IL-1
IL-6
TNF- alpha
IFN
+
+
+
+
+
+
+
+
Anti- inflammatory cytokines
IL-4
IL-10
-/?
-/?
?/?/-
Leonard B. Neurochem Res 2007; 32: 1749-56
Possible link between chronic depression and dementia
Leonard B. Neurochem Res 2007; 32: 1749-56
Conclusions and future directions.
 Depression in dementia is a heterogeneous condition that in about
50% of the cases is of chronic nature. Because of weak evidence for
treatment effect new studies (observational and treatment) should
be carried out with:
 Larger sample
 Alternative outcome as, “sadness +¨, and cluster of symptoms
 There is an overlap of symptoms, common risk factors, and common
biological findings in AD and depression. The mechanism behind
these common denominators should be further explored:
 Structural brain damages
 Vascular factors
 Inflammatory processes