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The real pathology
of Depression
Dr André F Joubert MB,ChB; M.Med(Psych); D.Med Cape Town, South Africa Copenhagen, Denmark
Depression hypothesis
Joubert In preparation
Depression hypothesis
Joubert In preparation
Depression hypothesis
Joubert In preparation
Depression hypothesis
Joubert In preparation
Tryptophan depletion
•
Depression hypothesis
Joubert In preparation
Tryptophan depletion
• •
Depression hypothesis
Joubert In preparation
Tryptophan depletion
• • • • • •
BDNF promoting Synaptogenesis leading to hippocampal volume & receptor increases
Antidepressant effects on plasma BDNF
• BDNF is hypothesised as being a key factor in neuroplasticity • This study evaluated the pre- and post-treatment levels of BDNF in
a group of depressed patients (n=20) and compared them with healthy controls (n=20)
• All were treated with escitalopram 10 mg/day over 6 weeks
Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256–1260
Anxiety and depression – the controversy
• The links between depression and anxiety are complex and difficult to untangle
• Researchers, from as early as the 1920s, have been classified into two opposing groups
Van Praag 1960; Montgomery 1990
'Lumpers' 'Splitters'
One disorder Two discrete disorders
Cumulative age of onset curves of depressive and anxiety disorders
Cumulative hazard rate (%)
0
5
10
15
20
25
30
35
0 10 20 30 40 50 60
Age of onset (years) NCS data
Depression Anxiety
Wittchen et al. Psychol Med 1998
Proportion of individuals having one or more comorbid disorders
Proportion of anxiety disorders that are pure, comorbid with one, two, and three or more other anxiety disorders
Pure Comorbid 1 Comorbid 2 Comorbid 3+ Panic disorder
Agoraphobia
GAD
SAnD
Specific phobia
Phobia NOS
PTSD
OCD
24.6
31.0
43.6
49.0
63.2
48.0
34.1
32.4
36.7
21.9
23.5
26.6
26.8
35.3
21.1
31.5
13.3
24.3
13.0
12.6
12.0
17.5
13.4
23.5
22.7
21.0
11.8
27.0
23.0
0 10 20 30 40 50 60 70 80 90 100
6.6
Pure and comorbid (%)
Comorbid disorder
Wittchen et al. Psychol Med 1998
Comorbidity – which disorder comes first?
Which disorder comes first – GAD or others?
29.2
31.2
58.3
44.8
78.2
72.3
52.3
21.4
0 10 20 30 40 50 60 70 80 90 100
Major depression
Dysthymia
Panic disorder
Agoraphobia
Simple phobia
SAnD
Alcohol disorder
Drug disorder
Prior to GAD Same year Secondary to GAD
Comorbid disorder
Lifetime proportions (%)
Wittchen et al. Psychol Med 1998
Proportions (prevalence) of pure and depression-comorbid anxiety disorders among 14-17 years old: baseline
0,8
1,3
2,2
5,1
13
2,2
19
0,2
0,1
0,3
1
1,9
0,3
2,5
0% 20% 40% 60% 80% 100%
Panic Disorder
GAD
Agoraphobia
Social Phobia
Specific Phobia
Separation Anx
Any Anxiety
pure MD-comorbid
Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press
Anxiety Disorders 2 years later - How many are Pure, How many comorbid?
1
2,1
2,2
5,1
14,7
2,2
21,2
0,6
1,3
1
2,2
4,5
1,2
6,9
0% 20% 40% 60% 80% 100%
Panic disorder
GAD
Agoraphobia
Social phobia
Specific phobia
Separation anxiety
Any anxiety disorder
Pure Comorbid major depression
Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press
5 years later - How many anxiety disorders are still pure and how many comorbid?
0,8
1,5
1,7
4,4
14,3
1,6
17,5
1,6
3,2
2,7
5,3
10,9
2,7
17,7
0% 20% 40% 60% 80% 100%
Panic disorder
GAD
Agoraphobia
Social phobia
Specific phobia
Separation anxiety
Any anxiety
Pure Comorbid MD
Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press
Comorbidity Issues
• Independent symptoms
• Separate onset ?
• Separately attributal functional impairment
Joubert, In preparation
Separately attributable functional impairment
Depression GAD
Normal function
GAD with impaired function
GAD with Depression symptoms
GAD with Major Depression
Comorbidity Issues
• Independent symptoms
• Separate onset ?
• Separately attributal functional impairment
Joubert, In preparation
If these are criteria are not met:
“Lumping” of anxiety and depression
Anxiety and depression – the controversy
• The links between depression and anxiety are complex and difficult to untangle
• Researchers, from as early as the 1920s, have been classified into two opposing groups
Van Praag 1960; Montgomery 1990
'Lumpers' 'Splitters'
One disorder Two discrete disorders
Comorbidity Terminology
• Co-morbidity : life-time vs co-occuring
• Co-occurrence : at the same time
• Consequential : unitary syndromes of consequence
(Complication)
Joubert In preparation
Degeneration hypothesis
Psychological stress
Physical stress
Serotonin Serotonin receptors
Tryptophan
IL1β IL2 IL6 IL12 IFNγ TNFα
IL1Ra IL4 IL10 IL13 TGFβ
IDO
Kynurenine
Major Depression Myint and Kim, Medical Hypothesis, 2003
Quinolinate Kynurenate
HPA
Neurodegeneration Neuroprotection
A/Inflamm Inflamm
Degeneration hypothesis
Psychological stress
Physical stress
Serotonin Serotonin receptors
Tryptophan
IL1β IL2 IL6 IL12 IFNγ TNFα
IL1Ra IL4 IL10 IL13 TGFβ
IDO
Kynurenine
Major Depression Myint and Kim, Medical Hypothesis, 2003
Quinolinate Kynurenate
HPA
Neurodegeneration Neuroprotection
A/Inflamm Inflamm
Cumulative age of onset curves of depressive and anxiety disorders
Cumulative hazard rate (%)
0
5
10
15
20
25
30
35
0 10 20 30 40 50 60
Age of onset (years) NCS data
Depression Anxiety
Wittchen et al. Psychol Med 1998
Time depressed and hippocampal volume
Sheline et al. J Neurosci 1999; 19: 5034–5043
Time depressed (days)
Tota
l hip
poca
mpa
l vol
ume
(mm
3 )
4,800
4,300
3,800
3,300
2,800
5,800
5,300
4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 0
Antidepressants may help restore communication in depression
1. Manji HK, et al. Biol Psychiatry. 2003;53:707-742. 2. Nestler EJ, et al. Neuron. 2002;34:13-25.
Micrograph images reprinted with permission from Elsevier. Illustrations reprinted with permission from Cell Press
Dendritic sprouting in hippocampal pyramidal neurons
Micrograph1
Micrograph1
Depression Reduced
Post-treatment Increased
Graphic representation2
Graphic representation2
BDNF levels and HAM-D scores of depressed female patients and healthy female controls
Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256–1260
**p=0.002; ***p<0.001 (pre-treatment vs post-treatment; Wilcoxon signed ranks test) †p=0.010 (pre-treatment vs healthy controls; Mann–Whitney U-test) p=ns (post-treatment vs healthy control BDNF levels; Mann–Whitney U-test)
BD
NF
(ng/
ml)
05
1015202530354045 Mean BDNF (ng/ml) Mean HAM-D score 45
40 35 30 25 20 15 10 5 0
HA
M-D
score
**
***
†
Pre-treatment Post-treatment Healthy controls (n=20) Depressed patients (n=20)
The real pathology
of Depression
Dr André F Joubert MB,ChB; M.Med(Psych); D.Med Cape Town, South Africa Copenhagen, Denmark
Real antidepressant effect
Requirement of Hippocampal Neurogenesis for
the Behavioral Effects of Antidepressants Luca Santarelli, Michael Saxe, Cornelius Gross, Alexandre Surget,
Fortunato Battaglia, Stephanie Dulawa, Noelia Weisstaub, James Lee, Ronald Duman, Ottavio Arancio, Catherine Belzung, Rene Hen.
Science, August 2003 Joubert In preparation
5 years later - How many anxiety disorders are still pure and how many comorbid?
0,8
1,5
1,7
4,4
14,3
1,6
17,5
1,6
3,2
2,7
5,3
10,9
2,7
17,7
0% 20% 40% 60% 80% 100%
Panic disorder
GAD
Agoraphobia
Social phobia
Specific phobia
Separation anxiety
Any anxiety
Pure Comorbid MD
Proportion with pure and MD-comorbid anxiety Wittchen et al. Arch Gen Psychiatry In press
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry
2007
Joubert, In preparation
Brain cytokine (IL-1) levels
0
1
2
3
4
5
6
7
8
Normal mouse +injection of water
Normal mouse +peripheral infection
Dementia mouse +injection of water
Dementia mouse +peripheral infection
pg/m
l pro
tein
Combrinck et al. Neuroscience 2002; Cunningham et al. J Neurosci 2005
Brain Cell Death
1 1x 5x 10x
Mood symptoms Depression
Apathy Social Withdrawal
Anxiety Agitation
Body symptoms
Malaise Fatigue
Somnolence Decreased Appetite Sleep disturbance
Memory symptoms Concentration
Executive function Short term memory Psychomotor speed
The Spectrum of Symptoms in Alzheimer’s Disease
Mood symptoms Depression
Apathy Social Withdrawal
Anxiety Agitation
Body symptoms
Malaise Fatigue
Somnolence Decreased Appetite Sleep disturbance
Fever
Memory symptoms Concentration
Executive function Short term memory Psychomotor speed
The Spectrum of Sickness Behaviour
Hypothesis
• In Alzheimer’s disease systemic inflammation leads to an exaggerated brain cytokine response (with more sickness behaviour) causing the death of brain cells and increased cognitive decline
• Evidence • Animal models • Clinical studies
• anecdotal observations • the effects of systemic inflammation on clinical progression
in Alzheimer’s Disease cohorts
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry
2007
• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002
Joubert, In preparation
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry
2007
• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002
• Hypersecretion of cortisol reduces “synaptogenesis” Tripathi and Verma, Biochem Mol Biol 2003
• Accumulation of neurotoxic factors in depression and Alzheimer’s Disease similar Hock et al. Eur Neurol 1998
Joubert, In preparation
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry
2007
• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002
• Hypersecretion of cortisol reduces “synaptogenesis” Tripathi and Verma, Biochem Mol Biol 2003
• Accumulation of neurotoxic factors in depression and Alzheimer’s Disease similar Hock et al. Eur Neurol 1998
• Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett
2004
Joubert, In preparation
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry
2007
• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002
• Hypersecretion of cortisol reduces “synaptogenesis” Tripathi and Verma, Biochem Mol Biol 2003
• Accumulation of neurotoxic factors in depression and Alzheimer’s Disease similar Hock et al. Eur Neurol 1998
• Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett
2004
• Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007
Joubert, In preparation
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry
2007
• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002
• Hypersecretion of cortisol reduces “synaptogenesis” Tripathi and Verma, Biochem Mol Biol 2003
• Accumulation of neurotoxic factors in depression and Alzheimer’s Disease similar Hock et al. Eur Neurol 1998
• Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett
2004
• Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007
• Each depr episode increases dementia risk by 13% Kessing 2004 Joubert, In preparation
Kessing and Andersen, J Neurol, Neurosurg, Psychiatry, 2004.
Risk of dementia increases with the number of depression episodes
N Hazard ratio (95 % CI)
1 episode 15085 1 (ref.)
2 episodes 1324 1.00
3 episodes 735 2.89
4 episodes 459 2.70
> 5 episodes 983 6.16
Episodes 18586 1.13 (1.09 - 1.16)
“When the facts change, I change
my mind. What do you do,
sir?”
John Maynard Keynes
The Great Depression
Lost Prophets: An Insider's History of the Modern Economists (1994) Alfred L. Malabre
Anxiety is …..
• Prevalent • Predictable • Preventable • Predisposes other psychiatric disorders • Promises substance abuse
• Anxiety is the (psychiatry’s) new Black
Joubert In preparation
Tryptophan depletion
• • • • • •
BDNF promoting Synaptogenesis leading to hippocampal volume and receptor increases
Depression hypothesis
Degeneration hypothesis
Psychological stress
Physical stress
Serotonin Serotonin receptors
Tryptophan
IL1β IL2 IL6 IL12 IFNγ TNFα
IL1Ra IL4 IL10 IL13 TGFβ
IDO
Kynurenine
Major Depression Myint and Kim, Medical Hypothesis, 2003
Quinolinate Kynurenate
HPA
Neurodegeneration Neuroprotection
A/Inflamm Inflamm
Degeneration hypothesis
Psychological stress
Physical stress
Serotonin Serotonin receptors
Tryptophan
IL1β IL2 IL6 IL12 IFNγ TNFα
IL1Ra IL4 IL10 IL13 TGFβ
IDO
Kynurenine
Major Depression Myint and Kim, Medical Hypothesis, 2003
Quinolinate QA Kynurenate KA
HPA
Neurodegeneration Neuroprotection
A/Inflamm Inflamm
3-HK
5HT depletion during recovery from depression and anxiety
50%
100%
0 6 12 18 Months
SSRI Treatment Well
Relapse rates
after TD
Recovery due to other factors Growth factors Neurogenesis
NA / DA BDNF 5HT
dependent recovery
Nutt, Inst Mag, 2006
Time depressed and hippocampal volume
Sheline et al. J Neurosci 1999; 19: 5034–5043
Time depressed (days)
Tota
l hip
poca
mpa
l vol
ume
(mm
3 )
4,800
4,300
3,800
3,300
2,800
5,800
5,300
4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 0
Antidepressants and neuroplasticity
1. Manji HK, et al. Biol Psychiatry. 2003;53:707-742. 2. Nestler EJ, et al. Neuron. 2002;34:13-25.
Micrograph images reprinted with permission from Elsevier. Illustrations reprinted with permission from Cell Press
Dendritic arborization in hippocampal pyramidal neurons
Micrograph1
Micrograph1
Depression Reduced
Post-treatment Increased
Graphic representation2
Graphic representation2
Antidepressant effects on plasma BDNF
• BDNF is hypothesised as being a key factor in neuroplasticity • This study evaluated the pre- and post-treatment levels of BDNF in
a group of depressed patients (n=20) and compared them with healthy controls (n=20)
• All were treated with escitalopram 10 mg/day over 6 weeks
Aydemir et al. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1256–1260
DSM-5 proposal
The person was exposed to the following event(s): • death or threatened death, • actual or threatened serious physical injury • actual or threatened sexual violation in one or more of the following ways:
DSM-5 proposal
In one or more of the following ways: 1.Experiencing the event(s) him/herself 2.Witnessing the event(s) as they occurred to others 3.Learning that the event(s) occurred to a close relative
or close friend 4.Experiencing repeated or extreme exposure to
aversive details of the event(s) (e.g first responders to body parts; police officers repeatedly exposed to details of child abuse)
Depression and anxiety – the Zürich study
• The perception of depression and anxiety as separate illnesses disregards the evidence from epidemiological studies
• The Zürich study is one of the main sources of data in this area
Angst et al. 1990
Primary diagnosis minor depression
49% also suffer from major or
minor depression
60% also suffer from anxiety
disorders
36% also suffer from anxiety
disorders
Primary diagnosis major depression
Primary diagnosis anxiety
Results
Study
7.5% (6.5%)
5.6% (5.0%)
4.6% (1.3%)
ICD-10 anxiety and depression
Sartorius et al. 1996
Patients affected by anxiety
Patients affected by depression
(+ subthreshold anxiety) (+ subthreshold depression)
• Anxiety (total): 10.2% • Depression (total): 12.1%
Overlap and discrimination of GAD and depression
Anticipatory anxiety Nervous tension Muscular tension
Restlessness Tension pains
Physiological arousal
Apathy Retardation Withdrawal
Loss of interest Morning depression Poor concentration Self confidence ↓
Hopelessness
Fatigue Dysphoria Irritability
Sleep disturbance Appetite disturbance
Sensitivity (criticism)
GAD Depression
Nutt et al. 2002
Cumulative age of onset curves of depressive and anxiety disorders
Cumulative hazard rate (%)
0
5
10
15
20
25
30
35
0 10 20 30 40 50 60
Age of onset (years) NCS data
Depression Anxiety
Wittchen et al. Psychol Med 1998
Proportion of individuals having one or more comorbid disorders Proportion of anxiety disorders that are pure, comorbid with one, two, and three or more other anxiety disorders
Pure Comorbid 1 Comorbid 2 Comorbid 3+ Panic disorder
Agoraphobia
GAD
SAnD
Specific phobia
Phobia NOS
PTSD
OCD
24.6
31.0
43.6
49.0
63.2
48.0
34.1
32.4
36.7
21.9
23.5
26.6
26.8
35.3
21.1
31.5
13.3
24.3
13.0
12.6
12.0
17.5
13.4
23.5
22.7
21.0
11.8
27.0
23.0
0 10 20 30 40 50 60 70 80 90 100
6.6
Pure and comorbid (%)
Comorbid disorder
Wittchen et al. Psychol Med 1998
Comorbidity – which disorder comes first?
Which disorder comes first – GAD or others?
29.2
31.2
58.3
44.8
78.2
72.3
52.3
21.4
0 10 20 30 40 50 60 70 80 90 100
Major depression
Dysthymia
Panic disorder
Agoraphobia
Simple phobia
SAnD
Alcohol disorder
Drug disorder
Prior to GAD Same year Secondary to GAD
Comorbid disorder
Lifetime proportions (%)
Wittchen et al. Psychol Med 1998
Separately attributable functional impairment
Depression GAD
Normal function
GAD with impaired function
GAD with Depression symptoms
GAD with Major Depression
Comorbidity Issues
• Independent symptoms
• Separate onset ?
• Separately attributal functional impairment
Joubert, In preparation
If these are criteria are not met:
“Lumping” of anxiety and depression
Comorbidity Terminology
• Co-morbidity : life-time vs co-occuring
• Co-occurrence : at the same time
• Consequential : unitary syndromes of consequence
(Complication)
Joubert In preparation
Untreated anxiety leads to depression
• Chronic stress model • Hypersecretion of cortisol blocks proteien synthesis - leading to decreased synaptogenesis (neuroplasticity)
Tripathi and Verma, Biochem Mol Biol 2003
• Hypercortisolemia blocks glucose activity in the brain Tripathi and Verma, Biochem Mol Biol 2003
• Wittchen’s epidemiological data Wittchen et al. Arch Gen Psychiatry In press
Joubert, In preparation
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol
Psychiatry 2007
Joubert, In preparation
0,
2,
4,
6,
8,
Normal mouse + injection of water
Normal mouse + peripheral infection
Dementia mouse + injection of water
Dementia mouse + peripheral infection
pg/m
l pro
tein
Brain cytokine (IL-1) levels
Combrinck et al. Neuroscience 2002; Cunningham et al. J Neurosci 2005
Brain Cell Death
1 1x 5x 10x
Mood symptoms Depression
Apathy Social Withdrawal
Anxiety Agitation
Body symptoms Malaise Fatigue
Somnolence Decreased Appetite Sleep disturbance
Memory symptoms Concentration
Executive function Short term memory Psychomotor speed
The Spectrum of Symptoms in Alzheimer’s Disease
Mood symptoms Depression
Apathy Social Withdrawal
Anxiety Agitation
Body symptoms Malaise Fatigue
Somnolence Decreased Appetite Sleep disturbance
Fever
Memory symptoms Concentration
Executive function Short term memory Psychomotor speed
The Spectrum of Sickness Behaviour
Untreated depression leads to dementia
• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol
Psychiatry 2007
• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002
• Hypersecretion of cortisol reduces “synaptogenesis” Tripathi and Verma, Biochem Mol
Biol 2003
• Accumulation of neurotoxic factors in depression and Alzheimer’s Disease similar Hock et al. Eur Neurol 1998
• Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett 2004
• Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007
• Each depr episode increases dementia risk by 13% Kessing 2004
Joubert, In preparation
Kessing and Andersen, J Neurol, Neurosurg, Psychiatry, 2004.
Risk of dementia increases with the number of depression episodes
N Hazard ratio (95 % CI)
1 episode 15085 1 (ref.)
2 episodes 1324 1.00
3 episodes 735 2.89
4 episodes 459 2.70
> 5 episodes 983 6.16
Episodes 18586 1.13 (1.09 - 1.16)
The real pathology
of Depression
Dr André F Joubert MB,ChB; M.Med(Psych); D.Med Cape Town, South Africa Copenhagen, Denmark
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