The real pathology of Depression - EFPT Porto 2015€¦ · Anxiety and depression – the controversy • The links between depression and anxiety are complex and difficult to untangle

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







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


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 (%)


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


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


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





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)


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



Physical stress


Tryptophan



IDO

Kynurenine



HPA


A/Inflamm Inflamm



0

5

10

15

20

25

30

35

0 10 20 30 40 50 60


Depression Anxiety


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


BDNF levels and HAM-D scores of depressed female patients and healthy female controls


**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


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


Untreated depression leads to dementia

• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol Psychiatry

2007


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



Anxiety Agitation

Body symptoms

Malaise Fatigue


Fever



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



2007

• Antidepressants decrease inflammatory CNS diseases Vollmar et al. Int J Neuropsychopharm 2008; Kenis and Maes, Int J Neuropsychopharm 2002




2007


• 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




2007




• Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett

2004




2007





2004

• Serotonin antidepressants reduce ß-amyloid and tau pathologies Pakaski et al. Neurochen Int 2005; Nelson et al. Exp Neurol 2007




2007





2004


• 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



• • • • • •

BDNF promoting Synaptogenesis leading to hippocampal volume and receptor increases




Physical stress


Tryptophan



IDO

Kynurenine



HPA


A/Inflamm Inflamm



Physical stress


Tryptophan



IDO

Kynurenine


Quinolinate QA Kynurenate KA

HPA


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



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


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



0

5

10

15

20

25

30

35

0 10 20 30 40 50 60


Depression Anxiety


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


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 (%)


Separately attributable functional impairment

Depression GAD

Normal function

GAD with impaired function

GAD with Depression symptoms

GAD with Major Depression

Comorbidity Issues





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)


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



• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol

Psychiatry 2007


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



Anxiety Agitation

Body symptoms Malaise Fatigue




The Spectrum of Symptoms in Alzheimer’s Disease



Anxiety Agitation

Body symptoms Malaise Fatigue


Fever



The Spectrum of Sickness Behaviour


• Increase in pro-inflammatory cytokines in the brain Kim et al. Prog Neuropsychopharmacol Biol

Psychiatry 2007


• Hypersecretion of cortisol reduces “synaptogenesis” Tripathi and Verma, Biochem Mol

Biol 2003


• Chronic 5HT dysfunction increases the synthesis of ß-amyloid Steurenburg et al. Neuro Endocrinol Lett 2004


• Each depr episode increases dementia risk by 13% Kessing 2004


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


Documents

The real pathology of Depression - EFPT Porto 2015€¦ · Anxiety and depression – the controversy • The links between depression and anxiety are complex and difficult to untangle