1.
Depression: the brain, the mind,
the family, and work
Pierre Blier, MD, Ph.D
Endowed Chair and Director
Mood Disorders Research
Institute of Mental Health Research
University of Ottawa, Ontario
Canada Research Chair, Psychopharmacology

2.
Global burden of diseases-World Health Organization
DALYs: disability adjusted life years; WHO 2008 report

3.
Global burden of diseases-World Health Organization
DALYs: disability adjusted life years; WHO 2008 report

4.
Global burden of diseases-World Health Organization
+50%
+30%
DALYs: disability adjusted life years; WHO 2008 report

5.
Mortality and severe mental illness
 >15,000 patients with bipolar disorder diagnosis studied (Sweden)1
 Standardized mortality ratio (all causes) in bipolar patients was 2.5
for males, 2.7 for females (values >1.0 indicate greater risk than
general population)
 Most frequent cause of death for bipolar patients
•
Cardiovascular disease: 31%
•
Suicide: 19%
•
Cancer: 14%
 Patients with severe schizophrenia, bipolar disorder, and
depression lose 25 or more years of life expectancy, with most of
the premature deaths due to cardiovascular disease2, 3,4
1. Osby et al. Arch Gen Psychiatry 2001;58:844-850.
2. Angst et al. J Affect Disord 2002;68:167-181.
3. Newcomer and Hennekens. JAMA 2007;298:1794-1796.
4. Colton and Manderscheid. Prev Chronic Dis 2006;3:A42.

6.
Depression worsens outcome of
many medical conditions
 Depression worsens morbidity and mortality after myocardial
infarction1,2
 Depression increases morbidity and mortality in patients with
congestive heart failure3,4
 Depression increases risk of mortality in patients
in nursing homes5
 Depression worsens morbidity post-stroke6
 Depression may worsen outcomes of cancer,
diabetes, AIDS, and other disorders7
1. Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.
2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58:221227.
3. Jiang W, et al. Arch Intern Med. 2001;161:1849-1856.
4. Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205.
5. Rovner BW, et al. JAMA. 1991;265:993-996.
6. Pohjasvaara T, et al. Eur J Neurol. 2001;8:315-319.
7. Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl
1):80-84.

7.
Depression Has an Impact on Mean Health Scores
More Than Other Chronic Conditions
“Depression had the largest effect on worsening mean health scores”
100
*p<0.0001
p<0.01
N=245,404
†
90.6 = No chronic condition
90
80
*
1
1
80
*
2
1
3
1
80
79
*
70
60
*
4
1
*
1
79
73
Depression only
†
†
†
1
2
3
65
66
67
†
4
59
Conditions
1.Asthma
2.Angina
3.Arthritis
4.Diabetes
0
One Chronic Condition
Depression +
One Chronic Condition
*Depressed respondents had lowest mean score among all chronic conditions (p<0.0001).
†
Depressed respondents with another chronic condition had lower mean health scores than
respondents with the chronic condition alone (p<0.01).
Moussavi et al. Lancet 2007;370(9590):851-58.

8.
DEPRES-STUDY
78,463 ADULTS
I
I
5,414 (6.9%)
MAJOR DEPRESSIVES
100%
31%
28%
24%
5%
NO CONSULTATION
NO DRUG TREATMENT
NON-ANTIDEPRESSANT DRUG
INADEQUATE DOSE OF AN
ANTIDEPRESSANT DRUG
12%
ADEQUATE DOSE OF AN
ANTIDEPRESSANT DRUG
INT. CLIN. PSYCHOPHARMACOL. 12 : 19, 1997

9.
Only one patient in three fully
recovers after a first medication trial
Antidepressant Effects After 6-8 Weeks
Partial Response
33%
Full Remission
33%
33%
No response
Kennedy et al, Human Psychopharmacology 2001

10.
Residual Symptoms Following Acute
Remission of Depression
Percentage of Subjects
50
Threshold
38%
40
30
Subthreshold
44%
28%
20
10
0
Mood Diminished Weight
Sleep
PsychoDisturbance motor
Pleasure or
Interest
Fatigue
Guilt
Concentration
Symptoms of Depression
Nierenberg AA, Keefe BR, Leslie VC, et al. J Clin Psychiatry. 1999(Apr);60(4):221-225
© 2009 Canadian Psychiatric Association. All rights reserved.
(N=215)
Suicidal
Ideation

11.
The many faces of major depression
DSM-IV criteria
35 y.o. female
+ Depressed mood
+ Hypersomnia
+ Increased appetite/weight
+ Psychomotor retardation
+ No energy
+ Suicidal ideation
70 y.o. male
- Marked loss of interest/pleasure
- Insomnia
- Decreased appetite/weight
- Psychomotor agitation
- Impaired concentration/decision
- Inappropriate guilt

12.
Evidence of Hippocampal Atrophy
and Loss in MDD Patients
 Compared to controls,
patients with depression
had smaller hippocampal
volumes1
Images reprinted with permission of JD Bremner.
1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118.
2. Sheline YI, et al. J Neurosci. 1999;19:5034-5043.
3. Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93:3908-3913.
4. Sheline YI, et al. Am J Psychiatry. 2003;160:1516-1518.
 Decreased hippocampal
volume may be related to
the duration of depression2-4

13.
Hippocampal Volumes Are Decreased In Depressed Patients with
Multiple Episodes (ME)but Not In The First Episode (FE)
4000
Control
FE
Control
3500
3500
3000
3000
2500
2500
2000
2000
1500
1500
1000
FE
1000
Right
Left
3500
3500
3000
3000
2500
2500
2000
2000
1500
1500
1000
1000
Control
MacQueen et al, PNAS, 2003
ME
Control
ME

14.
Alteration of Brain Volume in Depression
Phillips et al, J Clin Psychiiatry 2012

15.
Antidepressants and Neurotrophic Factors May Help
Restore Communication in Depression
Normal
Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Depressed
Treated
Reprinted with permission from Elsevier.

16.
Functional Overlap Between Aminergic
Systems: Features of Depression
NE
5-HT
Energy
Interest
Anxiety
Irritability
Impulsivity
Mood, emotion,
cognitive function
Motivation
Drive
Dopamine
Sex
Appetite
Aggression

17.
Functional
connectivity
5-HT2A for NE neurons
5-HT2C for DA neurons

18.
LOCUS
COERULEUS
5-H
T
(+)
5-HT
(-)
RAPHE
α2
(-)
SSRI?
5-HT
α 1 α2
(-)
1
α
T 1A
-H
5
(-)
POSTSYNAPTIC
NEURON
(-)
5-HT
β1
(+)
α
2
(-)
α
2
1A
HT
5-

19.
SSRIs decrease NE transmission
(Szabo and Blier, 2000; Kawahara et al, 2007)
Normal
: Norepinephrine (NE)
Long-term treatment with a SSRI
Amygdala
Locus coeruleus
9
2
*
1
0
90
Cont
54
Citalopram
Fmoles/sample
Spikes/sec
3
6
3
0
*
Cont Citalopram

20.
Reciprocal interactions between
monoaminergic neurons
DOPAMINE
D2 (-)
?
(-) 5-HT 2A
5-HT1A
(-)
5-HT
α
)
1(+
NE
α 1 (+)
-)
α2 (

21.
Inhibitory Effect of Escitalopram
(X 14 days) on VTA Dopamine Neuronal Firing
Control (11 cells/6 rats)
10
Escitalopram (22 cells/5 rats)
9
8
7
6
5
*
*
*
3
*
4
2
1
0
Rate (Hz)
Bursts/10 sec
Spikes/Bursts
% Spikes Occurring
in Bursts (x10)
Dremencov et al, J Psychiat Neurosci 2009

22.
Reciprocal interactions between
monoaminergic neurons
DOPAMINE
D2 (-)
(-) 5-HT 2C
(-) 5-HT 2A
5-HT1A
(-)
5-HT
α1
NE
α 1 (+)
-)
α2 (

23.
Atypical Antipsychotic Medication:
Meta-analysis of Response Rates
Odds Ratios of Response Rates With Atypical and Placebo
Trials Nested by Drug
Olanzapine trials
Shelton 2001
Shelton II 2005
Corya 2006
Thase 2006
Thase II 2006
OR (Fixed) 95% CI
Subtotal
1.83 [1.18, 2.82]; Z=2.71, p=0.007
Subtotal
1.61 [1.24, 2.09]; Z=3.56, p=0.0004
Subtotal
Quetiapine trials
1.39 [1.05, 1.84]; Z=2.30, p=0.02
Subtotal
Risperidone trials
Mahmoud 2007
Keitner 2009
Reeves 2008
2.07 [1.58, 2.72]; Z=5.28, p=0.00001
Khullar 2006
Mattingly 2006
McIntyre 2006
Earley 2007
El-Khalili 2008
Aripiprazole studies
Berman 2007
Marcus 2008
Berman 2008
1.69 [1.46, 1.95]; Z = 7.00, p< 0.00001
Test for overall effect:
0.1 0.2 0.5 1
Favors Control
Nelson JC and Papakostas GI Am J Psychiatry, 2009
2
5 10
Favors Treatment
Double-blind, placebo-controlled add on trials

24.
Acute Study Design
Depressed Patients With Unipolar Major Depression
Washout
+
Screening
Day Day
0
-7
Day
7
Day
14
Day
21
Day
42
Fluoxetine 20
+
Placebo
Fluoxetine 20
+
Mirtazapine
30
Venlafaxine 75 Venlafaxine 150 Venlafaxine 225
+
+
+
Mirtazapine 30 Mirtazapine 30 Mirtazapine 30
Bupropion 150
+
Mirtazapine 30
Blier et al, Am J Psychiat 167:281-8,2010

25.
Effectiveness of drug combinations
Fluoxetine (n = 28)
HAMD 17 scores (+ SEM)
25
Fluoxetine + Mirtazapine (n = 25)
Bupropion + Mirtazapine (n = 26)
Venlafaxine + Mirtazapine (n = 26)
20
15
10
*
5
0
1
4 7 10 14
21
28
35
42
Day of treatment
* P = 0.011 when comparing the combination groups with fluoxetine
Blier et al, Am J Psychiat 167:281-8,2010

26.
Remitters
Hamilton-17 Depression Score ≤ 7
Fluoxetine
(7/28)
25%
Fluoxetine + mirtazapine (13/25)
52%*
Bupropion + mirtazapine (12/26)
46%
Venlafaxine + mirtazapine (15/26)
58%*
Blier et al, Am J Psychiat 167:281-8,2010

27.
Actual Dropouts
Treatment groups
Causes
Fluoxetine Fluoxetine Bupropion Venlafaxine
+ Mirtazap + Mirtazap + Mirtazap
Adverse events
XX
X
X
Lack of efficacy
XX
X
X
Lost to follow up
X
X
XX
XXX
4/26
(15%)
3/26
(12%)
Protocol violation
Total: 16/105
(15%)
X
5/28
(18%)
4/25
(16%)

28.
Remission rates in monotherapy vs
combination from treatment initiation
Patients (%) achieving
remission
100
75
50
25
49
45
SSRI
Mirtazapine
SSRI
20-30 mg
0.0
21
30 mg
20-30 mg*
Blier et al, Eur Neuropsychopharmacol 2009
Blier et al, Am J Psychiat 2010; * Paroxetine 20-30, Fluoxetine 20
25
25
Bupropion Venlafaxine
150 mg
225 mg
+ Mirtazapine 30 mg

29.
Remitters
Hamilton-17 Depression Score ≤ 7
(N=88)
Dropouts*
1 site
Escitalopram (mean: 35 mg/day)
42%
3/31
Bupropion
28%
6/28
52%
3/29
(mean: 375 mg/day)
Combination (mean: 33/380)
*Mean dropout rate: 13%

30.
Antidepressants modulate interconnected
signaling cascades
(-)
(-)
Adapted from: Charney DS, et al. Science STKE. 2004;225 re5:1-10.
(-)

31.
Rapid Antidepressant of Ketamine (iv)
Zarate et al. Arch Gen Psychiat 63: 856-63, 2006

32.
Rapid Antidepressant of Ketamine (iv)
Zarate et al. Arch Gen Psychiat 63: 856-63, 2006

33.
Attenuation of suicidal ideation by ketamine
Price et al, Biol Psychiat 66:522-6,2009

34.
Our experience with ketamine
 Monitoring of pulse, EKG, blood pressure, and
EKG, and O2 saturation
 230 infusions in 16 patients taking antidepressants
 6 remitters, 5 responders, 5 non-responders
 Duration of action: starting from 60 minutes to 12
hours, for a total time of 24 hours to 3 weeks
 0.5 mg/kg, iv/40 min > 0.2 mg/kg, iv/bolus
 Marked anti-suicidal ideation effect
 No evidence of neurotoxicity or dependence
* Blier, Zigman & Blier, Biological Psychiatry 2013

35.
A case of remission
 37 y.o. female, married, 4 kids, works as teacher
 Physical History: not contributory
 Psychiatric History
• 2 episodes of depression
• Paroxetine 30 mg w/ response
Zigman & Blier, J Clin Psychopharmacol 2013

36.
Current episode
 Relapse in Dec 2009, no trigger
 Feb 2010 – Venlafaxine up to 300 mg, no response
 Nov 2010 - Started NIH study, MADRS 39
• Up to Escitalopram 40 mg + bupropion XL 450 mg
 Mar 2011 – End of phase 1 (12 weeks), MADRS 36
 Mar 2011 – Suicide attempt by overdose

37.
Current Episode
 Mar -> Sept 2011
• Trials of Duloxetine + Quetiapine XR, Duloxetine +
Aripiprazole, Duloxetine + Risperidone
• Persistent moderate to severe depressive symptoms
 Oct 2011
• Lithium added to Duloxetine + Risperidone
• “I feel better than I have in 2 years”
 Nov 2011 – Feb 2012
• Relapsed after 1 month
• Lithium restarted, Duloxetine switched to Moclobemide
• Persistent moderate depressive symptoms

38.
Current Episode
 Feb 2012 –
• Lithium tapered to discontinuation because of loss of
benefits
 Patient presents to office 2 weeks later in severe
distress, intense suicidal ideation, MADRS 48
 Offered admission + ECT or trial of ketamine

39.
Ketamine infusion #1
 Given 0.5 mg / kg ketamine over 40 min
 Reported feeling “numb”, “dopy” and “as if floating”
 No psychotic symptoms
 Subjectively:
Pre
Post (60min)
Dysphoria
10/10
3/10
Anxiety
8/10
0/10
Suicidal ideation
9/10
0/10

40.
Ketamine infusion # 2
 Relapsed after 2 weeks
 Given 0.5 mg / kg ketamine over 40 min
 Subjectively:
Pre
Post (60min)
Dysphoria
10/10
1/10
Anxiety
7/10
0/10
Suicidal ideation
3/10
0/10

41.
Follow up and Medications
 Patient had a third ketamine infusion with the same
response as the first two
 Sustained remission in the Fall of 2012
• Nortriptyline 125 mg/day
• Lithium 600 mg/day
• Vyvanse 20 mg/day
 Partial relapse in January 2013
• Nortriptyline switched to Anafranil 75 mg/day
• Return to normal within a few days

42.
Take home messages
 We all have a role to play in decreasing the stigma of
depression to get people in treatment
 Depression must be treated aggressively because it
worsens all other medical disorders and shrinks the brain
 In most cases, depression does not take months to bring
to remission because there are efficacious treatments
 There are new treatments on the horizon