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Transcript of Update on neurochemistry: Decision-making for …€¦ · Pierre Blier, MD, Ph.D Professor,...
Pierre Blier, MD, Ph.DProfessor, Psychiatry
and Cellular & Molecular Medicine
University of Ottawa
Endowed Chair and Director
Mood Disorders Research
Institute of Mental Health Research
Canada Research Chair, Psychopharmacology
Update on neurochemistry:
Decision-making for Clinicians
Objectives of the Presentation
Provide a summary of the mechanism of action of
antidepressant strategies on the serotonin system
Describe the functional connectivity between
monoaminergic systems from a clinical viewpoint
Emphasize target engagement when using
psychotropic agents
Describe the receptor profile of “atypical
antipsychotics” that makes them useful in MDD
normal
acute treatment with aSSRI (and SNRIs)
long-term treatment with aSSRI (and SNRIs)
5-HT transmission and 5-HT reuptake inhibition
Meyer et al, Am J Psychiatry 2004
Average occupancy of the 5-HTT transporter based on striatal binding
↑○↓SNRI
↑○↓○↓Bupropion*
↑○↓○↓Mirtazapine*
↑↑○○○ECS
↑↑↓○○Tricyclics
↑○n.d○↓5-HT1A
agonists
↑○ or ↓↓○↓MAOI
↑○○↓↓SSRI
Net effect net
on 5-HT
transmission
Postsynaptic
5-HT1A receptor
responsiveness
Terminal a2-
adrenoceptor
responsiveness
on 5-HT terminals
Terminal 5-HT1B
autoreceptor
responsiveness
Cell body 5-HT1A
autoreceptor
responsiveness
↓○
Vagus Nerve St* ○ n.d n.d ↑
*These treatments increase the firing rate of 5-HT neurons
Agomelatine* ○ n.d n.d ○ ↑
Blier et al, 1980-2013
○
Lamotriginen.d ↓ ○ ↑n.d
Treatments
The Serotonin (5-HT) System
Serotonin Syndrome:
• Increased heart rate & blood pressure
• Myoclonus, increased CPK
• Hyperthermia
• Abdominal cramps/diarrhea
• Increased tendon reflexes (+ve Babinski)
• Agitation and/or Confusion
• Death
MAO
X
X
Courtesy of ST Szabo, MD,PhD
Vortioxetine: pharmacological profile
SERT, serotonin transporter; 5-HT, serotonin
Uptake inhibitor Agonist Partial agonist Antagonist
5-HT1A
5-HT1B
5-HT1D
5-HT3
5-HT7
SERT
Vortioxetine
++
+
-
-
-
Stenkrona et al, Eur Neuropsychopharmacol 2013; Areberg et al, 2012
11C-MADAM binding
Dose-dependent occupancy of the 5-HT
transporter by Vortioxetine (LU AA21004)
Vortioxetine 5-10 mg
Vortioxetine ~20 mg
Sexual dysfunction, assessed
using the ASEX scale
No difference from placebo for 5
mg to 15 mg doses of vortioxetine2
Increase in TESD from
5 mg to 20 mg vortioxetine,
but there was no clear
dose–response relationship1
Vortioxetine 20 mg was
associated with an increase
in TESD (46%)1
Sexual dysfunction
TEAEs, treatment-emergent adverse events;
TESD, treatment-emergent sexual dysfunction;
ASEX, Arizona Sexual Experiences Scale
1. Vortioxetine EPAR;2. Vortioxetine Summary of
Product Characteristics, 2013
5 mg 10 mg 15 mg 20 mgPlacebo
Incid
en
ce
of T
ES
D b
ase
d o
n
AS
EX
sco
rin
g (
%)
Vortioxetine
60 mg
Duloxetine
Sexual dysfunction, reported as TEAEs during treatment with vortioxetine,
was low (1.6%) and similar to the placebo group (0.9%)1
40
60
80
100
0 2 4 6 8 10 12 14 16
Sym
pto
m s
eve
rity
Evolution of approximate 5-HT transporter occupancy with antidepressants
20
Days
VenlafaxineEscitalopram
Vortioxetine
Possibility of
discontinuation
problems
Fluoxetine
Ap
pro
xim
ate
oc
cu
pa
nc
y
of
the
5-H
TT
(%
)
Consider a crossover
of 2 weeks when
switching to Vortioxetine
(-)
(-) (-)
(+)
5-HT
5-HT
LOCUSCOERULEUS
RAPHE
POSTSYNAPTICNEURON
5-HT
1
SSRI?
Normal
Long-term treatment with a SSRI
SSRIs decrease NE transmission(Szabo and Blier, 2000; Kawahara et al, 2007)
Citalopram
Spik
es/s
ec
90 54
*
Cont
1
2
3
0
Locus coeruleus
: Norepinephrine (NE)
*Cont
Fm
ole
s/s
am
ple
Citalopram0
3
6
9
Amygdala
Decrease in CSF noradrenergic metabolite
by SSRIs (fluoxetine, fluvoxamine)
Sheline et al, J Clin Psychopharmacol 1997
N = 24
Functional Overlap Between Aminergic
Systems: Features of Depression
NE 5-HT
Dopamine
Mood, emotion,
cognitive function
Motivation
Sex
Appetite
Aggression
Anxiety
IrritabilityEnergy
InterestImpulsivity
Drive
Courtesy of S. Stahl
DA
(-)
(-) (-)
(+)
5-HT
5-HT
VENTRAL TEGMENTALAREA
RAPHE
POSTSYNAPTICNEURON
5-HT
2
SSRI?
Inhibitory Effect of Escitalopram
(X 14 days) on VTA Dopamine Neuronal Firing
Control10
9
8
7
6
5
4
3
2
1
0
Escitalopram
Rate (Hz) Bursts/10 sec Spikes/Bursts % Spikes Occurring
in Bursts (x10)
* *
* *
Dremencov et al, J Psychiat Neurosci 34:223-229, 2009
SSRIs Decrease Hedonic Tone
fMRI study of neural response in healthy participants to reward after 7 days of citalopram (20mg), reboxetine (4mg b.i.d) or placebo (n=15 per group)
Citalopram resulted in decreased neural response to the sight and taste of chocolate in the ventral striatum and orbitofrontal cortex (sight + taste) compared to placebo
Reboxetine had an enhanced response to the sight and taste of chocolate in the OFC compared to placebo
Suggests dampening of reward response with SSRIs
McCabe et al, 2010
Sight of Chocolate
Sight + Taste of
Chocolate
p<.001, Citalopram vs. Placebo
p=.05, Reboxetine vs. Placebo
Common Residual Symptoms Despite
Remission, or Iatrogenic Symptoms?
Fatigue (mental and physical)
Concentration
Decreased interest or pleasure
Cognitive impairment
Nutt D, et al. Journal of Psychopharmacology 2007; 21(5): 461-471.
Trivedi MH, Hollander E, Nutt D, Blier P. J Clin Psychiatry 2008; 69: 246-258.
Target engagement!!!
(-)
(-) (-)
(+)
5-HT
5-HT
RAPHE
POSTSYNAPTIC
NEURON
5-HT
1
LOCUS
COERULEUS
The SNRI myth!
Control Situation
NE
TYR
MAO
MHPG
NE Blood
Pressure
Timem
mof
Hg
0
50
100
150
200
Following NE Reuptake Blockade(nortriptyline, desipramine, reboxetine)
NE
TYR
MAO
MHPG
NE Blood
Pressure
Timem
mof
Hg
0
50
100
150
200
Venlafaxine?
Duloxetine?
Desvenlafaxine?X
-5
0
5
10
15
20
25
Nortriptyline
(50 mg BID)Placebo
6 6 4 6 65
Baseline
Day 7
Tyramine dose (mg i.v.)
3 4 6 3 4 6 3 4 6 3 4 6
*
Pressor response to tyramine in healthy volunteers
Gobbi et al, J Clin Psychopharmacol 2001
Sys
toli
c b
loo
d p
res
su
re c
ha
ng
e
(mm
Hg
)
NE Reuptake Inhibiting Action of Atomoxetine on NE Reuptake in Depressed Patients
Blier et al, Int J Neuropsychopharmacol 24 (Suppl 3): 143S, 2010
30
25
20
15
10
5
0
3 mg 4 mg 6 mg
Baseline 25 mg 43 mg 60 mg 80 mg
*
Similarities between the NE and the DA systems
(transporters and receptors)
Lack of Inhibitory Action of Paroxetine on NE Reuptake in Depressed Patients
Blier et al, Int J Neuropsychopharmacol 24 (Suppl 3): 143S, 2010
Baseline 20 mg 30 mg 40 mg 50 mg
3 mg 4 mg 6 mg
30
25
20
15
10
5
0
Dose-Dependent Inhibition of NE Reuptake by Venlafaxine in Depressed Patients
Blier et al, Int J Neuropsychopharmacol 24 (Suppl 3): 143S, 2010
*
ED30 = Dose of tyramine (iv) required to induce a 30 mm Hg increase in systolic BP
Debonnel et al, Int J Neuropsychopharmacol 2007
*
ED
30
Va
lue
s
(mg
of
Tyra
min
e ±
SE
M)
Day
Baseline 7 14
Low dose
High dose
4
0
6
8
10
21 28
75 mg/day
225 mg/day
375 mg/day
*
Pressor Response to Intravenous Tyramine
STAR*D Remission Rates at Treatment Exit
32.9(n = 943)
32.9(n = 94)
39.0(n = 108)
25.0
(n = 62)
25.5(n = 61)
26.6(n = 63) 24.7
(n = 18)
13.2
(n = 9)12.4
(n = 15)8.0
(n = 9)
15.7(n = 8) 13.8
(n = 8)
0
5
10
15
20
25
30
35
40
45
CIT
(n
= 2
87
6)
BU
S (
n =
28
6)
BU
P-S
R (
n =
27
9)
VE
N-X
R (
n=
25
0)
BU
P-S
R (
n =
23
9)
SE
RT
(n
= 2
38
)
T3
(n
= 7
3)
Li (n
= 6
9)
NT
P (
n =
12
1)
MIR
T (
n =
11
4)
VE
N-X
R +
MIR
T
(n =
51
)
TC
P (
n =
58
)
Re
mis
sio
n R
ate
s (
%)
Level 1 (n = 2876)
Level 2 (Augment) (n= 565)
Level 2 (Switch) (n = 727)
Level 3 (Augment) (n = 142)
Level 3 (Switch) (n = 235)
Level 4 (Switch) (n = 109)
Adapted from Warden D, et al. Curr Psychiatry Rep 2007: 9: 449-459.
Venlafaxine = Augmentation (SNRI)
Mean dose: 190 mg/day
Proportion of Patients With Remission†
0
10
20
30
40
50
60
Observed Cases LOCF
Patients
(%)
Venlafaxine: 272 mg
Paroxetine: 36 mg
Poirier MF, Boyer P. Br J Psychiatry. 1999;175:12-16.
P = 0.01 P = 0.02
(n=124)
***
Tyramine Pressor Response with ODV and Plasma Levels
0
5
10
15
20
50 100Baseline 200
Daily dose of ODV (mg)Incre
ase i
n i
n s
ysto
lic b
loo
d p
ressu
re
(mm
Hg
)4 mg
6 mg
**
184 434 936
Plasma level of ODV (ng/ml)
Pristiq
Effexor
Plasma level of VEN + ODV in ng/ml (daily dose in mg)
190
(75)
690
(225)
906
(375)
Turcotte et al, Neuropsychopharmacology 2001
Pressor Response to 6 mg of IV Tyramine in Healthy Volunteers
PLACEBO CLOMIPRAMINE
100 mg/day
DULOXETINE
20 mg/day
DULOXETINE
40 then 60 mg/day
**
5
0
10
20
30
40
INC
RE
AS
E I
N S
YS
TO
LIC
BL
OO
D P
RE
SS
UR
E
(mm
Hg
)
6
BASELINE
DAY 7
DAY 14
8 6
0 80 120 160 200 240
20
16
12
8
4
0
Vincent et al, Circulation 109:3205, 2004
Daily Regimens of Duloxetine Necessary toInhibit NE Reuptake in Healthy Volunteers
ED
30
mm
Hg
-Tyra
min
e (
mg
)
Duloxetine Dose (mg)
* **
**
**
Enhanced response to duloxetinein SSRI non-responders (open labelled)
Sagman et al, Int J Psychiat Clin Pract 2011
60 mg/day 60 mg/day
60 mg/day 120 mg/day
5-HT NE
a1 (+)
Reciprocal interactions between
monoaminergic neurons
(-)
Svensson et al, 1975; Mongeau et al, 1998
(-)5-HT?
5-HT2A antagonism reverses the inhibition
of NE neurons by escitalopram
0
50
100
150
*
#
* *
Co
ntro
l
SB
24
20
84
Co
nt
Ha
ldo
l
SB
Ha
ldo
l
MD
L 1
00
,90
7
MD
L 1
00
,90
7
ESCITALOPRAM SALINE
Dremencov, El Mansari, Blier, Biological Psychiatry 2007
5-HT NE
DOPAMINE
(-) 5-HT2A
a1 (+)
Reciprocal interactions between
monoaminergic neurons
D2 (-)
(-)
(-) 5-HT?
Dremencov E et al. J Psychiatry Neurosci 2009;34:223-9
5-HT2C antagonism reverses the inhibition of
dopamine neurons by an SSRI
0
60
120
200
20
40
80
100
140
160
180
Firing rate,
spikes/sec
Number of
bursts/10 sec
Number of
spikes/burst
Proportion of
spikes occurring
in bursts
Escitalopram
Escitalopram + SB 242084 0.5 mg/kg/day
Escitalopram + SB 242084 2.0 mg/kg/day
***
##
* ***
*** *
*
*#
*p<0.05; ***p<0.001 vs vehicle; #p<0.05 vs escitalopram alone
SEM, standard error of mean;
SSRI, selective serotonin reuptake inhibitor
5-HT NE
DOPAMINE
(-) 5-HT2C
(-) 5-HT2A
a1 (+)
Reciprocal interactions between
monoaminergic neurons
D2 (-)
(-)
Pharmacology of Mirtazapine:
Mirtazapine
a16.4 : Decreased 5-HT action
a27.0
H19.3
M26.2
5-HT2A8.3
5-HT2C8.4
5-HT37.1
5-HT77.4
* The larger the number, the greater is the affinity (pKi )
: Sedation
: Antidepressant effect
: Restoration of sleep architecture
and anxiolytic/antidep. effect
: Anti-nausea effect
: Antidepressant effect?
Target engagement!!!
(-)
(-) (-)
(+)
5-HT
Locus
Coeruleus
Raphe
Postsynaptic
Neuron
5-HT
1
mirtazapine
mirtazapine
mirtazapine
Day of treatment
0
5
10
15
20
25
1 4 7 10 14 21 28 35 42
HA
MD
17 s
co
res (
+S
EM
)
Fluoxetine (n = 28)
Fluoxetine + Mirtazapine30 mg (n = 25)
Bupropion + Mirtazapine 30 mg (n = 26)
Venlafaxine 225 mg+ Mirtazapine 30 mg (n = 26)
Effectiveness of drug combinations
* P = 0.011 when comparing the combination groups with fluoxetine
*
Blier et al, Am J Psychiat 167:281-8,2010
Dropout: 15%
0.0
25
75
100
Remission rates in monotherapy vs
combination from treatment initiation
SSRI
20-30 mg
Pati
en
ts (
%)
ach
ievin
g
rem
issio
n
49 21
Blier et al, Eur Neuropsychopharmacol 2009
Blier et al, Am J Psychiat 2010; * Paroxetine 20-30, Fluoxetine 20
Mirtazapine
30 mg
SSRI
20-30 mg*
50
45
Bupropion
150 mg
Venlafaxine
225 mg
25 25
+ Mirtazapine 30 mg
CO-MED Study: open and single-blinded
17 mg/day
(Not
blinded)
288 mg/day
+13 mg/day
192 mg/day
+20 mg/day
Rush et al, Am J Psychiat 168:689, 2011
(TRIAL DESIGN)
Functional
connectivity:
(-)(-)(-)
Why Use Antipsychotics to Treat MDD?
Historically, the typical antipsychotic haloperidol,
which predominately acts as a potent D2/3
antagonist, is not effective in the treatment of MDD
Atypical antipsychotics, however, are effective as
adjunctive therapies for MDD at lower doses than
are effective in schizophrenia
Therefore, properties other than D2/3 receptor
blockade accounts for the therapeutic action of
atypical antipsychotics in MDD
Affinity Ki [nM] for D2 and 5-HT receptors
Haloperidol
Clozapine
Olanzapine
Quetiapine
Risperidone
Paliperidone
Ziprasidone
Aripiprazole
2A
45
16
5
300
0.5
1
0.4
3.4
2C
NS
10
11
NS
25
23
1
15
1A
NS
200
NS
720
210
240
3
1.7
1D
NS
NS
800
NS
170
150
2
ND
Receptor Pharmacology of Antipsychotic Medications
•An important metabolite of quetiapine, norquetiapine is a potent 5-HT2C antagonist
•Aripiprazole is a partial D2 agonist
D2
1
160
44
580
2
3
4
0.3
Placebo-controlled trials of “atypicals” as
adjuncts in unipolar depression
Cariprazine + SSRI/SNRI 1 (trials) 819 (patients)
Olanzapine + fluoxetine 5 1000
Risperidone + SSRI/SNRI 3 386
Quetiapine XR + SSRI/SNRI 5 1028
Aripiprazole + SSRI and SNRI 6 2057
Ziprasidone + SSRI/SNRI 1 139
Adapted from Shelton RC, Papakostas GI., Acta Psychiatr Scand. 2008;117(4):253-259; Kamijima et al, J Affect Dis, 2013 ;
Lenze et al, Lancet 2015; Papakostas et al, Am J Psychiat 2015; Thase et al, J Clin Psychiat, 2015a,b; Durgam et al. 2016
Brexpiprazole + SSRI/SNRI 2 980
Detailed receptor pharmacology
of atypical antipsychotics
Atypical
antipsychotic
5-HT2A/C
antagonism
a2
antagonism
5-HT1A
partial
agonism
5-HT7
antagonism
5-HT1B/D
antagonism
Clozapine + + + + O
Risperidone + + O + +
Olanzapine + O O + O
Quetiapine + + + O O
Brexpiprazole + + + + O
Ziprasidone + O + + +
Aripiprazole + O + + O
Asenapine + + + + +
Lurasidone +/O + + + O
Iloperidone + O + O O
Amisulpiride O O O + O
O indicates no activity; + indicates significant activity
D2/3
partial
agonism
O
O
O
O
+
O
O
O
O
O*
+
Cariprazine O/+ O + O O +
Atypical antipsychotics reverse the
inhibition of NE neurons
produced by SSRIs
2.5
2.0
1.5
1.0
0.5
0
*
2.5
2.0
1.5
1.0
0.5
0
*
*
Firin
g r
ate
of N
E n
euro
ns ##
5-HT
DA
(-)
D2
NE
Postsynaptic
Neurons
D2
All
Atypicals and specific receptor affinities &
depressive symptoms
Atypicals 5-HT2A/C
antagonisma2
antagonism
5-HT1A
agonismD2
agonism
NE
reuptake
inhibition
Aripiprazole + O + + O
Asenapine + + + O O
Lurasidone +/O + + O O
Olanzapine + O O O O
Paliperidone + + O O O
Quetiapine + + + O +
Risperidone + + O O O
Ziprasidone + O + O O
O: indicates no activity and (+) significant activity
Clinical evidence for an antidepressant
effect of 5-HT1A receptor agonism
Three double-blind studies showed the efficacy of the
selective 5-HT1A agonist gepirone ER in MDD 1-3
Bupropion and the 5-HT1A agonist buspirone
augmentation of citalopram: equal effectiveness in
STAR*D 2
1. Feiger et al, Psychopharmacol Bull 32:659-665,1996
2. Feiger et al, J Clin Psychiat 64:243-249, 2003
3. Bielsky et al, J Clin Psychiat 69:571-577, 2008
4. Trivedi et al, NEJM 2007
5-HT
DA
(-)
D2
NE
Postsynaptic
Neurons
D2
X
Atypicals and specific receptor affinities &
depressive symptoms
Atypicals 5-HT2A/C
antagonisma2
antagonism
5-HT1A
agonismD2
agonism
NE
reuptake
inhibition
Aripiprazole + O + + O
Asenapine + + + O O
Lurasidone +/O + + O O
Olanzapine + O O O O
Paliperidone + + O O O
Quetiapine + + + O +
Risperidone + + O O O
Ziprasidone + O + O O
O: indicates no activity and (+) significant activity
5-HT
DA
(-)
D2
NE
Postsynaptic neurons
D2
Ari
Clinical evidence for an antidepressant
effect of D2 receptor agonism
A double-blind, placebo- and fluoxetine-controlled
study showed the efficacy of the D2 receptor agonist
pramipexole in MDD 1
A double-blind, placebo-controlled positive trial of
pramipexole augmentation in MDD was recently
reported2
1. Corrigan et al, Depression Anxiety 11:58-65, 2000
2. Cusin et al, J Clin Psychiat 74: e636-41, 2013
-12
-10
-8
-6
-4
-2
00 1 2 3 4 5 6
***
***
***
***
***
***
**
****
**
**
*
Mea
n C
han
ge
in M
AD
RS
tota
l score
Week
*: p<0.05, **: p<0.01, ***: p<0.001 vs. adjunctive placebo (ANCOVA)
Mean baseline MADRS total scores: aripiprazole 3-15 mg/day 25.3;
3 mg/day 25.2; placebo 25.5.
Kamijima, K.,et al., J. Affective Disorders, 2013
-12
-10
-8
-6
-4
-2
0
0 1 2 3 4 5 6
placebo (n=195)
3-15 mg/d (n=194)
3 mg/d (n=197)
***
***
***
**
***
******
**
**
****
*
Aripiprazole as Adjunctive Antidepressant:
Study in Japan (ADMIRE)
Placebo (n=195)
3-15 mg/d (n=194)
3mg/d (n=197)
Conclusions
We have new drugs with novel mechanisms
of action since the late 1950’s, we have
made progress!
Remission rates in MDD are low in large part
because of inadequate implementation of
treatment protocols
Unfortunately, we have no reliable predictors
of response
Conclusions
Antidepressants in real life are often more effective
than they appear in controlled trials because of the
constraints of the studies (i.e. suicidal patients)
Use the neurobiological algorithm: never do the
same thing twice!
Avoid irrational polypharmacy (Rx with the same
properties)
Hopelessness is good predictor of suicide: the
physician must convince him/herself and the
patient of the depth of the tool box