55
Alec Coppen Keynote Lecture January 29, 1923 March 15, 2019
Alec Coppen Keynote Lecture
January 29, 1923
March 15, 2019
Alec Coppen, MD, DSc, FRCP • Founding member of the British Association of
Psychopharmacology (BAP)
• CINP President (1988-1990)
• CINP Pioneer in Psychopharmacology Award (2000)
• Among the first to investigate the link between the
neurotransmitter serotonin (5-HT) and clinical
depression
• Proposed tryptophan would help those who were
already on antidepressants to get better faster than
those who were treated with antidepressants alone
one of the most influential in psychopharmacology
(Lancet 1963)
• One of the very first researchers to suggest that lithium
was anti-suicidal
Dr. Alec Coppen: June 2018
Alec Coppen Keynote Lecture
The pivotal role of serotonin and its
receptors in the antidepressant
response
Pierre Blier, MD, PhD
Fellow of The Royal Society of Canada
Mood Disorders Research Unit
Institute of Mental Health Research
University of Ottawa, Canada
Objectives of the Presentation
Provide an overview of the effects of antidepressant
strategies on 5-HT transmission
Explain the indirect effects of bupropion on the 5-HT
system, and its rapid antidepressant action in
combination with a SSRI
Describe the reciprocal interactions between the
5-HT and norepinephrine (NE) and dopamine (DA)
systems
Present clinical results of enhanced antidepressant
activity of drug combinations that have
complementary 5-HT/NE/DA interactions
Warning: this presentation is compliant with
the Neuroscience-based Nomenclature
and may be confusing to some viewers
The serotonin (5-HT) system
5-HT projections to the brain originate
mainly from the rostral raphe nuclei: the
dorsal and median raphe nuclei. All 5-HT
receptors are located postsynaptically, but
5-HT1A and 5-HT1B/1D receptors are also
located presynaptically where they
normally inhibit 5-HT firing and release,
respectively.
Courtesy of Steve T Szabo, MD, PhD
Relapse of formerly depressed patients
Smith et al, Lancet 349: 915-919, 1997
5-HT NEURON
POSTSYNAPTIC NEURON
5-HT1 A
5-HT1D-LIKE
1A
5-HT
Electrophysiological paradigm to study the
5-HT system in vivo in the rat brain
↑○↓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
normal
5-HT transmission and 5-HT reuptake/MAO
inhibition or 5-HT1A agonism
long-term treatment
subacute treatment
↑○↓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
Enhancement of 5-HT transmission in the
rat hippocampus after 14 days of various
antidepressant treatments
Chaput, de Montigny, Blier, Neuropsychopharmacology 1991
Increased sensitivity of postsynaptic 5-HT
receptors by ECS and imipramine, not
MAOI or SSRI
Chaput, de Montigny, Blier, Neuropsychopharmacology 1991
↑○↓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
LOCUS COERULEUS NE NEURONS
CONTROL
103BUPROPION
98
**
BUPROPION+
IDAZOXAN
IDAZOXAN
260
1
2
3
4
5
DA NEURONS IN VTA
0
4
2
6
8
49 26CONTROL
BUPROPION
DORSAL RAPHE 5-HT NEURONS
0
1
2
90 137
*
CONTROL
BUPROPION
77
NE-LESION+
BUPROPION
28
*Firin
g r
ate
(H
z +
SE
M)
Effects of sustained bupropion administration on
the spontaneous firing of monoaminergic neurons
Dong & Blier, Psychopharmacology 2001
Alteration of the firing of rat 5-HT and NE neurons
during sustained bupropion administration
El Mansari et al, Neuropharmacology 55: 1191-1198, 2008
Desensitization of the 5-HT1A
autoreceptor after 2 days Desensitization of the a2-
autoreceptor after 14 days
Basis for monoaminergic firing
adaptations with bupropion
El Mansari et al, Neuropharmacology 2018
A. Tonic activation of 5-HT1A receptors B. 5-HT1A receptor sensitivity
Enhancement of 5-HT1A transmission in the rat
hippocampus by sustained bupropion
Ghanbari et al, Psychopharmacology 217: 61-73, 2011
Functional
connectivity
X
X
XX
0
0.5
1
1.5
2
2.5
3
37 27 41
NaCl ESC BUP
Nu
mb
er
of
Sp
ikes /
Sec
30
ESC+BUP
**
***
Escitalopram and bupropion on 5-HT neuronal firing
2-day administration
Ghanbari et al, J Psychopharmacol 24:39-50 , 2011
*
Combination of escitalopram and bupropion
to hasten remission in MDD
Zuilhof et al, Neuropsychiatric Disease Treatment 14: 3209-3218, 2018
Double-blind combination of a SSRI and
bupropion to hasten remission in MDD
Zuilhof et al, Neuropsychiatric Disease Treatment 14: 3209-3218, 2018
300/20 mg
450/40 mg/day
(-)
(-) (-)
(+)
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
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
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
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
Functional
connectivity
5-HT2A for NE neurons
5-HT2C for DA neurons
Pharmacology of Mirtazapine: (similar to Quetiapine)
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?
(-)
(-) (-)
(+)
5-HT
Locus
Coeruleus
Raphe
Postsynaptic
Neuron
5-HT
1
mirtazapine
mirtazapine
mirtazapine
Controls; MIR, mirtazapine; PRX, paroxetine; Mirtazapine + Paroxetine
Besson A, et al. Eur Neuropsychopharmacol. 2000;10:177-88.
Incre
ase in f
irin
g a
ctivity o
f
CA
3 p
yra
mid
al neuro
ns
(% ±
SE
M)
A- B-2 days 21 days
WAY-100635 (µg/kg, IV)
0 25 50 75 100
0
50
150
100
200
300
250
WAY-100635 (µg/kg, IV)
0
50
150
100
200
300
250
0 25 50 75 100
Hippocampus 5-HT1A transmission in the
rat brain by a SSRI & 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 + Mirtazapine (n = 25)
Bupropion + Mirtazapine (n = 26)
Venlafaxine + Mirtazapine (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
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
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 ofDA/5-HT 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 adjuncts with
DA/5-HT properties 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 5 2250
Detailed receptor pharmacology
of DA/5-HT medications
Drugs 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 +
Relationship between the occupation of D2 and 5-HT2A receptors for haloperidol, olanzapine
and risperidone in the human brain
Kapur S et al, Am J Psychiat 2000; 157:514-520
-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 an adjunctive medication
in inadequate response in MDD
Placebo (n=195)
3-15 mg/d (n=194)
3mg/d (n=197)
Onset of action of aripiprazole additionFigure 1.
-1.6 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0
Concentration difficulties
Reduced sleep
Inner tension
Reduced appetite
Pessimistic thoughts
Suicidal thoughts
Inabilty to feel
Lassitude
Reported sadness
Apparent sadness
Aripiprazole 3-15 mg/d
Aripirpazole 3 mg/d
Placebo
Mean change in MADRS individual item
Significant improvement within 1 week
Significant improvement within 2 week
Significant improvement within 3 week
Improvement not significantly greater than placebo
**
** **
***
***
* *
*
*** *
*** ***
**
Acc
epte
d A
rtic
le
Ozaki et al, Psychiat ClinNeurosci 69:34-42, 2015
Drug 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 +
Detailed receptor pharmacology
of DA/5-HT medications
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
Chernoloz et al, Psychopharmacology 2009
Aripiprazole reverses the inhibition of 5-HT
neurons produced by a SSRI X 2 days
Aripiprazole desensitizes the
5-HT1Aautoreceptor within 2 days
Chernoloz et al, Psychopharmacology 2009
5-HT
DA
(-)
D2
NE
Postsynaptic
Neurons
D2
X
Drug 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 +
Detailed receptor pharmacology
of DA/5-HT medications
Pharmacology of the Aripiprazole,
Brexpiprazole and Cariprazine
Aripiprazole Brexpiprazole Cariprazine
Dopamine 2 0.34 0.30 0.49
Dopamine 3 0.8 1.1 0.09
5-HT2A 1.7 0.12 2.6
5-HT2C 15 NR 130
5-HT1A 1.7 0.12 2.6
NE-alpha 2 38 0.59 NR
Histamine 1 61 19 23
Values represent affinities in nM concentrations (Ki): the smaller the number, the
higher the affinity. Kiss et al, JPET333:3228, 2010, Maeda et al, JPET 350:599, 2014
Dopamine+
partial agonist
Dopamine+
antagonist
Dopamine
Partial agonists regulate dopamine
signaling D2 receptor
0
50
100
[Drug]
% M
axim
al D
A r
esponse
10-10 10-9 10-8 10-7 10-6 10-5
Partial agonist
Antagonist
Saturation
No receptor activity 3,4
Partial
receptor activity 2,4
Full receptor activity 3,4
1. Lawler CP et al. Neuropsychopharmacology. 1999;20:612-627; 2. Burris KD et al. J Pharmacol Exp Ther. 2002;302:381-
389; 3. Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. New York, NY:
Cambridge University Press; 2000; 4. Jordan S et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007
Chernoloz et al, Psychopharmacology 2009
Aripiprazole reverses the inhibition of DA
neurons produced by a SSRI X 14 days
5-HT
DA
(-)
D2
NE
Postsynaptic neurons
D2
Agonist
Clinical evidence for an antidepressant
effect of D2-like receptor agonism
A double-blind, placebo- and fluoxetine-controlled
study showed the efficacy of the D3/2 receptor
agonist pramipexole in MDD 1
A double-blind, placebo-controlled study showed the
antidepressant efficacy of pramipexole in patients with
Parkinson’s disease 2
A double-blind, placebo-controlled positive trial of
pramipexole augmentation in MDD was reported3
1. Corrigan et al, Depression Anxiety 11:58-65, 2000
2. Barone et al, Lancet Neurology 9:573-580, 2010
3. Fava et al, ACNP 51: 309, 2012
Conclusions
Medications that lead to enhanced 5-HT1A autoreceptor
activation desensitize it in 2-3 weeks
Bupropion and aripiprazole desensitize the 5-HT1A
autoreceptor within 2 days, possibly via interactions
with catecholamine receptors on the cell body of 5-HT
neurons
Combinations of bupropion, mirtazapine and/or
aripiprazole can lead to a more rapid and/or
pronounced antidepressant effects
These results exemplify the important role of the 5-HT
system and its receptors in the antidepressant
response
