Alec Coppen Keynote Lecture 2019 - Pierre Blier - 5 October...Alec Coppen Keynote Lecture The...

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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

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

↑↑○○○ECS

↑○n.d○↓5-HT1A

agonists

↑○○↓↓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

↓○

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

↑↑○○○ECS

↑○n.d○↓5-HT1A

agonists

↑○○↓↓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

↓○

Treatments

LOCUS COERULEUS NE NEURONS

CONTROL

103BUPROPION

BUPROPION+

IDAZOXAN

DA NEURONS IN VTA

49 26CONTROL

BUPROPION

DORSAL RAPHE 5-HT NEURONS

90 137

CONTROL

BUPROPION

NE-LESION+

BUPROPION

*Firin

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

37 27 41

NaCl ESC BUP

ikes /

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

(-) (-)

LOCUSCOERULEUS

POSTSYNAPTICNEURON

Normal

Long-term treatment with a SSRI

SSRIs decrease NE transmission(Szabo and Blier, 2000; Kawahara et al, 2007)

Citalopram

Locus coeruleus

: Norepinephrine (NE)

Citalopram0

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

ESCITALOPRAM SALINE

Dremencov, El Mansari, Blier, Biological Psychiatry 2007

(-) (-)

VENTRAL TEGMENTALAREA

POSTSYNAPTICNEURON

Inhibitory Effect of Escitalopram

(X 14 days) on VTA Dopamine Neuronal Firing

Control10

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

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

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?

(-) (-)

Coeruleus

Postsynaptic

Neuron

mirtazapine

Controls; MIR, mirtazapine; PRX, paroxetine; Mirtazapine + Paroxetine

Besson A, et al. Eur Neuropsychopharmacol. 2000;10:177-88.

ase in f

ctivity o

al neuro

A- B-2 days 21 days

WAY-100635 (µg/kg, IV)

0 25 50 75 100

WAY-100635 (µg/kg, IV)

0 25 50 75 100

Hippocampus 5-HT1A transmission in the

rat brain by a SSRI & mirtazapine

Day of treatment

1 4 7 10 14 21 28 35 42

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

Remission rates in monotherapy vs

combination from treatment initiation

20-30 mg

Blier et al, Eur Neuropsychopharmacol 2009

Blier et al, Am J Psychiat 2010; * Paroxetine 20-30, Fluoxetine 20

Mirtazapine

20-30 mg*

Bupropion

150 mg

Venlafaxine

225 mg

+ Mirtazapine 30 mg

Affinity Ki [nM] for D2 and 5-HT receptors

Haloperidol

Clozapine

Olanzapine

Quetiapine

Risperidone

Paliperidone

Ziprasidone

Aripiprazole

Receptor Pharmacology ofDA/5-HT Medications

•An important metabolite of quetiapine, norquetiapine is a potent 5-HT2C antagonist

•Aripiprazole is a partial D2 agonist

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

5-HT1A

partial

agonism

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

partial

agonism

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

00 1 2 3 4 5 6

l score

*: 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

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

Improvement not significantly greater than placebo

*** ***

Ozaki et al, Psychiat ClinNeurosci 69:34-42, 2015

Drug 5-HT2A/C

antagonism

5-HT1A

partial

agonism

antagonism

5-HT1B/D

antagonism

Clozapine + + + + O

Asenapine + + + + +

partial

agonism

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

Postsynaptic

Neurons

Drug 5-HT2A/C

antagonism

5-HT1A

partial

agonism

antagonism

5-HT1B/D

antagonism

Clozapine + + + + O

Asenapine + + + + +

partial

agonism

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

[Drug]

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

Aripiprazole reverses the inhibition of DA

neurons produced by a SSRI X 14 days

Postsynaptic neurons

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

Alec Coppen Keynote Lecture 2019 - Pierre Blier - 5 October...Alec Coppen Keynote Lecture The...

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