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