Neurobiology of Stress, Depression, and Antidepressants: … · 2019-12-17 · response to ketamine...

Neurobiology of Stress, Depression, and Antidepressants:

Remodeling Synaptic Connections

Ronald S. Duman, PhD

Department of Psychiatry

Yale University School

of Medicine

Mood Disorders

• Depression affects ~17% of the

population: higher risk for women

(2:1).

• Economic cost is over $100 billion

annually.

• Available treatments require weeks to

months.

• Causes of depression and mechanisms of treatment

response have not been identified.

• Studies demonstrate a role for neuronal atrophy and

loss of neurotrophic factor support.

Evidence of Atrophy of Limbic and Cortical Regions In Major Depressive Disorder (MDD)

• Decreased hippocampalvolume in MDD patients; reduction in volume is related to the duration of depression, and is blocked or reversed by antidepressant treatment

• Decreased prefrontal cortex volume and hypofunction, correlates with disease severity in both MDD and BD.

Evidence of Neuronal Atrophy and Loss in Response to Stress: Preclinical Studies

• Chronic stress, which can lead to depression, decreases

synaptic connections in the prefrontal cortex and

hippocampus.

PFC layer V pyramidal neurons; Liu and Aghajanian, 2008

Control Stress Control Stress



Chronic stress, which can lead to depression, decreases synaptic

connections in the PFC and hippocampus; decreased synapses

also reported in postmortem PFC of depressed subjects.

Loss of connections decreases circuit control of emotion,

mood, and cognition, contributing to depressive symptoms.

Typical Antidepressants: Limitations

•Act on serotonin and/or norepinephrine

monoamines (e.g., block reuptake transporter).

•Do not directly influence spine number and

function.

•Delayed response of weeks to months.

•Low rate of efficacy: ~1/3 of patients respond to

1st drug, up to 2/3’s with multiple trials.

•Treatment resistant depression (TRD) of ~1/3 of

patients.

Transcription

CREB

CREB

Nucleus

SSRI 5-HT Transporter

Second Messengers

(e.g. cAMP)

PKA

AC

Gs

Nucleus

P

P

Regulation of BDNF

Gene Expression

5-HT neurotransmitter

system: Slow

Modulation

Antidepressant Responses :

Neuroprotection,Neuroplasticity,

Neurogenesis

Delayed

Adaptive

ResponsesMultiple Physiological Effects

R

Delayed and Low Response to Typical Antidepressants

Transcription

CREB

CREB

Nucleus

Second Messengers

(e.g. cAMP)

PKA

AC

Gs

Nucleus

P

P

Na+,Ca2+

CAMK

NMDA

Regulation of BDNF

Gene Expression

Activity-dependent

Release of BDNF

Glutamate

Fast Excitation

Na+

AMPA

Rapid Antidepressant Response

Delayed ResponseRapid Response

Multiple Physiological Effects

1

2

R

Drugs Acting on the Glutamate Neurotransmitter System

SSRI 5-HT Transporter

5-HT neurotransmitter system: Slow Modulation

Ketamine

Ketamine Produces Rapid Antidepressant Effects

Berman, Heninger, Charney, Krystal, and colleagues 2000

Me

an

Ch

an

ge

HD

RS

• NMDA receptor antagonist and dissociative anesthetic at hi doses.

• At low doses, ketamine produces a rapid response in treatment resistant depressed patients

Larger Replication Study DemonstratingRapid Antidepressant Actions of Ketamine

Zarate, Charney, et al., at NIMH et al., 2006

Zarate et al., 2012; Biological Psychiatry

Therapeutic actions of ketamine in bipolar depressed patients

A preliminary naturalistic study of

low-dose ketamine for depression

and suicide ideation in the

emergency department (2011)

Larkin and Beautrais, Int J

Neuropsychopharmacol: 14(8):1127-

31. Epub 2011 May 5.

Effects of intravenous ketamine on

explicit and implicit measures of

suicidality in treatment-resistant

depression (2009) Price et al., Biol

Psychiatry: 66(5):522-6.

Ketamine and Suicide Ideation

A preliminary naturalistic study of

low-dose ketamine for depression

and suicide ideation in the

emergency department (2011)

Larkin and Beautrais, Int J

Neuropsychopharmacol: 14(8):1127-

31. Epub 2011 May 5.

Effects of intravenous ketamine on

explicit and implicit measures of

suicidality in treatment-resistant

depression (2009) Price et al., Biol

Psychiatry: 66(5):522-6.

Ketamine and Suicide Ideation

These effects are particularly

relevant given that: -

36,000 individuals die from suicide/yr,

twice as many as by homicide (Center

for Disease Control).

-23% of suicide victims were on

antidepressant treatments at the time

of death.

Multiple Replication Studies

Percent of Patients classified as Responders

aan het Rot et al. Biol Psychiatry 2012

Development of Antidepressant Drugs

The discovery that ketamine produces rapid antidepressant

effects in treatment resistant depressed patients, by a novel

mechanism (NMDA receptor blockade), is arguably the most

significant advance in the field in over 50 years.

Failures: Subst P CRF

Antagonist Antagonist

Time Line of Drug Discovery

•Lithium TCA/MAOI SSRI (SNRI/TRI) Ketamine

~1950 1960 1970 1980 1990 2000 2010

Development of Antidepressant Drugs

The discovery that ketamine produces rapid antidepressant

effects in treatment resistant depressed patients, by a novel

mechanism (NMDA receptor blockade), is arguably the most

significant advance in the field in over 50 years.

Failures: Subst P CRF

Antagonist Antagonist

Time Line of Drug Discovery

•Lithium TCA/MAOI SSRI (SNRI/TRI) Ketamine

~1950 1960 1970 1980 1990 2000 2010

What is the mechanism for the rapid actions of ketamine?

Synaptogenesis and rapid actions of ketamine?

Control Stress

• Might ketamine, thru effects on glutamate

act via regulation of the number and

function of spine-synapses?

• Synapses undergo rapid remodeling in

response to glutamate activity.

• Typical antidepressants do not directly

effect synapses.

• What is the effect of low dose ketamine

on spine synapses in the PFC?

What are Synaptic Connections?

Single neuron BranchConnection/Synapse



Chronic stress, which can lead to depression, decreases synaptic

connections in the PFC and hippocampus; decreased synapses

also reported in postmortem PFC of depressed subjects.

Loss of connections decreases circuit control of emotion,

mood, and cognition, contributing to depressive symptoms.

Ketamine Rapidly Increases Neuronal Connections

Control KetamineControl Ketamine

PSD95GluR1

Syn I

Ketamine Rapidly Increases Synaptic Proteins in PFC

Synapse number in function

In slices of PFC

Ketamine dosing

0 24 hr

• Increased spine number, including

• Increased number of “mushroom”or mature spines

**

0

2

4

6

8

10*

*

Distal tuft Proximal tuft

control

ketamine

Control KetamineLayer V neurons of the medial prefrontal cortex

Li et al., Science, 2010

PSD95GluR1

Syn I

Ketamine Rapidly Increases Synaptic Proteins in PFC

Nick Li and Boyoung Lee

SynaptoneurosomePreparation

Ketamine Time Course

0 1 2 6 24 72 hr

Western BlotSynaptic Proteins

Time Course for the Induction of Synaptic Proteins Corresponds to the

Time Course for the Clinical Response

-60 40 80 110 230 1 d 2 d 3 d 7 dmin min min min min

Zarate et al., 2006

PSD95GluR1

Ketamine, Synapses, and Behavior

• Ketamine has rapid actions in forced swim and learned helplessness models of depression.

• Chronic unpredictable stress (CUS) causes depressive behaviors (e.g., anhedonia) & decreases synapses.

• Antidepressants (e.g., fluoxetine) take weeks.

• Rigorous rodent test of the rapid actions of ketamine to reverse the spine and behavioral deficits caused by stress.

23 day

Chronic Unpredictable Stress (23 days, 2/day)

2221day 0

Spine/behavior

KetamineCUS Paradigm

Control CUS CUS+ketSpines

Depressive Behavior:Anhedonia

Ketamine rapidly reverses the spine and behavioral deficits

caused by chronic stress (3 weeks)

Pathophysiology and treatment

of depressive behaviors are

associated with the number and

function of synaptic connections.

What is the mechanism by which ketamine

increases spine number and function?

Control Ketamine

How does administration of

an of NMDA receptor

antagonist cause an increase

in synaptogenesis?

Glutamate

Spine SynapseNumber &Function

AMPA

GSK3

NMDA

LTP-like

Synaptogenesis

Glutamate

AMPA

PP1

GSK3

Ketamine Blocks the Firing of GABAergic Interneurons

that Inhibit Glutamatergic Transmission

mGluR2/3

NMDA

GABA

Ketamine

Houman and Moghaddam, 2007: “NMDA receptors preferentially drive the

activity of cortical inhibitory interneurons suggesting that NMDA receptor

inhibition causes cortical excitation by disinhibition of pyramidal neurons.”

NMDAGlutamate Burst Glutamate Burst

• mTOR mediates long-term, protein synthesis dependent learning and memory.

• mTOR regulates translation initiation.

• Present in dendrites, as well as cell bodies.

• Regulated by phosphorylation: phospho-mTOR.

Signaling Mechanisms for regulation of Synaptogenesis: Role of the Mammalian

Target of Rapamycin (mTOR)

Glutamate Burst

mTOR

BDNFTrkB

AktERK

Akt

Increased translation

of synaptic proteins:

e.g., GluA1 and PSD95

GABA

Ketamine

Glutamate

Glutamate

AMPANBQX

Rapamycin

mGluR2/3

NMDA


PP1

GSK3

AMPA

GSK3

Rapamycin Blocks

the induction of:

•Synaptic proteins

•Spine number

and function

•Antidepressant

behavior

Rapamycin, a Selective inhibitor of mTOR,

Blocks the Antidepressant Actions of Ketamine

NMDA

Glutamate Burst

mTOR

BDNFTrkB

AktERK

Akt




GABA

Ketamine

Glutamate

Glutamate

AMPANBQX

Rapamycin

mGluR2/3

NMDA


PP1

GSK3

AMPA

GSK3

Mechanisms for the rapid actions of ketamine:

Role for Brain Derived Neurotrophic Factor

NMDA

BDNF

• BDNF is required for the survival of neurons in adult animals.

• BNDF is also required for activity-dependent induction of

synaptic function.

Transcription

nucleus

P

P

TrkB

TrkB

ERK

Rsk

MEK

RasGrb

Raf

Neurotrophic Factors

Regulation of BDNF

Gene Expression

1

Activity-

dependent

Release of

BDNF

2

Developing brain:

growth, guidance, and

survival of neurons.

Adult brain: regulate

neuronal function, and

growth/survival.

Regulated by neuronal

activity (e.g., learning

and memory).

Nucleus

Neurotrophic/Growth Factor Families

Implicated in Stress and Depression

Family Stress/Depression Antidepressant

Brain Derived Decrease Increase

Neurotrophic Factor

Vascular Endothelial Decrease Increase

Growth Factor

Fibroblast Decrease Increase

Growth Factor

Insulin-Like no change Increase

Growth Factor

BDNF Val66/Met Polymorphism

Associated with:

• Reduced episodic memory

performance and executive

function.

• Decreased hippocampal volume

in normal subjects, MDD subjects,

and bipolar patients.

Krishnan and

Nestler, 2008

BDNF Met allele

• Decreases processing

and activity-dependent

BDNF release.

• Incidence: ~25% of the

population.

• Increases vulnerability for depression: gene x stress

interaction, (Kaufman et al., 2006; Kim et al., 2007; Gatt et al.,

2009).

Rong-Jian Liu et al., 2012, Biol Psych

Consistent with Autry et al., 2011.

Ketamine Induction of spines and antidepressant behavior is

blocked in BDNF Met mice

WT Met/Met

WT Met/Met

Ket

Veh

** *

Met/Met blocks

Blocks BDNF

release

Xiao-Yuan Li and Rong-Jian Liu

BDNF Val66Met Polymorphism and Antidepressant

Efficacy of Ketamine in Depressed Patients

Gonzalo Laje, Níall Lally, Daniel Mathews, Nancy Brutsche, Anat Chemerinski, Nirmala Akula,

Benjamin Kelmendi, Arthur Simen, Francis J. McMahon, Gerard Sanacora, and Carlos Zarate

Biol Psychiatry. 2012 Jul 5. [Epub ahead of print]

•Based on the findings in BDNF Met/Met mice, hypothesized that patients

carrying a BDNF Met substitution would show an attenuated antidepressant

response to ketamine infusion compared with Val/Val patients.

•Met carriers showed a significantly reduced (~50%) response

to ketamine compared to Val carriers. (F = 5.59, df = 4, p = .0007).

•Val66Met allele can be used as a marker to identify patients who

are responders or nonresponders to ketamine.

Glutamate Burst

mTOR

TrkB

AktCa2+




GABA

Ketamine

Glutamate

Glutamate

AMPANBQX

Rapamycin

mGluR2/3

NMDA


PP1

GSK3

AMPAVDCC

VDCC

PSD95GluA1

BDNF

•Ketamine, via glutamate-synaptic activity, increases BDNF release.

•Typical ADTs increase BDNF expression, but no evidence of release.

•This could account for the rapid and efficacious actions of ketamine.

BDNF

Release

Influence of ketamine vs. typical antidepressants on

BDNF: release vs. expression

Stress decreases synaptic connections: Rapid reversal

by ketamine

Ketamine produces nascent spines on pyramidal

neurons in the PFC: stabilization?

Ketamine

SynaptogenesisStress

Stress

NormalNormal

Stabilize?

Recruit/stabilize?

Control of mood/emotion requires synaptic integrity of PFC neurons

Amygdala

What connections/circuits underlie the antidepressant actions of ketamine as well as stress and depression?

Control of mood/emotion requires synaptic integrity of PFC and

inhibitory connections with the amygdala and other brain regions

PFC

Control of

Emotion

Dorsal RapheNucleus Accumbens

Antidepressant Response

Ketamine is a drug of abuse with side effects: Need for safer rapid acting, ketamine-like antidepressants

Hamilton Depression

Scale: p=.0001

VAS, “High”

P=.0001

BPRS, Positive

Symptoms of

Schizophrenia

P=.007

Berman et al., Biol Psychiatry 2000

• Ketamine, repeated dosing and nasal administration: both have

shown efficacy and provide evidence for approval of ketamine.

• Nonselective NMDA antagonists: drugs with fewer side effects;

AZD6367, reported to be effective with repeated IV dosing.

• Selective NR2B receptor antagonists: CP-101,606 reported to

have antidepressant effects (Preskorn et al., 2007); Ro 25-6981,

basic studies.

• mGlu2/3 receptor antagonists: basic studies of LY341495,

MGS0039 increase glutamate by blocking autoreceptors.

• NMDA-glycine receptor agents(GLYX-13 and D-cycloserine)

reported to have clinical efficacy after single dose or chronic dosing.

• Muscarinic receptor antagonists: Scopolamine reported to

produce rapid antidepressant actions in depressed patients.

Development of Safer Rapid Acting Agents With Fewer Side Effects

Postsynaptic

NMDA

Receptors?Glutamate Burst

mTOR

BDNFTrkB

AktERK

PP1

GABA

NMDA antagonists:

Ketamine, CP-101,606, AZD6765,

Ro 25,6981

Glutamate

Glutamate

AMPA

Rapamycin

mGluR2/3

NMDA/

MuscR

Spine Synapse

Number &

Function

PP1

GSK3

AMPA

GSK3

Rapid reversal of the Synaptic Loss Caused by Stress and Depression

Depression Relapse

mGluR2/3 antagonists:

LY341495, MGS0039

Muscarinic antagonists:

Scopolamine,

Telenzapine

GSK-3 antagonists:

Lithium, SB216763

AMPA Receptor

Potentiating

drugs

Development of Safer Rapid Acting Antidepressants

Control Stress

What are the signaling mechanisms underlying neuronal atrophy?

• Neuronal atrophy caused by

relatively mild stress (1 wk)

• Could have wide spread

consequences: MDD, PTSD,

schizophrenia, cognitive deficits,

other.

• Does stress decrease mTOR

signaling and synaptic protein

synthesis?

mTOR

S6K eEF2K 4E-BP

Translation

P PP

mTORC1

P

P

Does stress decrease spine synapses via

inhibition of mTOR signaling: Mechanisms?

Control Stress/MDD

REDD1 (Regulated in

Development and DNA

damage)

REDD1 is induced by

glucocorticoids in muscle

and brain

REDD1 inhibits cell

growth and protein

synthesis directed by

mTOR via stabilization of

TSC1/2 (tuberin)

HPA Axis-Glucocorticoid

Tsc2

Rheb

Tsc1REDD1

REDD1 Expression is increased in by chronic

stress in rat PFC

Figure'1'(Ota'et'al.)'

21 Days CUS Sacrifice 4 Hrs d.

Total ERK

p-ERK

p-Akt Total Akt

p-S6K

CT

RL

C

US

p-4EBP1 GAPDH p-mTOR

Total mTOR

Total S6K

1 Day Mild Stress Sacrifice 4 Hrs

CT

RL

1

D M

ild

Total S6K

p-4EBP1

GAPDH

Total ERK

p-ERK

p-Akt

Total Akt

Total mTOR

e.

REDD1

GAPDH

b.

c.

REDD1

GAPDH


21 Days CUS Sacrifice 4 Hrs a.

p-mTOR

p-S6K



Total ERK

p-ERK

p-Akt Total Akt

p-S6K

CT

RL

CU

S


Total mTOR

Total S6K


CT

RL

1D

Mild

Total S6K

p-4EBP1

GAPDH

Total ERK

p-ERK

p-Akt

Total Akt

Total mTOR

e.

REDD1

GAPDH

b.

c.

REDD1

GAPDH



p-mTOR

p-S6K



Total ERK

p-ERK

p-Akt Total Akt

p-S6K

CT

RL

CU

S


Total mTOR

Total S6K


CT

RL

1D

Mild

Total S6K

p-4EBP1

GAPDH

Total ERK

p-ERK

p-Akt

Total Akt

Total mTOR

e.

REDD1

GAPDH

b.

c.

REDD1

GAPDH



p-mTOR

p-S6K



Total ERK

p-ERK

p-Akt Total Akt

p-S6K

CT

RL

CU

S


Total mTOR

Total S6K


CT

RL

1D

Mild

Total S6K

p-4EBP1

GAPDH

Total ERK

p-ERK

p-Akt

Total Akt

Total mTOR

e.

REDD1

GAPDH

b.

c.

REDD1

GAPDH



p-mTOR

p-S6K

Ota et al., Nature Medicine, 2014

REDD1 mRNA Expression is increased in

postmortem dlPFC of depressed subjects

Two independent cohorts

Total of 38 controls

and 38 MDD

~65% increase

in MDD

Ota et al., Nature Medicine, 2014

RTP801 knock out mice are resilient to CUS-induced

decreases in sucrose consumption and mTOR signaling in

the PFC

REDD1 knock out mice are resilient to the synaptic and

behavioral deficits (anhedonia) caused by chronic stress

c. b.


a.

d.

e.

CTRL

WT

CTRL

KO

CUS

WT

CUS

KO 5 µm

CUS KO CTRL KO

Basal Basal Basal

5-HT 20 µM 5-HT 20 µM 5-HT 20 µM

Hcrt 200 nM Hcrt 200 nM Hcrt 200 nM

200 ms

10

0 p

A

Basal

Hcrt 200 nM

5-HT 20 µM

CTRL WT CUS WT

21 Days CUS Sacrifice 4 Hrs Behavioral Testing 1 Week

Recovery

CT

RL

WT

CU

S W

T

CT

RL

KO

CU

S K

O

p-S6K Total-S6K p-4EBP1 GAPDH p-mTOR

Total mTOR

WT REDD1 KO WT + CUS KO + CUSSpine density

mTOR

TrkB

PI3K

ERK

MEK

S6K eEF2K 4E-BP

Translation

P PP

mTORC1

GluR1

P

P

GluR1

Insertion

PSD95

Synaptic Proteins

GluR1, PSD95

Tsc2

Rheb

Tsc1REDD1

Stress and Depression decrease mTOR

signaling via induction of REDD1

Control Stress/MDD

BDNF

Akt

Stress/MDD

a

ERK

AMPA

AMPA

PP1

GSK3

StressBDNF/mTOR

(LTD-like)

Coping, exercise,Enrichment; Synaptic

Homeostasis

DepressionSynaptic destabilization

KetamineGlutamate Burst

(LTP-like)

mTOR

BDNFTrkB

AktERK

Akt

NMDA

AMPA

GSK3Depression RelapseFailure of Synaptic

Homeostasis

Rapid AntidepressantSynaptogenesis

Regular MoodSynaptic Homeostasis

Model of Depression and Rapid Antidepressant Response: Remodeling of Synaptic Connections

• Develop novel synaptogenic treatments with fewer side effects.

• What causes relapse after 7-10 d? Loss of spines coincides with relapse?

• What treatments sustain the increase in spine number and function?

Acknowledgements• Nick Li

• Boyoung Lee

• Maha Elsayed

• Bhavya Voleti

• Andrea Navarria

• Mounira Banasr

• Xiao-Yuan Li

• Neil Fournier

• Manabu Fuchikami

• Ashley Lepack

• Jason Dwyer

• Kristie Ota

• Sophie Dutheil

• Astrid Becker

• Masaaki Iwata

• Pawel Licznerski

• Rose Terwilliger

• Alexandra Thomas

• George Aghajanian

• Rong-Jian Liu

• Samuel Sathyanesan

• Cathy Duman

• Gerard Sanacora

Funding Sources

• NIMH

• NARSAD

• State of CT

• Yale

Neurobiology of Stress, Depression, and Antidepressants: … · 2019-12-17 · response to ketamine...

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Transcript of Neurobiology of Stress, Depression, and Antidepressants: … · 2019-12-17 · response to ketamine...