Module 2A - Neurotransmitter Functioning In Major Depressive …€¦ · ·...

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Neurotransmitter Functioning In Major Depressive Disorder

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Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

January 2017 MRC2.CORP.D.00181


This program was developed with the support of Otsuka Pharmaceutical Development &

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• Imbalance theory describes patients with depression having deficient1:– Dopamine (DA), – Serotonin (5-HT), – Norepinephrine (NE)

• Monoaminergic deficiencies may be caused by depleted or dysregulated2:– Monoamine synthesis– Monoamine receptor signaling

• The efficacy of SSRIs, SNRIs, and dopamine agonists as antidepressants supports this theory3

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Monoamine Imbalance Theory of Major Depressive Disorder (MDD)

Tryptophan Tyrosine

Tryptophanhydroxylase

Tyrosinehydroxylase

5-HT NE

MAO-Ametabolism

Presynaptic neuron

5-HT1B

5-HT1A Vesicles

α2-adrenergicreceptor

NEtransporter

PI-coupledmonoamine

receptorscAMP-coupled

monoaminereceptors

G proteins

Secondary messengers effect downstream signaling and gene

expression in postsynaptic neuron

cAMPIP3DAG

Cytoplasm

Nucleus

5-HT transporter

Figure adapted from Perovic et al. 201021. Delgado PL. J Clin Psychiatry. 2006;67 Suppl 4:22-6.2. Perovic B, et al. Neuropsychiatr Dis Treat. 2010;6:343-364.3. Tran P, et al. J of Psychiatric Research. 2012;46:64-71.

AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; MAO-A, monoamine oxidase A; PLC, phospholipase-C; PI, phosphoinositide; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.



Monoamine Pathways Overlap in Several Areas of the Brain1–8

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Norepinephrine

Serotonin

A = amygdalaACC = anterior cingulate cortexC = cerebellumH = hippocampusHy = hypothalamusNA = nucleus accumbensPFC = prefrontal cortexS = striatumT = thalamusVTA = ventral tegmental area.

A1, A2, A5, A7 Locus coeruleus

Cerebral cortex

Substantia nigra and VTA

Dopamine

Raphe nuclei

PFC

ACC

Hy

T

S

A

H

C

1. Fuchs E, Flugge G. Dialogues Clin Neurosci. 2004;6(2):171-183; 2. Stahl SM. Chapter 7. In: Stahl SM, ed. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Application. 4th ed; 2013:284-369; 3. Jacobs BL, Azmitia EC. Physiol Rev. 1992;72(1):165-229; 4. Abercrombie ED, et al. J Neurochem. 1989;52(5):1655-1658; 5. Stanford SC. Pharmacol Ther. 1995;68(2):297-242; 6. Meana JJ, et al. Biol Psychiatry. 1992;31:471-490; 7. Garcia-Sevilla JA, et al. J Neurochem. 1999;72(1):282-291; 8. Roiser JP, Sahakian BJ. CNS Spectr. 2013;18(3):139-149.



Neural Circuitry of Monoamines and GABAergic Neurons Overlap

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5-HTX, serotonin receptor X; α/βX, noradrenaline receptor X; GABA, gamma-aminobutyric acid; GABAX, gamma-aminobutyric acid receptor X; DX, dopamine receptor X; DA, dopamine; FCX, frontal cortex; NA, noradrenaline.

Millan MJ. Pharmacol Ther. 2006;110:135-370.

• GABAergic interneurons provide a link between several classes of serotonergic receptors and monoaminergic neurons

• “Long-loop” feedback inhibition is likely mediated by descending glutamatergic neurons which act via stimulation of GABAergic interneurons

Image from Millan et al. 2006



Overlap Between Monoamine Neurotransmitter Systems Plays a Role in Emotional Behavior

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5-HT, serotonin; DA, dopamine: NE, norepinephrine.

Zajecka J, et al. J Clin Psychiatry. 2013;74:407-414.

Drive

Impulsive BehaviorEnergy, Interest

AnxietyIrritable

Behavior

SexAppetite

Aggressive Behavior

Motivation

Mood, EmotionCognitive Function

5-HTNE

DA



Serotonin (5-HT)

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1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786.2. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th Edition. New York, NY:

Cambridge University Press; 2013.

5-HT projections in the brain2Findings from research with depressed patients1:

– Low levels of blood platelet 5-HT

– Low plasma levels of L-tryptophan

– Depletion of dietary tryptophan induces depression

– Tryptophan administration seems to provide beneficial effects



5-HT1A

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1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786.2. Panesar K, et al. 5-HT1A Receptors in Psychopharmacology. Psychopharmacology Institute. Available at: http://psychopharmacologyinstitute.com/cns-receptors/5-ht1a-receptors/

5-HT cell body

Presynaptic 5-HT1A

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• Auto-receptor • Regulates 5-HT release• Rapidly desensitize

after activation

Postsynaptic5-HT1A

1

• Hetero-receptor• Regulate inhibition of

non-5-HT neurons• Do not desensitize

5-HT1A

5-HT1A

5-HT(1A), serotonin (receptor 1A). Image adapted from Panesar K, et al.2



5-HT1B

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1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786.2. Saitow F, et al. J Neurophysiol. 2009;101(3):1361-1374.

• Similar to 5-HT1A, 5-HT1Bis expressed1:

− Presynaptically (auto-receptor)− Postsynaptically (hetero-receptor)

• Densely expressed in basal ganglia, nucleus accumbens, and substantia nigra1

• Stress upregulates 5-HT1B receptor expression in the dorsal raphe nucleus1

• Antidepressants dramatically effect 5-HT1B, possibly underlying their antidepressant and anxiolytic effects1

GABA

Glutamate

5-HT1A

5-HT1B

5-HT1A5-HT1B

Image from: Saitow et al. 200925-HT(1A/1B), serotonin (receptor 1A/1B); GABA, gamma-aminobutyric acid.



5-HT2A

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1. Siegel GJ et al. Basic Neurochemistry – Molecular, Cellular and Medical Aspects. 7th Edition. Boston, MA: Elsevier; 2006; 2. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786; 3. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. New York, NY: Cambridge University Press; 2000.

• Highly expressed in the frontal cortex, basal ganglia, and parts of the limbic system1

• Depressed patients have greater 5-HT2A receptor density2

• Promotor region of 5-HT2Avariant shows increased risk of depression2

• Some SSRIs downregulate 5-HT2A

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5-HT(2A), serotonin (receptor 2A); SSRI, selective serotonin reuptake inhibitor.

5-HT2Areceptor

Serotonin

Dopamine

Dopamine neuron

Serotonin neuron

5-HT2Areceptor

Image adapted from Stahl. 20003



• 5-HT projections connect with glutamatergic pyramidal neurons in the cortex

• Cortical 5-HT1A receptor stimulation inhibits glutamatergic neurons, increasing DA release in the striatum

• Cortical 5-HT2A receptor activation stimulates glutamatergic neuron, inhibiting DA release in the striatum

• Therefore, it is proposed that blockade of cortical 5-HT2A receptors relieves inhibition of DA release (functionally analogous to 5-HT1A stimulation)

Modulating DA Activity via 5-HT Receptors

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th Edition. New York, NY: Cambridge University Press; 2013.

Proposed Actions:

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5-HT2A

Glu

5-HT1A

DA

Solid line = active

Dotted line = inactive



5-HT Transporter (SERT)

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1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786.2. Zhao Z, et al. Neuropsychopharmacology. 2009;34(6):1467-1481.

• Removes excess 5-HT from extracellular space1

• Main target of antidepressants, SSRIs and SNRIs1,2

• Mainly expressed by 5-HT neurons1

• Genetic link to SERT: patients with a functional polymorphism tend to have higher probability of depression1

• SERT undergo adaptive changes with SSRI treatment1

SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin re-uptake inhibitors.;

Image adapted from Fakhoury. 20161



Dopamine (DA)

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1. Robinson DS. Primary Psychiatry. 2007;14(5):21-23; 2. Dunlop BW, et al. Arch Gen Psychiatry. 2007;64(3):327-337; 3. Whitton AE, et al. Curr Opin Psychiatry. 2015;28(1):7-12.

• Observed dopaminergic dysregulation in patients with depression includes: – Functional deficiencies in synaptic DA1

– Reduced homovanillic acid (HVA)1

– Lower DA binding to the DAT1

– Genetic alterations in D4 receptors, DAT, and COMT2

• Neural activation during reward processing tasks differ in patients with depression versus healthy controls:– A single major depressive episode, or

recurrent MDD, is associated with reduced activation in the caudate and nucleus accumbens3

D1 D2

D2 autoreceptor

GGAC

AC

GAC

Dopamine

L-dopa

L-tyrosine

3-MTHVA

+ -cAMP

Downstream signaling

3-MT HVA

DAT

VMAT

Presynaptic neuron

Postsynaptic neuron

TH

Dopaminergic Signaling

3-MT, 3-methoxytyramine; AC, adenyl cyclase: cAMP, cyclic AMP; COMT, catechol O-methyltransferase; DX, dopamine receptor subtype X; DAT, dopamine transporter; G, G protein; MAO-B, monoamine oxidase B; MDD, major depressive disorder; TH, tyrosine hydroxylase; VMAT, vesicular monoamine transporter.

Dopamine

Image from Dunlop et al. 20072



Norepinephrine (NE)

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1. Moret C, et al. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):9-13. 2. Tully K, et al. Mol Brain. 2010;3:15.

• Post-mortem tissue and functional imaging studies have elaborated on adrenergic modulations in depression1:

– Suicide victims with depression have shown an altered α2 receptor density and sensitivity

– Patients with MDD demonstrated decreased norepinephrine transporter (NET) binding in the locus coeruleus

• Depleting NE levels during remission in patients with depression resulted in the rapid reappearance of depressive symptoms1*

* Patients were in remission and no longer taking any antidepressant medication.α2, alpha-2 adrenergic receptor; PFC, prefrontal cortex.

Image from Tully K, et al. 2010.2



α Receptors Appear to Modulate 5-HT Release in MDD1,2

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1. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd Edition. New York, NY: Cambridge University Press; 2011. (Image based on Stahl).

2. Cedraz-Mercez PL, et al. Exp Physiol. 2007;92.5:923-931.

• NE reciprocally regulates 5-HT neurons:– α1 receptors (located on 5-HT

neurons) promote 5-HT release – α2 receptors (located

postsynaptically on 5-HT neurons) indirectly attenuate 5-HT release

• Antagonism of α2 receptors indirectly decreases 5-HT inhibition

NE5-HT

NEneuron

5-HTneuron

Presynaptic α2 receptor

α1 receptor

Postsynapticα2 receptor

5-HT, serotonin; α, alpha adrenergic receptor; NE, norepinephrine.



Theorized Involvement of Non-monoamine Neurotransmitters in MDD Pathophysiology1

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Zhao et al. J Affect Disord. 2012;138(3):494-502.

Image from: Zhao et al. 20125-HT, serotonin; GABA, GABA, gamma-aminobutyric acid MDD, major depressive disorder; NE, norepinephrine.



Sanacora G et al. Nat Rev Drug Discov. 2008;7(5):426-437.

• Glutamatergic dysregulation has been implicated in the pathophysiology of several psychiatric and neurological disorders

• Compared with healthy controls, observed alterations in the glutamate system in patients with MDD include:

– Neuroanatomically specific modulations in glutamate levels– Reduced NMDA receptor-binding affinity– Reduced glutamate transporter expression

• Antidepressants and mood stabilizers used in the treatment of mood disorders affect many facets of the glutamate system

• Several agents that affect the glutamate system have been explored as potential treatments in mood disorders. These include:

– Inhibitors of glutamate release– NMDA antagonists– NMDA partial antagonists

Glutamate Hypothesis of Depression

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NMDA, N-methyl-D-aspartate.


© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD

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Neurotransmitter Functioning In Major Depressive Disorder

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

January 2017 MRC2.CORP.D.00181

Module 2A - Neurotransmitter Functioning In Major Depressive …€¦ · ·...

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