Neurobiology of Norepinephrine

&

The Role of SNRI in Depression

The Mind Body Clinical Story of an Intriguing Neurotransmitter

Rakesh Jain, MD, MPHAssociate Clinical Professor

University of Texas Medical SchoolHouston, Texas USA

The information presented herein has been developed by a third party independent from

Pfizer, Pfizer does not necessarily share or endorse the information contained herein, and it

is not responsible for the opinions, images, pictures, videos or any other material contained herein or for the accuracy or parameters of such

presentation. Pfizer did not participate in the development of the content of this presentation.

What is it?

Norepinephrine is a catecholamine [an organic compound that has a catechol (benzene with two hydroxyl side groups) and

a side-chain amine.] with multiple roles including as a hormone and a neurotransmitter.

And Why We Care?The noradrenergic neurons originate both in the locus coeruleus and the lateral tegmental field. The axons of the neurons in the locus coeruleus act on adrenergic receptors in:

AmygdalaCingulate gyrusCingulumHippocampusHypothalamusNeocortex

Spinal cordStriatumThalamusSome Brainstem nucleiCerebellum

What is it’s function?Neurotransmitter:

One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons affecting the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions.1

Hormone: As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled.2 Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply.3 Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus.4

Drug: When norepinephrine acts as a drug, it increases blood pressure by increasing vascular tone (tension of vascular smooth muscle) through α-adrenergic receptor activation; a reflex bradycardia homeostatic baroreflex is overcome by a compensatory reflex preventing an otherwise inevitable drop in heart rate to maintain blood pressure.

http://en.wikipedia.org/wiki/Norepinephrine. Retrieved 2013-02-041. Guyton, Arthur; Hall, John (2006). "Chapter 10: Rhythmical Excitation of the Heart". In Gruliow, Rebecca (Book). Textbook of Medical Physiology (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc.. p. 122. ISBN 0-7216-0240-1; 2. Tanaka2000 Tanaka M, et al. (2000). Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. doi:10.1016/S0014-2999(00)00569-0; 3. The Hormone Foundation. "The Endocrine System & Types of Hormones.“; 4. Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A. 17:6058–6063 doi:10.1073/pnas.0909586107 PMID 20231476

The Life Cycle of NE – And Therapeutic Opportunities

Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of Norepinephrine (NE) or by uptake by surrounding cells.

• Biosynthesis• Vesicular transport• Release• Receptor binding• Termination• Uptake• Degradation

http://en.wikipedia.org/wiki/Norepinephrine. Retrieved 2013-02-04

Where Does NE Come From ?

Sperner-Unterweger B, et al. Progg Neuro-Psychopharm Bio Psych 2012.

Norepinephrine is synthesized by a series of enzymatic steps in

the adrenal medulla and postganglionic neurons of the

sympathetic nervous system from the amino acid tyrosine.

Mechanism: UptakeUptake: Extracellular uptake of norepinephrine into the cytosol is done either presynaptically (uptake 1) or by non-neuronal cells in the vicinity (uptake 2). Furthermore, there is a vesicular uptake mechanism from the cytosol into synaptic vesicles.

1. Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167; 2. Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

Comparison of norepinephrine uptake

Uptake Transporter Vmax(nmol/g/min)1 KM

1 Specificity2 Location Inhibitors3

Uptake 1 Norepinephrine transporter3 1.2 0.3

norepinephrine >epinephrine > isoprenaline

presynaptic

• Cocaine• Tricyclic antidepressants

(e.g. desipramine)• Phenoxybenzamine• Amphetamine

Uptake 2 100 250epinephrine > norepinephrine >isoprenaline

cell membrane of non-neuronal cells4

• normetanephrine• steroid hormones (e.g.,

corticosterone)• phenoxybenzamine

Vesicular VMAT3 ‒3 ~0.23norepinephrine > epinephrine > isoprenaline3

Synaptic vesicle membrane3

• Reserpine3

• Tetrabenazine

Mechanism: Degradation

Degradation:In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are:

• Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT)• 3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO)• Vanillylmandelic acid (3-Methoxy-4-hydroxymandelic acid), also referred to as vanilmandelate or VMA (via MAO)• 3-Methoxy-4-hydroxyphenylethylene glycol, "MHPG“ or "MOPEG" (via MAO)• Epinephrine (via PNMT) 2

Flower R, Rang HP, Dale MM; Ritter JM. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

Norepinephrine degradation. Enzymes are shown in boxes.1

Adrenergic Receptor Classification

Noradrenergic Receptors

Alpha

Beta

Beta 1

Beta 2

Beta 3

Alpha 2

Alpha 1 Alpha 1B

Alpha 1A

Alpha 2B

Alpha 2A

Alpha 2B

Focus on the Alpha Family Of Noradrenergic Receptors

• Currently, three Alpha subtypes, designated Alpha 1, Alpha 2, and Alpha 3, have been cloned and pharmacologically characterized

• The mammalian heart expresses primarily Alpha 1 (75–85%), a substantial number of Alpha 2 can be detected in cardiac tissue

• The Alpha 2 are primarily expressed in cells other than cardiac myocytes (e.g. endothelial cells, fibroblasts, and vascular smooth cells)

Post SR, et. al. Annu Rev. Pharmacol. Toxicol 1999.39:343-60

1. Arnsten AFT, et al. J Child Adolesc Psychopharmacol. 2007;17:393-406; 2. Franowicz JS, Arnsten AFT. Psychopharmacology. 2002;162:304-312; 3. MacDonald E, et al. Trends Pharmacol Sci. 1997;18:211-219.

Most prevalent subtype in the PFC, also located in the locus ceruleus1

Critical to PFC functioning1

• Attention• Behavior• Emotions

Associated with sedative and hypotensive effects1,2

Least prevalent subtype3

Most concentrated in the thalamus3

Associated with sedative effects1

Much less prevalent than A; present in cortex and locus ceruleus3

Associated with sedative and hypotensive effects1

AA BB CC

Alpha -2 Receptors are Very Important in Mental Health

Alpha-2 agonists have varying degrees of affinity for the three alpha-2 receptor subtypes

Excitatory signal

a2A receptor

NE

Ion channel

Reuptake transporter

Postsynaptic neuron

NE presynaptic terminal

Wang M, et al. Cell. 2007;129:397-410.

Transmission of Neuronal Signal is Modulated by the α-2A Receptor

Gribble FM. N Engl J Med. 2010 Jan 28;362(4):361-2

But, Alpha 2 Receptor Agonism, Which is Distributed in the Body too, may Lead to Insulin resistance

Ablad B. et al Drugs. 1976;11 SUPPL 1:100-11; Minneman PK et al. Annu Rev Neurosci. 1981;4:419-61

Turning Our Attention to Beta Adrenergic Receptors: Focus on Beta 1 Distribution

Ablad B. et al Drugs. 1976;11 SUPPL 1:100-11; Minneman PK et al. Annu Rev Neurosci. 1981;4:419-61

Turning Our Attention to Beta Adrenergic Receptors: Focus on Beta 2 Adrenergic Receptor Distribution

Adrenergic Receptors – a True Brain-Body Distribution & Function

The primary regulators of adipose tissue lipolysis, are the catecholamines bind to the alpha 2, beta 1, beta 2, and beta 3 adrenergic receptors.

- The alpha 2 receptor couples with Gi-proteins to inhibit lipolysis- - while the beta receptors couple with Gs-proteins to stimulate

lipolysis. - The beta 1 receptor may mediate low level catecholamine stimulation - the beta 3 receptor, which is activated by higher levels of

catecholamines, may deliver a more sustained signal

Carey GB Adv Exp Med Biol. 1998;441:157-70

Adipose Tissue and NE Receptors

NE Alpha 2 Receptor Stimulation –

Decreased Lipolysis

NE Beta 1 and 2 Receptor

Stimulation – Increased Lipolysis

Beta 1 receptor may mediate low level catecholamine stimulation,

Beta 2 receptor may mediate intermediate level catecholamine stimulation

Beta 3 receptor, which is activated by higher levels of catecholamines, may deliver a more sustained signal

Carey GB Adv Exp Med Biol. 1998;441:157-70

Noradrenergic Beta 3 Receptor – Critical Role on Obesity and Lipolysis

• If genetic polymorphisms of gene coding for Beta 3 Receptors are present, an individual is at higher risk for visceral fat, metabolic syndrome, aggravated lipid metabolism, and elevated blood pressure

• Beta 3 stimulation leads to thermogenesis. Beta 3 receptors are mainly located on adipose cell membranes

• Beta 3 appears crucial for two tasks – a) thermogenesis and b) lipolysis. Therefore its critical for body weight management

Oguri K, et. al Acta Paediatr. 2013 Jan 3. doi: 10.1111/apa.12149Birerdinc A. et al Prog Lipid Res. 2013 Jan;52(1):51-61. doi: 10.1016/j.plipres.2012.08.001

Could Noradrenergic Dysfunction Lead to Obesity? Launois-Bensaude syndrome

Interestingly, treatment with a salbutamol (a beta-2 agonist) –

a noradrenergic drug, lead to adipose tissue reduction and

weight loss

Leung NW. Et al. Clin Endocrinology 1987. 27(5):60106

Brain Aspects of Norepinephrine (NE)

Monoamine Innervation of Prefrontal Cortices

A B

Robbins TW, Arnsten AF. Annu Rev Neurosci. 2009;32:267-287

NE and LC firing: tonic and phasic activity

• Two firing patterns from the LC - tonic and phasic.• Tonic firing is steady-state, background firing that occurs at rest (awake

and alert). – In depression, low tonic firing correlates with fatigue, cognitive dullness.– Chronic stress and depression with low tonic activity and low inhibitory auto

regulation allows excessive phasic NE firing.• Phasic firing occurs in response to a strong stimulus. It correlates with

threat or a significant stressor. Result of robust NE firing.– Increases vigilance.– Enhances sensorimotor reflex responses.– Increases acoustic startle reflex.– Reduces immobility.– Primes the “fight or flight” response. – Associated with anxiety and panic disorders.

1. Morilak DA, Frazer A. Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioral effects in depression and anxiety disorders. Int J Neuropsychopharm. 2004;7:193-218

Several Neurotransmitters Are Involved in Regulating Mood

Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. Cambridge, UK: Cambridge Univ Press; 2000:152.

Norepinephrine Serotonin

Dopamine

Mood, emotion,cognitive function

Motivation

Sex,appetite,

aggression

Anxiety,irritability

Energy, interest Impulsivity

DrivePleasure

Brain Regions and MDD Symptoms: Possible Role of Serotonin Pathways

Arango V et al. Brain Res. 1995;688:121-33. Houdouin F et al. Brain Res. 1991;565:48-56; Hrdina PD et al. Brain Res. 1993;614:37-44; Leibowitz SF et al. Pharmacol Biochem Behav. 1990;37:735-42. Nolte J, Angevine JB Jr. The Human Brain in Photographs and Diagrams. 2nd ed. 2000; Talbot PS, Cooper SJ. Neuropsychopharmacol. 2006;31:1757-67. Walsh SL, Wagner GC. J Pharmacol Exp Ther. 1992;263:617-26; Zangen A et al. Psychopharmacol. 2001;155:434-39.

Raphe nuclei

Changes in mood Suicidal behavior

Psychomotorsymptoms

Loss of weight or appetiteTrouble sleeping

Suicidal ideation

Loss of interestor pleasure

Brain Regions and MDD Symptoms:Possible Role of Norepinephrine Pathways

SSRI = selective serotonin reuptake inhibitor;SNRI = serotonin norepinephrine reuptake inhibitor

Avery RA et al. Neuropsychopharmacol. 2000;23:240-9; Kuratsune H et al. NeuroImage. 2002;17:1256-65. Kurose Y, Terashima Y. Brain Res. 1999;828:115-8. Mao ZM et al. Biol Psychiatry. 1999;46:1259-65; Nolte J, Angevine JB Jr. The Human Brain in Photographs and Diagrams. 2nd ed. 2000; Vetrivelan R et al. Neurosci. 2006;139:1141-51. Watson M, McElligott JG. Brain Res. 1984;296:129-38.

CH

Insomnia/hypersomniaLoss of weight or appetite

dlPF

C

Physical fatigue

Cognitive dysfunction

Locus coeruleus

Reuptake transporter

Presynaptic neuron

Postsynaptic neuron

Catecholamines in the extraneuronal spaceClosed HCN Channel

Propagation of Synapse

HCN=hyperpolarization-activated cyclic nucleotide-gated

Pharmacological block on Re-uptake

Extraneuralcatecholamineconcentration

How Increasing Norepinephrine Availability can Improve Attention and Working Memory

1) Arnsten A. Expert Rev Neurother.2010;10(10):1595-1605; 2) Wang M, et al. Cell.2007;129(2):397-410.

Functional Connectivity Across the “Big Three” Monoamine Systems:

Serotonin, Norepinephrine, and Dopamine

Kennedy SH et al. J Affect Disord. 2011;132(Suppl 1):S21-S23; Trivedi MH et al. J Clin Psychiatry. 2008;69(2):246-258.

5-HT

NEDA

++-

5-HT1A D2

α1

α2 5-HT1B

-

D2

-

α2

D2α2

PostsynapticNeuron

Interneuron5-HT2A for NE neurons5-HT2C for DA neurons

Gupta RK, et al. Aust N Z J Psychiatry. 2003;37(2):190-195.

Interactions Between 5-HT and NE

Cortex/Hippocampus

5-HT1B(-)

NA

5-HT

5-HT1A(-)

1

(+)

5-HT2(-)

2

(-)

2

(-)2

(-)

Locus Coeruleus

Raphé Nucleus

SSRIs Induced NE “over-regulation andthe “noradrenergic cluster”

Core symptoms of depression which respond less well or more slowly to SSRIs-1,2

• Lassitude

• Loss of energy

• Retardation of thoughts and actions

• Concentration difficulties, loss of alertness

• Loss of interest, anhedonia, emotional indifference or blunting

• Sleep difficulties, sometimes worsened by SSRIs

• Appetite loss, sometimes worsened by SSRI nausea1. Bech P et al. Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects of four fixed

citalopram doses compared to placebo in patients with major depression. Psychopharmacology 2002;163:20-25.2. Wade A, et al. The onset of effect for escitalopram and its relevance for the clinical management of depression. Current Med Res Opin.

2006;22:2101-2110.

r = 0.40, p = 0.007

Time A:BDI Time B: BDI

MH

PG

ng

/ml

144 subjects (44 men, 100 women) were reassessed by the BDI. Baseline sMHPG levels in men with a BDI score of ≤9 at time A and a BDI score of ≥10 at time B

Watanabe et al, 2012, Int J Geriatr Psychiatry; 27: 321–326.

Increased NE turnover in MDD

A Psychosocial stress,social isolation, personality

factors

IL-1, TNF-, IL-6

IL-6

EuthymiaStress resilience

Major depression sickness behavior

G

Immunoregulation

k t

i

HP

A -

axi

s-

c

IL-10, TGF-

NE

/-AR IL-1,

TNF-, IL-6

NF-B

ACh TLR

7nAChr

GR

Infection, tissue trauma, neoplasm Macrophage GCs

IL-10, TGF-

Raison et al, Arch Gen Psychiatry. 2010;67(12):1211-1224

Stress and inflammation in MDD

NE – via Locus Ceruleus, Impacts Microglia & Controls Neuro-inflammation

• NE stimulation of microglia suppresses cytokine and chemokine production

• NE stimulation increases microglia migration and phagocytosis

• Alzheimer's Disorder – there is LC degeneration and decreased NE in forebrain

Heneka MT PNAS 2010. 107(13):6058-6063

NE – Its Critical Role on Optimum Astrocyte, Microglia and Neuronal Health

O’Donnel J, et.al Neurochem Res 2012. 37:2496-2512

• Normal vs Depressed – Post mortem study

• Gene expression using quantitative end-point polymerase chain reaction conducted with laser-captured astrocytes from locus ceruleus tissue from matched pairs of

• psychiatrically healthy controls(open symbols)

• men with major depressive disorder(closed symbols).

• Both SLC1A3 and SLC1A2 are glutamate related genes

Szebeni CK, et al. J of Psychiatric Neuroscience 2013. DOI: 10:1503/jpn.120110

In Depressed Humans, Norepinephrine Producing LC (Locus Ceruleus) Have Impaired Astrocytes

NE and Major Depression:Diagnostic and Therapeutic Implication

weight/appetite changes

sleep disturbances

psychomotor fatigue

worthlessness executive dysfunction

suicidal ideation

four more of these required

guilt

depressed mood

apathy/loss of interest

one of these required

Stahl’s essential psycopharmacology: neuroscientific basis and practical applications, 3rd edition, Cambridge University Press, 2008

Constructing a Diagnosis: The Categorical Approach

Associations between the percent changes in pMHPG levels and the percent improvement in HRSD scores before and 4 weeks after paroxetine treatment. 41 inpatients who met the DSM-IV criteria for major depressive disorder scored at least 15 on the HRSD.

Shinkai et al, J Clin Psychopharmacol 2004;24:11–17

Change in NE turnover after SSRI treatment

Antidepressants Are Not Created Equal: Differential Effects on Retardation

HDRS item 8==Retardation score. Includes slowness of thought and speech, impaired concentration and decreased motor activity. Schecter D et al. A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Dis. 2004;83:233-236

Proof Of Concept – a NE Medication Can Improve Both Depression and Fatigue

B. Pangallo et al. Journal of Psychiatric Research 45 (2011) 748e

LY2216684 (Edivoxetine) is a potent, Norepinephrine Reuptake Inhibitor (NRI)

Severity of overall fatigue

during past week

p = .008

Fatigue interference with

daily activities during past week

p = .024

VAS-F scores

N = 217

Week of TreatmentEstimated Probability of Montgomery-Asberg Depression Rating

Scale (MADRS) Remission (Repeated Measures Analysis)

*p < 0.05** p < 0.01

Prob

abili

ty o

f Rem

issi

on (%

)

Placebo Edivoxetine

-25

-20

-15

-10

-5

0

-16.69

-23.30

-18.62

-24.28

How Norepinephrine Interacts With Serotonin: Role of Receptors

• Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. 2000:254.

Presynaptic Alpha 2 Autoreceptor

Postsynaptic Alpha 2 Hetero Receptor

Alpha 1 Receptor

Alpha 2 Antagonist

5-HT

NE

5-HT NeuronRelease the5-HT brake

NE Neuron

Step on 5-HT Accelerator

depressed moodloss of happiness (joy)

loss of interest/pleasureloss of energy/enthusiasm

decreased alertnessdecreased self-confidence

Reduced positive affect

++

++ +

DAdysfunction

NE

dysfunction

Targeting More than One Mechanism – Does That Offer Any Further Help ?

Normalmood

depressed moodguilt/disgust fear/anxiety

hostilityirritabilityloneliness

Increased negative affect

-- - -

-

NEdy

sfunc

tion

5HT

dysfunction

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 3 rd Ed. NY, NY: Cambridge Univ Press; 2008.

Even Treatments Such as Deep Brain Stimulation (DBS) work via NE / DA / 5HT

Animal study of DBS (Deep Brain Stimulation) of Nac (Nucleus Accumbens) and Examination of neurotransmitter elevation in OFC (Orbitofrontal Cotrex)

Clearly, all the neurotransmitters are impacted even by therapies for resistant depression – such as DBS

Dijk A et.al J Neurochemistry 2012. 123:897-903

Norepinephrine &Neurobiology of Exercise

ANS, autonomic nervous system; BDNF, brain-derived neurotrophic factor; CNS, central nervous system; CREB, cyclic adenosine monophosphate response element-binding protein; CVD, cardiovascular disease; DA, dopamine; ERK, extracellular signal-regulated kinase; 5-HT, 5-hydroxytryptamine; GABA, gamma amino butyric acid; IBD, inflammatory bowel disease; NA, noradrenaline; NFκB, nuclear factor of kappaB; ROS, reactive oxygen species; TrkB, tyrosine residue kinase receptor-type 2; VTA, ventral tegmental area; WAT, white adipose tissue.

Dishman RK et al. Obesity. 2006;14(3):345-356.

Function DiseaseStructure

Executive ControlsPrefrontal & Cingulate Cortex

Emotional ControlsAmygdala, Prefrontal Cortex

External Input• Visual• Olfactory• Acoustic• Gustatory• Somatosensory

ANS&

Endocrine Systems

DA↓

Parkinson’s Disease

↑ROS

Alzheimer’sDementia

Schizophrenia

Depression

Sleep Disorders

Obesity

Diabetes

CVD

Immune Disorder

IBD, Constipation Colon Cancer

Learning & Memory

Immune Control

Gastrointestinal Control

MuscleCardiovascular Consequences

Metabolic ConsequencesLiver, WAT, Pancreas

Thermal Consequences

Behavior• Social• Sexual• Coping• Addictive• Escape• Fight &

Flight• Stress• Sleep• Ingestive

Motor ControlsMotor CortexStriatum, Brainstem, Cerebellum, Spinal Cord

Motivational ControlsReward,Wanting,SelectionHypothalamus, Accumbens, VTA

Cognitive ControlsHippocampus, Cortex

NeuralPrimary Afferents

“Exercise”

Internal Feedback“Consequences of exercise”

Humoral Factors

CNS

Energy Balance

RepairPlasticityProtectionNeurogenesisTranscriptionNA, 5-HT,GABA, Glutamate, GlycineBDNF/TrkBERK/CREBNFKB

Meditation/Yoga: As a Mind-Body Intervention

Streeter CC et al. Med Hypotheses. 2012;78(5):571-579.

Mean thalamic GABA levels in participants with Major Depressive Disorder (MDD) and low back pain (LBP) (n=2) compared to normal participants (n=19) before (Scan 1) and after (Scan 2) a 12-week yoga intervention

Stress Yoga-Based Practices

Sympathetic Nervous System (SNS) Parasympathetic Nervous System

Hypothalamic-pituitary-adrenal Axis Hypothalamic-pituitary-adrenal Axis

GABA Activity GABA Activity

Prefrontal Cortex GABA-R

ThalamusGABA-R

InsulaGABA-R Hypothalamus

GABA-R

PeriaqueductalGABA-R

Nucleus Ambiguus GABA-R

Dorsal Medial Nucleus GABA-R

Brainstem Nuclei

Vagal Efferents

Pharynx, Larynx, Lungs Cardiac Gastrointestinal

Vaga

l Affe

rent

s

Amygdala GABA-R

Pituitary

Adrenal

Hippocampus GABA-R

Vagal-GABA Circuits Key GABA-R, gamma aminobutyric acid receptorsAutonomic, GABA and other neurotransmitter pathwaysHypothalamic pituitary adrenal axis neuroendocrine pathways

Parabrachial NucleusGABA-R

Nucleus Tractus Solitarius GABA-R

Cognition: Presence of Norepinephrine Can Exert Objective Changes in Cognition

(desvenlafaxine as an example)

Reddy S, st al. Presented at the 2011 CPNP Annual Meeting, May 1-4, 2011, Phoenix, Arizona.

Cognition: Role Various Receptors Play in Various Aspects of Cognition and Memory

O’Donnel J, et.al Neurochem Res 2012. 37:2496-2512

NE Containing Anti-Depressants Show Wide Spectrum of Symptoms & Wellness Coverage

Focus on SDS and WHO-5

Guico-Pabia CJ, et al. Poster Presentation, American Academy of Nurse Practitioners, 2010

First-Line Antidepressants: Guidelines

CANMAT APA

SNRIs Desvenlafaxine, duloxetine, venlafaxine

Desvenlafaxine, duloxetine, venlafaxine

SSRIs Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

TCAs Amitriptyline, doxepin, imipramine, nortriptyline, protriptyline, maprotiline trimipramine

Serotonin modulators Nefadozone, trazodone

Norepinephrine-serotonin modulator

Mirtazapine Mirtazapine

MAOIs Moclobemide Isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine

DNRI Bupropion Bupropion

APA = American Psychiatric Association; TCA = tricyclic antidepressant; MAOI = monoamine axidase inhibitor; DNRI = dopamine norepinephrine reuptake inhibitorAmerican Psychiatric Association. Am J Psychiatry. 2010;[in press]. Lam RW, et al. J Affect Disord. 2009;117(Suppl 1):S26-S43.

Remission Rates with SSRIs vs. SNRIs Debate: What is the Latest?

SNRI remission rates were 5.7% higher

A meta-analysis of head-to-head SSRIs vs. SNRIs trials Remission as the outcome measured

Machado M et al. J Clin Pharm Ther. 2010;35(2):177-188.

Odds RatioIV, Random, 95% CI

1 2Favors SNRIs

0.2 0.5 5Favors SSRIs

600

300

400

200

1.51

0.50

-0.5-1

-1.5

100

500

Number of Patients in Each Trial (N)

In (

odds

rat

io)

Norepinephrine/ Dopamine Facilitation

A Reciprocal & Positive Relationship Between Medication Induced NE / DA Increase and Exercise

Stenman E, Lilja A. Medical Hypothesis 2013. (80):47-49

• Fatigue and Impaired Cognitive Function are often linked to NE/ DA neurotransmission

• Physical Activity Improves these neurotransmitters

• However, a a depressed individual the presence of a NE / DA medication may reduce fatigue and improve motivation to increase odds of patient exercising

Physical Exercise

To Summarize – Part I..

• NE is widely distributed in the Brain and Body, making it a perfect “Mind-Body” Regulator of diverse functions

• In the periphery, it is critical in Adipose Tissue Lipogenesis / Lipolysis

• In the CNS it has surprisingly diverse roles to play

To Summarize – Part II.

• In the CNS, Norepinephrine regulates a vast array of functions– Microglia Inflammation

– Astrocyte Function Optimization

– Attention / Cognition

– Energy / Fatigue

– Mood / Stress Regulation

– Positive Psychology Symptoms – Novelty seeking/ Positive affect, etc

To Summarize – Part III

• NE has not been central to Clinician’s thinking until recently, but it truly should be

• Exercise, Psychotherapy, and Meditation are valid Non-Pharmacological modulators of NE

• A number of pharmacological NE treatment options are available, and more are emerging