Overcoming the Treatment Challenges in MDD:
Examining the
Mind-Body Aspects
of Norepinephrine in
Depression
Sponsored by
Supported by an independent
educational grant from Lilly USA,
LLC.
Faculty
Rakesh Jain, MD, MPH
Associate Clinical Professor
Department of Psychiatry & Behavioral Sciences
University of Texas Medical School
Houston, TX
Director, Psychopharmacology Research
R/D Clinical Research Center
Lake Jackson, TX
Faculty Disclosure
• Dr. Jain: Consultant—Addrenex, Forest, Lilly (and
spouse), Merck, Pamlab (and spouse), Pfizer, Shionogi,
Shire, Sunovion; Promotional Speakers Bureau—
Addrenex, Forest, Lilly, Merck, Pamlab, Pfizer,
Shionogi, Shire, Sunovion; Grant/Research Support—
AstraZeneca, Forest, Lilly, Pfizer, Shire; Scientific
Advisor—Addrenex, Lilly, Merck, Pamlab, Pfizer,
Shionogi, Shire, Sunovion
Disclosure
• The faculty have been informed of their responsibility to
disclose to the audience if they will be discussing offlabel or investigational use(s) of drugs, products, and/or
devices (any use not approved by the U.S. Food and
Drug Administration [FDA])
• Applicable CME staff have no relationships to disclose
relating to the subject matter of this activity
• This activity has been independently reviewed for
balance
Off-Label Uses and
Investigational Agents
• The following medications are not approved by the U.S.
Food and Drug Administration for the treatment of
major depressive disorder: atomoxetine, reboxetine,
trazodone, nefazodone, guanfacine, clonidine, beta
agonists, milnacipran, edivoxetine, levomilnacipran
Learning Objectives
• Outline the challenges associated with achieving
durable remission of MDD with traditional first‐line
pharmacotherapies
• Describe norepinephrine’s neurobiological and
receptor‐specific mechanisms responsible for mood
related and residual symptoms of MDD, such as
cognition and fatigue
• Describe clinical data on newer and investigational
agents for MDD pharmacotherapy and factors involved
in treatment selection
Accreditation
In support of improving patient care, North American Center for Continuing Medical Education, LLC
(NACCME) is accredited by the Accreditation Council for Continuing Medical Education (ACCME), the
Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center
(ANCC) to provide continuing education for the health care team.
CME
NACCME designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians
should claim only the credit commensurate with the extent of their participation in the activity.
CNE
This continuing nursing education activity awards 1.5 contact hours.
Provider approved by the California Board of Registered Nursing, Provider #13255 for 1.5 contact hours.
APA
North American Center for Continuing Medical Education, LLC (NACCME) is approved by the American
Psychological Association to sponsor continuing education for psychologists. NACCME maintains
responsibility for this program and its content.
Physician assistants, nurse practitioners and nurses may participate in this educational activity and earn a
certificate of completion as AAPA, AANP and ANCC accept AMA PRA Category 1 Credits™ through their
reciprocity agreements.
Other health care professionals treating patients with mental health disorders should check with their state
licensing and certification boards to determine if this activity meets their continuing education
requirements.
Instructional Level: Advanced
ARS Question
What is the most important factor that influences your
treatment decision in selecting an antidepressant?
1. Safety
2. Patient preference
3. Efficacy
4. Treatment side effects
5. Medication costs
ARS Question
How do you rate your understanding of norepinephrine’s
neurobiological and receptor-specific mechanisms
responsible for mood related and residual symptoms of
MDD, such as cognition and fatigue?
1. Excellent
2. Good
3. Fair
4. Poor
ARS Question
How do you rate your understanding of clinical data on
newer and investigational agents for MDD
pharmacotherapy and factors involved in treatment
selection?
1. Excellent
2. Good
3. Fair
4. Poor
ARS Question
What proportion of patients with MDD fail to achieve
remission on initial antidepressant therapy?
1. One-third
2. One-half
3. Two-thirds
4. Three-quarters
ARS Question
In animal models of cognitions, all of the following
receptors are thought be involved EXCEPT:
1. Delta serotonin receptors
2. 2B serotonin receptors
3. Alpha 2 noradrenergic receptors
4. Beta 2 noradrenergic receptors
ARS Question
Regarding lipid and fat metabolism, which of the following
statements best describes the interaction between
noradrenergic receptors?
1. Noradrenergic receptors are involved in lipolysis
(fat release) only
2. Noradrenergic receptors are involved in lipogenesis
(fat storage) only
3. Depending on the noradrenergic receptor, it is
involved with either lipolysis or lipogenesis
4. None of the above
Let’s Not Underestimate Our Enemy:
Depression Is THE Leading Cause of Disability
Leading Contributors to Disability
Unipolar Depression
10.3
Ischaemic Heart Disease
6.76
Alcohol Use Disorders
4.08
Chronic Obstructive Pulmonary Disease
3.65
Trachea/Bronchus/Lung Cancer
3.07
Hearing Loss, Adult Onset
3.07
Alzheimer's/Dementia
3.01
Cerebrovascular Disease
2.96
0
5
10
15
20
Percent of Total Disability-Adjusted Life Years
(DALYs)a
aDALYs
represent the total number of years lost to illness, disability, or premature death within a
given population. They are calculated by adding the number of years of life lost to the number of
years lived with disability for a certain disease or disorder.
National Institute of Mental Health. Leading individual diseases/disorders.
www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed May 20, 2013.
The Kupfer Curve:
The Life Story of Depression
Response
Remission
Relapse
Recovery
Relapse
Recurrence
Continuation
Maintenance
“Normalcy”
Symptoms
Syndrome
Treatment Phases
Acute
Kupfer DJ, Frank E. Am J Psychiatry. 1987;144(1):86-88.
STAR*D Results Demonstrate
Diminishing Effectiveness of Treatments
STAR*D Remission Rates1-6
Patients in Remission
40%
30%
Level 1
Level 2
Level 3
Level 4
Remission:
(HAM-D-17 ≤7)
29.9%
27.5%
21.2%
20.3%
20%
16.1%
13.7%
10%
6.9%
0%
Mono
High
Aug
Switch
Aug
Switch
Window of Opportunity
Aug
Switch
Low
STAR*D = Sequenced Treatment Alternatives to Relieve Depression; HAM-D-17 = 17-item Hamilton Rating Scale for
Depression.
1Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40; 2Trivedi MH, et al. N Engl J Med. 2006;354(12):1243-1252; 3Rush
AJ, et al. N Engl J Med. 2006;354(12):1231-1242; 4Nierenberg AA, et al. Am J Psychiatry. 2006;163(9):1519-1530; 5Fava
M, et al. Am J Psychiatry. 2006;163(7):1161-1172; 6McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541.
STAR*D Reveals Its Secrets
The Dangers of Residual Symptoms
Cumulative Probability of Relapse
Overall 40% Relapse Rate
1.00
Residual Symptoms:
• Sleep disturbance
• Sad mood
• Appetite/
weight change
• Concentration
• Outlook
• Suicidal ideation
• Involvement
• Energy/fatigue
• Psychomotor
0.75
Residual
Symptom Domains
0.50
0 domains
1 domain
2 domains
3 domains
4 domains
5 domains
0.25
0.00
0
10
20
30
40
50
60
QIDS Relapse Time, Weeks
Increasing number of symptom domains leads to increased risk of relapse
(x2[5]=17.7155, P=.0033)
QIDS = 16-item Quick Inventory of Depressive Symptomatology.
Nierenberg AA, et al. Psychol Med. 2010;40(1):41-50.
What Is Remission?
It Depends on Whom You Ask
Are the
symptoms gone?
What is the
score on rating
instrument?
A Researcher’s Definition
A Clinician’s Definition
Are the symptoms gone?
Am I functioning well?
Do I feel optimistic and
self-confident?
A Patient’s Definition
Zimmerman M, et al. Am J Psychiatry. 2006;163(1):148-150.
Remission’s Importance:
Its Impact on Patients’ Lives
Impacts Physical
Functioning1,2
Impacts Social
Functioning1,2
Impacts Children’s
Mental Well-being3
1Sobocki
Impacts Occupational
Functioning1,2
Impacts Marital
Functioning4
Increased Relapse
Risk; Faster Relapse1,2
P, et al. Int J Clin Pract. 2006;60(7):791-798; 2Keller MB. JAMA. 2003;289(23):3152-3160;
MM, et al. JAMA. 2006;295(12):1389-1398; 4Bromberger JT, et al. J Nerv Ment Dis. 1994;
182(1):40-44; 5Thase M, et al. Am J Psychiatry. 1992;149(8):1046-1052; 6Judd LL, et al. J Affect Disord.
1998;50(2-3):97-108.
3Weissman
MCI and Vascular Disease Were Correlated
with Severity of Depressive Symptoms
No depressive symptoms
Low depressive symptoms
Moderate or high depressive symptoms
N=2,220
2.5
Odds Ratio
2.0
1.5
1.0
0.5
0.0
Unadjusted Demographics
Vascular
Events
Subclinical
Vascular
Disease
Vascular
Disease
on MRI
Adjustment
MCI = mild cognitive impairment; MRI = magnetic resonance imaging.
Barnes DE, et al. Arch Gen Psychiatry. 2006;63(3):273-279.
All
What Does a Prospective Study Reveal about
Differences between Nonremitters and Remitters?
3-year follow-up study (38 patients, 30 controls)
Gray matter density decline in nonremitted patients vs remitted patients
Statistically smaller areas in nonremitted patients were:
anterior cingulum, hippocampus, amygdala, DLPFC, and DMPFC
DLPFC = dorsolateral prefrontal cortex; DMPFC = dorsomedial prefrontal cortex.
Frodl TS, et al. Arch Gen Psychiatry. 2008;65(10):1156-1165.
Brain Aspects of
Norepinephrine
What Is Its 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 coeruleus4
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
1Guyton
A, Hall J. In: Textbook of Medical Physiology, Eleventh Edition. Philadelphia, PA: Elsevier Inc; 2006:122;
M, et al. Eur J Pharmacol. 2000;405(1-3):397-406; 3Hormone Health Network. The Endocrine System: Diseases,
Types of Hormones & More. www.hormone.org/endo101. Accessed May 30, 2013; 4Heneka MT, et al. Proc Natl Acad Sci
U S A. 2010;107(13):6058-6063; http://en.wikipedia.org/wiki/Norepinephrine. Accessed May 30, 2013.
2Tanaka
Origins: Norepinephrine System
• The noradrenergic neurons in the brain form a neurotransmitter system,
that, when activated, exerts effects on large areas of the brain. The effects
are alertness and arousal, and influences on the reward system
• 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
– Amygdala
– Spinal cord
– Cingulate gyrus
– Striatum
– Cingulum
– Thalamus
– Hippocampus
– Some brainstem nuclei
– Hypothalamus
– Cerebellum
– Neocortex
Smith HR, et al. Neuroscience. 2006;138(2):703-714; http://en.wikipedia.org/wiki/Norepinephrine.
Accessed May 30, 2013.
The Life Cycle of Norepinephrine—
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 or by uptake by
surrounding cells
– Biosynthesis
– Termination
– Vesicular transport
– Uptake
– Release
– Degradation
– Receptor binding
Alousi A, Weiner N. Proc Natl Acad Sci U S A. 1966;56(5):1491-1496;
http://en.wikipedia.org/wiki/Norepinephrine. Accessed May 30, 2013.
Where Does Norepinephrine
Come from?
O
OH
NH2
Phenylalanine
Phenylalanine hydroxylase
+BH4
O
OH
HO
NH2
+O2
Tyrosine
OH
Tyrosine hydroxylase
+BH4 O
HO
HO
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.
OH
NH2
HO
+O2
HO
Epinephrine
HN
CH3
Phenylethanoamine
N-methyltranferase
L-DOPA
+CH3
OH
DOPA decarboxylase
+O2
HO
HO
HO
-CO2
NH2
Dopamine
HO
NH2
Norepinephrine
Dopamine β-hydroxylase
Sperner-Unterweger B, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2012 October 17;[Epub
ahead of print].
Mechanism: Degradation
HO
Normetanephrine
CH
O
CHO
Normetanephrine
aldehyde
HO
Catechol-O-methyltransferase (COMT)
HO
OH Norepinephrine
OH
HO
OH
CHO
Norepinephrine
aldehyde
Aldehyde reductase
NH2
Oxidase (MAO)
OH
Aldehyde dehydrogenase
NH2
O
Monoamine
CH
CH
CH
O
HO
O
Vanillylmandelic acid
COMT
CH
HO
CH
HO
O
3,4-dihydroxymandelic acid
CH
CH
O
HO
3-Methoxy-4-hydroxy
phenylglycol (MHPG)
COMT
CH
HO
CH
HO
3,4-dihydroxyphenylglycol
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)
Rang HP, et al. Rang and Dale’s Pharmacology, Sixth Edition. London: Churchill Livingstone; 2007.
Monoamine Innervation of
Prefrontal Cortices
A
B
Ventral tegmental area
(dopamine)
Locus coeruleus
(norepinephrine)
Robbins TW, Arnsten AF. Annu Rev Neurosci. 2009;32:267-287.
Dorsal raphe
(serotonin)
NE and LC Firing:
Tonic and Phasic Activity
• 2 firing patterns from the LC: tonic and phasic1
• 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
autoregulation 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
LC = locus coeruleus.
1Morilak DA, Frazer A. Int J Neuropsychopharmacol. 2004;7(2):193-218.
Several Neurotransmitters
Are Involved in Regulating Mood
Norepinephrine
Serotonin
Energy,
Interest
Anxiety,
Irritability
Impulsivity
Mood,
Emotion,
Cognitive
Function
Motivation
Sex,
Appetite,
Aggression
Drive,
Pleasure
Dopamine
Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Second
Edition. Cambridge, UK: Cambridge University Press; 2000:152.
So, to Be Clear…
• Norepinephrine is but only 1 of the neurotransmitters
thought to be involved in the genesis of major
depression
• Serotonin, dopamine, and glutamate pathways are also
involved
Brain Regions and MDD Symptoms:
Possible Role of Serotonin Pathways
Psychomotor
symptoms
Loss of interest
or pleasure
Raphe
nuclei
Changes in
mood
Suicidal
behavior
Loss of weight or
appetite
Trouble sleeping
Suicidal ideation
Arango V, et al. Brain Res. 1995;688(1-2):121-133; Houdouin F, et al. Brain Res. 1991;565(1):48-56; Hrdina PD, et al.
Brain Res. 1993;614(1-2):37-44; Leibowitz SF, et al. Pharmacol Biochem Behav. 1990;37(4):735-742; Nolte J, Angevine
JB Jr. The Human Brain in Photographs and Diagrams. Second Edition. St. Louis, MO: Mosby; 2000; Talbot PS,
Cooper SJ. Neuropsychopharmacology. 2006;31(8):1757-1767; Walsh SL, Wagner GC. J Pharmacol Exp Ther.
1992;263(2):617-626; Zangen A, et al. Psychopharmacology. 2001;155(4):434-439.
Brain Regions and MDD Symptoms:
Possible Role of Norepinephrine Pathways
Cognitive
dysfunction
H
C
Physical
fatigue
Insomnia/hypersomnia
Loss of weight or
appetite
Locus
Coeruleus
Avery RA, et al. Neuropsychopharmacology. 2000;23(3):240-249; Kuratsune H, et al. Neuroimage. 2002;17(3):1256-1265;
Kurose Y, Terashima Y. Brain Res. 1999;828(1-2):115-118; Mao ZM, et al. Biol Psychiatry. 1999;46(9):1259-1265; Nolte J,
Angevine JB Jr. The Human Brain in Photographs and Diagrams. Second Edition. St. Louis, MO: Mosby; 2000;
Vetrivelan R, et al. Neuroscience. 2006;139(3):1141-1151; Watson M, McElligott JG. Brain Res. 1984;296(1):129-138.
NE and “Fine-Tuning” in the
Prefrontal Cortex
• The primary regulation of arousal, attention, emotion, cognition,
and behavioral response is mediated through prefrontal subcortical
circuits
• The cortical-striatal-thalamic-cortical loops begin and end with
pyramidal neurons in the cortex
• The primary neurotransmission in these loops is mediated by
glutamate (excitatory) and GABA (inhibitory) in an “on-off” fashion
• Monoamine neurotransmitters “fine tune” neurotransmission by
enhancing “signal” to “noise” ratios via metabolic and receptor
activities. ADs can “retune” or “untune” the overall function of these
circuits1
GABA = gamma-aminobutyric acid; ADs = antidepressants.
1Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications.
Third Edition. New York, NY: Cambridge University Press; 2008:207-222.
How Increasing Norepinephrine Availability
Can Improve Attention and Working Memory
Presynaptic
neuron
Reuptake
transporter
Postsynaptic
neuron
 Extraneural
catecholamine
concentration
Propagation
of Synapse
Pharmacological block on reuptake
Catecholamines in the extraneuronal space
Closed HCN Channel
HCN = hyperpolarization-activated cyclic nucleotide-gated.
Arnsten AF. Expert Rev Neurother. 2010;10(10):1595-1605; Wang M, et al. Cell. 2007;129(2):397-410.
Functional Connectivity across
the “Big Three” Monoamine Systems:
Serotonin, Norepinephrine, and Dopamine
+
-
-
Postsynaptic
Neuron
+
-
Interneuron
5-HT2A for NE neurons
5-HT2C for DA neurons
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.
Receptors—
Examining the Role They Play
in Mood Regulation
What Is a Receptor?
• The term “receptor” specifically refers to proteins that participate in
intracellular communication via chemical signals
• Upon recognition of an appropriate chemical signaling molecule (ligand),
receptor proteins transmit the signal into a biochemical change in the
target cell
• Ligands include drugs as well as endogenous signaling molecules such as
hormones and neurotransmitters
• The beneficial therapeutic effects and unwanted toxic effects of drugs are
elicited through interactions with proteins
– Enzymes (aspirin + cyclooxygenase)
– Transporters/carriers (fluoxetine + serotonin reuptake transporter)
– Ion channels (local anesthetics + Na+ channels)
– Receptor proteins (cimetidine + histamine receptor)
Shoichet BK, Kobilka BK. Trends Pharmacol Sci. 2012 Apr 13;[Epub ahead of print]; Brunton L, et al.
Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; 2008.
Ligand-gated
ion channels
ions
Change in
membrane potential
or
ionic concentration
Tyrosine
kinase-linked
receptors
G-protein
coupled
receptors
Protein
phosphorylation
Intracellular
2o
messenger
(eg, cAMP)
Ligand-activated
transcription
factors
nucleus
mRNA
Protein
Cellular
effect
Cellular
effect
Cellular
effect
Cellular
effect
Nicotinic acetylcholine
receptor
(milliseconds)
Insulin
receptor
(seconds-minutes)
β-adrenergic
receptor
(seconds-minutes)
Estrogen
receptor
(hours)
Samartzis N, et al. Reprod Biol Endocrinol. 2012;10(1):30; Philippidou P, et al. Proc Natl Acad Sci
U S A. 2011;108(2):852-857.
The Lock and Key Model of
Ligand-Receptor Interaction
HORMONE OR
NEUROTRANSMITTER
RECEPTOR
•
A ligand such as a hormone or neurotransmitter
(the “key”) bind to specific receptors (the “lock”)
•
This binding “unlocks” the cell’s response
•
Many drugs work by mimicking a naturally occurring
hormone or neurotransmitter
•
If the drug causes the receptor to respond in the same
way as the naturally occurring substance, then the drug
is referred to as an agonist
•
These are drugs that can “pick the lock”
•
•
Other drugs work in the opposite way—as antagonists
•
Because the drug prevents the receptor from binding to
the normal hormone or neurotransmitter, it has an
inhibitory effect on the naturally occurring substance
AGONIST
ANTAGONIST
These drugs bind to the receptor, but do not produce a
response
Brunton L, et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill
Professional; 2008.
What Does a Receptor Look Like?
Serotonin 5-HT7 as an Example
• There is a considerable amount
of evidence supporting a role for
the 5-HT7 receptor in
depression
• Both blockade and inactivation
of the receptor have resulted in
an antidepressant-like profile in
models of depression
• Supporting evidence has also
been obtained in sleep studies
• Especially interesting are the
augmented effects achieved by
combining antidepressants and
5-HT7 receptor antagonists
Hedlund PB. Psychopharmacology (Berl). 2009;206(3):345-354.
Neurotransmitter – Receptor – Intracellular
– Gene Transcription Interactions
Glutamate
NMDA
5-HT/NE
alpha1
5-HT2
BDNF
5-HT/NE
TrkB
beta-R,
5-HT4,7
SoS
Ras
SHC
Gs
alpha2,
beta-R,
5-HT1A/7
AC
Raf
CaM-kinase IV
cAMP
CaM-kinase II
MEK
ERK1/2
PKA
RSK2
P
Akt
GSK-3b
GluR1
BDNF
Fos
P
CREM
CREB CREB
ARC
P
P
CREB CREB
Racagni G, et al. World J Biol Psychiatry. 2011;12(8):574-587.
Modulation
of gene
transcription
Norepinephrine—
Clinical Applications
Receptors:
Their Central Role in the Pharmacological
Treatment of Depression
5-HT1A
Presynaptic region
SSRI
SNRI
SARI
SRE
X
X
Synapse
5-HT
MAO
X
5-HT1B/1D
X
X
5-HT2A/2C
5-HT3
5-HT
Postsynaptic region
5-HT in vesicles
5-HT transporter
Postsynaptic 5-HT receptor
Somatodendritic 5-HT receptor
Inhibition
5-HT6
X
MAO
Inhibitors
5-HT1A & other
metabolites
NaSSA
5-HT7
SARI = serotonin antagonist and reuptake inhibitor; SRE = serotonin reuptake enhancers; NaSSA =
noradrenergic and specific serotonergic antidepressant.
Rajkumar R, Mahesh R. Curr Neuropharmacol. 2008;6(3):215-234.
Noradrenergic Receptor Classification
Alpha 1A
Alpha 1
Alpha 1B
Alpha 2
Alpha 2A
Alpha
Noradrenergic
Receptors
Alpha 2B
Beta 1
Beta
Beta 2
Beta 3
Alpha 2C
Adipose Tissue and NE Receptors
NE Alpha 2
Receptor
Stimulation –
Decreased
Lipolysis
NE Beta 1 and 2
Receptor
Stimulation –
Increased Lipolysis
Carey GB. Adv Exp Med Biol. 1998;441:157-170.
• 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
Potential Take-Home Message Here
Is…
• NE is involved in regulating adipose tissue
• This relationship is different depending on the NE
receptor involved
• Therefore, the pharmacological effects of our
interventions need to be carefully thought out
Focus on the Alpha Family
of Noradrenergic Receptors
• Currently, 3 Alpha subtypes—designated Alpha 1,
Alpha 2, and Alpha 3 – have been cloned and
pharmacologically characterized
• The mammalian heart expresses primarily Alpha 1
(75% to 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 (eg, endothelial cells, fibroblasts, and
vascular smooth cells)
Post SR, et al. Annu Rev Pharmacol Toxicol. 1999;39:343-360.
Alpha-2 Receptors Are Very Important
in Mental Health
AA
 Most prevalent subtype in
the PFC, also located in the
locus coeruleus1
 Critical to PFC functioning1
•
•
•
Attention
Behavior
Emotions
B
 Least prevalent subtype3
 Most concentrated in the
thalamus3
 Associated with
sedative effects1
C
 Much less prevalent
than A; present in cortex
and locus coeruleus3
 Associated with sedative
and hypotensive effects1
 Associated with sedative
and hypotensive effects1,2
Alpha-2 agonists have varying degrees of affinity for the
3 alpha-2 receptor subtypes
1Arnsten
AF, et al. J Child Adolesc Psychopharmacol. 2007;17(4):393-406; 2Franowicz JS, Arnsten AF.
Psychopharmacology. 2002;162(2):304-312; 3MacDonald E, et al. Trends Pharmacol Sci.
1997;18(6):211-219.
Transmission of Neuronal Signal Is
Modulated by the Alpha-2A Receptor
NE presynaptic
terminal
Excitatory signal
Reuptake transporter
NE
a2A receptor
Ion channel
Wang M, et al. Cell. 2007;129(2):397-410.
Postsynaptic
neuron
Cognition: Role Various Receptors Play in
Various Aspects of Cognition and Memory
Short-term
Memory Phase
Time (min)
0
Intermediate-term A
10
5HT2B
20
Intermediate-term B
30
40
2 β2
Glycogenesis
Glycogenolysis
SB 221284
Long-term
50
60
2 β2
Glycogenesis
Glycogenolysis
ARC-239 Propranolol
or ICI 118551
O’Donnell J, et al. Neurochem Res. 2012;37(11):2496-2512.
Glycogenolysis
ARC-239
Propranolol,
ICI 118551,
or DAR
But, Alpha-2 Receptor Agonism, Which Is Distributed
in the Body Too, May Lead to Insulin Resistance
Gribble FM. N Engl J Med. 2010;362(4):361-362.
Turning Our Attention to Beta-Adrenergic Receptors:
Focus on Beta-1 Distribution
β-1 receptors
Renal juxtaglomerular
cells
Heart
Increased
chronotropy and
inotropy
Increased
renin release
Increased
AV-node
conduction
velocity
Ablad B, et al. Drugs. 1976;11(Suppl 1):100-111; Minneman PK, et al. Annu Rev Neurosci. 1981;4:
419-461.
Turning Our Attention to Beta-Adrenergic Receptors:
Focus on Beta-2-Adrenergic Receptor Distribution
β-2 receptors
Bronchial smooth
muscle
Bronchodilation
Uterine muscle
β-2 receptors
Bladder detrusor
muscle
Relaxation
Eye ciliar muscle
Relaxation
GI tract
Decreased
motility
Liver
Increased
glucose
metabolism,
lipolysis
Smooth muscle
Relaxation
Uterine relaxation
(tocolysis)
Ablad B, et al. Drugs. 1976;11(Suppl 1):100-111; Minneman PK, et al. Annu Rev Neurosci. 1981;4:
419-461.
Adrenergic Receptors—
A True Brain-Body Distribution and Function
• The primary regulators of adipose tissue lipolysis, are the
catecholamines that 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;441:157-170.
Could Noradrenergic Dysfunction Lead to Obesity?
Launois-Bensaude Syndrome
Interestingly, treatment with
salbutamol (a beta-2 agonist)
– a noradrenergic drug, leads
to adipose tissue reduction
and weight loss
Leung NW, et al. Clin Endocrinol. 1987;27(5):601-606.
5-HT and Modulation of DA and NE
• 5-HT projections from the raphe nucleus to the LC
impose tonic inhibition on the firing of NE neurons
– Removal of this inhibition by use of a 5-HT synthesis inhibitor
or lesion of the LC results in increase of NE firing
– Increasing 5-HT via SSRI results in progressive decrease in
spontaneous firing of LC neurons
– Chronic SSRI administration lowers NE and DA in the PFC
– Inhibition of NE firing is mediated via 5-HT2A heteroreceptors
Haddjeri N, et al. Br J Pharmacol. 1997;120(5):865-875; Szabo ST, et al. Int J Neuropsychopharmacol.
2000;3(1):1-11; Kawahara Y, et al. Psychopharmacology. 2007;194(1):73-81; Gupta RK, et al. Aust N Z J
Psychiatry. 2003;37(2):190-195.
Importance of Serotonin Receptors:
Focus on 5-HT1A and 5-HT1B & Alpha NE Receptors
Cortex/Hippocampus
5-HT1B
(-)
2
(-)
2
(-)
5-HT2
(-)
5-HT1A
(-)
2
(-)
5-HT
1
(+)
NA
Locus Coeruleus
Raphé Nucleus
Gupta RK, et al. Aust N Z J Psychiatry. 2003;37(2):190-195.
MHPG ng/mL
Increased NE Turnover in MDD
35
35
30
30
25
25
20
20
15
15
10
10
5
5
0
0
0
20
40
r=0.40, P=0.007
r = .40, P = .007
0
Time A: BDI
20
Time B: BDI
144 participants (44 men, 100 women) were reassessed by the BDI.
Baseline saliva MHPG levels in men with a BDI score of ≤9 at time A and
a BDI score of ≥10 at time B.
BDI = Beck Depression Inventory.
Watanabe I, et al. Int J Geriatr Psychiatry. 2012;27(3):321-326.
40
• 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
MDD, scored at least
15 on the HRSD
% Improvement of HRSD (%HSRD)
Change in NE Turnover after
SSRI Treatment
Paroxetine
100
80
60
40
20
0
-50
0
50
100
% Change of Plasma MHPG
(%MHPG)
HRSD = Hamilton Rating Scale for Depression; pMHPG = plasma methoxy-4hydroxyphenylethyleneglycol.
Shinkai K, et al. J Clin Psychopharmacol. 2004;24(1):11-17.
150
SSRIs Induced NE “Overregulation”
and the “Noradrenergic Cluster”
• Core symptoms of depression that respond less well
or more slowly to SSRIs
– 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 nausea
Bech P, et al. Psychopharmacology. 2002;163(1):20-25; Wade A, Friis Andersen H. Curr Med Res Opin.
2006;22(11):2101-2110.
In Depressed Humans, Norepinephrine
Producing LC Have Impaired Astrocytes
• Healthy vs depressed—
postmortem study
– Men with MDD (closed symbols)
• Both SLC1A3 and SLC1A2 are
glutamate-related genes
Geometric Mean
**
6
5
4
3
2
1
0
SLC1A3
(EAAT1)
C
Number of Cells Captured
– Psychiatrically healthy
controls(open symbols)
*
7
Target Gene Expression
• Gene expression using
quantitative end-point polymerase
chain reaction conducted with
laser-captured astrocytes from
locus coeruleus tissue from
matched pairs of
A
SLC1A2
(EAAT2)
*
200
**
150
100
50
0
SLC1A3
(EAAT1)
*P < .01, **P < .001.
Chandley MJ, et al. J Psychiatry Neurosci. 2013 Feb 19;[Epub ahead of print].
SLC1A2
(EAAT2)
NE – Its Critical Role on Optimum
Astrocyte, Microglia, and Neuronal Health
1
2
β1
Na/K ATPase
O’Donnell J, et al. Neurochem Res. 2012;37(11):2496-2512.
GLT1/GLAST
[1st HIT]
Stress & Trauma
During Childhood
NE – through Alpha and Beta Receptors on Microglia
Exerts Anti-Inflammatory Effects on Microglia
Neuron-Microglia Interactions in the CNS
Resting Microglia
Direct-Touching
with Synapses
Microglial
Activating Factors
Neuron
Over-Activated Microglia
(Ameboid Type)
(ATP, interferon-y, LPS, etc)
Modulate
[2nd HIT]
Various Psycho-Social Stress
Activated Microglia
[Inflammation]
TNF-
IL-1β
IL-6
etc
[Oxidative Stress]
Nitric Oxide (NO)
Neuron
Superoxide (O2-)
Peroxynitrite(ONOO-)
etc
Acute/Prolonged Immunological Reactions
Modification from the original neuron-glial formations
Psychotropic Drugs
Resting Microglia
(Ramified Type)
1A/2A
Aβ
[Ca2+]i

PKC
*
B1/β2
Norepinephrine
IL-1β
LPS
ATP
β
cAMP
MAPK
Epac
Phagocytosis
NFkB
Nucleus
IL-1β
IL-6
TNF-
MCP-1
Phagocytosis
Migration
Psychiatric Disorders (Onset, Recurrence, etc)
Improve
Are Therapeutic Effects of Psychotropic Drugs on Psychiatric Disorders Induced by
Microglial Modulation? Microglia are activated by various
immunological/inflammatory activators during stressful life episodes (eg, infections
and physical/psychological traumas) both in pre- and post- natal states,
developmental states and other life events. Activated microglia release proinflammatory cytokines and free radicals. These mediators are known to cause
brain dysfunctions such as neuronal degeneration, decreased neurogenesis and
white matter abnormalities. These neuron-microglia interactions may thus be one of
the important factors in the pathophysiology of psychiatric disorders. Psychotropic
drugs such as antipsychotics, antidepressants and antiepileptics have therapeutic
effects on psychiatric patients possibly by reducing microglial
inflammatory/oxidative reactions and following neuronal protective effects, which
puts forward a novel therapeutic hypothesis beyond the neuron-neurotransmittersynapse doctrine in the field of psychiatric research.
Kato TA, et al. Curr Med Chem. 2013;20(3):331-344.
mFPR2
PGE2
COX2
NO
ROS
IL-1ra
IL-1R
Norepinephrine Modulates Microglial Activation via β-adrenergic Receptor-cAMPMAPK-NFκB Signaling. Microglia are activated by pro-inflammatory cytokines (eg, IL1β), endogenous antigens (eg, Aβ), exogenous antigens (eg, LPS), or ATP, and
produce pro-inflammatory cytokines, chemokines and free radicals through the
activation of signaling pathways such as MAPK and NFκB via PKC or intracellular
calcium signaling. Norepinephrine has properties to inhibit microglial inflammatory
reactions through the activation of cAMP and suppression of downstream MAPK
and/or NFκB. On the other hand, norepinephrine has the controversial effect of
activating MAPK and/or NFκB, and results in production of pro-inflammatory cytokine
IL-1β. Norepinephrine-stimulated microglia produces various substances such as IL1ra, IL-1RII and mFPR2 via activating MAPK and/or NFκB signaling. Therefore,
norepinephrine can play both roles as a facilitator or suppressor of microglial
inflammatory reactions via activating cAMP and positive or negative modulation of
downstream MAPK and NFκB signaling.
*
NE – via LC, Impacts Microglia
and Controls Neuroinflammation
• NE stimulation increases
microglia migration and
phagocytosis
• Alzheimer’s disease –
there is LC degeneration
and decreased NE in
forebrain
CXCL-1
120
% of Aβ Induced Release
• NE stimulation of
microglia suppresses
cytokine and chemokine
production
TNF-
100
80
60
***
40
20
***
***
10 µM
100 µM
0
10 nM
100 nM
***P < .001.
Heneka MT, et al. Proc Natl Acad Sci U S A. 2010;107(13):6058-6063.
1 µM
NE
NE Tasks: It’s a Multi-Tasking
Neurotransmitter
Rapid effects
• NE participates in rapid modulation of cortical circuits and
cellular energy metabolism
Slower effects
• NE impacts cellular neuroplasticity and inflammation
Tonic bursts from LC
• Wakefulness, sleep regulation, attention, stress, and
inflammation management
Phasic burst
• Novelty and pleasure seeking
O’Donnell J, et al. Neurochem Res. 2012;37(11):2496-2512.
NE and Major Depression:
Diagnostic and
Therapeutic Implications
Neurobiology of Exercise: A Complex Cascade That
Also Involves Neurotransmitters and Receptors
Structure
External Input
• Visual
• Olfactory
• Acoustic
• Gustatory
• Somatosensory
Cognitive Controls
Hippocampus, Cortex
Executive Controls
Prefrontal & Cingulate Cortex
Emotional Controls
Amygdala, Prefrontal Cortex
Motivational Controls
Internal Feedback
“Consequences of exercise”
Reward,Wanting,Selection
Neural
Motor Cortex
Striatum, Brainstem, Cerebellum,
Spinal Cord
Primary Afferents
Muscle
Cardiovascular Consequences
“Exercise”
Repair
Plasticity
Protection
Neurogenesis
Transcription
NA, 5-HT,GABA,
Glutamate,
Glycine
BDNF/TrkB
ERK/CREB
NFKB
Hypothalamus, Accumbens, VTA
Motor Controls
Humoral
Factors
CNS
Metabolic Consequences
Liver, WAT, Pancreas
Thermal Consequences
DA
↓
Parkinson’s
Disease
↑
ROS
ANS
&
Endocrine
Systems
Function
Disease
Learning
& Memory
Alzheimer’s
Dementia
Behavior
• Social
• Sexual
• Coping
• Addictive
• Escape
• Fight &
Flight
• Stress
• Sleep
• Ingestive
Schizophrenia
Depression
Sleep Disorders
Obesity
Energy
Balance
Diabetes
CVD
Immune
Control
Gastrointestinal Control
Immune Disorder
IBD, Constipation
Colon Cancer
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.
Psychotherapy and Receptor Changes
Is This Even Possible?
• This is the first direct demonstration
of a specific neurotransmitter
mechanism involved in the
neurobiology of psychotherapy
• Increased serotonin 5-HT1A
receptor binding in multiple cortical
regions following psychotherapy in
patients with MDD
• Significant increase in 5-HT1A
density in the PSY group
compared to the FLU group in the
frontal, temporal, and parietal
cortex (angular gyrus, medial
prefrontal cortex, orbitofrontal
cortex)
Short-term PSY (n=8) or FLU (20 mg/day,
increased up to 40 mg/day if needed,
n=15) for 16 weeks
PSY = psychodynamic psychotherapy; FLU = fluoxetine.
Karlsson H, et al. Psychol Med. 2010;40(3):523-528.
Does the Mechanism of Action of an
Antidepressant Affect Social Adaptation?
SASS Score Improvement
in All Patients
(8-week study)
SASS Score Improvement
in Patients in Remission
(4-week study)
P < .01
P < .01
% Improvement of
Overall SASS Score
45
P < .05
45
30
30
15
15
0
0
NRI
reboxetine
8 mg/d
(n=126)
SSRI
fluoxetine
20 mg/d
(n=127)
Placebo
(n=128)
NRI
reboxetine
8 mg/d
(n=53)
SSRI
fluoxetine
20 mg/d
(n=60)
SASS = Social Adaptation Self-evaluation Scale; NRI = norepinephrine reuptake inhibitor.
Kasper S, et al. Neuropsychiatr Dis Treat. 2011;7(Supp1):21-27; Dubini A, et al. J Psychopharmacol.
1997;11:(4 Suppl):S17-S23; Massana J, et al. Int Clin Psychopharmacol. 1999;14(2):73-80.
Proof of Concept—An NE Medication
Can Improve Both Depression and Fatigue
LY2216684 (Edivoxetine) Is a Potent NRI
Probability of Remission, %
N = 217
35
Placebo
30
Edivoxetine
0
**
-5
25
*
20
15
*P < .05
**P < .01
-10
-15
-16.69
-18.62
10
-20
5
-23.20
0
-24.28
-25
Week 1 Week 3 Week 5 Week 7 Week 10
Week of Treatment
Estimated Probability of MADRS Remission
(Repeated Measures Analysis)
Severity of
Overall Fatigue
During Past Week
P = .008
Fatigue
Interference With
Daily Activities
During Past Week
P = .024
MADRS = Montgomery-Åsberg Depression Rating Scale; VAS-F = Visual Analog Scale for Fatigue.
Pangallo B, et al. J Psychiatr Res. 2011;45(6):748-755.
Highly Noradrenergic Antidepressant—
Levomilnacipran SR is Effective
MADRS Mean Score Change from Baseline to Week 8
(modified ITT population, MMRM analysis)
Weeks
LS Mean Change from Baseline
0
1
2
4
6
8
0
-3
Placebo
Levomilnacipran SR 40 mg/d
-6
Levomilnacipran SR 80 mg/d
Levomilnacipran SR 120 mg/d
-9
-12
-15
-18
Placebo n = 175
Levomilnacipran SR
40 mg, n = 176
80 mg, n = 177
120 mg, n = 176
*
**
*
**
**
*
**
***
*P < .05; **P < .01; ***P < .001(all vs placebo).
ITT = intent to treat; MMRM = mixed-effects model for repeated measures; SR = sustained release.
Asnis GM, et al. J Clin Psychiatry. 2013;74(3):242-248.
Even Treatments Such as DBS Work
via NE / DA / 5-HT
Animal Study of DBS of NAC and Examination of
Neurotransmitter Elevation in OFC
Dopamine OFC
Percentage %
200
*
150
*
100
50
Clearly, all the neurotransmitters
are impacted even by therapies
for resistant depression,
such as DBS
300
Control
0
0
1
2
3
4
5
6
7
8
9
10
Percentage %
200
Percentage %
Samples
Serotonin OFC
150
100
50
300
Control
0
0
1
2
3
4
5
6
7
8
9
10
Noradrenaline OFC
200
11
150
*
*
*
*
100
*
*
*
50
300
Control
0
0
1
2
3
4
5
6
7
8
Samples
11
Samples
*P < .05 compared to first baseline sample.
DBS = deep brain stimulation; NAC = nucleus accumbens; OFC = orbitofrontal cotrex.
van Dijk A, et al. J Neurochem. 2012;123(6):897-903.
9
10
11
Targeting More Than One Mechanism
Does That Offer Any Further Help?
Normal Mood
Reduced
Positive Affect
+
+ +
+
+
Depressed
mood
Loss of happiness
(joy)
Loss of interest/pleasure
Loss of energy/enthusiasm
Decreased alertness
Decreased self-confidence
Increased
Negative Affect
- -
-
Depressed
mood
Guilt/disgust
Fear/anxiety
Hostility
Irritability
Loneliness
Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications.
3rd Edition. New York, NY: Cambridge University Press; 2008:207-222
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, NE 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 Clinicians’ thinking until
recently, but it truly should be
• Exercise, psychotherapy, and meditation are valid
Nonpharmacological modulators of NE
• A number of pharmacological NE treatment options are
available, and more are emerging
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