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Campaign Development
Training Materials and Medical Illustration
Marketing Programs and Slide Presentations
TRG Communications, LLC
Rich Franco, President
(m) 919.606.2908
(e) [email protected]
communications
LLC
TRG Communications, LLC
Rich Franco, President
(m) 919.606.2908
(e) [email protected]
communications
LLC
Campaign Development
TESTOPEL® Turn It On
FAMILION Family
C-GAAP Gears
Hylenex® recombinant REVEAL...
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Campaign Development | TESTOPEL® Turn It On
communications
LLC
Product: TESTOPEL®
Client: Slate Pharmaceuticals, a division of Actient Pharmaceuticals
Campaign: Turn It On
Concept: TESTOPEL®, the only long-acting treatment for men with Low T. Once
implanted (Turned On), men were spontaneously compliant with therapy.
This feature would enable men to enjoy the benefits of testosterone
therapy without the hassle of saw tooth T-levels while avoiding the daily
hassle of administering a topical therapy.
Creative: We used the universal “On” symbol (as seen on a multitude of devices
used today) as highlight recognizable inconography to denote the patient
being “Powered On” for 3-6 months once TESTOPEL® is placed.
Select Materials
Developed: Core sales aid, patient education materials, posters
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Campaign Development | FAMILION Family
communications
LLC
Product: FAMILION, family of genetic tests for inherited cardiac diseases
Client: PGxHealth, Transgenomic
Campaign: Family
Concept: Inherited cardiac diseases represent an unsuspecting risk to the families
they affect. FAMILION represents an opportunity to make the unknown
risk known so it can be treated and/or tracked through at-risk families.
Creative: Tie together real life family scenes with pedigree graphic to illustrate the
existence of the unknown risk.
Select Materials Test kit, core sales aid for channelopathies and cardiomyopathies, patient
Developed: and family education
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Campaign Development | C-GAAP Gears
communications
LLC
Product: C-GAAP Genetic Test for Clopidogrel Response
Client: Transgenomic
Campaign: Gears Working Together
Concept: The C-GAAP Clopidogrel Response Test was the only genetic test to
include CYP2C19 and ABCB1, thus there were two genes that worked
synergistically to predict a patient’s response to clopidogrel. We developed
a well understood graphic to illustrate why it was important to genotype
both genes as opposed to just CYP2C19.
Creative: Each gear represents one of the genes included as part of the test.
Graphically this illustrated that both genes ultimately impact the
metabolism or absorption of clopidogrel.
Select Materials
Developed: Core sales aid
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Campaign Development | Hylenex® recombinant REVEAL... communications
LLC
Product: Hylenex® recombinant (hyaluronidase human injection)
Client: Halozyme Therapeutics
Campaign: REVEAL…
Concept: Most clinicians were unaware of which hyaluronidase they were using.
It was time that they had the source of each version of hyaluronidase
revealed. Hylenex® recombinant is the only recombinant human
hylauronidase available. Despite being the only recombinant human
hyaluronidase, it was priced at a discount to the other FDA-approved
product on the market.
Creative: Hyaluronidase is most commonly used as part of an anesthetic regimen
administered prior to various ocular surgeries. The brightly colored eye
with a DNA strand simply reiterates that when doctors use Hylenex®
recombinant they are using the only recombinant human FDA-approved
hyaluronidase available.
Select Materials
Developed: Sales Aid, Tabletop Panels
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
communications
LLC
Training Materials
& Medical Illustration
Viibryd™ 7 Module Learning System
Hylenex® recombinant Infusion Illustrations
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Training Materials & Medical Illustration
communications
LLC
Viibryd™ 7 Module Learning System
Product: Viibryd™ (vilazadone HCl)
Client: Trovis Pharmaceuticals
Material: 7 module learning system with original illustrations
Background: Trovis was posed to launch a novel antidepressant into a very crowded
market. We were asked to develop a written set of training materials
that could then be incorporated into a web based training program. The
materials developed included disease background, market background,
competitors, About Viibryd and Objection Handling modules. All illustrations
and copy were produced in-house.
Full module example included at the end of this PDF.
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
communications
Training Materials & Medical Illustration
LLC
Hylenex® Recombinant Infusion Illustrations
Product: Hylenex® recombinant for use with insulin pumps
Client: Halozyme
Material: Patient Instruction sheets featuring original medical illustrations
Background: As part of preparing for potential commercialization of Hylenex recombinant
for use with insulin pumps, a series of patient instructions for use needed
to be created. We were asked to develop original medical illustrations
depicting several different infusion sets. Our goal was to be medically
accurate but as patient-friendly as possible. All illustrations and copy were
produced in-house.
Vial
Adapter/
Connector
Package
Vial
Cannula End
of Tubing
Vial
Cap
Syringe
Package
Vial
Adapter/Connector
Syringe
Plunger
Luer
Lock
Tubing
Package
Cannula
Housing
(not included)
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
communications
LLC
Marketing Programs
& Slide Presentations
TESTOPEL® Patient Rebate Program
FAMILION Family Slide Presentation
Transgenomic Capital Campaign
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
communications
Marketing Programs & Slide Presentations
LLC
TESTOPEL® Patient Rebate Program
Product: TESTOPEL®
Program: TESTOPEL® Patient Rebate Program
Client: Slate Pharmaceuticals, a division of Actient Pharmaceuticals
Background: TESTOPEL is most commonly purchased and billed by clinicians, retail
pharmacy visit as few. Slate Pharmaceuticals wanted to offer a rebate
to patients. We developed the entire rebate process and oversaw the
execution of the program with our fulfillment partner. The goal was to
be compliant with all laws governing rebate programs and appropriate
based upon regulatory/medical review.
Materials: Clinician/staff education materials, patient enrollment/education
materials and all fulfillment materials (check and letter), weekly status
reports, patient survey
TES-M1051
NO POSTAGE
NECESSARY
IF MAILED
IN THE
UNITED STATES
01/13
BUSINESS REPLY MAIL
FIRST-CLASS MAIL
PERMIT NO. 626
CHAPEL HILL, NC
POSTAGE WILL BE PAID BY ADDRESSEE
TESTOPEL Patient Rebate Program Headquarters
c/o Beechwood Associates
PO Box 1190
Morrisville, NC 27560
USPS BRM Template #10 Envelope 4-1/8" x 9-1/2"
Working Layer
January 2001
File Name: b10.pdf
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Marketing Programs & Slide Presentations
communications
LLC
FAMILION Family Slide Presentation
Product: FAMILION, family of genetic tests for inherited cardiac diseases
Slide Presentation: FAMILION Slides
Client: PGxHealth, Transgenomic
Background: We were asked to create a multi-module professional slide presentation
that doctors or nurses could use to present to either other HCPs or patients.
Shown here are the first several slides of one of the presentation decks.
Materials: Slide decks were assembled for each disease state for which there was
a FAMILION test.
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Marketing Programs & Slide Presentations
communications
LLC
Transgenomic Capital Campaign
Product: Transgenomic Company Slide Presentation
Slide Presentation: Transgenomic Capital Campaign
Client: PGxHealth, Transgenomic
Background: We were asked to work with senior leadership at Transgenomic to
assemble a slide presentation intended to raise capital. The presentation
had to represent each one of Transgenomic’s business units and clearly
articulate the unique value it represented. Shown here are the first several
slides of the presentation deck.
www.trgcommunications.us | Rich Franco, President | (m) 919.606.2908 | [email protected]
Module • 2
The Central Nervous System and Pathophysiology of
Major Depressive Disorder (MDD)
CONFIDENTIAL
For Internal Use Only. The information contained in this training module is for educational
purposes only. It is designed to provide you with the information you need to be educated
on the product, disease and competitive environment and is not to be distributed or used
in detailing.
2
CONFIDENTIAL: For Internal Use Only.
2
2
Table of Contents
Chapter 1: Theories About the Causes of MDD................................................3
1.1. Theories About the Causes of MDD....................................................................................3
1.2. Select Emotions, Behaviors and Bodily Functions
Regulated by Neurotransmitters..........................................................................................5
Chapter 2: The Central Nervous System..............................................................7
2.1. Regions of the Brain...................................................................................................................7
2.2. Spinal Cord.................................................................................................................................10
2.3. Peripheral Nervous System..................................................................................................10
2.4. Summary of Central Nervous System..............................................................................11
Chapter 3: Neuroanatomy Related to MDD.................................................... 13
3.1. The Neuron................................................................................................................................13
3.2. Neurotransmission..................................................................................................................14
3.3. Neurotransmitters, Receptors and Ion Channels......................................................... 16
3.3.1. Neurotransmitters.......................................................................................................16
3.3.2. Ion Channels.................................................................................................................17
3.3.3. Receptors........................................................................................................................18
3.4. Biochemical Theory of Depression....................................................................................19
Brain Booster............................................................................................................... 21
Definitions..................................................................................................................... 23
References..................................................................................................................... 25
Learning Objectives
Review theories of the causes of MDD.
Review the neurotransmission process.
Review neuroanatomic structures associated with MDD.
Describe different neurotransmitters associated with MDD.
Understand how the dysregulation of neurotransmitters may occur.
1
CONFIDENTIAL: For Internal Use Only.
2
Chapter 1: Theories on the Causes of MDD
The exact cause
of depression
is unknown;
however, the vast
majority of health
care professionals
accept the
biochemical
theory as the preeminent cause of
depression.
To have a successful discussion with a health care professional about MDD you must
have a solid working knowledge of the central nervous system (CNS) and the role of
neurotransmitters. The theories of the cause of depression outlined in Table 1 are not
mutually exclusive. For example, researchers might discover a link between the biochemical
and heredity theories in which a genetic polymorphism(s) may better predict people at
increased risk of developing depression.
1.1. Theories About the Causes of MDD
The exact cause of depression is unknown; however, the vast majority of health care
professionals accept the biochemical theory as the pre-eminent cause of depression.
Table 1: Theories of the Cause of Depression
Theory
Description
Biochemical Theory
Dysfunction of neurotransmitters (serotonin, norepinephrine,
dopamine) in the brain are thought to be responsible
for causing depression.
Psychological Theories
Factors such as low self-esteem, harsh superego,
and dependent personalities account for most depression.
Social Theories
Life events and stress cause depression.
Heredity/genetic Theories
Some evidence exists that suggests a specific gene or genes
might be responsible for depression.
Integrative Theory
Depression involves biological, experiential and behavioral
components; factors such as biological vulnerability and
physiological and psychosocial stressors all contribute
to depression.
None of these theories provides a singular explanation for all MDD. However, the mechanism
of action of antidepressants lends support to the belief that the biochemical theory is the
most appropriate explanation for most MDD.
3
2
2
Chapter 1: Theories on the Causes of MDD
The relationship between the effect of neurotransmitters on the brain and body is often
referred to as the mind-body link. Figure 1 and several other sections of this module serve to
explain the roles of neurotransmitters in depression.
Figure 1: Dysregulation of Serotonin (5-HT) is Believed
to be the Primary Cause of MDD1,2,3,4
Dysregulation of 5-HT (serotonin) is
strongly associated with MDD.
5-HT (serotonin) and other
neurotransmitters help modulate
certain bodily functions via
the descending pathway.
CONFIDENTIAL: For Internal Use Only.
4
2
2
Neurotransmitters
are chemical
substances that
transmit nerve
impulses.
1.2. Select Emotions, Behaviors and Bodily Functions
Regulated by Neurotransmitters
Neurotransmitters are chemical substances that transmit nerve impulses. Key neurotransmitters, like serotonin, originate in the midbrain and project to various locations throughout the
human nervous system.
Within the brain, neurotransmitters help mediate numerous emotional and behavioral
functions. A brief list of emotions and/or behaviors regulated by neurotransmitters is shown
below. For MDD patients certain neurotransmitters may dysfunction and result in an inability
to regulate emotions and/or behaviors.
Sadness
Anxiety
Irritability
Pleasure
Guilt
Concentration
Appetite
Sexual function
Projections from the brain stem descend down the spinal cord where they have a role in
helping to regulate certain bodily functions. A brief list of these functions is shown below.
Vasoconstriction
Urethral sphincter contractions
Bladder wall relaxation
Gastrointestinal motility
Pilomotor contraction (goose bumps)
Normally, the sensations associated with the routine functioning of the body, such as digestion
in the abdomen, urogenital function, and/or routine inputs to the musculoskeletal system
throughout the body, are suppressed from our awareness so that attention can be paid to
events occurring outside of the body and the central nervous system can react appropriately.
5
CONFIDENTIAL: For Internal Use Only.
6
2
2
Chapter 2: The Central Nervous System
Together, the spinal cord and brain are known as the central nervous system (CNS). The CNS
acts as the control center of the entire nervous system, interpreting incoming information
and issuing responses.
2.1. Regions of the Brain
As shown in Figure 2, the brain has the following major regions:
Cerebrum
Cerebellum
Diencephalon (thalamus & hypothalamus)
Brainstem
Figure 2: The Major Regions of the Human Brain
Cerebrum
Diencephalon
(thalamus & hypothalamus)
Cerebellum
Midbrain
Pons
Brainstem
Medulla
Oblongata
Spinal Cord
The cerebrum is the largest region of the brain. It controls voluntary motor functions;
coordinates physical, sensory, visual and auditory sensations; and integrates consciousness,
memory, use of language, and emotions.
7
Chapter 2: The Central Nervous System
Human emotion
involves the entire
nervous system,
but there are two
parts of the CNS
that are especially
important: the
limbic system and
the autonomic
nervous system.
The surface of the cerebrum is called the cerebral cortex and is composed of six layers. It is
made of gray matter, which is also found in the other parts of the nervous system. Because
this gray matter enlarges more than the rest of the brain during development, it rolls and
folds upon itself to produce convolutions (also known as gyri), fissures and sulci. The most
prominent fissure separates the cerebrum into 2 halves—the right and left hemispheres of
the brain.
The interior of the cerebrum, underneath the cerebral cortex, is known as the white matter.
It consists mainly of the axons of neuronal cells connecting different regions of the cortex
and the cortex with other parts of the brain and spinal cord.
The cerebellum, the second largest region of the brain, functions to control skeletal muscles,
primarily in terms of coordination and balance.
Human emotion involves the entire nervous system, but there are two parts of the CNS
that are especially important: the limbic system and the autonomic nervous system.
The limbic system is a complex set of structures that lies on both sides of the thalamus,
just under the cerebrum. It includes the diencephalon (thalamus and hypothalamus), the
hippocampus, the amygdala, and other nearby areas (see Figure 3). It is primarily responsible
for our emotional life, and the formation of memories. The thalamus coordinates all sensory
impulses, except for the sense of smell. It also plays a role in emotions by associating sensory
impulses with feelings of pleasantness and unpleasantness. The hypothalamus controls
many body activities, and it is one of the major regulators of homeostasis in the brain. It also
serves as a link between the nervous system and the endocrine system. The hypothalamus
modulates human urges, such as eating, drinking and sexual arousal, as well as emotional
and behavioral patterns.
The brainstem includes the medulla oblongata, pons and midbrain. These areas regulate
autonomic (involuntary) behaviors, including respiration, cardiac function and vasomotor
functions.
CONFIDENTIAL: For Internal Use Only.
8
2
2
Table 2: Functions of Major Brain Regions
Region
Function
·
·
·
Controls voluntary motor functions.
Cerebellum
·
Controls skeletal muscles primarily in coordination and balance.
Diencephalon
·
Thalamus coordinates all sensory impulses except for olfaction,
including those for touch, pain and temperature. Also associates
sensory impulses with feelings of pleasantness and unpleasantness.
·
The hypothalamus controls many body activities, and it is one
of the major regulators of homeostasis in the brain; also serves as
a link between the nervous system and the endocrine.
·
·
Composed of medulla oblongata, pons and midbrain.
Cerebrum
Brainstem
Coordinates physical, sensory, visual and auditory sensations.
Integrates consciousness, memory, use of language and emotions.
Controls involuntary processes; regulates respiration, cardiac
function, vasomotor functions, and facial nerve reflexes.
Figure 3: The Limbic System
Cingulate cortex
Cerebrum
Fornix
Mammillary body
Thalamus
Diencephalon
Amygdala
(thalamus & hypothalamus)
Hippocampus
Pituitary Gland
Midbrain
Cerebellum
Pons
Medulla
oblongata
Spinal cord
9
Brainstem
Chapter 2: The Central Nervous System
Thirty-one pairs
of spinal nerves
emerge from the
spinal cord, these
serve as a means of
neurotransmitter
projection to the
peripheral nervous
system.
2.2. Spinal Cord
The spinal cord is protected by the vertebral column as well as the meninges, which also
surround the brain. The gray matter of the spinal cord is shaped like the letter H. It is made
up of the cell bodies of neurons and unmyelinated axons and dendrites. Thirty-one pairs
of spinal nerves emerge from the spinal cord, these serve as a means of neurotransmitter
projection to the peripheral nervous system.
2.3. Peripheral Nervous System The peripheral nervous system includes all nerves external to the CNS. These include
the cranial and spinal nerves that emerge from and enter the CNS, and their terminal
projections—the axon terminals that synapse with muscle fibers, glands, or other cells
stimulated by nerves. These peripheral nerves relay impulses between the sense organs, the
CNS, and muscles and glands throughout the body. Overall, the peripheral nervous system
gathers information from the periphery, routes it to the CNS for interpretation, and then
transmits a response from the CNS back to the periphery.
The peripheral nervous system may be further subdivided into:
The somatic (voluntary) nervous system
The autonomic (involuntary) nervous system, which is further divided into
sympathetic and parasympathetic branches
CONFIDENTIAL: For Internal Use Only.
10
2
2
Malfunctioning
neurotransmitters
can cause illnesses
like MDD, GI
upset and urinary
incontinence.
2.4. Summary of the Central Nervous System
Figure 4 summarizes information presented to this point and provides an aggregate view of
the CNS. Neurotransmitter regulation is essential to the central nervous system functioning
properly. Malfunctioning neurotransmitters can cause illnesses like MDD, GI upset and
urinary incontinence.
Figure 4: The Central Nervous System
Nervous system
Central nervous system (CNS)
Peripheral nervous system (PNS)
Brain
Input
Output
Spinal Cord
Somatic
(voluntary)
Autonomic
(involuntary)
Sympathetic
Skeletal muscle, such as the facial
muscles, and the muscles found
in the limbs, such as the biceps
and triceps.
11
Parasympathetic
Cardiac muscle, smooth
muscle and glands.
CONFIDENTIAL: For Internal Use Only.
12
Chapter 3: Neuroanatomy Related to MDD
3.1. The Neuron
The neuron, or nerve cell, is the basic functional unit of all nervous system tissue. As shown in
Figure 5, all neurons contain the same basic features:
Cell Body
Dendrite
Axon
The cell body contains the nucleus and other organelles that carry out the processes
that maintain the life of the cell. Each neuron has one or more dendrites, which are highly
branched extensions that receive nerve signals from other neurons and conduct these
signals to the cell body. Each neuron also has at least one axon, a tubular extension that
carries nerve impulses away from the cell body toward other neurons. Each axon ends in
many fine branches that have specialized endings called terminals, the regions at which
neurons actually transmit impulses to other neurons.
Surrounding the axons of many neurons is a fatty substance called myelin. The myelin
sheath insulates the axons and increases the transmission rate of impulses and is formed by
specialized cells that wrap themselves around axons.
Figure 5: Neuron Structures
Cross section
Dendrites
Myelin Sheath
Axon
Nucleus
Cell body
Myelin
Axon terminals
Organelles
13
2
2
Chapter 3: Neuroanatomy Related to MDD
To be transmitted
from neuronto-neuron, the
electrical charge
must be translated
into a chemical
signal, called
neurotransmitters,
which cross the
synaptic cleft.
3.2. Neurotransmission
Information is transmitted along a neuron by means of a moving electrical charge. This
electrical charge must then be transmitted to the next neuron across a gap known as the
synaptic cleft. To be transmitted from neuron-to-neuron, the electrical charge must be
translated into a chemical signal, called neurotransmitters, which cross the synaptic cleft.
Once across the synaptic cleft the chemical signal reverts back to an electrical signal.
The complete juncture between an axon terminal and another cell is known as the synapse. The
synapse consists of the surface of the axon terminal, known as the presynaptic surface, and a
postsynaptic surface, which is most often the dendrite of an adjoining cell. As shown in Figure 6,
there are receptors and ion channels on both the presynaptic and postsynaptic surfaces.
Figure 6: Synapse Structure
Presynaptic surface
Presynaptic neuron
Vesicles containing
neurotransmitters
Neurotransmitters
Synaptic cleft
Receptors/
Ion channels
Postsynaptic neuron
Postsynaptic surface
Figure 7 illustrates the basic sequence of events that occur in neurotransmission. Synaptic
vesicles containing neurotransmitters are located in the axon terminal of the presynaptic
neuron. When triggered by an electrical impulse, ion channels in the presynaptic membrane
open, allowing calcium ions (Ca2+) to flow into the cell.
This influx of Ca2+ causes the vesicles to release the stored neurotransmitters into the synaptic
cleft. The neurotransmitters diffuse across the synaptic cleft and bind to specific receptors on
the postsynaptic membrane. This binding causes ion channels in the postsynaptic membrane
to open or close. Depending on the type of ion channel and the ions that move into or out
CONFIDENTIAL: For Internal Use Only.
14
2
2
Each neuron may
receive impulses
from many other
neurons, some
excitatory and
some inhibitory,
therefore the
behavior of
a neuron is
determined by
the sum of the
incoming impulses
it receives.
For patients
with MDD,
neurotransmitters
may be reabsorbed
by the presynaptic
terminal in a
process known as
reuptake.
Many classes of
antidepressants,
including the SSRIs,
are believed to
relieve the symptoms
of depression
by blocking the
reuptake of serotonin
by the presynaptic
neuron.
of the cell, the cell is either activated and propagates the electrical signal, or inhibited from
propagating the signal. Each neuron may receive impulses from many other neurons, some
excitatory and some inhibitory, therefore the behavior of a neuron is determined by the sum of
the incoming impulses it receives.
Figure 7: Neurotransmission
1
Action potential in
nerve terminal opens
Ca2+ channels
2
3
Presynaptic
axon terminal
Receptor/
ion channel
Neurotransmitters
cross synaptic
cleft and bind to
receptors
Ca2+ entry causes
vesicles to release
neurotransmitters
Neurotransmitters
Ca2+
Ca2+
Ca2+ Ca2+
Ca2+
Ions
4
5
Ion channels open,
ions enter the
postsynaptic cell
Postsynaptic cell
Cell is either
activated and
propagates signal or
signal is inhibited
The binding of a neurotransmitter to a receptor is reversible. When the complex formed
between the neurotransmitter and the receptor dissociates, both neurotransmitter and
receptor are free to function again.
Neurotransmitters crossing the synaptic cleft and binding to a postsynaptic receptor is not the
only thing that can occur when neurotransmitters are released from the presynaptic neuron.
For patients with MDD, neurotransmitters may be reabsorbed by the presynaptic terminal in
a process known as reuptake. Specific pumps in the membrane of the presynaptic cell carry
neurotransmitter molecules from the synaptic cleft back into the axon terminal. Once in the
axon terminal, the neurotransmitters are either reincorporated into vesicles or broken down by
enzymes. Two other alternatives are that the neurotransmitters released into the synaptic cleft
may diffuse away or be enzymatically broken down. Many classes of antidepressants, including
the SSRIs, are believed to relieve the symptoms of depression by blocking the reuptake of
serotonin by the presynaptic neuron.
15
Chapter 3: Neuroanatomy Related to MDD
The roles and
actions of
neurotransmitters,
the receptors
they bind to, and
the ion channels
they activate are
interrelated.
3.3. Neurotransmitters, Receptors and Ion Channels
The roles and actions of neurotransmitters, the receptors they bind to, and the ion channels
they activate are interrelated.
3.3.1. Neurotransmitters
As mentioned, functional neurotransmitters are chemical compounds carried through neurons
in vesicles and are intended to bind to post-synaptic neuron receptors. There are several
different groups of neurotransmitters, as listed in Table 3.
Table 3: Summary of Key Neurotransmitters in MDD
Neurotransmitter
Origin
Associated Effects
Serotonin (5-HT)
Raphe Nuclei
Mood, emotional behavior, sleep,
memory, appetite, sexual functioning,
painful physical symptoms
Norepinephrine (NE)
Locus Ceruleus
Mood, emotions, cognition, attention,
anxiety, lack of energy, vigilance,
sweating, painful physical symptoms
Dopamine (DA)
Midbrain
Body motion, motivational drive,
muscle coordination
It was once believed that each neuron contained only a single type of neurotransmitter,
and the neuron was named after the neurotransmitter it contained. For example, neurons
containing serotonin would have been known as serotonergic neurons. Now it is known that
many neurons may contain at least 2 neurotransmitters. Table 3 also shows the emotions or
biological functions mediated by the three primary neurotransmitters associated with MDD.
CONFIDENTIAL: For Internal Use Only.
16
2
2
3.3.2. Ion Channels
Ion channels and receptors both reside on the postsynaptic cell. Ion channels are gated
pores spanning the cell membrane. By changing the electrical charge on both sides of the
membrane, ion channels play a key role in propagating a nerve impulse. Ion Channels:
Open and close like a gate in response to specific signals.
Recognize specific ions and only allow the ions to pass through them when the pores
are open.
Ion channels are quite selective for the ions they allow to pass through them. For example,
there are specific channels each for potassium (K+), sodium (Na+), calcium (Ca2+), and Chloride
(Cl-), among others. Each ion channel is associated with a different type of receptor. Thus,
one type of Ca2+ channel may be regulated by one neurotransmitter receptor subtype,
while another type of Ca2+ channel may be regulated by a receptor subtype for a different
neurotransmitter.
Figure 8: Ion Channel
Cl
-
Cl-
Cl-
Pore
Cell membrane
Extracellular
Intracellular
Gate
Cl-
ClCl
-
ClCl-
ClClNerve impulse propagation
17
Chapter 3: Neuroanatomy Related to MDD
Postsynaptic
receptors act
to regulate the
propagation or
inhibition of the
impulse in the
postsynaptic cell.
3.3.3. Receptors
Receptors are complex proteins with special configurations that allow specific molecules, such
as neurotransmitters or drugs, to bind with them. Understanding the interaction between
neurotransmitter receptors and their biologic function upon drug binding is very important
when discussing MDD and the various drug classes used to treat MDD. Most psychoactive are
either receptor agonists or antagonists. These terms relate to their effect upon the receptor. This
binding may modify the receptor’s behavior and leads to one of the following changes:
Receptor agonism – A drug or neurotransmitter binds to a specific cell receptor
and triggers a response by the cell. The response triggered is often the cell’s natural
biologic function.
Receptor antagonism – A drug binds to a specific cell receptor and blocks it from
performing a specific biologic function.
Figure 7 in this module illustrates that neurotransmitter receptors are located on both the
presynaptic and postsynaptic cell surfaces. Presynaptic receptors primarily act to regulate
the release of neurotransmitters from that neuron. Postsynaptic receptors act to regulate the
propagation or inhibition of the impulse in the postsynaptic cell.
CONFIDENTIAL: For Internal Use Only.
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The biochemical
theory suggests
that depression
is the result of a
neurochemical
imbalance or
a functional
deficiency of
one or more key
neurotransmitters.
3.4. Biochemical Theory of Depression
While no single theory explains all MDD, the biochemical theory is widely accepted. The
biochemical theory suggests that depression is the result of a neurochemical imbalance or
a functional deficiency of one or more key neurotransmitters. While 5-HT is most commonly
associated with MDD both norepinephrine and dopamine are also believed to influence
depression.
The biochemical theory is based on the following observations:
Drugs that promote the augmentation of these key neurotransmitters, especially 5-HT,
can alleviate depressive symptoms.
Drugs that impede the activity of these neurotransmitter systems (e.g.,
antihypertensives) can induce depression.
Autopsy data have shown low concentration of neurotransmitters in the brains of
suicidal and/or depressed patients.
Concentrations of neurotransmitters also tend to be lower in the cerebrospinal fluid
(CSF) and the peripheral blood of depressed patients.
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CONFIDENTIAL: For Internal Use Only.
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Brain Booster
Brain Booster – Prepare for your online quiz. Module 2
certification requires a score of ≥85%. These questions
should help you prepare.
1. List the 5 theories of the cause of depression and the circle the one that is most accepted.
2. What is the name of the group of areas within the brain are responsible for our emotional health?
A. Cerebellum
3.
B. Cerebrum
C. Limbic System D. Hypothalamus
What is a neurotransmitter carried within in the presynaptic neuron?
A. Lipoprotein B. Versicle C. Dopamine
D. Receptor
4. List the neurotransmitters associated with depression.
5. Drugs have one of two effects on receptors, name their potential effects and describe each:
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Brain Booster
6. What is the basic functional unit of the human nervous system?
A. Ion Channel
B. Receptor
C. Neuron
D. None of these
7. The following process is described as an electrical charge being transmitted
to the next neuron across synaptic cleft.
A. Antagonism
B. Agonism
C. Neurotransmission
D. None of these
8. The diencephalon contains what two portions of the brain important
to human emotion and memory creation?
A. Cerebellum and Hypothalamus
B. Brain Stem and Thalamus
C. Hypothalamus and Thalamus
D. None of these
CONFIDENTIAL: For Internal Use Only.
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Definitions
Afferent Neuron: A neuron that carries impulse toward the CNS.
Autonomic Nervous System: Part of the nervous system that regulates activity of smooth
muscle, cardiac muscle and glands.
Axon: A tubular extension that carries nerve impulses away from the cell body toward other neurons.
Brainstem: Stalklike portion of the brain connecting cerebral hemispheres with the spinal cord;
controls involuntary process such as respiration.
Central Nervous System (CNS): One of the two main divisions of the nervous system,
consisting of the brain and the spinal cord.
Cerebellum: The second largest region of the brain; functions to control skeletal muscles
primarily in coordination and balance.
Cerebrum: Largest region of the brain; controls voluntary motor functions; coordinates physical,
sensory, visual and auditory sensations; integrates consciousness, memory, use of language and
emotions.
Cortex: The convoluted layer of gray matter covering each cerebral hemisphere.
Dendrite: Highly branched extensions that receive nerve signals from other neurons and
conduct these signals to the cell body.
Diencephalon: Portion of the brain that contains the thalamus and the hypothalamus.
Dorsal Horn: Crescent-shaped projection of gray matter in spinal cord.
Efferent Neuron: Nerve fibers that carry impulses outward, away from the brain and spinal cord.
Fissures: The deep grooves between folds of brain tissue.
Gray Matter: Those regions of the brain and spinal cord that are made up primarily of the cell
bodies and dendrites of nerve cells, rather than myelinated axons.
Gyri: Prominent rounded elevations of brain tissue that form the cerebral hemispheres.
Homeostasis: A state of equilibrium or a tendency to reach equilibrium, either metabolically
within a cell or organism or socially and psychologically within an individual or group.
Hypothalamus: Brain region primarily involved in autonomic (involuntary) nervous system
functions, hormone secretion, and mood; major regulatory of homeostasis.
Limbic System: A group of neuronal pathways that connect parts of the cerebrum,
diencephalon and brainstem.
Midbrain: Also called mesencephalon; the short part of the brainstem just above the pons; the
center for visual reflexes.
Medulla Oblongata: The base of the brain, which is formed by the enlarged top of the spinal
cord; directly controls breathing, blood flow, and other essential functions.
Meninges: The 3 membranes enclosing the brain and the spinal cord, comprising of the dura
matter, the pia matter and the arachnoid membrane.
23
Definitions
Myelin Sheath: A fatty substance that insulates the nerve fiber and helps to speed nerve
impulse transmission.
Neurochemical: Pertaining to chemicals involved in nervous system function.
Neurotransmitter: Chemical substance that enables communication between nerve cells.
Noradrenergic: Using norepinephrine as a neurotransmitter, norepinephrine is also called
noradrenaline.
Norepinephrine (NE): Neurotransmitter widely distributed throughout the nervous system;
involved in regulating sleep, wakefulness, learning, memory and mood.
Nucleus: An organelle that is the location of the genetic material of the cell.
Organelles: A specialized part of a cell that has its own function .
Parasympathetic Nervous System: A branch of the autonomic nervous system; slows the
heart rate, increases the intestinal and gland activity, and relaxes the sphincter muscle.
Pons: A prominence on the ventral (front) surface of the brainstem, between the medulla
oblongata and the midbrain.
Presynaptic Neuron: Nerve cell that transmits the signal across the synaptic cleft by releasing
neurotransmitters.
Postsynaptic Neuron: Nerve cell that receives the signal transmitted across the synaptic cleft.
Serotonergic: Using serotonin as a neurotransmitter.
Serotonin (5-HT): Neurotransmitter found in many regions of the brain and other parts of the
body; involved in the regulation of mood, emotional behavior, sleep, memory and appetite, as
well as modulation of the dopamine system.
Somatic Nervous System: Part of the peripheral nervous system that allows for interaction
with the external environment; composed of afferent and efferent neurons.
Sulci: Grooves or furrows on the surface of the brain, bounding the several convolutions, or gyri.
Sympathetic Nervous System: Branch of the autonomic nervous system that accelerates the
heart rate, constricts blood vessels, and raises blood pressure.
Synapse: The junction between an axon terminal and another neuron.
Synaptic Cleft: The space between the presynaptic and postsynaptic surfaces.
Thalamus: Brain region located above midbrain; relays sensory information to the cerebral cortex.
Transmission: The process of movement of nerve impulse along neural pathways in the body.
White Matter: Bundles of myelinated axons located in the brain and spinal cord.
CONFIDENTIAL: For Internal Use Only.
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References
1. Fields H. Depression and pain: A neurobiological model. Neuropsychiatry Neuropsychol
Behav Neurol. 1991;4(1):83-92.
2. Bair MJ,Robinson RL,Katon W,Kroenke K. Depression and pain comorbidity. Arch Intern
Med. 2003;163:2433-2445.
3. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and
anxiety disorders and pain. J Psychiatry Neurosci. 2001;26(1):37-43.
4. Nitti VW. Duloxetine: a new pharmacologic therapy for stress urinary incontinence. Rev
Urol. 2004;6(suppl 3):S48-S55
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Copyright © 2011 Trovis Pharmaceuticals. VIL-AMT-015 02/2011
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CONFIDENTIAL
For Internal Use Only. The information contained in this training module is for educational
purposes only. It is designed to provide you with the information you need to be educated
on the product, disease and competitive environment and is not to be distributed or used
in detailing.