Understanding_Depression_Cover.

ai 1 9/30/2009 12:24:12 PM

Understanding and Managing the Pieces of

Major Depressive Disorder

CM

MY

CY

CMY

NEI PRESS Release Date: August 15, 2009

Sponsored by Neuroscience Education Institute
www.neiglobal.com CME Credit Expires: August 14, 2012
Understanding and Managing
the Pieces of
Major Depressive Disorder

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Every effort has been made in preparing this book to provide accurate and up-to-date
information that is in accord with accepted standards and practice at the time of pub-
lication. Nevertheless, the author, editors, and publisher can make no warranties that
the information contained herein is totally free from error, not least because clinical
standards are constantly changing through research and regulation. The author, edi-
tors, and publisher therefore disclaim all liability for direct or consequential damages
resulting from the use of material contained in this book. Readers are strongly advised
to pay careful attention to information provided by the manufacturer of any drugs or
equipment that they plan to use.

PUBLISHED BY NEI PRESS, an imprint of NEUROSCIENCE EDUCATION INSTITUTE

Carlsbad, California, United States of America

NEUROSCIENCE EDUCATION INSTITUTE

1930 Palomar Point Way, Suite 101
Carlsbad, California 92008

http://www.neiglobal.com

Copyright © 2009 Neuroscience Education Institute.

All rights reserved.

This publication is in copyright. Subject to statutory exception and to the provisions of

relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Neuroscience Education Institute.

Printed in the United States of America

First Edition, August 2009

Typeset in Myriad Pro

Library of Congress Cataloging-in-Publication Data

ISBN 1-4225-0062-4

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Table of Contents

CME Information .............................................................................................................iv

Chapter 1: Neurobiology of Depression .................................................................1

Chapter 2: Treatments for Depression .....................................................................35

Section 1: Selective Serotonin Reuptake Inhibitors and

Serotonin Norepinephrine Reuptake Inhibitors .........................................36

Section 2: Norepinephrine Dopamine Reuptake Inhibitors

and Norepinephrine Reuptake Inhibitors .....................................................49

Section 3: Alpha 2 Antagonists and Serotonin

Antagonist/Reuptake Inhibitors .......................................................................54

Section 4: Tricyclic Antidepressants and Monoamine

Oxidase Inhibitors ..................................................................................................61

Section 5: Possible Trimonoamine Modulators ...............................................71

Section 6: Augmenting Strategies and New Treatments

on the Horizon ........................................................................................................79

Section 7: The Importance of Treatment ............................................................83

Chapter 3: Comorbidities and a Woman’s Life Cycle ..........................................89

Summary ............................................................................................................................115

References .........................................................................................................................117

CME Posttest and Activity Evaluation ......................................................................119

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CME Information

Overview
The successful treatment of major depressive disorder depends largely on a proper diagnosis, an adequate choice of
medication, and adherence to pharmacotherapy. This booklet explains the mechanisms of action of antidepressants,
illustrates how to treat women across their life cycle, and discusses various comorbidities of major depressive disorder.

Target Audience
This CME activity has been developed for MDs specializing in psychiatry. There are no prerequisites for this activity.
Physicians in all specialties who are interested in psychopharmacology, as well as nurses, psychologists, and pharma-
cists, are welcome for advanced study.

Statement of Need
The following unmet needs regarding major depressive disorder were revealed following a critical analysis of activ-
ity feedback, expert faculty assessment, literature review, and through new medical knowledge:
• Clinicians continue to amass information on the neurobiology of depression, which can only help to
serve their understanding of symptoms and select appropriate treatment options
• Treatments for major depressive disorders continue to evolve; older generation antidepressants may still
be useful, whereas newer generation antidepressants and novel treatment options continue to surface
• Treating specific populations with major depressive disorder can be difficult—special considerations are
indicated for pediatric populations, as well as women and the elderly

To help fill these unmet needs, quality improvement efforts need to provide education regarding:
1. The neurophysiology and mechanisms that contribute to depression
2. Current and emerging treatment options for depression
3. The recognition and management of comorbid conditions often associated with depression, in
addition to recognizing specialized care for subpopulations

Learning Objectives
After completing this activity, participants should be better able to fulfill the following learning objectives:
• Identify neural implications of depression and describe neurobiologic symptoms
• Utilize treatment options available for depression on a per-case basis
• Discuss comorbidities associated with depression

Accreditation and Credit Designation Statements

The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians.

The Neuroscience Education Institute designates this educational activity for a maximum of 3.0 AMA PRA Category 1
Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Also
available will be a certificate of participation for completing this activity.

Nurses in most states may claim full credit for activities approved for AMA PRA Category 1 Credits™ (for up to half of their
recertification credit requirements). This activity is designated for 3.0 AMA PRA Category 1 Credits.

Activity Instructions
This CME activity is in the form of a printed monograph and incorporates instructional design to enhance your reten-
tion of the information and pharmacological concepts that are being presented. You are advised to go through the
figures in this activity from beginning to end, followed by the text, and then complete the posttest and activity evalua-
tion. The estimated time for completion of this activity is 3.0 hours.

iv

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Instructions for CME Credit
To receive your certificate of CME credit or participation, please complete the posttest (you must score at least 70%
to receive credit) and activity evaluation found at the end of the monograph and mail or fax them to the address/
number provided. Once received, your posttest will be graded and a certificate sent if a score of 70% or more was
attained. Alternatively, you may complete the posttest and activity evaluation online and immediately print
your certificate. There is no fee for CME credits for this activity.

NEI Disclosure Policy

It is the policy of the Neuroscience Education Institute to ensure balance, independence, objectivity, and scientific
rigor in all its educational activities. Therefore, all individuals in a position to influence or control content develop-
ment are required by NEI to disclose any financial relationships or apparent conflicts of interest that may have a di-
rect bearing on the subject matter of the activity. Although potential conflicts of interest are identified and resolved
prior to the activity being presented, it remains for the participant to determine whether outside interests reflect a
possible bias in either the exposition or the conclusions presented.

These materials have been peer-reviewed to ensure the scientific accuracy and medical relevance of information
presented and its independence from commercial bias. The Neuroscience Education Institute takes responsibility
for the content, quality, and scientific integrity of this CME activity.

Individual Disclosure Statements

Author
Laurence Mignon, PhD
Senior Medical Writer, Neuroscience Education Institute, Carlsbad, CA
Stockholder: Aspreva Pharmaceuticals Corporation; Vanda Pharmaceuticals Inc.; ViroPharma Incorporated

Content Editors
Meghan Grady
Director, Content Development, Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.

Stephen M. Stahl, MD, PhD

Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA
Grant/Research: Forest; Johnson & Johnson; Novartis; Organon; Pamlab; Pfizer; Sepracor; Shire; Takeda; Vanda;
Wyeth
Consultant/Advisor: Arena; Azur; Bionevia; Boehringer Ingelheim; Bristol-Myers Squibb; CeNeRx; Dainippon
Sumitomo; Eli Lilly; Endo; Forest; Janssen; Jazz; Johnson & Johnson; Labopharm; Lundbeck; Marinus; Neuronet-
ics; Novartis; Noven; Pamlab; Pfizer; Pierre Fabre; Sanofi-Synthélabo; Sepracor; Servier; Shire; SK; Solvay; Somaxon;
Tetragenix; Vanda.
Speakers Bureau: Pfizer; Wyeth

Peer Reviewer
Scott A. Irwin, MD, PhD
Director, Psychiatry Programs, The Institute for Palliative Medicine at San Diego Hospice, San Diego, CA
No other financial relationships to disclose.

Design Staff
Nancy Muntner
Director, Medical Illustrations, Neuroscience Education Institute, Carlsbad, CA
No other financial relationships to disclose.

Disclosed financial relationships have been reviewed by the Neuroscience Education Institute CME Advisory Board to
resolve any potential conflicts of interest. All faculty and planning committee members have attested that their financial
relationships do not affect their ability to present well-balanced, evidence-based content for this activity.

Disclosure of Off-Label Use

This educational activity may include discussion of products or devices that are not currently labeled for such use by
the FDA. Please consult the product prescribing information for full disclosure of labeled uses.

Depression_Booklet.indd Sec3:v 9/30/2009 12:25:03 PM

Disclaimer
The information presented in this educational activity is not meant to define a standard of care, nor is it intended to
dictate an exclusive course of patient management. Any procedures, medications, or other courses of diagnosis or
treatment discussed or suggested in this educational activity should not be used by clinicians without full evalua-
tion of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manu-
facturer’s product information, and comparison with recommendations of other authorities. Primary references and
full prescribing information should be consulted.

Participants have an implied responsibility to use the newly acquired information from this activity to enhance
patient outcomes and their own professional development. The participant should use his/her clinical judgment,
knowledge, experience, and diagnostic decision-making before applying any information, whether provided here
or by others, for any professional use.

Sponsorship Information
This activity is sponsored by Neuroscience Education Institute.

Support
This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Com-
pany; and Lilly USA, LLC. For further information concerning Lilly grant funding visit, www.lillygrantoffice.com.

Date of Release/Expiration
Release Date: August 15, 2009 CME Credit Expiration Date: August 14, 2012

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Chapter 1
Neurobiology of Depression
Depression can affect every aspect of life. A patient undergoing a major depres-
sive episode who receives treatment with any antidepressant will often experience
symptomatic improvement. However, oftentimes treatment does not reach the goal
of remission (complete cessation of all symptoms of depression) until several different
pharmacotherapies have been utilized, possibly in combination. Understanding the
neurobiology underlying depressive symptomatology may give clinicians the opportu-
nity to treat the symptoms specifically, based upon brain mechanisms and the inter-
play among genes, circuits, and symptoms.

This chapter aims to identify neural implications of depression and describe neurobio-
logical symptoms in order to provide advanced education regarding the neurophysiol-
ogy of depression and mechanisms that contribute to the disorder.

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Major Depressive Disorder

Mood Chart

FIGURE 1.1. Mood charts illustrate a spectrum of syndromal states upon which a pa-
tient’s mood can be charted over time. Mood monitoring can be conducted intermit-
tently in a clinical setting or continuously via patient self-report in the form of a mood
diary. Tracking the course of illness can greatly assist in identifying disease states,
diagnosing accurately, and assessing treatment response.

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Chapter 1

Depressive Temperament
and Dysthymia

FIGURE 1.2. Patients with a depressive temperament may be regularly sad or apa-
thetic but do not have a sufficient degree or number of symptoms to qualify for the
diagnosis of dysthymia or a major depressive episode. Individuals with depressive
temperament may be more at risk for future mood disorders.

FIGURE 1.3. Dysthymia is a less severe form of depression than major depressive dis-
order, but is long-lasting and generally unrelenting for two years or more.

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Major Depressive Disorder

Identifying Mood Disorders:

Depression and Double Depression

FIGURE 1.4. Major depressive disorder (MDD) is characterized by a single or recurrent

major depressive episode(s); most people with MDD will experience recurrent episodes.

FIGURE 1.5. Double depression is characterized by unremitting dysthymia interrupted

by major depressive episode(s), and accompanied by poor inter-episode recovery
between episodes.

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Chapter 1

Unipolar vs. Bipolar Depression

FIGURE 1.6. Although both patients in this mood chart are presenting with identical
current symptoms of a major depressive episode over the past several days (A), patient 1
has unipolar depression whereas patient 2 has bipolar depression. So, what is the differ-
ence? The pattern of past symptoms (B) is quite different; for example, patient 1 has expe-
rienced a prior depressive episode while patient 2 has experienced a prior hypomanic
episode. Furthermore, it has been suggested that un(der)treated unipolar depression can
develop into a bipolar spectrum condition, and eventually lead to treatment resistance.

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Major Depressive Disorder

Circuits and Symptoms in Depression:

Part 1

FIGURE 1.7. (A) As per the Diagnostic and Statistical Manual, version IV (DSM-IV), di-
agnosis of major depressive disorder requires at least one of the symptoms in the top
row, and at least four of the symptoms in the bottom two rows. (B) Malfunctioning of
certain brain regions, manifesting as either hypo- or hyperactivity, may hypothetically
be altered due to aberrant neuronal activity and information processing, leading to
the different presenting symptoms of depression.

PFC: prefrontal cortex. S: striatum. BF: basal forebrain. NA: nucleus accumbens. T: thalamus. H: hippocampus.
Hy: hypothalamus. NT: brain neurotransmitter center. C: cerebellum. SC: spinal cord. A: amygdala.

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Chapter 1

Circuits and Symptoms in Depression:

Part 2

FIGURE 1.8. (A) Inefficient or dysfunctional serotonin (5HT), norepinephrine (NE), and/
or dopamine (DA) projections to the amygdala (A) and ventromedial prefrontal cortex
(VMPFC) are hypothetically involved in depressed mood. (B) Inefficient information
processing in the prefrontal cortex (PFC; 5HT, NE, and DA projections), the cerebellum
(C; 5HT and NE projections), the striatum (S; 5HT and DA projections), and the nucleus
accumbens (NA; 5HT and DA projections) is hypothetically involved in psychomo-
tor agitation or retardation. (C) Hypoactivation of 5HT, NE, and DA projections from
brainstem nuclei to the hypothalamus (Hy), thalamus (T), basal forebrain (BF), and PFC
is hypothetically involved in sleep disturbances.

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Major Depressive Disorder

Circuits and Symptoms in Depression:

Part 3

FIGURE 1.9. (A) Inefficient information processing from norepinephrine (NE) and
dopamine (DA) projections to the dorsolateral prefrontal cortex (DLPFC) is hypotheti-
cally linked to problems with emotional regulation, self-monitoring, goal-setting,
priority planning, and organization, all of which could lead to executive dysfunction.
(B) Inefficient information processing from NE projections to the prefrontal cortex
(PFC) and hypothalamus (Hy) and the DA projections to the PFC, Hy, and nucleus
accumbens (NA) is hypothetically linked to apathy. Although superficially similar to
depressed mood, apathy is actually a distinct symptom of depression, associated with
lack of pleasure including decreased libido, linked to loss of interest and motivation,
and often experienced by geriatric patients. Additionally, apathy is also hypothetically
regulated by different brain circuits than depressed mood. (C) Inefficient information
processing from NE and DA projections to the PFC is hypothetically involved in mental
fatigue. Physical fatigue is linked to deficient NE functioning in the descending spinal
cord (SC) and deficient DA functioning in the striatum, NA, Hy, and spinal cord.

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Chapter 1

Circuits and Symptoms in Depression:

Part 4

FIGURE 1.10. (A) Inefficient or dysfunctional serotonin (5HT) projections to the amyg-
dala (A) and the ventromedial prefrontal cortex (VMPFC) could theoretically cause
feelings of guilt and worthlessness, which are regulated by these “emotional” brain re-
gions. (B) Inefficient or dysfunctional 5HT projections to the hypothalamus (Hy) could
theoretically lead to problems with weight and appetite. (C) 5HT projections to the
“emotional” brain regions including the amygdala, VMPFC, and orbital frontal cortex
(OFC), could hypothetically be involved in suicidal ideation.

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Major Depressive Disorder

Monoamine Hypothesis of Depression

FIGURE 1.11. (A) As seen in Figures 1.8 through 1.10, dopamine (DA), norepinephrine
(NE), and serotonin (5HT) are the three key monoamines involved in depression. (B)
The classical “monoamine hypothesis of depression” states that depression results from
a deficiency in one or more of these three neurotransmitters.

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Chapter 1

Monoamine Hypothesis of Antidepressant Action

FIGURE 1.12. Theoretically, antidepressant medications should be able to normalize

the levels of the three neurotransmitters affected in depression by blocking presynap-
tic monoamine transporters (also called reuptake pumps), and thereby increasing the
synaptic availability and actions of these monoamines.

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Major Depressive Disorder

Monoamine Receptor Hypothesis of Depression

FIGURE 1.13. The monoamine receptor hypothesis builds on the classic monoamine
hypothesis of depression by suggesting that decreased activity of monoamine neu-
rotransmitters (dopamine, norepinephrine, and serotonin) causes upregulation of
postsynaptic receptors (red circle) which may lead to depression.

12

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Chapter 1

Monoamine Receptor Hypothesis of

Antidepressant Action

FIGURE 1.14. The monoamine receptor hypothesis suggests that if depression is

caused by upregulation of monoamine receptors, antidepressants act by ultimately
downregulating monoamine receptors over time. (A) An antidepressant can acutely
block the reuptake pump, allowing for more neurotransmitter (NT) in the synapse (red
circle). (B) A chronic increased availability of neurotransmitter over time can lead to
the downregulation of receptors (red circle). The time course for this downregulation
to occur (days to weeks) is consistent with both the delayed onset of antidepressant
effects and the time required to develop tolerance to side effects.

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Major Depressive Disorder

Monoamine Hypothesis of Antidepressant

Action on Gene Expression

FIGURE 1.15. Based on the monoamine hypothesis of depression, antidepressants

can theoretically create a return to a normal mood state by increasing the levels of
monoamines. The downstream consequences of increased monoamine production by
antidepressants leads to a cascade of effects such as expression of critical genes and
down or upregulation of various gene products.

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Chapter 1

Time Course of Antidepressant Effects

FIGURE 1.16. Antidepressant drugs have three time courses: one for clinical changes,
a second one for neurotransmitter changes, and a third one for receptor sensitivity
changes. While the neurotransmitter changes often occur rapidly after initial admin-
istration, clinical changes and receptor changes (i.e., downregulation) take longer to
occur. This observation has resulted in the hypothesis that neurotransmitter receptor
sensitivity may mediate the clinical changes seen after antidepressant administration,
including the production of therapeutic antidepressant effects and the development
of tolerance to side effects, all of which occur over a few weeks of time.

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Major Depressive Disorder

Serotonin Pathways

FIGURE 1.17. As mentioned previously, serotonin plays an integral part in mediat-

ing the symptoms of depression. Depicted in this figure are the major serotonergic
projections. Ascending projections originate from the raphe nucleus to the cerebel-
lum, thalamus, hypothalamus, basal forebrain, prefrontal cortex, striatum, nucleus
accumbens, amygdala, and hippocampus. Mood, appetite, suicidal ideation, and sleep
are regulated and affected by 5HT (see Figures 1.8 and 1.10). Descending projections
to the spinal cord affect pain pathways.

PFC: prefrontal cortex. S: striatum. BF: basal forebrain. NA: nucleus accumbens. T: thalamus. H: hippocampus.
Hy: hypothalamus. NT: brain neurotransmitter center. C: cerebellum. SC: spinal cord. A: amygdala.

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Chapter 1

Synthesis and Metabolism of Serotonin

FIGURE 1.18. Serotonin (5HT) is one of the three principal monoamines involved in
depression. (A) Serotonin is synthesized from the amino acid tryptophan (TRY), which
enters the serotonin neuron via the tryptophan transporter, a transporter that is distinct
from the serotonin transporter (SERT). After tryptophan is pumped into the serotonin
neuron, it is hydroxylated to 5-hydroxy-tryptophan (5HTP) by the rate-limiting enzyme
tryptophan hydroxylase (TRY-OH). 5HTP is then decarboxylated to 5HT by the enzyme
aromatic amino acid decarboxylase (AAADC), and is packaged into vesicles by the
vesicular monoamine transporter 2 (VMAT2) pump. There it is stored until released dur-
ing neurotransmission. (B) After 5HT has been released into the synapse it can either be
transported back into the serotonin neuron via the serotonin transporter (SERT) or it
can be metabolized and destroyed extraneuronally by either monoamine oxidase A or
B (MAO-A or MAO-B). If 5HT is transported into the neuron, but not repackaged rapidly
enough into synaptic vesicles, it will be destroyed intraneuronally by MAO-B.

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Major Depressive Disorder

Serotonin Receptors:
Part 1

FIGURE 1.19. (A) Presynaptic 5HT1B/D receptors are located on the axon terminal, and
act as “gatekeeper” for their neurotransmitter. (B) When serotonin builds up in the syn-
apse and binds to 5HT1B/D receptors (red circle), the further release of serotonin will
be inhibited. These receptors aid in modulating the appropriate release of serotonin.

18

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Chapter 1

Serotonin Receptors:
Part 2

FIGURE 1.20. (A) Presynaptic 5HT1A receptors are located on the cell body and
dendrites of a neuron, and are thus termed somatodendritic autoreceptors. (B) When
serotonin (5HT) binds to these somatodendritic receptors (red circle), they will reduce
neuronal electrical activity leading to a shutdown of 5HT impulse flow and therefore a
decrease in the amount of 5HT released at the synapse (on the right).

19

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Major Depressive Disorder

Norepinephrine Pathways

FIGURE 1.21. Norepinephrine (NE) also plays an integral part in mediating the
symptoms of depression. Ascending projections originate from the locus coeruleus
of brainstem to the cerebellum, thalamus, hypothalamus, basal forebrain, prefrontal
cortex, amygdala, and hippocampus. Mood, arousal, and cognition are regulated and
affected by NE (see Figures 1.8 and 1.9). Descending projections from the spinal cord
affect pain pathways.

PFC: prefrontal cortex. S: striatum. BF: basal forebrain. NA: nucleus accumbens. T: thalamus. H: hippocampus.
Hy: hypothalamus. NT: brain neurotransmitter center. C: cerebellum. SC: spinal cord. A: amygdala.

20

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Chapter 1

Synthesis and Metabolism of Norepinephrine

FIGURE 1.22. (A) Norepinephrine (NE) is synthesized from the amino acid tyrosine
(TYR), which is transported into the NE neuron by the tyrosine transporter, a transport-
er that is distinct from the NE transporter (NET). After tyrosine is pumped into the NE
neuron, it is hydroxylated to DOPA by the rate-limiting enzyme tyrosine hydroxylase
(TOH). DOPA is then decarboxylated to dopamine (DA) by the enzyme DOPA decarbox-
ylase (DDC). In the DA neuron, synthesis stops here. However, in the NE neuron, DA is
hydroxylated to NE by the enzyme dopamine beta hydroxylase (DBH) which is actually
located at synaptic vesicles. NE is then packaged into synaptic vesicles via the vesicular
monoamine transporter 2 (VMAT2). There it is stored until released during neurotrans-
mission. (B) After NE is released into the synapse, it is either transported back into
the NE neuron or metabolized and destroyed extraneuronally by either monoamine
oxidase A or B (MAO-A or MAO-B), or by catechol-O-methyl transferase (COMT). If
NE is transported into the neuron, but not repackaged rapidly enough into synaptic
vesicles, it will be destroyed intraneuronally by MAO-A or MAO-B.

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Major Depressive Disorder

Norepinephrine Receptors:
Part 1

FIGURE 1.23. (A) Presynaptic alpha 2 norepinephrine (NE) receptors on the NE neu-
ron’s axon terminals work similarly to the 5HT1B/D receptors, acting as “gatekeepers”
for their neurotransmitter. (B) When NE builds up in the synapse and binds to alpha 2
receptors (red circle), the further release of NE will be inhibited. These receptors aid in
modulating the appropriate release of NE.

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Chapter 1

Norepinephrine Receptors:
Part 2

FIGURE 1.24. (A) Presynaptic alpha 2 adrenergic somatodendritic autoreceptors,

located on the cell body and dendrites of a norepinephrine (NE) neuron, work similarly
to somatodendritic 5HT1A receptors. (B) When NE binds to these somatodendritic
autoreceptors (red circle), this will lead to a reduction in neuronal electrical activity
leading to a shutdown of NE impulse flow and therefore a decrease in the amount of
NE released at the synapse (on the right).

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Major Depressive Disorder

Dopamine Pathways

FIGURE 1.25. Dopamine (DA) projections ascend from the brainstem to the prefrontal
cortex, basal forebrain, nucleus accumbens, striatum, thalamus, hypothalamus, amyg-
dala, hippocampus, and cerebellum. DA neurotransmission is associated with cogni-
tion, psychosis, pleasure and reward, movement, and other functions (see Figures 1.8
and 1.9).

PFC: prefrontal cortex. S: striatum. BF: basal forebrain. NA: nucleus accumbens. T: thalamus. H: hippocampus.
Hy: hypothalamus. NT: brain neurotransmitter center. C: cerebellum. SC: spinal cord. A: amygdala.

24

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Chapter 1

Synthesis and Metabolism of Dopamine

FIGURE 1.26. (A) Dopamine (DA) is synthesized from the amino acid tyrosine (TYR)
which is transported into the DA neuron by the tyrosine transporter, a transporter
that is distinct from the DA transporter (DAT). After tyrosine is pumped into the DA
neuron, it is hydroxylated to DOPA by the rate-limiting enzyme tyrosine hydroxylase
(TOH). DOPA is then decarboxylated to DA by the enzyme DOPA decarboxylase (DDC).
DA is then packaged into synaptic vesicles via the vesicular monoamine transporter
2 (VMAT2). There it is stored until released during neurotransmission. (B) After DA is
released into the synapse, it is either transported back into the DA neuron or metabo-
lized and destroyed extraneuronally by either monoamine oxidase A or B (MAO-A or
MAO-B), or by catechol-O-methyl transferase (COMT). If DA is transported into the
neuron, but not repackaged rapidly enough into synaptic vesicles, it will be destroyed
intraneuronally by MAO-A or MAO-B.

25

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Major Depressive Disorder

Dopamine Receptors:
Part 1

FIGURE 1.27. (A) Presynaptic dopamine (DA) D2 receptors on the DA neuron’s axon
terminals work similarly to 5HT1B/D and alpha 2 receptors, acting as “gatekeepers” for
their neurotransmitter. (B) When DA builds up in the synapse and binds to D2 recep-
tors (red circle), the further release will be inhibited. These receptors aid in modulating
the appropriate release of DA.

26

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Chapter 1

Dopamine Receptors:
Part 2

FIGURE 1.28. (A) Presynaptic D2 somatodendritic autoreceptors, located on the cell

body and dendrites of a dopamine (DA) neuron, work similarly to somatodendritic
5HT1A and alpha 2 receptors. (B) When DA binds to these somatodendritic autorecep-
tors (red circle), this will lead to a reduction in neuronal electrical activity leading to a
shutdown of DA impulse flow and therefore a decrease in the amount of DA released
at the synapse (on the right).

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Major Depressive Disorder

Monoamine Interactions

FIGURE 1.29. (A) Norepinephrine (NE) can boost serotonin (5HT) release via an ex-
citatory input from the locus coeruleus projecting to the raphe and acting at alpha 1
receptors on serotonergic cell bodies and dendrites in the raphe (5HT accelerator; red
box, bottom left). NE can also reduce 5HT release via an inhibitory input from NE nerve
terminals acting at 5HT nerve terminals on alpha 2 receptors on 5HT axon terminals
(5HT brake; red box, top right).

(B) In the nigrostriatal dopamine (DA) pathway, the release of 5HT acts as a brake on
DA release. 5HT leads to inhibition of DA release, both at the level of DA cell bodies in
the substantia nigra (red circle, bottom left) and at the level of axon terminals in the
striatum (red circle, top right).

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Chapter 1

Norepinephrine-Serotonin Interactions:
Norepinephrine Regulation of Serotonin

FIGURE 1.30. (A) The serotonin (5HT) accelerator: When norepinephrine (NE) binds
alpha 1 receptors on somatodendritic regions of 5HT neurons (red circle), this causes
excitation of the 5HT neuron, with increased neuronal impulse flow and increased
release of 5HT from its axon terminals. (B) The 5HT brake: When NE occupies alpha
2 heteroreceptors on 5HT axon terminals (red circle), this causes inhibition of 5HT
release from the 5HT neuron.

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Major Depressive Disorder

Serotonin-Dopamine Interactions:
5HT2A and 5HT1A Receptors Have Opposite Actions
on Dopamine Release

FIGURE 1.31. Serotonin (5HT) neurons can act on somatodendritic regions of dopa-
mine (DA) neurons. Specifically, 5HT1A and 5HT2A receptors have opposite actions
on DA release. Stimulation of 5HT1A receptors increases DA release, and thus 5HT1A
receptors act as a DA accelerator. Stimulation of 5HT2A receptors inhibits DA release;
thus 5HT2A receptors act as a DA brake. 5HT can regulate DA release directly or indi-
rectly. (A) When 5HT binds to 5HT2A receptors on DA neurons or on GABA neurons, DA
release is decreased directly or via inhibition through GABA release, respectively. (B)
Upon binding to 5HT1A receptors, 5HT causes inhibition of its own release. A lack of
5HT results in disinhibition of DA release, and therefore increased DA output.

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Chapter 1

Serotonin-Dopamine-Norepinephrine Interactions:
5HT2C Receptors Reduce Release of Dopamine and
Norepinephrine in Prefrontal Cortex

FIGURE 1.32. 5HT2C receptors inhibit both dopamine (DA) and norepinephrine (NE)
release. This occurs when serotonin (5HT) binds to 5HT2C receptors on GABA interneu-
rons in the brainstem and excites them, causing release of the inhibitory neurotrans-
mitter GABA onto both NE (on the left) and DA neurons (on the right).

31

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Major Depressive Disorder

Neuroimaging of Brain Activation in Depression

FIGURE 1.33. (A) Neuroimaging studies indicate that the resting activity in the dor-
solateral prefrontal cortex (DLPFC, black circle) is decreased in depressed patients. (B)
On the other hand, the resting activity in the amygdala and ventromedial prefrontal
cortex (VMPFC, black circles) is increased in depressed patients. (C) Additionally, de-
pressed patients show underactivation in response to induced happiness and overacti-
vation of VMPFC and amygdala in response to induced sadness.

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Chapter 1

From Genes to Circuits to Symptoms

FIGURE 1.34. Major depressive disorder (MDD) may not be inherited per se, but
risk for MDD may be inherited as a series of risk genes (indicated here as P, Q, and R).
Whether a risk manifests itself as overt MDD may depend upon exposure of geneti-
cally vulnerable circuits to stress. In the presence of major stressors, circuits rendered
vulnerable by risk genes to developing inefficient information processing under stress
may break down, and if sufficient symptoms prevail, MDD may result.

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Major Depressive Disorder

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Chapter 2
Treatments for Depression
Today’s psychopharmacologist has a vast array of medications to choose from when
treating major depressive disorder, and depending on their mechanism of action some
medications may be more useful than others for various individuals. This chapter aims
to provide education regarding current and emerging treatment options for depression,
with an emphasis on mechanisms of action. Therefore, this chapter is separated into dif-
ferent sections based on the mechanisms of actions of the medications discussed.
Section 1 reviews some of the most commonly used first-line antidepressant drug op-
tions, the selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine
reuptake inhibitors (SNRIs). For patients who do not completely remit on an SSRI or SNRI,
oftentimes augmentation and/or combinations are introduced or the patient is switched
to a second-line treatment.
Section 2 reviews the antidepressant drugs that are norepinephrine dopamine reup-
take inhibitors (NDRIs) and selective norepinephrine reuptake inhibitors (NRIs). NDRIs are
considered first-line treatment, and NRIs are often used as second-line options.
Section 3 reviews the antidepressant drugs that work as alpha 2 antagonists and are
also known as serotonin and norepinephrine disinhibitors (SNDIs; i.e., mirtazapine) or the
drugs that work as serotonin antagonist/reuptake inhibitors (SARIs; i.e., trazodone and
nefazodone). The focus is on the unique characteristics of alpha 2 antagonism and SARIs,
both of which are second-line treatment options.
Section 4 reviews the classical antidepressants known as monoamine oxidase inhibi-
tors (MAOIs) and tricyclic antidepressants (TCAs). The focus here is on mechanisms of
action of these particular drugs and how these “old-fashioned” medications can be quite
powerful options for treating depression.
Section 5 reviews the concepts of trimonoamine modulators and gives various exam-
ples of some trimonoamine modulators that have proven efficacy in treating depression.
Section 6 introduces novel treatment options and augmenting agents used to treat
depression.
Section 7 finally summarizes the importance of treating depression and offers different
“pharmacies” to do so.

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Major Depressive Disorder

Selective Serotonin Reuptake Inhibitors and

1 Serotonin Norepinephrine Reuptake Inhibitors

FIGURE 2.1.1. The depression pharmacy illustrates the vast number of treatment
options used in depression. For section 1, only selective serotonin reuptake inhibitors
(SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) are highlighted on the
shelf to indicate that these treatments are first-line monotherapies. This figure will be
utilized throughout the book to indicate where on the pharmacy shelves the various
pharmacotherapies under discussion fall in the sequence of selecting treatments for
depression.

NDRI: norepinephrine dopamine reuptake inhibitors. SDA: serotonin dopamine antagonists. α 2 antagonist: alpha
2 antagonists. NRI: selective norepinephrine reuptake inhibitors. TCA: tricyclic antidepressants. SARI: serotonin 2A
antagonist/reuptake inhibitors. MAOI: monoamine oxidase inhibitors. 5HT1A: serotonin 1A partial agonists. BZ:
benzodiazepines. DPA: dopamine partial agonists. MTHF: L-5-methyl-tetrahydrofolate. T3/T4: thyroid hormone.
ECT: electroconvulsive therapy. IPT: interpersonal therapy. VNS: vagus nerve stimulation.

36

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Chapter 2

Selective Serotonin Reuptake Inhibitors:

Overview

FIGURE 2.1.2. (A) Six agents are considered selective serotonin reuptake inhibitors
(SSRI): fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram.
Each shares the common property of inhibiting the serotonin transporter (SERT)
leading to serotonin reuptake inhibition (SRI) which is the core feature of this class of
drugs. (B) By binding to SERT and thereby inhibiting the reuptake of serotonin, SSRIs
allow for more neurotransmitter to remain in the synapse which results in their anti-
depressant effect. The molecular mechanism of action of SSRIs, including downstream
effects on receptors, is illustrated in detail on the following pages.

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Major Depressive Disorder

Mechanism of Action of Selective Serotonin Reuptake

Inhibitors: Parts 1 and 2

FIGURE 2.1.3. The depressed state is characterized by low serotonin (5HT) levels, up-
regulated receptors, and a low number of signals in the neuron to release more 5HT.

FIGURE 2.1.4. By blocking SERT, selective serotonin reuptake inhibitors (SSRI) cause a
rapid increase in 5HT in the somatodendritic area (red circle) with only a little increase
in 5HT at the axon (right).

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Chapter 2

Mechanism of Action of Selective Serotonin Reuptake

Inhibitors: Parts 3 and 4

FIGURE 2.1.5. The increase in serotonin (5HT) causes the autoreceptors to desensi-
tize/downregulate (red circle).

FIGURE 2.1.6. Once the autoreceptors have downregulated, there is no longer an

inhibition of impulse flow in the 5HT neuron, and neuronal impulse flow is thus turned
on. This leads to increased release of 5HT at the axon terminal (red circle).

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Major Depressive Disorder

Mechanism of Action of Selective Serotonin Reuptake

Inhibitors: Part 5

FIGURE 2.1.7. The increase of serotonin (5HT) at the axon causes the postsynaptic
receptors to desensitize/downregulate (red circle). This desensitization may result in a
reduction of side effects of selective serotonin reuptake inhibitors as tolerance develops.

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Chapter 2

Other Pharmacological Actions of

Selective Serotonin Reuptake Inhibitors

FIGURE 2.1.8. While selective serotonin reuptake inhibitors (SSRI) all share their high
affinity for serotonin reuptake inhibition (SRI), each has different secondary pharmaco-
logical actions, which include norepinephrine reuptake inhibition (NRI), dopamine reup-
take inhibition (DRI), 5HT2C antagonism, muscarinic/cholinergic antagonism (m-ACh),
sigma-1 receptor actions (σ), and inhibition of NOS (nitric oxide synthetase) and various
CYP450 enzymes such as 2D6, 3A4, and 1A2. Pharmacologic properties of each of the six
SSRIs are shown in the following figures.

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Major Depressive Disorder

Main Selective Serotonin Reuptake Inhibitors: Part 1

FIGURE 2.1.9. Besides its actions at the

serotonin (5HT) reuptake pump, fluox-
etine has antagonist actions at 5HT2C
receptors, leading to norepinephrine (NE)
and dopamine (DA) release. Normally 5HT
inhibits DA and NE release at 5HT2C re-
ceptors (Figure 1.32). When 5HT2C recep-
tors are blocked, the inhibition is stopped,
which is also called “disinhibition.” Thus,
blockade of 5HT2C receptors results in
NE and DA disinhibition; therefore 5HT2C
antagonists such as fluoxetine are NE and
DA disinhibitors (NDDIs). Fluoxetine also
inhibits CYP450 2D6 and 3A4. Fluoxetine
has a long half-life, while its active me-
tabolite has an even longer half-life; these factors may reduce the incidence of sudden
withdrawal symptoms. Fluoxetine may be useful in conjunction with atypical anti-
psychotics, including olanzapine, to increase the effectiveness of their antidepressant
action in bipolar depression.

FIGURE 2.1.10. Paroxetine is often pre-

ferred in the treatment of depression for
patients with anxiety symptoms. This may
be due to paroxetine’s anticholinergic ef-
fects (M1 muscarinic antagonism). In ad-
dition to this and the serotonin reuptake
inhibition (SRI) properties, paroxetine has
weak norepinephrine transporter (NET)
inhibition properties, thus acting as a nor-
epinephrine reuptake inhibitor (NRI) with
potent inhibitory actions at CYP450 2D6.
Paroxetine is a substrate as well as an
inhibitor of 2D6, which can lead to a rapid
decline in its plasma drug levels when
paroxetine is discontinued, contributing
to the withdrawal symptoms experienced upon sudden discontinuation. Inhibition of
nitric oxide synthetase (NOS) may contribute to its sexual dysfunction side effects.

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Chapter 2

Main Selective Serotonin Reuptake Inhibitors: Part 2

FIGURE 2.1.11. Sertraline is unique

in that it binds to sigma-1 receptors as
well as the dopamine transporter (DAT),
acting as a dopamine reuptake inhibitor
(DRI) in addition to its serotonin reuptake
inhibitory (SRI) properties. While sigma-1
actions are not well understood, they may
contribute to anxiolytic effects and may
be useful in psychotic depression. The
actions at DAT may be weak, but perhaps
only a small amount of DAT inhibition is
enough to cause improvement of certain
depressive symptoms when utilized
in conjunction with inhibition of the
serotonin transporter. Sertraline may be
added to bupropion, another DAT inhibitor, increasing that property and aiding in al-
leviation of depressive symptoms.

FIGURE 2.1.12. Fluvoxamine has poten-

tially important secondary actions at sig-
ma-1 receptors as well. This action is more
potent for fluvoxamine than sertraline,
with fluvoxamine’s properties thought to
be agonistic at sigma-1 receptors, con-
tributing to its efficacy as an anxiolytic.
Additionally, fluvoxamine is also thera-
peutically effective as a treatment option
in psychotic and delusional depression.
Currently available as a controlled-release
formulation, once-a-day administration
is possible and favored, with clinical
trials reporting robust remission rates
in obsessive compulsive disorder and
anxiety disorder. Fluvoxamine is also available in immediate-release formulation, but
due to shorter half-life, this requires twice-daily administration. Fluvoxamine was one
of the first antidepressants marketed worldwide, though it was never approved for
depression in the U.S. (currently used more often in treatment of obsessive compulsive
disorder and anxiety). It is a potent inhibitor of CYP450 1A2 and 3A4.

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Major Depressive Disorder

Main Selective Serotonin Reuptake Inhibitors: Part 3

FIGURE 2.1.13. Citalopram consists of

two enantiomers, R and S. Taken to-
gether, this agent is known as racemic
citalopram, with mild antihistamine and
2D6 inhibitory properties residing in
the R enantiomer. Citalopram is gener-
ally a well-tolerated selective serotonin
reuptake inhibitor (SSRI) and is useful in
treating elderly patients with depression.
However, at its lowest dose, citalopram
may be somewhat inconsistent in thera-
peutic action, potentially requiring a dose
increase to optimize treatment response.
This may be due to a recent finding that
the R enantiomer may be active at the
serotonin transporter (SERT), thus interfering with the ability of the S enantiomer to in-
hibit SERT. This interference could lead to reduced inhibition of SERT, reduced synaptic
serotonin, and possibly reduced therapeutic action.

FIGURE 2.1.14. Escitalopram is, in es-

sence, citalopram without the R enan-
tiomer. In this case, the pure active SERT
properties of the S enantiomer are the
cause of its antidepressant properties.
By removing the R enantiomer, this also
removes the antihistaminic and CYP450
2D6 inhibitory properties of citalopram.
Additionally, by removing the R enantio-
mer, which can interfere with SERT, the
lowest dose of escitalopram may be more
effective. Escitalopram is known as one of
the better-tolerated SSRIs with the few-
est CYP450-mediated drug interactions,
though it is comparatively expensive, as
no generic is yet available.

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Chapter 2

Mechanism of Action of Serotonin Norepinephrine

Reuptake Inhibitors: Part 1

FIGURE 2.1.15. Serotonin norepinephrine reuptake inhibitors (SNRI) act on two mono-
amines specifically. (A) In the prefrontal cortex, the serotonin reuptake inhibition (SRI)
property of SNRIs plugs into the serotonin transporter (SERT) resulting in an increase in
synaptic serotonin and an antidepressant effect. (B) In this brain area, the SNRIs will also
block the norepinephrine transporter (NET) and through their norepinephrine reuptake
inhibition (NRI) property, they will lead to an increased amount of norepinephrine in the
synapse and again an antidepressant effect.

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Major Depressive Disorder

Mechanism of Action of Serotonin Norepinephrine

Reuptake Inhibitors: Part 2

FIGURE 2.1.16. (A) In the prefrontal cortex (PFC), the dopamine (DA) neuron is devoid
of DA transporters. Here, DA is inactivated by the norepinephrine transporter (NET). Thus
after being released, DA diffuses until it reaches a NET on a norepinephrine (NE) neuron.
(B) NETs actually have higher affinity for DA than they do for NE! Thus, in the PFC, NETs
inactivate both NE and DA, and blockade of NETs will lead to an increase in both NE and
DA levels.

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Chapter 2

Main Serotonin Norepinephrine Reuptake

Inhibitors: Part 1
FIGURE 2.1.17. Venlafaxine was the
first serotonin norepinephrine reuptake
inhibitor (SNRI) on the U.S. market, and
has become one of the most frequently
prescribed antidepressants on the mar-
ket. Venlafaxine has varying degrees of
inhibition of norepinephrine reuptake
(NRI) depending on the dose, whereas
serotonin reuptake inhibition (SRI) is
moderately potent and present at all ap-
proved doses. Venlafaxine is a substrate
for CYP450 2D6, which converts it to the
active metabolite desvenlafaxine. After
venlafaxine is administered, plasma levels
of venlafaxine are normally around half
that of desvenlafaxine. If a CYP450 2D6 inhibitor is taken concurrently, this may shift
the plasma levels more toward venlafaxine, reducing the amount of norepinephrine
transporter (NET) inhibition. This variability of plasma levels may also accompany
CYP450 2D6 genetic polymorphisms, with poor metabolizers shifting the plasma
concentration more toward venlafaxine, which may result in a reduction of NET inhibi-
tion. Dose titration of venlafaxine or administration of desvenlafaxine itself may solve
this problem. Venlafaxine may have withdrawal reactions, especially after sudden
discontinuation. The extended-release formulation is much better tolerated than the
immediate-release formulation.

FIGURE 2.1.18. Desvenlafaxine has

greater NET inhibition than serotonin
transporter (SERT) inhibition compared
to venlafaxine. Since desvenlafaxine is
not a substrate of CYP450 enzymes
including 2D6, plasma levels should be
more consistent than with venlafaxine.
Desvenlafaxine is also unaffected by
genetic polymorphisms of CYP450. Thus,
the relative amount of NET versus SERT
inhibition should also be more consistent,
and greater at comparable doses. Des-
venlafaxine has been tested for treatment
of vasomotor symptoms associated with
perimenopause, with positive results.

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Major Depressive Disorder

Main Serotonin Norepinephrine Reuptake

Inhibitors: Part 2
FIGURE 2.1.19. Duloxetine is the first
serotonin norepinephrine reuptake
inhibitor (SNRI) approved for treatment of
painful neuropathy (diabetic peripheral
neuropathic pain), in addition to treating
major depression and generalized anxiety
disorder. This agent appears to be useful
in treating the painful physical symp-
toms associated with a major depres-
sive episode, as well as treating geriatric
depression, which is often associated
with cognitive dysfunction. Duloxetine
has shown efficacy in treating the pain
associated with fibromyalgia and may
also be useful for cognitive symptoms
in fibromyalgia. Improvement of cognition in various disorders may be due to inhibi-
tion of prefrontal cortical norepinephrine transporters (NET). Duloxetine is a CYP450
2D6 inhibitor, which may result in various drug interactions that should be monitored.
Duloxetine may be administered once daily, though in some difficult-to-treat patients,
higher doses may be utilized, which may be dosed twice daily.

FIGURE 2.1.20. Milnacipran is somewhat

different in that among the four approved
SNRIs, it has the strongest relative ac-
tions at the norepinephrine transporter
(NET) versus the serotonin transporter
(SERT). Other SNRIs generally exhibit the
opposite properties. Data suggest that
milnacipran may have efficacy both for
pain and cognitive symptoms in fibromy-
algia. In several countries outside the U.S.,
milnacipran is approved for the treatment
of depression, and approval for fibromy-
algia is pending worldwide. Milnacipran
may be more energizing and activating
than some other SNRIs due to its relative-
ly potent noradrenergic actions, and may cause more sweating and urinary hesitancy.
Milnacipran is generally given twice daily due to its short half-life.

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Chapter 2

Norepinephrine Dopamine Reuptake Inhibitors and

2 Norepinephrine Reuptake Inhibitors

FIGURE 2.2.1. Norepinephrine dopamine reuptake inhibitors (NDRIs) are on the first-
line treatment shelf, whereas norepinephrine reuptake inhibitors (NRIs) are considered
second-line monotherapies.

SSRI: selective serotonin reuptake inhibitors. SNRI: serotonin norepinephrine reuptake inhibitors. SDA: serotonin
dopamine antagonists. α 2 antagonist: alpha 2 antagonists. TCA: tricyclic antidepressants. SARI: serotonin 2A
antagonist/reuptake inhibitors. MAOI: monoamine oxidase inhibitors. 5HT1A: serotonin 1A antagonists. BZ: ben-
zodiazepines. DPA: dopamine partial agonists. MTHF: L-5-methyl-tetrahydrofolate. T3/T4: thyroid hormone. ECT:
electroconvulsive therapy. IPT: interpersonal therapy. VNS: vagus nerve stimulation.

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Major Depressive Disorder

Mechanism of Action of Norepinephrine Dopamine Reuptake

Inhibitors vs. Selective Norepinephrine Reuptake Inhibitors

FIGURE 2.2.2. As their name suggests, norepinephrine dopamine reuptake inhibitors

(NDRI) inhibit both the norepinephrine (NET) and the dopamine transporter (DAT),
whereas selective norepinephrine inhibitors (NRI) only inhibit NET. This will lead to differ-
ent actions in different brain regions, depending on the presence of NETs and DATs.

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Chapter 2

Comparing the Regional Effects of Norepinephrine Dopamine

Reuptake Inhibitors vs. Norepinephrine Reuptake Inhibitors

FIGURE 2.2.3. Both norepinephrine dopamine reuptake inhibitors (NDRI) and selective
norepinephrine reuptake inhibitors (NRI) raise both norepinephrine (NE) and dopamine
(DA) levels in the prefrontal cortex (PFC) via inhibition of norepinephrine transporters
(NET; top figures). Due to a lack of NE terminals and therefore NETs in the striatum and
nucleus accumbens, NRIs will lack any effect in these areas, while NDRIs will raise only DA
in those two areas.

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Major Depressive Disorder

Norepinephrine Dopamine Reuptake Inhibitor

FIGURE 2.2.4. Bupropion blocks the nor-

epinephrine and dopamine transporters
(NET and DAT) less potently than selec-
tive serotonin reuptake inhibitors (SSRI)
and serotonin norepinephrine reuptake
inhibitors (SNRI) block the serotonin
transporter (SERT). This implies that (1)
NET and DAT inhibition are insufficient
explanations of bupropion’s antidepres-
sant actions, or that (2) lesser amounts
of NET and DAT inhibition are necessary
to be an antidepressant compared to the
inhibition of SERT. The latter possibility is
supported by observations that much
less NET inhibition than SERT inhibi-
tion occurs with SNRI use and that high degrees of DAT inhibition include abusable
stimulants such as amphetamine, cocaine, and methylphenidate, rather than anti-
depressants. Thus, low levels of combined NET plus DAT inhibition may be ideal for
a non-abusable antidepressant like bupropion. Bupropion may be useful in treating
nicotine addiction due to its ability to occupy DAT in the striatum and nucleus accum-
bens, mitigating cravings but not becoming abusable itself. Bupropion was originally
marketed in the United States only, in an immediate-release formulation. Recent
formulations have been developed in twice-daily (bupropion SR) and once-daily doses
(bupropion XL). These advances not only provide convenience but are also beneficial
in reducing the risk of seizures at peak plasma drug levels associated with the original
formulation. Bupropion is generally a stimulating agent, and does not appear to cause
sexual dysfunction that may be associated with use of other antidepressants. Bupro-
pion has been very useful for patients who experience reduced positive affect, or the
“dopamine-deficiency syndrome.” Oftentimes, augmentation with bupropion to an
existing SSRI or SNRI can be useful for patients who have not responded to previous
serotonergic-focused treatment.

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Chapter 2

Norepinephrine Reuptake Inhibitors

FIGURE 2.2.5. Atomoxetine was never

developed as an antidepressant in the
United States, and it is currently marketed
only for attention deficit hyperactivity dis-
order. Nevertheless, due to its mechanism
of action as norepinephrine reuptake in-
hibitor (NRI), it may be useful when given
as an augmenting agent with selective
serotonin reuptake inhibitors or other
agents for treatment-resistant depression.

FIGURE 2.2.6. Reboxetine is approved

as an antidepressant in Europe, but not
in the United States. Reboxetine may
be useful as an augmenting agent in
treatment-resistant depression, similar to
atomoxetine, or on its own as a mono-
therapy after selective serotonin reuptake
inhibitors have failed or “pooped out.”

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Major Depressive Disorder

Alpha 2 Antagonists and Serotonin

3 Antagonist/Reuptake Inhibitors

FIGURE 2.3.1. The alpha 2 antagonist mirtazapine and the serotonin antagonist/
reuptake inhibitors (SARI) trazodone and nefazodone are listed as second-line mono-
therapies. They may be useful as monotherapies in situations where patients have not
experienced full remission while taking a selective serotonin reuptake inhibitor (SSRI)
and/or a serotonin norepinephrine reuptake inhibitor (SNRI), or as augmentation and/
or combination strategies with SSRIs/SNRIs.

NDRI: norepinephrine dopamine reuptake inhibitors. SDA: serotonin dopamine antagonists. α 2 antagonist: alpha
2 antagonists. NRI: selective norepinephrine reuptake inhibitors. TCA: tricyclic antidepressants. MAOI: monoamine
oxidase inhibitors. 5HT1A: serotonin 1A partial agonists. BZ: benzodiazepines. DPA: dopamine partial agonists.
MTHF: L-5-methyltetrahydrofolate. T3/T4: thyroid hormone. ECT: electroconvulsive therapy. IPT: interpersonal
therapy. VNS: vagus nerve stimulation.

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Chapter 2

Alpha 2 Antagonists or Serotonin

Norepinephrine Disinhibitors

FIGURE 2.3.2. Unlike serotonin norepinephrine reuptake inhibitors (SNRI), alpha 2

antagonists do not block monoamine transporters to achieve their therapeutic effects.
By blocking alpha 2 receptors, alpha 2 antagonists result in norepinephrine (NE) no
longer being able to turn off its own release. This causes “disinhibition” of NE release
(i.e., an increase in NE). Similarly, alpha 2 antagonists do not allow NE to turn off sero-
tonin (5HT) release, resulting in “disinhibition” of 5HT release (i.e., an increase in 5HT) as
well. An additional mechanism of alpha 2 antagonists which aids in increasing 5HT re-
lease is the disinhibition of NE in the noradrenergic pathway to the midbrain raphe. NE
neurons from the locus coeruleus innervate cell bodies of 5HT neurons in the midbrain
raphe; thus, this pathway enhances 5HT release via stimulation of alpha 1 receptors
with an alpha 2 antagonist. Therefore, alpha 2 antagonists are serotonin and norepi-
nephrine disinhibitors (SNDIs), with dual action increases of both NE and 5HT release.

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Major Depressive Disorder

Mechanism of Action of Alpha 2 Antagonist

FIGURE 2.3.3. (A) Alpha 2 antagonists increase norepinephrine (NE) neurotransmis-

sion via “cutting the brake cable” by blocking presynaptic alpha 2 autoreceptors,
causing NE release to be disinhibited, i.e., increased. (B) The brake cable can also be
cut for serotonergic (5HT) neurotransmission via blockade of alpha 2 heteroreceptors,
resulting in disinhibition of 5HT release.

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Chapter 2

Noradrenergic and Specific Serotonergic Antidepressant

FIGURE 2.3.4. Mirtazapine has a com-

plex but very interesting pharmacology. It
has been called a noradrenergic and spe-
cific serotonergic antidepressant (NaSSA),
with actions at alpha 2 receptors as well
as at three serotonin (5HT) receptors—2A,
2C, and 3. In addition, mirtazapine blocks
histamine H1 receptors. By blocking
alpha 2 receptors, mirtazapine increases
both 5HT and norepinephrine (NE) and
is thus a serotonin and norepinephrine
disinhibitor or SNDI. Mirtazapine admin-
istration thus causes 5HT to be released
onto all receptors; however, since 5HT2A,
5HT2C, and 5HT3 receptors are blocked
by mirtazapine, the net stimulation falls on the 5HT1A receptors. This further results in
release of dopamine (DA), which may be helpful in depression as well as anxiety.

Mirtazapine’s antagonist actions at 5HT2A and 2C receptors also results in increased

release of DA and NE, and these 5HT2A and 5HT2C antagonist actions may also pro-
vide useful anxiolytic and antidepressant properties, as well as providing sleep-restor-
ing properties. In addition, mirtazapine is able to increase 5HT release without causing
sexual dysfunction.

Due to its 5HT2A and 5HT2C antagonist properties, and thus its ability to disinhibit
both NE and DA release, mirtazapine is further classified as a norepinephrine and
dopamine disinhibitor (NDDI). 5HT3 antagonist action may reduce nausea, with H1
action potentially relieving insomnia and improving anxiety, but causing weight gain.
So, this complex molecule is an NDDI (due to 5HT2A and 5HT2C antagonism), an SNDI
(due to alpha 2 antagonism), plus a 5HT3 and H1 antagonist!

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Major Depressive Disorder

Serotonin Antagonist/Reuptake Inhibitor

FIGURE 2.3.5. Serotonin2A antagonist/reuptake inhibitors (SARIs) block 5HT2A and

5HT2C receptors, the serotonin transporter (SRI), and alpha 1 adrenergic receptors. Tra-
zodone also has histamine H1 receptor antagonism properties, whereas nefazodone
also blocks the norepinephrine transporter (NRI).

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Chapter 2

Mechanism of Action of Serotonin

Antagonist/Reuptake Inhibitors

FIGURE 2.3.6. (A) At baseline postsynaptic action, the neuron fires. (B) Serotonin (5HT)
is excitatory at 5HT2A receptors. (C) 5HT is inhibitory at 5HT1A receptors. (D) 5HT2A
antagonism therefore potentiates the inhibitory actions of 5HT at 5HT1A receptors.

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Major Depressive Disorder

Main Serotonin Antagonist/Reuptake Inhibitors

FIGURE 2.3.7. In many ways, trazo-

done is two drugs: a low dose hypnotic
and a high dose antidepressant. At low
doses, trazodone’s most potent actions
at 5HT2A, alpha 1, and even H1 recep-
tors provide hypnotic actions. However,
blockade of the serotonin transporter
(SERT) from serotonin reuptake inhibition
(SRI actions) does not occur at levels great
enough to increase serotonin (5HT) levels
unless trazodone is given in high doses. It
is this SERT blockade working in synergy
with 5HT2A and 5HT2C antagonism that
gives trazodone its ability to act as an an-
tidepressant and why it is called an SARI
(serotonin 2A/2C antagonist and reuptake inhibitor) at high doses. Trazodone lacks
sexual side effects because of this SARI action.

FIGURE 2.3.8. Nefazodone has strong

5HT2A antagonist actions with weaker
5HT2C antagonism and weaker SERT inhi-
bition. This particular drug is currently not
used very often due to the potential for
rare liver toxicity. Similarly to trazodone,
nefazodone is approved for the treatment
of depression. Nefazodone can be ad-
ditionally used as a relapse prevention in
major depressive disorders.

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Chapter 2

Tricyclic Antidepressants and

4 Monoamine Oxidase Inhibitors

FIGURE 2.4.1. Tricyclic antidepressants (TCA) and monoamine oxidase inhibitors

(MAOI) are generally considered second- or third-line monotherapies. These agents
may be utilized in difficult-to-treat cases, where other first-line treatments may have
failed to produce results.

SSRI: selective serotonin reuptake inhibitors. NDRI: norepinephrine dopamine reuptake inhibitors. SNRI: serotonin
norepinephrine reuptake inhibitors. SDA: serotonin dopamine antagonists. α 2 antagonist: alpha 2 antagonists.
NRI: selective norepinephrine reuptake inhibitors. SARI: serotonin 2A antagonist/reuptake inhibitors. 5HT1A:
serotonin 1A partial agonists. BZ: benzodiazepines. DPA: dopamine partial agonists. MTHF: L-5-methyl-tetrahy-
drofolate. T3/T4: thyroid hormone. ECT: electroconvulsive therapy. IPT: interpersonal therapy. VNS: vagus nerve
stimulation.

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Major Depressive Disorder

Properties of Tricyclic Antidepressants

FIGURE 2.4.2. (A) All tricyclic antidepressants (TCA) block the norepinephrine trans-
porter (NET) and are therefore norepinephrine reuptake inhibitors (NRI); some also
block the serotonin transporter (SERT) and are therefore serotonin reuptake inhibi-
tors (SRI). Both properties can lead to an antidepressant effect. (B) In addition, all TCAs
share the secondary properties of inhibition of histamine H1, alpha 1, and muscarinic
cholinergic receptors (M1). (C) Finally, some have additional antagonist properties at
5HT2A and 5HT2C receptors. TCAs also block voltage-sensitive sodium channels, which
is why they can be lethal in overdose.

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Chapter 2

Mechanism of Action of Tricyclic Antidepressants:

Part 1

FIGURE 2.4.3. (A) Here a tricyclic antidepressant (TCA) is depicted inserted into the
serotonin (5HT) reuptake pump, blocking it and causing 5HT accumulation in the
synapse, which results in an antidepressant effect. (B) Also depicted here is the nor-
epinephrine reuptake inhibition (NRI) portion of the TCA inserted to cause synaptic
accumulation of norepinephrine which also results in an antidepressant effect.

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Major Depressive Disorder

Mechanism of Action of Tricyclic Antidepressants:

Part 2

FIGURE 2.4.4. (A) When tricyclic antidepressants (TCA) block serotonin 5HT2A recep-
tors, an antidepressant effect is achieved (perhaps through disinhibition of dopamine
(DA) and norepinephrine (NE) release, as previously discussed). In addition, sleep prob-
lems may improve. (B) TCAs inserted into the 5HT2C receptors result in their blockade
and also produce an antidepressant effect, perhaps through disinhibition of DA and
NE release as well.

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Chapter 2

Side Effects of Tricyclic Antidepressants

FIGURE 2.4.5. Some of the additional receptors of tricyclic antidepressants (TCA) can
lead to side effects. (A) Inhibition of alpha 1 receptors can lead to dizziness, drowsiness,
and decreased blood pressure. (B) Inhibition of H1 receptors is known to induce weight
gain and drowsiness. (C) Blockade of M1 receptors can result in constipation, blurred
vision, dry mouth, and drowsiness. (D) One of the properties of all TCAs is their ability to
block voltage-sensitive sodium channels. When these channels are blocked in the brain
and the heart, side effects can include coma and seizure (due to central nervous system
actions), arrythmia, and death (due to peripheral cardiac actions), especially in overdose.

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Major Depressive Disorder

Monoamine Oxidase A and B Inhibition

and Antidepressant Action

FIGURE 2.4.6. Monoamine oxidase A (MAO-A) metabolizes serotonin (5HT), norepi-

nephrine (NE), and dopamine (DA), whereas monoamine oxidase B (MAO-B) preferen-
tially metabolizes DA (left panels). Combined inhibition of MAO-A and MAO-B results
in greater increases in all three neurotransmitters than does inhibition of only MAO-A
or MAO-B (right panels).

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Chapter 2

Monoamine Oxidase Interaction With Serotonin

Reuptake Inhibitors

FIGURE 2.4.7. Serotonin (5HT) can be increased via the inhibition of the serotonin
transporter (SERT) by selective serotonin reuptake inhibitors or serotonin norepineph-
rine reuptake inhibitors (A) or via the inhibition of monoamine oxidase (MAO) by MAO
inhibitors (MAOI) (B). However, when both SERT and MAO are inhibited, 5HT levels can
dramatically increase. Thus, excessive stimulation of postsynaptic 5HT receptors can
occur to dangerous levels (C) and cause hyperthermia, coma, seizures, cardiovascular
problems, and death. This is known as the “serotonin syndrome” and is why the combina-
tion of an MAOI with any drug that inhibits serotonin reuptake is strictly contraindicated.

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Major Depressive Disorder

Drugs to Avoid With MAOIs

Potentially Dangerous Hypertensive Combos: Agents That, When Combined With

MAOIs, Can Cause a Hypertensive Crisis (Theoretically via Adrenergic Stimulation)

Decongestants
• phenylephrine (alpha1 selective agonist)
• *ephedrine (ma hunag, ephedra) (alpha and beta agonist; central NE and
DA releaser)
• *pseudoephedrine (active stereoisomer of ephedrine – same mechanism
as ephedrine)
• *phenylpropanolamine (alpha1 agonist; less effective central NE/DA
releaser than ephedrine)

Stimulants Antidepressants with NRI

• amphetamines • TCAs
• methylphenidate • NRIs
• SNRIs
Appetite Suppressants with NRI • NDRIs
• sibutramine
• phentermine
A

Potentially Lethal Combos: Agents That, When Combined with MAOIs, Can Cause
Hyperthermia/Serotonin Syndrome (Theoretically via SERT Inhibition)

Antidepresants Sibutramine (SNRI for weight loss)

• SSRIs
• SNRIs
• TCAs Opioids
• dextromethorphan
Other TCA Structures • meperidine
• Cyclobenzapine • tramadol
• Carbamazepine • methadone
• propoxyphene
B

TABLE 2.4.1. Pharmacotherapeutic agents that, when combined with a monoamine

oxidase inhibitor (MAOI), may result in potentially dangerous hypertensive reactions
(A) or potentially lethal combinations causing hyperthermia (B).

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Chapter 2

Identifying a Hypertensive Crisis and Ways to Avoid It

Hypertensive Crisis

• Defined as having a diastolic blood pressure > 120 mmHg

• Potentially fatal reaction characterized by:
• Occipital headache which may radiate frontally
• Palpitation
• Neck stiffness or soreness
• Nausea
• Vomiting
• Sweating (sometimes with fever)
• Dilated pupils, photophobia
• Tachycardia or bradycardia that can be associated with
constricting chest pain

Suggested Tyramine Dietary Modifications for MAO Inhibitors

Food to Avoid Food Allowed

Dried, aged, smoked, fermented, Fresh or processed meat, poultry, and
spoiled, or improperly stored meat, fish
poultry, and fish
Broad bean pods All other vegetables
Aged cheeses Processed and cottage cheese, ricotta
cheese, yogurt
Tap and nonpasteurized beers Canned or bottled beers and alcohol
(have little tyramine)
Marmite, sauerkraut Brewer’s and baker’s yeast
Soy products/tofu

TABLE 2.4.2. (A) Signs of a hypertensive crisis, and (B) ways that this crisis may be
avoided when using monoamine oxidase inhibitors (MAOI) with dietary restrictions.

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Major Depressive Disorder

How to Prevent Tyramine Reactions

FIGURE 2.4.8. (A) Monoamine oxidase A (MAO-A) is present in both the brain and the
gut. The need to block MAO-A in the brain to induce an antidepressant effect leads to
the dilemma that concomitant inhibition of MAO-A in the gut can lead to increased
risk of tyramine reaction. (B) The solution may be to use reversible inhibitors of MAO-
A (RIMA). In the case of RIMA, the norepinephrine (NE) released by tyramine (1) can
displace the RIMA (2), allowing for normal destruction of the extra NE. (C) Transdermal
selegiline is one solution for MAO-A and MAO-B antidepressant effects without tyramine
reactions. Bypassing the liver via transdermal administration allows for a high dose and
thus both MAO-A and MAO-B inhibition in the brain while bypassing delivery to the gut,
thus avoiding tyramine reactions due to low MAO-A inhibition in the gut.

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Chapter 2

Possible Trimonoamine Modulators

5

1. Lithium
2. Thyroid hormones (T3, T4)
3. L-methyl-folate (MTHF, 5-L-methyltetrahydrofolate)
4. S-adenosyl-methionine (SAMe)
5. Omega-3 fatty acids
6. Vitamin D
7. Estrogen
8. Testosterone
9. Buspirone
10. Brain stimulation/neuromodulation (ECT, VNS, TMS, DBS)
11. Psychotherapy

TABLE 2.5.1. Presented here are therapeutic interventions for major depression that
work in ways other than inhibiting monoamine transporters and which are often used
to augment drugs that inhibit monoamine transporters. Trimonoaminergic modulators
(TMMs) are similar in that they all modulate monoamines, though each one may work
in a different way to modulate/enhance monoamines and be of a different make-up
(e.g., hormone, vitamin, medical food, non-pharmaceutical, etc.)

ECT: electroconvulsive therapy. VNS: vagus nerve stimulation. TMS: transcranial stimulation. DBS: deep brain
stimulation.

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Major Depressive Disorder

Lithium

FIGURE 2.5.1. Although the mechanism of action of lithium is still not completely
known, it is posited to act by modulating G proteins (middle), or to inhibit second-
messenger enzymes such as inositol monophosphate (right), both of which affect signal
transduction. Lithium might also act within various downstream signal transduction
cascades (left). Lithium can be a useful booster of antidepressant action, both in patients
with unipolar depression that is non-responsive to antidepressant monotherapy, and in
bipolar depression to augment other mood stabilizers.

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Chapter 2

Lithium and Thyroid as

Trimonoamine Modulators

FIGURE 2.5.2. Lithium can boost the actions of all three monoamines, supposedly via
one of the mechanisms depicted in the previous figure. Lithium is commonly used as
an augmenting agent for patients who have not responded to previous antidepressant
treatment. Thyroid hormone (T3/T4) can also be considered a potential trimonoamine
modulator (TMM), as it binds to a nuclear hormone receptor that may lead to changes
in neuronal gene expression that modulates one or more of the three monoamine
neurotransmitters. Patients who are theoretically deficient in one or more of the three
monoamines (dopamine, norepinephrine, and serotonin), despite treatment with an
antidepressant (top), can have their monoamine activity theoretically restored when
lithium or T3/T4 are added (bottom).

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Major Depressive Disorder

How Does L-methylfolate Work? Part 1: L-methylfolate

is the Centrally Active Form of the Vitamin Folic Acid

FIGURE 2.5.3. Neurotransmitter synthesis for all monoamines is dependent upon L-

methylfolate (shown above as MTHF), which is formed from synthetic folic acid dietary
supplements, from natural dietary dihydrofolate (green vegetables, liver, etc.) or provid-
ed by direct treatment with synthetic L-methylfolate (MTHF) itself. In depressed patients,
conversion of folate/folic acid into MTHF can be reduced by poor diet (e.g., alcoholism,
eating disorder), by concomitant treatment with anticonvulsants that can interfere with
absorption (e.g., valproic acid, carbamazepine) or inhibit the enzyme DHFR (dihydro-
folate reductase) involved in L-methylfolate synthesis (e.g., lamotrigine), or by genetic
factors/polymorphisms that can reduce the activity of the enzyme MTHFR
(methylene tetrahydrofolate reductase), also involved in L-methylfolate synthesis. Since
folic acid itself cannot cross the blood-brain barrier, and multiple factors may interfere
with its conversion to L-methylfolate, treatment can be provided instead by giving L-
methylfolate itself.

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Chapter 2

How Does L-methylfolate Work? Part 2: L-methylfolate

Enhances BH4 Production and Trimonoamine Synthesis

FIGURE 2.5.4. (A) L-methylfolate ( MTHF) enhances the synthesis of tetrahydrobiopterin

(BH4), a critical cofactor for the rate-limiting enzymes, tyrosine hydroxylase for dopa-
mine (DA) and norepinephrine (NE) and tryptophan hydroxylase for serotonin (5HT). (B)
In the absence of BH4 cofactor, tyrosine hydroxylase is inactive (left, depicted as sleeping
blue enzyme). The blue enzyme lacks BH4 binding (depicted as an empty 4) and cannot
bind tyrosine (depicted as a stellate binding site that does not fit the tyrosine icon).
However, when BH4 binds to tyrosine hydroxylase, it “activates” the enzyme (depicted as
turning purple with the yellow 4 as cofactor), leading to a change in the stellate binding
site to a round shape in the purple enzyme. Now tyrosine can bind and be converted
into both DA and NE. (C) A similar action occurs at tryptophan hydroxylase, the rate-
limiting enzyme for 5HT.

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Major Depressive Disorder

L-methylfolate as a
Trimonoamine Modulator

FIGURE 2.5.5. L-methylfolate enhances the synthesis of all three monoamines (dopa-
mine, norepinephrine, and serotonin), and thus is another type of trimonoamine modu-
lator (TMM). Patients who are theoretically deficient in one or more of the monoamines
(top), despite treatment with an antidepressant, can have their monoamine activity
theoretically restored when L-methylfolate is added (bottom).

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Chapter 2

Neuromodulation as a Trimonoamine Modulator

FIGURE 2.5.6. Stimulation of specific

areas of the brain appears to be a useful
therapy for difficult-to-treat depression.
Vagus nerve stimulation (VNS) and deep
brain stimulation (DBS) both utilize im-
planted devices in the chest wall. In VNS,
a lead is wrapped around the vagus nerve
in the neck. This then sends signal pulses
to the midbrain raphe and locus coeruleus,
thereby boosting the monoamines sero-
tonin and norepinephrine, respectively.

FIGURE 2.5.7. Transcranial magnetic

stimulation (TMS) involves a coil placed
on the scalp which sends magnetic
stimulation specifically to the dorsolateral
prefrontal cortex (DLPFC). This may boost
trimonoamine neurotransmitter synthesis
and release, thereby improving depressed
symptoms. Whereas VNS is approved for
treatment of depression, TMS is not yet
approved. It is available in some countries,
and is currently being reviewed by the
Food and Drug Administration.

FIGURE 2.5.8. In deep brain stimulation

(DBS) leads are placed directly into the
brain, often in the ventromedial prefrontal
cortex and subgenual area of the anterior
cingulate cortex. An implanted electrical
stimulator sends repeated pulses and can
theoretically boost the synthesis or release
of the three monoamines.

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Major Depressive Disorder

Psychotherapy

FIGURE 2.5.9. Psychotherapy adjunct to pharmacotherapy has been shown to improve

overall quality-of-life in patients with major depressive disorder. Behavioral and educa-
tional therapies help improve factors such as total functioning, relationship functioning,
life satisfaction, compliance with medication, and personal coping mechanisms. Psycho-
therapy can provide a necessary regular forum for patients to express and work through
the progression of their illness and the coping mechanisms they use to overcome their
limitations.

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Chapter 2

Augmenting Strategies and New Treatments

6 on the Horizon

FIGURE 2.6.1. Insomnia is one of the most common symptoms of major depression
to persist following treatment with an antidepressant such as a selective serotonin
reuptake inhibitor (SSRI). Not surprisingly, treatment of such residual insomnia with a
hypnotic can improve this symptom. However, shown here is also the improvement
of remission rates of both major depression and generalized anxiety disorder (GAD)
when the hypnotic eszopiclone is added to an SSRI. Eszopiclone, like zolpidem and za-
leplon, is sometimes called a “Z-drug” or more precisely, a positive allosteric modulator
(PAM) of GABA-A receptors. Here, not only does insomnia improve in major depression
and GAD when eszopiclone is added to an SSRI, but so do other core symptoms of
these disorders, resulting in improvement of remission rates.

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Major Depressive Disorder

The Evolving Antidepressant Actions of

Atypical Antipsychotics

FIGURE 2.6.2. Atypical antipsychotics are best known as treatments of psychosis in

schizophrenia and acute mania in bipolar disorder. However, these agents are increas-
ingly being used to treat depression as well. This includes use as an augmenting agent
to selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibi-
tors for patients with major depression who have inadequate responses to first-line
monotherapy, i.e., for treatment-resistant unipolar depression. Aripiprazole is currently
approved by the FDA for this use, particularly at low doses, but all agents in this class
are used as augmenting agents in treatment-resistant unipolar depression. Atypical
antipsychotics are also employed both as first-line treatments for bipolar depression
and as augmenting agents to mood stabilizers for bipolar depression. Quetiapine is
currently approved by the FDA for this use, but all atypical antipsychotics are used
in bipolar depression. Finally, these agents are sometimes used as monotherapy for
major depression, and for anxiety disorders such as GAD, with pending FDA approval
of quetiapine for this use.

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Chapter 2

New Antidepressant Treatments on the Horizon

FIGURE 2.6.3. Triple reuptake inhibitors (TRIs)

block all three monoamine transporters, thus
building on the concept that if “two mechanisms
are better than one” (i.e., serotonin norepinephrine
reuptake inhibitors compared to selective sero-
tonin reuptake inhibitors), then “three mechanisms
may be better than two.” At this point, the question
is how much blockade of each of the three mono-
amine transporters would be ideal and several of
these agents are now in clinical trials. Some TRIs
that are in testing also have actions at multiple ad-
ditional neurotransmitter receptors.

FIGURE 2.6.4. Agomelatine is known as a norepi-

nephrine dopamine disinhibitor (NDDI) because of
its 5HT2C antagonist properties of inhibiting sero-
tonin (5HT), thereby disinhibiting dopamine (DA)
and norepinephrine (NE) release. In addition to its
5HT2C antagonist properties, agomelatine is also
an agonist at melatonin 1 (MT1) and melatonin 2
(MT2) receptors and has 5HT2B antagonist proper-
ties. Thus, in addition to being useful in treating
depression due to 5HT2C antagonist properties, its
actions at MT1 and MT2 receptors can aid in sleep
improvement. This agent is in clinical trials.

FIGURE 2.6.5. Saredutant, a neurokinin2 (NK2)

antagonist, may be effective in patients with major
depressive episodes. This agent has shown promis-
ing results in animal models of depression. Hypo-
thetically, conditions associated with excessive
release of endogenous neurokinin A (NKA) benefit
from blocking NK2 receptors which may explain
saredutant’s potential antidepressant effect. This
NK2 antagonist is currently in clinical trials.

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Major Depressive Disorder

Other Antidepressants in Development

Neurokinin 1 receptors
Also called substance P receptors
Agonist is substance P
Multiple substance P antagonists (also known as NK1 antagonists) tested
and failed in depression and pain
Neurokinin 2 receptors
Agonist is NKA (neurokinin A, and its extended and shortened versions)
Antagonist is saredutant, with preclinical evidence and preliminary clinical
evidence of efficacy as an antidepressant
Neurokinin 3 receptors
Agonist is NKB (neurokinin B)
Multiple NK3 antagonists in testing for depression, schizophrenia, and other
disorders
Monoamine mechanisms
5HT1A partial agonists (gepirone)
Beta-3 agonist (amebegron)
D3/D2 partial agonists (RGH-188/cariprazine; pramipexole; ropinirole; aripiprazole)
Glutamate mechanisms
Ketamine
Memantine
NMDA antagonists
Novel mechanisms
Glucocorticoid antagonists (mifepristone)
CRF1 antagonists
Vasopressin 1B (V1B) antagonists
Nemifitide (injectable pentapeptide)

TABLE 2.6.1. Three major neurokinins exist in the brain: substance P (also known as
neurokinin 1 or NK1) binds the NK1 receptor, neurokinin A (NKA) binds the neurokinin
2 (Nk2) receptor, and neurokinin B (NKB) binds the neurokinin 3 (NK3) receptor.

Treatment options are coming to light for major depressive disorder that previously
may not have been considered for use. Aripiprazole was recently approved for use as
an add-on for treating unipolar depression, and quetiapine is currently being tested
for use as a unipolar first-line treatment option. Some of the agents listed above were
discussed in this chapter. Please refer to Stahl’s Essential Psychopharmacology, 3rd ed.
for further detail.

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Chapter 2

The Importance of Treatment

7

FIGURE 2.7.1. (A) As seen during an eight-week clinical trial, treatment with most anti-
depressants will yield 67% responders and 33% non-responders. (B) Administration of
placebo, on the other hand, will lead to 33% responders and 67% non-responders.

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Major Depressive Disorder

Remission Rates in Major Depressive Disorder and Residual

Symptoms in Nonremitters

FIGURE 2.7.2. Only 1/3 of patients remit after initial antidepressant treatment (ADT).
After one year of treatment with four different antidepressants for 12 weeks each, only
2/3 of patients eventually achieve remission.

FIGURE 2.7.3. While antidepressants are more likely to improve mood, suicidal ideation,
and psychomotor retardation in depressed patients, several symptoms often remain in
nonremitters, especially insomnia, but also fatigue and problems concentrating.

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Chapter 2

Proportion of Major Depressive Disorder Relapses

FIGURE 2.7.4. Once remission is achieved, there appears to be a protective factor in

experiencing a relapse. However, as treatment administration increases, the protective
effect of remission decreases. Thus, as shown above, the chances of staying in remis-
sion decline as the number of treatments required to attain remission increases.

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Major Depressive Disorder

First-line Monotherapies Followed by Classical Evidence-

based Antidepressant Augmentation Therapies

FIGURE 2.7.5. The algorithm depicted above shows steps that may be taken when
treating depression. (A) First-line treatments regularly include SSRIs, SNRIs, and NDRIs
as monotherapy or in combination with each other (e.g., SSRI/SNRI plus NDRI). (B)
Thereafter augmentation strategies can be used if the monotherapy alone is not suf-
ficient. The most common augmentation therapies for major depression have often
included lithium, thyroid hormones, or the 5HT1A partial agonist buspirone. However,
recent evidence-based studies do not suggest which patient should get each of these
and are not able to determine which is superior to the others.
SSRI: selective serotonin reuptake inhibitors. SNRI: serotonin norepinephrine reuptake inhibitors. NDRI: norepi-
nephrine and dopamine reuptake inhibitors. 5HT1A: serotonin 1A agonists. T3/T4: thyroid hormone.

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Chapter 2

Second-line Monotherapies and Ancillary

Treatments for Depression

FIGURE 2.7.6. (A) If a monotherapy plus an augmenting agent are not successful in at-
taining symptom remission, a second-line monotherapy may be introduced. (B) Finally,
ancillary treatment options may also be recommended.
SSRI: selective serotonin reuptake inhibitors. NDRI: norepinephrine and dopamine reuptake inhibitors. SNRI:
serotonin norepinephrine reuptake inhibitors. ECT: electroconvulsive therapy. IPT: interpersonal therapy. VNS:
vagus nerve stimulation. NRI: norepinephrine reuptake inhibitors. TCA: tricyclic antidepressants. SARI: serotonin
2A antagonist/reuptake inhibitors. MAOI: monoamine oxidase inhibitors.

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Major Depressive Disorder

Following First-line Monotherapies With Symptom-based

Antidepressant Augmentation Strategies

FIGURE 2.7.7. (A) A symptom-based approach after failure of first-line monotherapies

could be a hypnotic for residual insomnia, modafinil for residual fatigue/problems
concentrating, or L-methylfolate for patient with problems tolerating prior treatments,
since this should have few if any side effects. (B) If the patient is still not in remission,
augmentation with an atypical antipsychotic (e.g., aripiprazole) starting at low doses
may be considered.

SSRI: selective serotonin reuptake inhibitors. NDRI: norepinephrine and dopamine reuptake inhibitors. SNRI: sero-
tonin norepinephrine reuptake inhibitors. DPA: dopamine partial agonists. MTHF: L-5-methyl-tetrahydrofolate.

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Chapter 3
Comorbidities and a Woman’s Life Cycle
This chapter aims to provide education regarding the recognition and management of
comorbid conditions often associated with depression. In order to reach full remission
of depression, the comorbid disorders should be addressed in parallel. The lifecycle of
a woman, with the accompanying fluctuating estrogen levels, can make her prone to
depression, and the most effective treatments may vary throughout her life. This chapter
will also discuss special considerations that are indicated for treating women at every
stage of their life.

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Major Depressive Disorder

Common Comorbidities in Major Depressive Disorder

FIGURE 3.1. Some common comorbidities in major depressive disorder (MDD) include
sleep/wake problems, anxiety, attention deficit hyperactivity disorder (ADHD), sub-
stance abuse, and chronic pain. For a patient to obtain full remission, it is imperative
to concomitantly treat all disorders. It is therefore a good idea to solicit information on
any of these comorbid conditions when taking the history of symptoms before and af-
ter treatment with an antidepressant intervention to assess underlying disorders and/
or residual symptoms. This will hopefully lead to the resolution of all symptoms and to
better quality-of-life.

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Chapter 3

Insomnia and Depression

Insomnia and Psychiatric Illnesses

Insomnia as a psychiatric “vital sign”
No remission unless sleep normalized
Increased risk of relapse unless sleep normalized
Panic disorders and nocturnal panic: insomnia through conditioned
arousal/conditioned insomnia
PTSD: nightmares, decreased stage 3∕4 sleep, increased arousal and
conditioned arousal, conditioned insomnia
Depression: increased and disrupted REM sleep, decreased stage 3∕4
sleep
Schizophrenia, mania: severe insomnia may precede relapse
Schizophrenia: Stage 3∕4 sleep decreases as negative symptoms increase

Insomnia and Medical Illnesses

The more diagnosed medical illnesses you have, the more insomnia you
have
Perimenopause: nocturnal awakenings correlate with hot flashes,
hypothalamic dysregulation, and relapse/onset of major depression
Dementia: disrupted sleep correlates with cognitive decline, especially
disturbed circadian rhythm and “sundowning,” nocturnal wandering,
daytime sleepiness
Parkinson’s disease: nighttime pain and rigidity as meds wear off,
nightmares, hallucinations, REM behavior disorder, sleep talking, and
narcolepsy-like daytime symptoms
Activation of HPA in OSA, obesity, and diabetes is a risk factor for
insomnia with decreased sleep associated with increased weight and
appetite

TABLE 3.1. Insomnia can be primary or it can be secondary, i.e., a side effect of a psy-
chiatric or medical condition. In either case, resolution of both the insomnia and the
depression will be enhanced if the other ailment is treated alongside.
PTSD: posttraumatic stress disorder. REM: rapid eye movement. HPA: hypothalamic pituitary axis.
OSA: obstructive sleep apnea

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Major Depressive Disorder

Attention Deficit Hyperactivity Disorder and Depression

FIGURE 3.2. Adults with attention deficit hyperactivity disorder (ADHD) can have
many different comorbid disorders including depression, anxiety disorders, substance
use disorders, and bipolar disorders. These can all have the same devastating effects,
both for the patients and for society as a whole. Patients with ADHD might need more
time to finish their projects than their non-ADHD counterparts, which may lead to
patients feeling depressed, anxious, and stressed. The initial diagnosis of ADHD, if it
occurs in adulthood, may also cause depression in patients, as they may feel they have
“missed opportunities” in their life due to the undiagnosed disorder. As the mechanism
of action of treatments for ADHD are similar to those for depression, namely increasing
monoamine levels, one medication may help alleviate some of the symptoms of the
other disorder. Full remission, however, may only be reached by augmenting a stimu-
lant with an antidepressant.

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Chapter 3

What Proportion of Mood Disorders Are Bipolar?

FIGURE 3.3. Over the last few years, there has been a paradigm shift with regards to
the recognition and diagnosis of mood disorders. In the old paradigm, many patients
were once considered to have major depressive disorder, but they are now, in the
shifting paradigm, recognized as having bipolar II disorder or another form of bipolar
illness within the bipolar spectrum. This paradigm shift is also likely to improve treat-
ment. If patients with bipolar disorder are first treated with an antidepressant, this may
lead to increased mood cycling, mixed states, conversion to hypomania and mania,
and contribute to an increase in suicidality especially in adult patients below twenty-
five years of age. These patients should be first treated with lithium, an anticonvulsant
mood stabilizer, and/or an atypical antipsychotic. Since symptomatic patients with
bipolar II disorder spend more time in the depressed state than the manic or hypo-
manic state, it can be quite difficult to differentiate depressed patients with bipolar II
disorder from major depressive disorder. The following figures will show how to better
diagnose depressed patients.

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Major Depressive Disorder

Unipolar vs. Bipolar Depression?

Check the History

FIGURE 3.4. Although both patients in this mood chart are “today” presenting with
identical current symptoms of a major depressive episode (blue dot on mood chart),
patient 1 has unipolar depression while patient 2 has bipolar depression. So, what is
the difference? The pattern of past symptoms is quite different and relevant, with pa-
tient 1 having experienced a prior depressive episode and patient 2 a prior hypomanic
episode. Gaining a complete picture may often require additional interviews with fam-
ily members or close friends of the patient.

FIGURE 3.5. Although they can occur in either disorder, some symptoms of depression
are more prevalent or frequent in bipolar depression than in unipolar depression. Ob-
serving patients’ sleep and eating habits and looking for the presence of anxiety, motor
slowing, mood lability, psychotic symptoms, and/or suicidal ideation can aid in differen-
tiating bipolar from unipolar depression.

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Chapter 3

Pain as a Concomitant Symptom

FIGURE 3.6. Pain can be a symptom of depression or anxiety; in fact it is one of the
most commonly complained-about presenting symptoms for these disorders. It has
been found that nearly 70% of patients with depression report only physical symp-
toms as the reason for their visit; more than 10% deny psychological symptoms of de-
pression on direct questioning. Patients who present with chief somatic complaints are
often repeatedly misdiagnosed, hindering their recovery. This highlights the need to
consider depression or anxiety when patients present with chief somatic complaints,
and also to consider pain disorders in patients for whom mood or anxiety disorders are
suspected. Clinicians should be sure that pain is treated with at least equal priority as
the depression, in order to achieve the greatest possible level of remission.

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Major Depressive Disorder

Pain as a Comorbidity of Mood and Anxiety Disorders

FIGURE 3.7. In patients with three or more physical symptoms, it has been found that
around 30% have comorbid major depressive disorder and over half have comorbid
anxiety disorder. The number of unexplained physical symptoms, in fact, correlates
directly with the likelihood of the presence of a treatable mood or anxiety disorder. In
patients with specifically painful symptoms, it has been found that nearly 30% have
comorbid major depressive disorder.
Anxiety and depression comorbidities have also been examined in more specific
populations. Comorbid anxiety disorders and mood disorders are present in 35% and
22%, respectively, of patients with osteoarthritic pain, and these rates are similar for
these comorbidities with spinal pain. Following severe accidental injury, patients with
chronic pain exhibit significantly more symptoms of PTSD, anxiety, and depression.
Among men with chronic back pain and depression, 58% said the depression followed
the onset of pain.
Although it is clear that there is a relationship between pain, anxiety, and mood disor-
ders, the directional causality of this relationship and the effects on disease course and
treatment are not clear. The prevalence of comorbidity highlights the need to recog-
nize and treat all existing symptoms for optimum patient outcome.

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Chapter 3

Fibromyalgia as a Comorbidity

FIGURE 3.8. Mood and anxiety disorders are commonly comorbid with fibromyalgia.
In total, over 73% of patients with fibromyalgia also have either major depressive
disorder or bipolar disorder and nearly 76% have some type of comorbid anxiety dis-
order. The figure breaks down particular types of mood and anxiety disorders that are
commonly comorbid with fibromyalgia.

OCD: obsessive compulsive disorder.

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Major Depressive Disorder

Is Fibromyalgia an Affective Spectrum Disorder?

Part 1

FIGURE 3.9. Pain is not a formal diagnostic feature of depression or anxiety disorders
but is frequently present in patients with these disorders. The reverse is also true: de-
pressed mood, anxiety, and other symptoms are common in pain disorders, especially
in functional somatic syndromes such as fibromyalgia, irritable bowel syndrome, and
various forms of headache. Thus, rather than being discrete groups of illnesses, affec-
tive spectrum disorders and functional somatic syndromes may instead exist along the
same spectrum, and this is supported by some of the neurobiological commonalities
of these symptoms.

GAD: generalized anxiety disorder. MDD: major depressive disorder.

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Chapter 3

Is Fibromyalgia an Affective Spectrum Disorder?

Part 2

FIGURE 3.10. Clinical observations suggest that there is a powerful association be-
tween painful symptoms on one hand and mood and anxiety symptoms on the other
hand, so that the higher the number of painful physical symptoms a patient has, the
greater the likelihood that a patient has a mood or anxiety disorder. Thus, the mod-
ern psychopharmacologists can no longer brush aside pain symptoms in mood and
anxiety disorders, or mood and anxiety symptoms in pain disorders, but they need to
address them simultaneously.

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Major Depressive Disorder

Children and Adolescents with Depression

FIGURE 3.11. (A) Diagnosing depressive disorders in children and adolescents can be
quite difficult as, depending on the developmental stage, the presentation of symptoms
can vary widely. Additionally, children can exhibit times of sadness, and adolescents are
known to be moody. So diagnosis needs to be done using a “developmental lens.” For
some children and adolescents with mild depressive symptoms, it may be sufficient to
use supportive counseling and problem-solving discussions as well as family education
to treat them. For more severe cases it may be necessary to use pharmacotherapy, such
as selective serotonin reuptake inhibitors (SSRI). (B) Determining which medication to
use may be tricky in adolescents. In 2006, the FDA found an increased risk of suicidality
in adolescent patients taking SSRIs versus placebo. Later studies, however, showed that
more adolescents benefit from SSRI treatment than are harmed, by a 14:1 ratio. Addition-
ally, it has been argued that since the black box warnings for SSRIs were implemented
and the number of prescriptions for SSRIs has decreased, the number of adolescent
suicide attempts has increased, suggesting that SSRI treatment of depression is saving
lives. Thus, it will be necessary to find the perfect balance between drug-induced versus
disease-induced suicide attempts in adolescents.

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Chapter 3

Rates of Depression Across the Life Span:

Men vs. Women

FIGURE 3.12. The rates of depression among women (top) and men (bottom) across
the life span. In women, there is a link with estrogen but in men there is no established
link with testosterone.

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Major Depressive Disorder

Depression and the Link to Fluctuating Estrogen Levels

Across the Female Life Cycle

FIGURE 3.13. Postpartum and perimenopausal periods indicate the highest risk of
depression for women across the life span. These periods correspond with the times of
greatest fluctuations of estrogen levels across the life span.

FIGURE 3.14. Pharmacotherapy use (including antidepressants and/or estrogen over

the female life cycle) may vary based on the time/age of administration. Illustrated above
are some of the issues that may arise in treating depression in women.

E2: estradiol. ERT: estrogen replacement therapy. SNRI: serotonin norepinephrine reuptake inhibitor.

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Chapter 3

Reproductive Hormones and Synaptogenesis

Across the Menstrual Cycle

FIGURE 3.15. In the early phase of the menstrual cycle, estradiol levels rise, inducing
dendritic spine formation and synaptogenesis. Progesterone peaks as well, resulting
in greatest spine formation after the first half of the cycle, when estrogen is also at
its highest. After this point though, estrogen levels begin to fall while progesterone
continues to rise. This leads to a downregulation of dendritic spines and removal of
formed synapses by the end of the menstrual cycle.

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Major Depressive Disorder

Activity-dependent Spine Formation by Estradiol

FIGURE 3.16. Estrogen exerts a cyclical inhibitory influence on gamma-aminobutyric

acid (GABA) interneurons, which in turn regulate pyramidal neurons. (A) When es-
trogen levels are low, GABA interneurons are active and thus pyramidal neurons are
inhibited. (B) As estrogen levels rise early in the menstrual cycle, this reduces GABA
inhibition, thus disinhibiting pyramidal neurons and leading to glutamate release.
(C) Sustained activation of N-methyl-d-aspartate (NMDA) receptors by glutamate,
achieved by the middle or late cycle, can trigger long-term potentiation and trophic
changes that include formation of dendritic spines. As estrogen levels fall by the end
of the menstrual cycle, GABA interneurons become active again and resume inhibition
of pyramidal neurons, preventing maintenance of dendritic spine formation (A).

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Chapter 3

Estrogen as a Transcription Factor

FIGURE 3.17. (A) Estrogen binds to estrogen receptors, modulating gene expression.
However, estrogen receptors differ from neurotransmitter receptors in that they are
located in the neuronal cell nucleus. Thus, the receptor is near the gene. (B) Estradiol
activation of these genes requires dimerization of two estrogen receptors after they
bind to estradiol (E2) in order to activate transcription. (C) Gene products expressed by
this process include nerve growth factor and brain-derived neurotrophic factor. Gene
products also include enzymes and receptors for monoamine neurotransmitters.

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Major Depressive Disorder

Depression, Perimenopause, or Both?

FIGURE 3.18. The clinical link between vasomotor symptoms of perimenopause/

menopause and depression involves a high degree of overlapping symptoms, includ-
ing low energy, poor concentration, insomnia, weight gain, and decreased libido.
Some experts consider vasomotor symptoms (hot flashes) as a sign of erratically fluc-
tuating estrogen levels and not just a symptom of perimenopause, but also a risk fac-
tor for onset or recurrence of a major depressive episode in a perimenopausal woman.

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Chapter 3

Estrogen as a Trimonoamine Modulator for

Vasomotor Symptoms

FIGURE 3.19. Vasomotor symptoms, also called hot flashes or flushes, are often ac-
companied by sweating and insomnia, all of which are well known symptoms that ac-
company perimenopause. Vasomotor symptoms are the clinical indication that estro-
gen levels are fluctuating irregularly and are increasingly recognized as a sign of onset
or relapse of major depression during perimenopause. Fluctuating estrogen levels can
theoretically create monoaminergic dysfunction in the brain. Hypothetically, dysregu-
lation of monoaminergic control of the hypothalamic thermoregulatory centers could
lead to vasomotor symptoms (left). Such patients could also hypothetically respond to
the administration of estrogen with reduction of vasomotor symptoms (right). Because
of its effects on promoting neuronal gene expression, estrogen could hypothetically
act as a trimonoamine modulator (TMM). Patients whose fluctuating estrogen levels
cause vasomotor symptoms via dysregulation of one or more of the monoamines
in hypothalamic thermoregulatory centers may restore monoamine function and
thereby relieve vasomotor symptoms when given estrogen. However, many women
are not willing to take estrogen for vasomotor symptoms, and most prescribers are not
willing to treat long-term with estrogen due to concerns about long-term health risks.
This has created the need for a non-estrogen treatment for vasomotor symptoms.

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Major Depressive Disorder

Selective Serotonin Reuptake Inhibitors for

Vasomotor Symptoms?

FIGURE 3.20. Vasomotor symptoms are theoretically linked to fluctuating estrogen

levels and may cause dysregulation of monoamines in hypothalamic thermoregula-
tory centers (top). Selective serotonin reuptake inhibitors (SSRI) show inconsistent
benefit for vasomotor symptoms (bottom), although there are some positive results
reported for paroxetine, which may in fact be a weak serotonin norepinephrine
reuptake inhibitor.

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Chapter 3

Selective Norepinephrine Reuptake Inhibitors for

Vasomotor Symptoms?

FIGURE 3.21. Vasomotor symptoms are theoretically linked to fluctuating estrogen

levels and may cause dysregulation of monoamines in hypothalamic thermoregula-
tory centers (top). Serotonin norepinephrine reuptake inhibitors (SNRI) may show
benefit for vasomotor symptoms (bottom), although such agents are not approved
for this use. Under investigation is whether SNRIs have the same effect size of benefit
as estrogen, and whether the benefit-to-risk ratio justifies the use of SNRIs in treating
vasomotor symptoms in perimenopausal women.

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Major Depressive Disorder

Estrogen as a Trimonoamine Modulator

for Depression?

FIGURE 3.22. As a trimonoamine modulator (TMM), estrogen can theoretically boost

the actions of one or more of the three monoamines (dopamine, norepinephrine,
and serotonin). Patients who are theoretically deficient in one or more of the three
monoamines, as may theoretically occur in women particularly in the postpartum and
perimenopausal periods when estrogen levels can fluctuate widely, or in the post-
menopausal period when estrogen levels are low (top), can have their monoamine
activity theoretically restored when estrogen is added (bottom). However, this is not
an approved use for estrogen, and many women and their prescribers wish to avoid
estrogen use due to long-term risks to health. An in-depth and up-to-date benefit-to-
risk ratio should always be determined when considering estrogen treatments.

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Chapter 3

Selective Serotonin Reuptake Inhibitors for Perimenopausal

or Postmenopausal Depression?

FIGURE 3.23. Due to the association of vasomotor symptoms with the onset or recur-
rence of a major depressive episode, experts now debate whether prescribers should
identify and treat vasomotor symptoms as well as the traditional symptoms of depres-
sion in perimenopausal women. Actually, the treatments for these two conditions
overlap. Treating vasomotor symptoms could theoretically prevent a major depressive
episode in vulnerable women. Furthermore, failure to treat vasomotor symptoms in
a perimenopausal woman who also has a major depressive episode may stand in the
way of reaching full remission of the major depressive episode, or of sustaining that
remission in the long run. That is, remission of the classic symptoms of depression
while vasomotor symptoms persist is a likely signal that fluctuating estrogen levels are
still affecting the brain and may continue to create vulnerability for relapse. Ongoing
research is seeking to determine whether targeting vasomotor symptoms in women
with depression or who are at risk for depression will achieve better outcomes. In the
meantime, if selective serotonin reuptake inhibitors (SSRI) for such women are not ef-
fective, it may be worthwhile to treat with serotonin norepinephrine reuptake inhibi-
tors (SNRI). Furthermore, SSRIs seem to work better in the presence of estrogen than
in the absence of estrogen (right). Thus, SSRIs may be more reliable in premenopausal
women or in peri- or postmenopausal women who are taking estrogen.

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Major Depressive Disorder

Serotonin Norepinephrine Reuptake Inhibitors for

Perimenopausal Depression?

FIGURE 3.24. To treat both vasomotor symptoms and symptoms of a major depres-
sive episode in a perimenopausal woman with fluctuating estrogen levels or in a
postmenopausal woman with low estrogen levels (top), serotonin norepinephrine
reuptake inhibitors (SNRI) may be preferred (bottom). There is some evidence that
SNRIs can not only relieve vasomotor symptoms, but also treat symptoms of a major
depressive episode in peri- and postmenopausal women, even if they are not taking
estrogen (bottom). However, further research is in progress.

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Chapter 3

What Should Be Treated First?

FIGURE 3.25. So what should a psychopharmacologist do with a patient with major

depressive disorder and comorbid disorders? Once the proper diagnosis has been
reached, it is imperative to treat all disorders appropriately, and in terms of highest
degree of impairment. This might mean that in one patient it is necessary to first stabi-
lize the alcohol abuse, while in another patient the symptoms of depression might be
more impairing than the underlying anxiety disorder. Additionally, some medications
used to treat these disorders could exacerbate the comorbid ailment. Thus, care needs
to be taken when choosing the appropriate treatment. An individualized treatment
plan should therefore be established for each patient, depending on his/her symptom-
atic portfolio.

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Major Depressive Disorder

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Summary
• Three neurotransmitters are involved in the regulation of depressive
symptomatology: serotonin (5HT), norepinephrine (NE), and dopamine
(DA)

• Circuits include pathways extensively traveled by 5HT, NE, and DA

• Various genes are risk factors for depression

• Depression can often be treatment-resistant, resulting in the need for

several different drug combinations prior to achieving response and full
remission

• There are currently many classes of antidepressants available, with

selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine
reuptake inhibitors (SNRI), and norepinephrine dopamine reuptake
inhibitors (NDRI) most often considered first-line treatment options

• Augmentation of these first-line treatments can be selected by using a

symptom-based strategy; that is, choose treatments most likely to
reduce each individual patient’s specific symptoms based upon the
underlying neurobiological rationale for these symptoms

• Several new treatments for depression are on the horizon

• Comorbidities should be addressed alongside major depressive
disorders if full remission is to be attained

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References
Avery DH, Holtzheimer III PE, Fawaz W, Russo J, Neumaier J, Dunner DL et al. Biol Psychiatry 2006;59:187–94.
Barone P, Scarzella L, Marconi R, Antonini A, Morgante L, Bracco F et al. J Neurol 2006;253:601–7.
Berman RM, Marcus RN, Swanink R, McQuade RD, Carson WH, Corey-Lisle PK et al. J Clin Psychiatry 2007;68:843–53.
Cavanagh J, Patterson J, Pimlott S, Dewar D, Eersels J, Dempsey MF et al. Biol Psychiatry 2006;59:301–8.
Cipriani A, Barbui C, Brambilla P, Furukawa TA, Hotopf M, Geddes JR. J Clin Psychiatry 2006;67(6):850–64.
Cipriani A, Pretty H, Hawton K, Geddes JR. Am J Psychiatry 2005;162:1805–19.
Cooper Kazaz R, Apter JT, Cohen R, Karagichev L, Muhammed-Moussa S, Grupper D et al. Arch Gen Psychiatry 2007;64:679–88.
Crossley NA, Bauer M. J Clin Psychiatry 2007;68:935–40.
DeMartinis NA, Yeung PP, Entsuah R, Manley AL. J Clin Psychiatry 2007;68:677–88.
Dew MA, Whyte EM, Lenze EJ, Houck PR, Mulsant BH, Pollock BG et al. Am J Psychiatry 2007;164:892–9.
Dording CM, Mischoulon D, Peterson TJ, Kornbluh R, Gordon J, Nierenberg AA et al. Ann Clin Psychiatry 2002;14(3):143–7.
Emslie GJ, Yeung PP, Kunz NR. CNS Spectr 2007;12(3):223–33.
Epstein J, Pan H, Kocsis JH, Yang Y, Butler T, Chusid J et al. Am J Psychiatry 2006;163:1784–90.
Fava M. Clin Psychiatry 2007;68(Suppl 10):4–7.
Fava M, Graves LM, Benazzi F, Scaia MJ, Iosifescu DV, Alpert JE et al. J Clin Psychiatry 2006;67(11):1754–8.
Frank E, Kupfer DJ, Buysse DJ, Swartz HA, Pilkois PA, Houck PR et al. Am J Psychiatry 2007;164:761–7.
Fu CHY, Williams SCR, Brammer MJ, Suckling J, Kim J, Cleawre AJ et al. Am J Psychiatry 2007;164:599–607.
Gibbons RD, Hur K, Bhumik DK, Mann JJ. Am J Psychiatry 2006;163:1898–904.
Goodwin FK, Jamison KR. (eds) (1990) Manic Depressive Illness. New York, Oxford University Press.
Gould GG, Altamirano AV, Javors MA, Frazer A. Biol Psychiatry 2006;59:408–14.
Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ. J Clin Psychiatry 2007;68:380–3.
Hedlund PB, Huitron-Resendiz S, Henriksen SJ, Sutcliffe JG. Biol Psychiatry 2005;58:831–7.
Hoyer D, Hannon JP, Martin GR. Pharmacol Biochem Behav 2002;71:533–54.
Keedwell PA, Andrew C, Williams SCR, Brammer MJ, Phillips ML. Biol Psychiatry 2005;58:495–503.
Keedwell PA, Andrew C, Williams SCR, Brammer MJ, Phillips ML. Biol Psychiatry 2005;58:843–53.
Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K et al. Arch Gen Psychiatry 2006;63:1337–44.
Kennedy SH, Konarski JZ, Segal ZV, Lau MA, Bieling PJ, McIntyre RS et al. Am J Psychiatry 2007;164:778–88.
Kessing LV, Sondergard L, Kvist K, Andersen PK. (2005) Suicide risk in patients treated with lithium. Arch Gen Psychiatry
2005;62:860–6.
Kuala A, Sanatoria G. CNS Spectr 2005;10(10):808–19.
Lemke MR, Brecht HM, Koester J, Reichmann H. J Neurol Sci 2006;248:266–70.
Levinson DF. Biol Psychiatry 2006;60:84–92.
Marek GJ, Martin-Ruis R, Abo A, Artigas F. Neuropsychopharmacology 2005;30:2205–15.
Mayberg HS. Biol Psychiatry 2007;61:729–30.
Mayberg HS, Lozano AM, Von V, McNeely HE, Seminowicz D, Hamani C et al. Neuron 2005;45:651–60.
McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski SR, Nierenberg AA et al. Am J Psychiatry 2006;163:1531–41.
McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF et al. Am J Hum Genetics 2006;78:804–14.
Meyer JH, McNeely HE, Sagrati S, Boovariwla A, Martin K, Verhoeff NPLG et al. Am J Psychiatry 2006;163:1594–602.
Michelson D, Adler LA, Amsterdam JD, Dunner DL, Nierenberg AA, Reimherr FW et al. Clin Psychiatry 2007;68(4):582–7.
Millan M. Eur J Pharmacol 2004;500:371–84.
Mitchell ES Neumaier JF. Pharmacol Ther 2005;108:320–33.
Montgomery SA, Andersen HF. Int J Clin Psychopharmacol 2006;21:297–309.

117

Depression_Booklet.indd 117 9/30/2009 12:30:37 PM

Major Depressive Disorder

References (cont.)

Najt P, Perez J, Sanches M, Peluso MAM, Glahn D, Soares JC. Eur Neuropsychopharmacol 2006;17:313–20.
Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR et al. Neuropsychopharmacology 2006;31:1345–55.
Nierenberg A, Bronwyn RK, Leslie VC, Alpert JE, Pava JA, Worthington JJ et al. J Clin Psychiatry 1999;60:221–5.
Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Am J Psychiatry 1994;151(7):1069–72.
Nierenberg AA, Cole JO, Glass L. J Clin Psychiatry 1992;53(3):83–5.
Nierenberg AA, Farabaugh AH, Alpert JA, Gordon J, Worthington JJ, Rosenbaum JF et al. Am J Psychiatry 2000;157:1423–8.
Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ et al. Am J Psychiatry 2006;163:1519–30.
Nierenberg AA, Ostacher M, Calabrese JR, Ketter TA, Marangell LB, Miklowitz DJ et al. Am J Psychiatry 2006;163:210–6.
Oquendo MA, Currier D, Mann JJ. Acta Psychiatr Scand 2006;114:151–8.
Pace TWW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miler AH et al. Am J Psychiatry 2006;163(9):1630–3.
Papakostas GI, Fava M. Eur Neuropsychopharmacology 2007;17:32–6.
Papakostas GI, Shelton RC, Smith J, Fava M. J Clin Psychiatry 2007;68(6):826–31.
Pae CU, Peindl K, Hooper-Wood C, Mannelli P, Ciccone P. J Clin Psychopharmacol 2006;26:653–6.
Pitchot W, Hansenne M, Pinto E, Reggers J, Fuchs S, Ansseau M. Biol Psychiatry 2005;58:854–8.
Prager LM. Pediatr Rev 2009;30:199–206.
Rapaport MH, Gharabawi GM, Canuso CM, Mahmoud RA, Keller MB, Bossie CA et al. Neuropsychopharmacology
2006;31:2505–13.
Roberson-Nay R, McClure EB, Monk CS, Nelson EE, Guyer AE, Fromm SJ et al. Biol Psychiatry 2006;60:966–73.
Robertson B, Wang L, Diaz MT, Aiello M, Gersing K, Beyer J et al. J Clin Psychiatry 2007;68:261–7.
Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME et al. N Engl J Med 2006;354(12):1231–42.
Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V et al. Biol Psychiatry 2007;61:822–5.
Schaefer HS, Putnam KM, Benca RM, Davidson RJ. Biol Psychiatry 2006;60:974–86.
Schechter LE, Ring RH, Beyer CE, Hughes ZA, Khawaja X, Malberg JE et al. NeuroRx 2005;2(4):590–611.
Schramm E, van Calker D, Dykierek P, Lieb K, Kech S, Zobel I et al. Am J Psychiatry 2007;164:768–77.
Shang Y, Gibbs MA, Marek GJ, Stiger T, Burstein AH, Marek K et al. J Clin Psychopharmacol 2007;27(1):71–5.
Shelton RC, Haman KL, Rapaport MH, Kiev A, Smith WT, Hirschfeld RMA et al. J Clin Psychiatry 2006;67(11):1674–81.
Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Biol Psychiatry 2007;61:198–209.
Skidmore FM, Rodriguez RL, Fernandez HH, Goodman WK, Foote KD, Okun MS. CNS Spectr 2006;11(7):521–37.
Stahl SM. Stahl’s Essential Psychopharmacology, 3rd edition. New York, NY: Cambridge University Press; 2008.
Stahl SM. Essential Psychopharmacology: The Prescriber’s Guide, 3rd edition. New York, NY: Cambridge University Press; 2009.
Stahl SM. Stahl’s Illustrated Antidepressants. New York, NY: Cambridge University Press; 2009.
Takano A, Suzuki K, Kosaka J, Ota M, Nozaki S, Ikoma Y et al. Psychopharmacology 2005;185:395–9.
Thase ME. J Clin Psychiatry 2006;67(12):1833–55.
Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA. J Clin Psychopharmacol 2006;25(5)482–8.
Thase ME, Corya SA, Osuntokun O, Case M, Henley DB, Sanger TM et al. J Clin Psychiatry 2007;68(2):224–36.
Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH, Luther JF et al. Am J Psychiatry 2007;164:739–52.
Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D et al. N Engl J Med 2006;354:1243–52.
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Wawrden D, Ritz L et al. Am J Psychiatry 2006;163:28–40.
Valenstein M, McCarthy JF, Austin KL, Greden JF, Young EA, Blow FC. Am J Psychiatry 2006;163:1219–25.
Vanover KE, Weiner DM, Makhay M, Veinbergs I, GardellLR, Lameh J et al. J Pharmacol Exp Ther 2006;317:910–8.
Wagner KD, Kowtch RA, Emslie GJ, Findling RL, Wilens TE, McCague K et al. Am J Psychiatry 2006;163:1179–86.
Wisniewski SR, Fava M, Trivedi MH, Thase ME, Warden D, Niederehe G et al. Am J Psychiatry 2007;164:753–60.
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. Arch Gen Psychiatry 2006;63:856–64.
Zarate CA, Singh JB, Quiroz JA, DeJesus G, Denicoff KK, Luckenbaugh DA et al. Am J Psychiatry 2006;163:153–5.
Zimmerman M, McGlinchey JB, Posternak MA, Friedman M, Attiullah N, Boerescu D. Am J Psychiatry 2006;163:148–50.

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CME Posttest
To receive your certificate of CME credit or participation, please complete the posttest (you must score at
least 70% to receive credit) and activity evaluation answer sheet found on the last page and return it by mail
or fax it to 760-931-8713. Once received, your posttest will be graded and, along with your certificate (if a
score of 70% or more was attained), returned to you by mail. Alternatively, you may complete these items
online and immediately print your certificate at www.neiglobal.com/cme. There is no fee for CME credits
for this activity.

Please circle the correct answer on the answer sheet provided.

1. What percentage of patients will achieve remission after four successive 12-week
antidepressant treatments over the course of one year?
A. 33%
B. 40%
C. 50%
D. 67%

2. Your patient has been taking his antidepressant medication as indicated for the last two weeks,
but his depressive symptoms have not subsided yet. He wonders whether this medication will
work for him. You are telling him that the time course of antidepressant effects depends on a
A. Decrease in monoamine levels
B. Downregulation of monoamine receptors
C. Decrease in neuronal firing

3. Serotonin 5HT2A and 5HT1A receptors have opposing actions on dopamine. The release of
dopamine can be decreased by:
A. Stimulation of 5HT1A and 5HT2A receptors
B. Stimulation of 5HT1A receptors or blockade of 5HT2A receptors
C. Blockade of 5HT1A receptors or stimulation of 5HT2A receptors
D. Blockade of 5HT1A and 5HT2A receptors

4. A patient on a monoamine oxidase inhibitor goes to a restaurant. Which menu should he

avoid?
A. Soy-based burger with locally produced tap beer
B. Spinach salad with raspberry iced tea
C. Fish taco with margarita
D. Beef burger with canned beer

5. A 59-year-old woman presents with depressed mood and vasomotor symptoms. She has not
seen her college-aged children in a while because it is hard to muster up the energy to leave
the house, and because she does not like to be in public when she starts sweating. If her levels
of estrogen are low, which class of medication would be best for her depression?
A. Serotonin norepinephrine reuptake inhibitor
B. Norepinephrine dopamine reuptake inhibitor
C. Selective serotonin reuptake inhibitor
D. Norepinephrine reuptake inhibitor

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Major Depressive Disorder

CME Posttest (cont.)

6. An overdose of tricyclic antidepressants can be lethal due to which of their properties:

A. Blockade of H1 receptors
B. Blockade of 5HT2A/2C receptors
C. Blockade of voltage-sensitive sodium channels
D. Blockade of voltage-sensitive calcium channels

7. A patient presents with depressed mood and feelings of guilt and worthlessness. Inefficient
information processing of monoamines in which brain areas could hypothetically best explain
these symptoms?
A. Striatum and orbitofrontal cortex
B. Amygdala and ventromedial prefrontal cortex
C. Nucleus accumbens and dorsolateral prefrontal cortex
D. Basal forebrain and anterior cingulate cortex

8. A 70-year-old patient is diagnosed with major depression. He is taking many medications for
various ailments, so the psychiatrist prescribes escitalopram as it is theoretically better
tolerated. What is the relationship between citalopram and escitalopram?
A. Citalopram is the parent drug; escitalopram is the metabolite
B. Citalopram is the racemic; escitalopram is the enantiomer
C. Citalopram is the prodrug; escitalopram is the active molecule

9. The medical food L-methylfolate can be advantageous in treating depression in patients with
low levels of folic acid. How does L-methylfolate impact the synthesis of monoamines?
A. It enhances the synthesis of tyrosine hydroxylase (TOH)
B. It enhances the synthesis of DOPA decarboxylase
C. It enhances the synthesis of tetrahydrobiopterin (BH4)
D. It enhances the synthesis of monoamine oxidase A (MAO-A)

10. Alpha 2 antagonists, such as mirtazapine, do not act on monoamine transporters to lead to
their therapeutic effect. How do they increase which monoamines?
A. Disinhibition of norepinephrine and serotonin
B. Disinhibition of dopamine and serotonin
C. Disinhibition of dopamine and norepinephrine

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Understanding and Managing the Pieces of Major Depressive Disorder
Posttest and Activity Evaluation Answer Sheet
Please complete the posttest and activity evaluation answer sheet on this page and return by mail or fax.
Alternatively, you may complete these items online and immediately print your certificate at www.neiglobal.
com/cme.

Please circle the correct answer.

Posttest Answer Sheet (score of 70% or higher required for CME credit)
1. A B C D 6. A B C D
2. A B C 7. A B C D
3. A B C D 8. A B C
4. A B C D 9. A B C D
5. A B C D 10. A B C

Activity Evaluation: Please rate the following, using a scale of:

1-poor 2-below average 3-average 4-above average 5-excellent

1. The overall quality of the content was… 1 2 3 4 5

2. The overall quality of this activity was… 1 2 3 4 5

3. The relevance of the content to my professional needs was… 1 2 3 4 5

4. The level at which the learning objective was met of teaching me to

identify neural implications of depression and describe neurobiologic
symptoms... 1 2 3 4 5

5. The level at which the learning objective was met of teaching me to

utilize treatment options available for depression on a per-case basis… 1 2 3 4 5

6. The level at which the learning objective was met of teaching me to

discuss comorbidities associates with depression... 1 2 3 4 5

7. The level at which this activity was objective, scientifically balanced,

and free of commercial bias was… 1 2 3 4 5

8. Based on my experience and knowledge, the level of this activity was…

Too Basic Basic Appropriate Complex Too Complex

9. My confidence level in understanding and treating this topic has ___________ as a result of
participation in this activity.
A. Increased
B. Stayed the same
C. Decreased

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Major Depressive Disorder

Understanding and Managing Major the Pieces of Depressive Disorder

Posttest and Activity Evaluation Answer Sheet (cont.)

10. Based on the information presented in this activity, I will…

A. Change my practice
B. Seek additional information on this topic
C. Do nothing as current practice reflects activity’s recommendations
D. Do nothing as the content was not convincing

11. What barriers might keep you from implementing changes in your practice you’d like to
make as a result of participating in this activity?

12. The following additional information about this topic would help me in my practice:

13. How could this activity have been improved?

14. Additional comments:

15. Number of credits I am claiming, commensurate with the extent of my participation in the
activity (maximum of 3.0): _________

Name: ____________________________________________________Credentials: ____________________

Address: ________________________________________________________________________________

________________________________________________________________________________________

City: _________________________________________ State: __________ Zipcode: ___________________

Email: __________________________________________________________________________________

Mail or fax both sides of this form to:

Mail: CME Department Fax: 760-931-8713
Neuroscience Education Institute Attn: CME Department
1930 Palomar Point Way, Suite 101
Carlsbad, CA 92008

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Understanding_Depression_Cover.ai 1 9/30/2009 12:24:12 PM

Understanding and Managing the Pieces of

Major Depressive Disorder

CM

MY

CY

CMY

NEI PRESS Release Date: August 15, 2009

Sponsored by Neuroscience Education Institute
www.neiglobal.com CME Credit Expires: August 14, 2012