2009_Depression_Booklet

Understanding and Managing the Pieces of

Major Depressive Disorder

Understanding and Managing the Pieces of Major Depressiv D epressivee Disorder Disorder

Understanding and Managing the Pieces of Major Depressiv D epressivee Disorder Disorder

Every efort has been made in preparing this book to provide accurate accurate and up-to-date inormation that is in accord with accepted standards and practice at the time o publication. Nevertheless, the author, author, editors, and publisher can make no warranties that the inormation contained herein is totally ree rom error, not least because clinical standards are constantly changing through research and regulation. The author, editors, and publisher thereore disclaim all liability or direct or consequential damages resulting rom the use o material contained in this book. Readers are strongly advised to pay careul attention to inormation provided provided by the manuacturer o any drugs or equipment that they plan to use.

PUBLISHED BY NEI PRESS, an imprint o NEUROSCIENCE EDUCATION INSTITUTE Carlsbad, Caliornia, Caliornia, United States o America

NEUROSCIENCE EDUCATION INSTITUTE 1930 Palomar Point Way, Suite 101 Carlsbad, Caliornia 92008

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Copyright © 2009 Neuroscience Education Institute. All rights reserved.

This publication is in copyright. Subject to statutory excep exception tion and to the provisions o relevant collective licensing agreements, agreements, no reproduction o any part par t may take place without the written permission o Neuroscience Education Institute.

Printed in the United States o America First Edition, August 2009

Typeset in Myriad Pro

Library o Congre Congress ss Cataloging Cataloging-in-Publica -in-Publication tion Data ISBN 1-4225-0062-4

Table o Contents CME Inormation ............................................................................................................. iv Chapter 1: Neurobiology o Depression ................................................................. 1 Chapter 2: Treatments or 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 o Treatment............................................................83 Chapter 3: Comorbidities and a Woman’s Lie Cycle ..........................................89 Summary ............................................................................................................................ 115 Reerences ......................................................................................................................... 117 CME Posttest and Activity Evaluation ...................................................................... 119

CME Inormation Overview The successul treatment o major depressive disorder depends largely on a proper diagnosis, an adequate choice o medication, and adherence to pharmacotherapy. This booklet explains the mechanisms o action o antidepressants, illustrates how to treat women across their lie cycle, and discusses various comorbidities o major depressive disorder. Target Audience This CME activity has been developed or MDs specializing in psychiatry. There are no prerequisites or this activity. Physicians in all specialties who are interested in psychopharmacology, as well as nurses, psychologists, and pharmacists, are welcome or advanced study. Statement o Need The ollowing unmet needs regarding major depressive disorder were revealed ollowing a critical analysis o activity eedback, expert aculty assessment, literature review, and through new medical knowledge: • • •

Clinicians continue to amass inormation on the neurobiology o depression, which can only help to serve their understanding o symptoms and select appropriate treatment options Treatments or major depressive disorders continue to evolve; older generation antidepressants may still be useul, whereas newer generation antidepressants and novel treatment options continue to surace Treating specic populations with major depressive disorder can be dicult—special considerations are indicated or pediatric populations, as well as women and the elderly

To help ll these unmet needs, quality improvement eforts need to provide education regarding: 1. 2. 3.

The neurophysiology and mechanisms that contribute to depression Current and emerging treatment options or depression The recognition and management o comorbid conditions oten associated with depression, in addition to recognizing specialized care or subpopulations

Learning Objectives Ater completing this activity, participants should be better able to ulll the ollowing learning objectives: • • •

Identiy neural implications o depression and describe neurobiologic symptoms Utilize treatment options available or 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 or Continuing Medical Education to provide continuing medical education or physicians. The Neuroscience Education Institute designates this educational activity or a maximum o 3.0 AMA PRA Category 1 Credits TM. Physicians should only claim credit commensurate with the extent o their participation in the activity. Also available will be a certicate o participation or completing this activity. Nurses in most states may claim ull credit or activities approved or AMA PRA Category 1 Credits™ (or up to hal o their recertication credit requirements). This activity is designated or 3.0 AMA PRA Category 1 Credits. Activity Instructions This CME activity is in the orm o a printed monograph and incorporates instructional design to enhance your retention o the inormation and pharmacological concepts that are being presented. You are advised to go through the gures in this activity rom beginning to end, ollowed by the text, and then complete the posttest and activity evaluation. The estimated time or completion o this activity is 3.0 hours.

Instructions or CME Credit To receive your certicate o CME credit or participation, please complete the posttest (you must score at least 70% to receive credit) and activity evaluation ound at the end o the monograph and mail or ax them to the address/ number provided. Once received, your posttest will be graded and a certicate sent i a score o 70% or more was attained. Alternatively, you may complete the posttest and activity evaluation online and immediately print your certifcate. There is no ee or CME credits or this activity. NEI Disclosure Policy It is the policy o the Neuroscience Education Institute to ensure balance, independence, objectivity, and scientic rigor in all its educational activities. Thereore, all individuals in a position to inuence or control content development are required by NEI to disclose any nancial relationships or apparent conicts o interest that may have a direct bearing on the subject matter o the activity. Although potential conicts o interest are identied and resolved prior to the activity being presented, it remains or the participant to determine whether outside interests reect a possible bias in either the exposition or the conclusions presented. These materials have been peer-reviewed to ensure the scientic accuracy and medical relevance o inormation presented and its independence rom commercial bias. The Neuroscience Education Institute takes responsibility or the content, quality, and scientic integrity o 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 nancial relationships to disclose. Stephen M. Stahl, MD, PhD Adjunct Proessor, Department o Psychiatry, University o Caliornia, San Diego School o Medicine, San Diego, CA Grant/Research: Forest; Johnson & Johnson; Novartis; Organon; Pamlab; Pzer; 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; Neuronetics; Novartis; Noven; Pamlab; Pzer; Pierre Fabre; Sano-Synthélabo; Sepracor; Servier; Shire; SK; Solvay; Somaxon; Tetragenix; Vanda. Speakers Bureau: Pzer; Wyeth Peer Reviewer Scott A. Irwin, MD, PhD Director, Psychiatry Programs, The Institute or Palliative Medicine at S an Diego Hospice, San Diego, CA No other nancial relationships to disclose. Design Staf Nancy Muntner Director, Medical Illustrations, Neuroscience Education Institute, Carlsbad, CA No other nancial relationships to disclose. Disclosed nancial relationships have been reviewed by the Neuroscience Education Institute CME Advisory Board to resolve any potential conicts o interest. All aculty and planning committee members have attested that their nancial relationships do not afect their ability to present well-balanced, evidence-based content or this activity. Disclosure o O-Label Use This educational activity may include discussion o products or devices that are not currently labeled or such use by the FDA. Please consult the product prescribing inormation or ull disclosure o labeled uses.

Disclaimer The inormation presented in this educational activity is not meant to dene a standard o care, nor is it intended to dictate an exclusive course o patient management. Any procedures, medications, or other courses o diagnosis or treatment discussed or suggested in this educational activity should not be used by clinicians without ull evaluation o their patients’ conditions and possible contraindications or dangers in use, review o any applicable manuacturer’s product inormation, and comparison with recommendations o other authorities. Primary reerences and ull prescribing inormation should be consulted. Participants have an implied responsibility to use the newly acquired inormation rom this activity to enhance patient outcomes and their own proessional development. The participant should use his/her clinical judgment, knowledge, experience, and diagnostic decision-making beore applying any inormation, whether provided here or by others, or any proessional use. Sponsorship Inormation This activity is sponsored by Neuroscience Education Institute. Support This activity is supported by educational grants rom AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; and Lilly USA, LLC. For urther inormation concerning Lilly grant unding visit, www.lillygrantoce.com.

Date o Release/Expiration Release Date: August 15, 2009

CME Credit Expiration Date: August 14, 2012

Chapter 1 Neurobiology of Depression Depression can afect every aspect o lie. A patient undergoing a major depressive episode who receives treatment with any antidepressant will oten experience symptomatic improvement. However, otentimes treatment does not reach the goal o remission (complete cessation o all symptoms o depression) until several diferent pharmacotherapies have been utilized, possibly in combination. Understanding the neurobiology underlying depressive symptomatology may give clinicians the opportunity to treat the symptoms specically, based upon brain mechanisms and the interplay among genes, circuits, and symptoms. This chapter aims to identiy neural implications o depression and describe neurobiological symptoms in order to provide advanced education regarding the neurophysiology o depression and mechanisms that contribute to the disorder.


Mood Chart

FIGURE 1.1. Mood charts illustrate a spectrum o syndromal states upon which a patient’s mood can be charted over time. Mood monitoring can be conducted intermittently in a clinical setting or continuously via patient sel-report in the orm o a mood diary. Tracking the course o illness can greatly assist in identiying disease states, diagnosing accurately, and assessing treatment response.

Chapter 1

Depressive Temperament and Dysthymia

FIGURE 1.2. Patients with a depressive temperament may be regularly sad or apathetic but do not have a sucient degree or number o symptoms to qualiy or the diagnosis o dysthymia or a major depressive episode. Individuals with depressive temperament may be more at risk or uture mood disorders.

FIGURE 1.3. Dysthymia is a less severe orm o depression than major depressive disorder, but is long-lasting and generally unrelenting or two years or more.


Identiying 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.

Chapter 1

Unipolar vs. Bipolar Depression

FIGURE 1.6. Although both patients in this mood chart are presenting with identical current symptoms o 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 diference? The pattern o past symptoms (B) is quite diferent; or example, patient 1 has experienced 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.


Circuits and Symptoms in Depression: Part 1

FIGURE 1.7. (A) As per the Diagnostic and Statistical Manual, version IV (DSM-IV), diagnosis o major depressive disorder requires at least one o the symptoms in the top row, and at least our o the symptoms in the bottom two rows. (B) Malunctioning o certain brain regions, maniesting as either hypo- or hyperactivity, may hypothetically be altered due to aberrant neuronal activity and inormation processing, leading to the diferent presenting symptoms o 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.

Chapter 1


FIGURE 1.8. (A) Inecient or dysunctional serotonin (5HT), norepinephrine (NE), and/ or dopamine (DA) projections to the amygdala (A) and ventromedial prerontal cortex (VMPFC) are hypothetically involved in depressed mood. (B) Inecient inormation processing in the prerontal 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 psychomotor agitation or retardation. (C) Hypoactivation o 5HT, NE, and DA projections rom brainstem nuclei to the hypothalamus (Hy), thalamus (T), basal orebrain (BF), and PFC is hypothetically involved in sleep disturbances.



FIGURE 1.9. (A) Inecient inormation processing rom norepinephrine (NE) and dopamine (DA) projections to the dorsolateral prerontal cortex (DLPFC) is hypothetically linked to problems with emotional regulation, sel-monitoring, goal-setting, priority planning, and organization, all o which could lead to executive dysunction. (B) Ine cient inormation processing rom NE projections to the prerontal cortex (PFC) and hypothalamus (Hy) and the DA projections to the PFC, Hy, and nucleus accumbens (NA) is hypothetically linked to apathy. Although supercially similar to depressed mood, apathy is actually a distinct symptom o depression, associated with lack o pleasure including decreased libido, linked to loss o interest and motivation, and oten experienced by geriatric patients. Additionally, apathy is also hypothetically regulated by diferent brain circuits than depressed mood. (C) Ine cient inormation processing rom NE and DA projections to the PFC is hypothetically involved in mental atigue. Physical atigue is linked to decient NE unctioning in the descending spinal cord (SC) and decient DA unctioning in the striatum, NA, Hy, and spinal cord.

Chapter 1


FIGURE 1.10. (A) Inecient or dysunctional serotonin (5HT ) projections to the amygdala (A) and the ventromedial prerontal cortex (VMPFC) could theoretically cause eelings o guilt and worthlessness, which are regulated by these “emotional” brain regions. (B) Ine cient or dysunctional 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 rontal cortex (OFC), could hypothetically be involved in suicidal ideation.


Monoamine Hypothesis o 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 o depression” states that depression results rom a deciency in one or more o these three neurotransmitters.

Chapter 1

Monoamine Hypothesis o Antidepressant Action

FIGURE 1.12. Theoretically, antidepressant medications should be able to normalize the levels o the three neurotransmitters afected in depression by blocking presynaptic monoamine transporters (also called reuptake pumps), and thereby increasing the synaptic availability and actions o these monoamines.


Monoamine Receptor Hypothesis o Depression

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

Chapter 1

Monoamine Receptor Hypothesis o Antidepressant Action

FIGURE 1.14. The monoamine receptor hypothesis suggests that i depression is caused by upregulation o monoamine receptors, antidepressants act by ultimately downregulating monoamine receptors over time. (A) An antidepressant can acutely block the reuptake pump, allowing or more neurotransmitter (NT) in the synapse (red circle). (B) A chronic increased availability o neurotransmitter over time can lead to the downregulation o receptors (red circle). The time course or this downregulation to occur (days to weeks) is consistent with both the delayed onset o antidepressant efects and the time required to develop tolerance to side efects.


Monoamine Hypothesis o Antidepressant Action on Gene Expression

FIGURE 1.15. Based on the monoamine hypothesis o depression, antidepressants can theoretically create a return to a normal mood state by increasing the levels o monoamines. The downstream consequences o increased monoamine production by antidepressants leads to a cascade o efects such as expression o critical genes and down or upregulation o various gene products.

Chapter 1

Time Course o Antidepressant Efects

FIGURE 1.16. Antidepressant drugs have three time courses: one or clinical changes, a second one or neurotransmitter changes, and a third one or receptor sensitivity changes. While the neurotransmitter changes oten occur rapidly ater initial administration, 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 ater antidepressant administration, including the production o therapeutic antidepressant efects and the development o tolerance to side efects, all o which occur over a ew weeks o time.


Serotonin Pathways

FIGURE 1.17. As mentioned previously, serotonin plays an integral part in mediating the symptoms o depression. Depicted in this gure are the major serotonergic projections. Ascending projections originate rom the raphe nucleus to the cerebellum, thalamus, hypothalamus, basal orebrain, prerontal cortex, striatum, nucleus accumbens, amygdala, and hippocampus. Mood, appetite, suicidal ideation, and sleep are regulated and afected by 5HT (see Figures 1.8 and 1.10). Descending projections to the spinal cord afect pain pathways.


Chapter 1

Synthesis and Metabolism o Serotonin

FIGURE 1.18. Serotonin (5HT) is one o the three principal monoamines involved in depression. (A) Serotonin is synthesized rom the amino acid tryptophan (TRY), which enters the serotonin neuron via the tryptophan transporter, a transporter that is distinct rom the serotonin transporter (SERT). Ater 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 during neurotransmission. (B) Ater 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). I 5HT is transported into the neuron, but not repackaged rapidly enough into synaptic vesicles, it will be destroyed intraneuronally by MAO-B.


Serotonin Receptors: Part 1

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

Chapter 1

Serotonin Receptors: Part 2

FIGURE 1.20. (A) Presynaptic 5HT1A receptors are located on the cell body and dendrites o 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 o 5HT impulse ow and thereore a decrease in the amount o 5HT released at the synapse (on the right).


Norepinephrine Pathways

FIGURE 1.21. Norepinephrine (NE) also plays an integral part in mediating the symptoms o depression. Ascending projections originate rom the locus coeruleus o brainstem to the cerebellum, thalamus, hypothalamus, basal orebrain, prerontal cortex, amygdala, and hippocampus. Mood, arousal, and cognition are regulated and afected by NE (see Figures 1.8 and 1.9). Descending projections rom the spinal cord afect pain pathways.


Chapter 1

Synthesis and Metabolism o Norepinephrine

FIGURE 1.22. (A) Norepinephrine (NE) is synthesized rom the amino acid tyrosine (TYR), which is transported into the NE neuron by the tyrosine transporter, a transporter that is distinct rom the NE transporter (NET ). Ater 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 decarboxylase (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 neurotransmission. (B) Ater 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 transerase (COMT). I 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.


Norepinephrine Receptors: Part 1

FIGURE 1.23. (A) Presynaptic alpha 2 norepinephrine (NE) receptors on the NE neuron’s axon terminals work similarly to the 5HT1B/D receptors, acting as “gatekeepers” or their neurotransmitter. neurotransmitter. (B) When NE builds up in the synapse and binds to alpha 2 receptors recepto rs (red circle), the t he urther release o NE will be inhibited. These receptors receptors aid in modulating the appropriate release o NE.

Chapter 1

Norepinephrine Receptors: Part 2

FIGURE 1.24. (A) Presynaptic alpha 2 adrenergic somatodendritic autoreceptors, located on the cell body and dendrites o a norepinephrine (NE) neuron, work similarly to somatodendritic 5HT1A receptors. receptors. (B) When NE binds to these somatodendritic autoreceptors autorec eptors (red circle), this will lead to a reduction in neuronal electrical activity leading to a shutdown o NE impulse ow and thereore a decrease in the amount o NE released at the synapse (on the right).


Dopamine Pathw Pathways ays

FIGURE 1.25. Dopamine (DA) projections ascend rom the brainstem to the prerontal cortex, basal orebrain, nucleus accumbens accumbens,, striatum, thalamus, hypothalamus, hypothalamus, amygdala, hippocampus, and cerebellum. DA neurotransmission is associated with cognition, psychosis, pleasure and reward, movement, and other unctions (see Figures 1.8 and 1.9).

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

2009_Depression_Booklet

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