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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF
Course ID: 298603 Course Content PDF

This document provides a print-optimized version of the text-based content and static graphics of the course. To view animations, refer to the online course.
Disclaimer Information within this training related to the market landscape is intended for your background only and is not for use in discussions with customers. The product information within this training is derived from the approved package labeling for each medication, as well as market research data. Information regarding the safety and efficacy of various medications cannot be compared unless it is derived from head to head clinical trials and meets other specific criteria. Therefore, unless you are provided an approved brand resource or verbatim, you may never compare the safety or efficacy information for different products.
Lilly Confidential: Do Not Copy. For Internal Use Only. Not for Use in Product Detailing. Not for use in promotion. TLD-0781 rev 0310 Lilly USA, LLC Sales Learning and Leadership Development
Contents
Contents........................................................................................................................................ 2 About This Course ........................................................................................................................ 9 Course Features and Tools Transcript ............................................................................. 11 Module 1: What is Depression? .................................................................................................. 12 Section 1: Introduction ......................................................................................................... 12 Scenario Transcript .......................................................................................................... 13 Module Objectives ............................................................................................................ 14 Section 2: Overview ............................................................................................................. 15 Overview Quick Check Transcript .................................................................................... 17 Section 3: Symptoms ........................................................................................................... 18 DSM-IV-TR Criteria for a Major Depressive Episode ....................................................... 21 Symptoms of Depression ................................................................................................. 22 Symptoms Quick Check Transcript .................................................................................. 23 Find Out More: SIG E CAPS ............................................................................................ 24 Section 4: MDD Specifiers ................................................................................................... 25 MDD Specifiers Transcript ............................................................................................... 26 MDD Specifiers Quick Check Transcript .......................................................................... 28 Section 5: Other Mood and Anxiety Disorders ..................................................................... 29 Other Mood Disorders Transcript ..................................................................................... 33 Anxiety Disorders ............................................................................................................. 36 Other Mood and Anxiety Disorders Quick Check Transcript ............................................ 37 Module 1 References ........................................................................................................... 38 Module 2: Epidemiology of Depression ...................................................................................... 40 Section 1: Introduction ......................................................................................................... 40 Scenario Transcript .......................................................................................................... 41 Module Objectives ............................................................................................................ 42 Section 2: Overview ............................................................................................................. 43
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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF Key Terminology Regarding the Course of MDD ............................................................. 48 Overview Quick Check Transcript .................................................................................... 49 Find Out More: National Comorbidity Survey Replication (NCS-R) ................................. 51 Section 3: Burden of Illness ................................................................................................. 52 Burden of Illness Quick Check Transcript ........................................................................ 54 Section 4: Patient Presentation ........................................................................................... 55 Patient Presentation Quick Check Transcript .................................................................. 57 Module 2 References ........................................................................................................... 58 Module 3: Diagnosing Depression .............................................................................................. 61 Section 1: Introduction ......................................................................................................... 61 Scenario Transcript .......................................................................................................... 62 Module Objectives ............................................................................................................ 63 Section 2: HCPs Involved in Depression ............................................................................. 64 Types of Medical Professionals Who Commonly Diagnose Depression Transcript......... 66 HCPs Involved in Depression Quick Check Transcript .................................................... 68 Section 3: Assessment and Diagnostic Procedures ............................................................ 69 Assessment and Diagnostic Procedures Transcript ........................................................ 73 Assessment and Diagnostic Procedures Quick Check Transcript ................................... 76 Find Out More: DSM-IV-TR Diagnostic Criteria for a Major Depressive Episode ............ 77 Find Out More: Zung Self-rating Depression Scale ......................................................... 78 Find Out More: Hamilton Depression Rating Scale ......................................................... 80 Section 4: Diagnostic Challenges ........................................................................................ 82 Diagnostic Challenges Quick Check Transcript ............................................................... 84 Module 3 References ........................................................................................................... 85 Module 4: What Causes Depression? ........................................................................................ 86 Section 1: Introduction ......................................................................................................... 86 Scenario Transcript .......................................................................................................... 87 Module Objectives ............................................................................................................ 88 Section 2: Theories of Depression ....................................................................................... 89
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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF Theories of Depression .................................................................................................... 91 Theories of Depression Quick Check Transcript .............................................................. 92 Section 3: Neurotransmission Process ................................................................................ 93 The Role of Neurotransmitters in Human Health Transcript ............................................ 96 The Neurotransmission Process Transcript ..................................................................... 97 Neurotransmission Process Quick Check Transcript ....................................................... 98 Find Out More: Effects of Neurotransmission ................................................................ 100 Section 4: Mood Regulation ............................................................................................... 101 Mood Regulation Quick Check Transcript ...................................................................... 103 Section 5: Serotonin and Norepinephrine .......................................................................... 105 Neurotransmitters Transcript .......................................................................................... 108 Neurotransmitter Systems Affected by Selected Antidepressant Agents ...................... 110 Serotonin and Norepinephrine Quick Check Transcript ................................................. 111 Module 4 References ......................................................................................................... 112 Module 5: Treating Depression ................................................................................................. 113 Section 1: Introduction ....................................................................................................... 113 Scenario Transcript ........................................................................................................ 114 Module Objectives .......................................................................................................... 115 Section 2: Treatment Goals ............................................................................................... 116 Treatment Goals Quick Check Transcript ...................................................................... 118 Section 3: Treatment Phases and Goals ........................................................................... 119 Treatment Phases Transcript ......................................................................................... 121 Treatment Phases Quick Check Transcript ................................................................... 122 Section 4: Approaches to Treatment ................................................................................. 124 Treatment Approaches Transcript .................................................................................. 126 Treatment Approaches Quick Check Transcript ............................................................ 128 Module 5 References ......................................................................................................... 129 Module 6: Market and Competition ........................................................................................... 130 Section 1: Introduction ....................................................................................................... 130
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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF Scenario Transcript ........................................................................................................ 131 Module Objectives .......................................................................................................... 132 Find Out More: Brand Name Table ................................................................................ 133 Find Out More: Pharmacokinetics of Agents .................................................................. 135 Section 2: SNRIs ............................................................................................................... 136 Effexor XR and Pristiq Transcript ................................................................................... 138 SNRIs Quick Check Transcript ...................................................................................... 141 Find Out More: About Cymbalta ..................................................................................... 142 Find Out More: Potential Adverse Events Associated with Blocking Selected Neurotransmitter Transporters and Receptors ............................................................... 144 Section 3: SSRIs................................................................................................................ 145 Prozac, Zoloft, Paxil CR, Lexapro, and Celexa Transcript ............................................. 149 SSRIs Quick Check Transcript ....................................................................................... 155 Section 4: Bupropion ......................................................................................................... 156 Wellbutrin XL Transcript ................................................................................................. 158 Bupropion Quick Check Transcript ................................................................................ 160 Boxed Warnings ............................................................................................................. 161 Module 6 References ......................................................................................................... 165 Module 7: Clinical Studies ......................................................................................................... 167 Section 1: Introduction ....................................................................................................... 167 Scenario Transcript ........................................................................................................ 168 Module Objectives .......................................................................................................... 169 Section 2: Efficacy Study Designs ..................................................................................... 170 Efficacy Study Designs Quick Check Transcript ............................................................ 172 Find Out More: Results of the Clinical Trials in MDD Prior to Registration .................... 173 Find Out More: Statistical Methods Used in Analyzing the Data .................................... 174 Section 3: Overview of Studies .......................................................................................... 175 Overview of Studies (HMBHa, HMBHb) ......................................................................... 178 Overview of Additional Studies (HMCR, HMFSa, HMFSb) ............................................ 180 Overview of Studies Quick Check Transcript ................................................................. 183 Find Out More: Select Inclusion and Exclusion Criteria ................................................. 184 5
Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF Section 4: Measures of Efficacy ........................................................................................ 186 Key Results of 60 mg Once-Daily Studies Transcript .................................................... 188 Measures of Efficacy Quick Check Transcript ............................................................... 191 Section 5: Older Patient Study ........................................................................................... 192 Focus on Older Patients Transcript ................................................................................ 194 Older Patients Quick Check Transcript .......................................................................... 195 Section 6: Relapse Study .................................................................................................. 196 Continuation, Maintenance, and Extended Treatment Transcript .................................. 198 Relapse Study Quick Check Transcript ......................................................................... 201 Section 7: Additional Adverse Event Information ............................................................... 202 Additional Adverse Event Information Quick Check Transcript ...................................... 205 Module 7 References ......................................................................................................... 206 Module 8: Cymbalta Prescribing Information ............................................................................ 210 Section 1: Introduction ....................................................................................................... 210 Module 8 Objectives ....................................................................................................... 211 Section 2: Indications and Usage ...................................................................................... 212 Indications and Usage Transcript ................................................................................... 215 Indications and Usage Quick Check Transcript ............................................................. 216 Section 3: Dosage and Administration ............................................................................... 218 Dosage Transcript .......................................................................................................... 224 Dosage and Administration Quick Check Transcript ...................................................... 226 Section 4: Dosage Forms and Strengths ........................................................................... 228 Section 5: Contraindications .............................................................................................. 229 Quick Check Transcript .................................................................................................. 230 Section 6: Warnings and Precautions ................................................................................ 231 Clinical Worsening and Suicide Risk .............................................................................. 238 Hepatotoxicity................................................................................................................. 240 Orthostatic Hypotension and Syncope ........................................................................... 241 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions ......... 242
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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF Abnormal Bleeding ......................................................................................................... 243 Discontinuation of Treatment with Cymbalta .................................................................. 244 Activation of Mania/Hypomania ...................................................................................... 245 Seizures ......................................................................................................................... 246 Effect on Blood Pressure ............................................................................................... 247 Clinically Important Drug Interactions ............................................................................ 248 Hyponatremia ................................................................................................................. 249 Use in Patients with Concomitant Illness ....................................................................... 250 Urinary Hesitation and Retention ................................................................................... 251 Laboratory Tests ............................................................................................................ 252 Warnings and Precautions Quick Check Transcript ....................................................... 253 Section 7: Adverse Reactions ............................................................................................ 256 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in PlaceboControlled Trials Transcript ............................................................................................ 262 Table 2: Adverse Reactions Occurring at an Incidence of 5% or More Among DuloxetineTreated Patients in Placebo-Controlled Trials ................................................................ 264 Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in MDD and GAD Placebo-Controlled Trials ...................................................................................... 266 Table 4: Treatment-Emergent Adverse Reactions Incidence of 2% or More in DPNP Placebo-Controlled Trials ............................................................................................... 268 Table 5: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in Fibromyalgia Placebo-Controlled Trials ......................................................................... 270 Table 6: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials 273 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine ........................................................................................ 274 Adverse Reactions Quick Check Transcript ................................................................... 276 Find Out More: Arizona Sexual Experience Scale ......................................................... 278 Section 8: Drug Interactions .............................................................................................. 279 Drug Interactions ............................................................................................................ 281 Drug Interactions Quick Check Transcript ..................................................................... 284 Section 9: Use in Specific Populations .............................................................................. 285 Use in Specific Populations ............................................................................................ 286 Use in Specific Populations Quick Check Transcript ..................................................... 289
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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF Section 10: Drug and Dependence .................................................................................... 290 Section 11: Overdosage .................................................................................................... 291 Overdosage Quick Check Transcript ............................................................................. 293 Section 12: Description ...................................................................................................... 294 Section 13: Clinical Pharmacology .................................................................................... 295 Clinical Pharmacology Quick Check Transcript ............................................................. 298 Section 14: Nonclinical Toxicology .................................................................................... 299 Section 15: Clinical Studies ............................................................................................... 300 Clinical Studies Transcript .............................................................................................. 302 Clinical Studies Quick Check Transcript ........................................................................ 307 Section 16: How Supplied/Storage and Handling .............................................................. 308 Section 17: Patient Counseling Information ....................................................................... 310 Find Out More: Medication Guide .................................................................................. 312 Module 8 References ......................................................................................................... 314 Course Completion ................................................................................................................... 315 Study Guide .............................................................................................................................. 316 Glossary .................................................................................................................................... 317 Help........................................................................................................................................... 324
AboutThisCourse
Program Overview Welcome to the Cymbalta for MDD course! This course is designed to introduce you to depression and the use of Cymbalta in the treatment of major depressive disorder (MDD). In this course, you will also learn about the MDD market and competition, clinical studies, and the Cymbalta prescribing information. Course Features and Tools Several tools are available in this course to help you navigate and ensure a positive learning experience. Click the following icon or read a transcript to learn about key course features and how to proceed through them. Course Features and Tools Several tools are available in this course to help you navigate and ensure a positive learning experience. Click the following icon to learn more about course features and how to proceed through them, or read a transcript.
. A Suggested Learning Strategy The following is the suggested learning strategy for getting the most from this course and passing any required knowledge tests: Use the learning objectives as a guide to what you need to know. Pass the Quick Checks with complete understanding before moving to the next section. Study and know all content presented as Critical Information, which is "must know" information. Practice or apply the learning with others.
U.S. SALES LEARNING AND LEADERSHIP DEVELOPMENT This is a self-instructional course designed for internal use by Lilly personnel for training purposes only. It is considered Company confidential information that must be protected and handled in 9
accordance with Lilly's policies on Asset Protection (as outlined in the Red Book). This information and data are not to be disseminated to others outside of the company or used for detailing in person or through written material unless subject to proper internal approval processes for advertising and labeling to ensure that all regulatory requirements governing the use of promotional materials by pharmaceutical manufacturers are met. Failure to handle this information as outlined above will be considered a violation of company policy, which can result in disciplinary and/or legal action. COMPANY CONFIDENTIAL
Lilly USA, LLC Sales Learning and Leadership Development For Internal Use Only. Not for use in Product Detailing. TLD-0781 rev 0310 Company Confidential, Copyright Lilly USA, LLC 2010
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Course Features and Tools Transcript

1. Navigation buttons listed on the left side of the screen provide access to each content section in the module. 2. Study Guide provides an electronic workbook to help you note points to review and/or information you think you will need to study in the future. You can use the learning objectives as a guide to what you need to know. 3. Glossary provides definitions for key vocabulary in this course. Some of the terms are followed by an audio icon. Click the icon to hear the term pronounced. (You will also find the audio icon beside terms in the Brand Name Table in Module 6.) Throughout the course content, you will find hyperlinked words that have associated glossary definitions. You may be tested on glossary terms and their definitions. 4. Help includes information about your learning path, navigating the course, and a description of the tools for this course. 5. Module Objectives are the basis for module content and indicate what you need to know to pass tests in this course, as well as the final Product Knowledge Test. In the first section of each module, you will find the learning objectives for that module. 6. Margin Notes offer additional information, such as links and job-aids, that are relevant to each section. Margin items are not required content, but they provide extra information to help you better understand the required content. 7. Quick Checks are interactive animations that you can use to check your knowledge of the information presented in that section. At the end of most sections, you will find a Quick Check. The Product Knowledge Test is designed to test your understanding and retention of the information presented in the course. To receive credit for the course, you must pass the Product Knowledge Test. The questions included in the Quick Checks are indicative of the questions you will encounter on the Product Knowledge Test. 8. Critical Information indicates concepts and data points that will form the foundation of your knowledge. You will be tested on the information that you can see by clicking the Open button beside the Critical Information designation. 9. Return to Main Menu closes the module window and returns you to the Main Menu screen. Along with links to the modules, you will see Course Completion on the Main Menu screen. Course Completion provides information on how to receive credit for completing the course. You must view all modules and sections before you can receive course credit.
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Module1:WhatisDepression?
Section1:Introduction
Annika is a new Cymbalta MDD sales representative at Lilly. She is learning about major depression so that she will be able to talk to health care professionals in their own languageand answer their questions intelligentlywhen she makes calls. Click the following icon to listen to Annika or read a transcript.
Annika has a number of questions about depression, including: What is major depression? What are its major specifiers or variants? What are some of the symptoms that may be observed in patients with depression? What are some other mood and anxiety disorders that are sometimes associated with depression? Look for answers to these questions as you read this module.
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Scenario Transcript
Annika: I've recently been hired as a Cymbalta MDD sales rep at Lilly. I know that there are patients with major depressive disorder who could benefit from using Cymbalta, but I can't help them unless I have credibility with doctors and other health care professionals. And I won't have that credibility unless I understand MDD and am able to talk about it knowledgeably when needed. For example, what if a doctor asks me a simple question related to the symptoms of depression and I have no idea what the doctor is talking about? I don't think that doctor will give me a chance to explain how Cymbalta might help patients! So, I need to know what happens when people experience depression. Specifically, I need to know what major depression is, how significant a problem this is in general, and the symptoms often presented by patients with depression. It will also help me to know about major variations in depression and other mood and anxiety disorders which may be associated with depression.
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Module Objectives
Upon completion of this module, you will be able to: Define psychiatric disorder and major depressive disorder. Identify common symptoms of depression. Identify specifiers that describe features of major depressive disorder. Describe other types of mood and anxiety disorders.
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Section2:Overview
What are Psychiatric Disorders? Psychiatric disorders are a broad category of disorders, with some of the most common types being: mood disorders anxiety disorders substance use disorders psychotic disorders. Depression is a common psychiatric condition that may affect a person physically, psychologically, and socially. Some reports suggest that approximately 19 million adults in the United States suffer from a depressive disorder.[1] Worldwide, depression is among the leading causes of disability and may affect as many as 121 million people.[2] While the social stigma of depression has improved with better awareness and treatment options, some patients may still be reluctant to accept a diagnosis of depression.
Critical Information! What are Psychiatric Disorders?

Depression is a common psychiatric condition that may affect a person physically, psychologically, and socially. Some reports suggest that approximately 19 million adults in the United States suffer from a depressive disorder.[1] Worldwide, depression is among the leading causes of disability and may affect as many as 121 million people.[2] While the social stigma of depression has improved with better awareness and treatment options, some patients may still be reluctant to accept a diagnosis of depression.
What is Depression? Depression is a serious psychiatric condition. Often, the term "depression" is used synonymously with major depressive disorder (MDD). MDD, which may also be referred to as unipolar depression, major depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that can interfere with the ability to work, study, eat, sleep, and enjoy activities that were once pleasurable. MDD differs from common emotional experiences of sadness, loss, and passing moods in that symptoms of MDD are persistent and severe enough that they can interfere significantly with one's ability to function in everyday life.[3]
Critical Information!
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What is Depression?
MDD, which may also be referred to as unipolar depression, major depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that can have multiple affects on a person including interference with ability to work, study, eat, sleep, and enjoy activities that were once pleasurable. MDD differs from common emotional experiences of sadness, loss, and passing moods in that symptoms of MDD are persistent and severe enough that they can interfere significantly with one's ability to function in everyday life.[3]
Once you have completed this section, open the Quick Check and check your understanding of what you have learned or read a transcript.
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Overview Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Depression is a common psychiatric condition that may affect a person: a. Physically b. Physically, psychologically, and socially c. Psychologically and socially d. Physically and socially 2. Approximately how many people may be affected by depression worldwide? a. 100,000 b. 1.2 million c. 121 million d. 1.2 billion 3. Symptoms of major depression are persistent and severe enough that they: a. Often become the cause of violent, antisocial behavior b. Create a sense of generalized panic c. Often require emergency services on initial onset d. Interfere significantly with one's ability to function in everyday life 4. Major depressive disorder (MDD) is a mood disorder that may also be referred to as all of the following EXCEPT: a. Unilateral depression b. Major depression c. Clinical depression d. Unipolar depression Answers 1. b. Depression is a common psychiatric condition that affects the person physically, psychologically, and socially. 2. c. Depression is estimated to affect approximately 121 million people worldwide. 3. d. MDD differs from common emotional experiences of sadness, loss, and passing moods. The symptoms of MDD are persistent and severe enough that they can interfere significantly with ones ability to function in everyday life. 4. a. Major depressive disorder (MDD) is a mood disorder that may also be referred to as unipolar depression, major depression, or clinical depression.
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Section3:Symptoms
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) states that MDD is characterized by one or more major depressive episodes.[4] Click the following to learn about the criteria for a major depressive episode.
Critical Information! DSM-IV-TR Criteria for a Major Depressive Episode

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) states that MDD is characterized by one or more major depressive episodes.[4] Criteria for a Major Depressive Episode[5] A. Five (or more) of the following symptoms have been present during the same 2week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.* (1) Depressed mood for most of the day, nearly every day (2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (3) Significant weight loss when not dieting, weight gain, or decrease or increase in appetite nearly every day (4) Insomnia or hypersomnia nearly every day (5) Psychomotor agitation or retardation nearly every day, that is observable by others (6) Fatigue or loss of energy nearly every day (7) Feelings of worthlessness, or excessive or inappropriate guilt nearly every day (8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing
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suicide B. The symptoms do not meet the criteria for a mixed episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., drug of abuse) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by bereavement. * Should not include symptoms that are clearly due to a general medical condition, mood-incongruent delusions, or hallucinations
A way to remember the common symptoms of MDD, in addition to the symptom of depressed mood, is through the acronym SIG E CAPS. Click the link under Find Out More in the margin to learn what this stands for. Not everyone who is depressed experiences every symptom listed. In addition, symptom severity varies among individuals and can vary over time within the same individual. Click the following to learn more about the symptoms of depression.
Although depression is one of the most frequently seen psychiatric disorders in the primary care setting, it is often underdiagnosed[7, 8] and inadequately treated[9, 10]. This may be due, in part, to the complexity of presentation. Some patients may emphasize physical symptoms of depression rather than emotional complaints. Due to the physical nature of the symptom presentation, a primary care physician (PCP) often has to rule out other medical problems before a diagnosis of depression can be made.[11] Once a diagnosis is made, some primary care physicians may choose to refer patients with depression to a psychiatrist for treatment, while others will choose to treat the patient.
Critical Information! Symptoms of Depression

Although depression is one of the most frequently seen psychiatric disorders in the primary care setting, it is often underdiagnosed[7, 8] and inadequately treated[9, 10]. This may be due, in part, to the complexity of presentation.
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DSM-IV-TR Criteria for a Major Depressive Episode

Criteria for a Major Depressive Episode[5] A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.* (1) Depressed mood for most of the day, nearly every day (2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (3) Significant weight loss when not dieting, weight gain, or decrease or increase in appetite nearly every day (4) Insomnia or hypersomnia nearly every day (5) Psychomotor agitation or retardation nearly every day, that is observable by others (6) Fatigue or loss of energy nearly every day (7) Feelings of worthlessness, or excessive or inappropriate guilt nearly every day (8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet the criteria for a mixed episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (e.g., drug of abuse) or a general medical condition (e.g., hypothyroidism). E. The symptoms are not better accounted for by bereavement. * Should not include symptoms that are clearly due to a general medical condition, mood-incongruent delusions, or hallucinations
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Symptoms of Depression
Depression can present with a broad range of symptoms, including:[6] emotional symptoms lack of interest, sadness, suicidality, or feelings of guilt physical symptoms changes in sleep, lack of energy, decrease concentration, changes in psychomotor skills, and appetite changes associated symptoms anxiety and phobias, brooding, obsessive rumination, tearfulness, excessive worry over physical health, pain, and irritability
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Symptoms Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Even though depression is one of the most frequently seen psychiatric conditions, why is it often underdiagnosed and inadequately treated? a. The patient presentation of depression is often complex. b. Most people try to hide the most obvious symptoms of depression. c. Treatment for depression is not covered under most healthcare plans. d. Symptoms of depression are often misdiagnosed as "old age" or dementia. 2. Which of the following factors are not included in the criteria for a major depressive episode? a. Depressed mood for most of the day, most days of the week b. Significant weight loss when not dieting c. Depressed mood and/or loss of interest or pleasure d. Feelings of worthlessness or excessive guilt 3. Which of the following is NOT one of the symptoms that meet the DSM-IV-TR criteria for a major depressive episode? a. Recurrent thoughts of suicide b. Reduced capacity to operate large machinery c. Diminished ability to concentrate d. Noticeable psychomotor agitation or retardation 4. Which of the following factors might preclude a diagnosis of a major depressive episode? a. Symptoms do not meet the criteria for a "mixed episode" b. Symptoms cause clinically significant distress or impairment c. Symptoms are not caused by substance abuse or a medical condition d. Symptoms may be accounted for by a recent death of a loved one Answers 1. a. Depression is often underdiagnosed due to the complexity of presentation. 2. c. According to the DSM-IV-TR, in a major depressive episode, one of the symptoms which must be present is one or both of (1) depressed mood or (2) loss of interest or pleasure. 3. b. Reduced capacity to operate large machinery is NOT one of the DSM-IV-TR criteria for a major depressive episode. 4. d. The DSM-IV-TR criteria for a major depressive episode include the requirement that the symptoms are not better accounted for by bereavement, such as that which may occur after the death of a loved one.
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Find Out More: SIG E CAPS

Sleep (too much or too little) Interest (lack of) Guilt Energy (lack of or too much) Concentration (lack of) Appetite (decreased or increased) Psychomotor (agitation or retardation) Suicide (thoughts of, plans for, or attempts)
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Section4:MDDSpecifiers
MDD Specifiers[12] Several specifiers can be used to describe MDD or a major depressive episode, which give further credence to the numerous variations in the presentation of the disorder. MDD is often classified as either single episode, referring to one occurrence of a major depressive episode, or recurrent, which refers to two or more major depressive episodes. Additional specifiers are described in the following table. Click the following icon or read a transcript to learn more about MDD specifiers.
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MDD Specifiers Transcript

MDD Specifiers[13]
Specifier
Description
MDD with psychotic features (may be referred to as psychotic depression)
Characterized by delusions and/or hallucinations that are usually moodcongruent, although mood-incongruent psychotic features may also occur
Chronic MDD (may be referred to as chronic depression)
Diagnostic criteria for a major depressive episode have been met continuously for at least the past two years
MDD with catatonic features (may be referred to as catatonic depression)
Characterized by at least two of the following symptoms: motor immobility or stupor; excessive motor activity; negativism or mutism; peculiar movements such as stereotyped movements, bizarre posturing, or prominent grimacing or mannerisms; echolalia (pathological and apparently senseless repetition of a word or phrase just spoken by another) or echopraxia (repetitive imitation of movements of another)
MDD with melancholic features (may be referred to as melancholic depression)
Characterized by loss of pleasure in all, or almost all, activities or lack of reactivity to usually pleasurable stimuli, and at least three of the following: quality of depressed mood is distinct; depression regularly worse in the morning; early morning awakening; marked psychomotor retardation or agitation; significant anorexia or weight loss; excessive or inappropriate guilt
MDD with atypical features (may be referred to as atypical depression)
Characterized by mood reactivity and at least two of the following: significant weight gain or increase in appetite; hypersomnia; leaden paralysis; long-standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment
MDD with postpartum onset (may be referred to as postpartum depression)
Onset of major depressive episode within four weeks postpartum
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MDD, recurrent, with seasonal pattern
Depressive disorder in which the onset and remission of depressive episodes occur rather predictably at a particular time of year for at least two consecutive years
* Not a complete list; see reference for a complete list
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MDD Specifiers Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Which MDD specifier is characterized by the DSM-IV-TR diagnostic criteria for a major depressive episode having been met continuously for the past two years or more? a. MDD with psychotic features b. MDD with catatonic features c. MDD with atypical features d. Chronic MDD 2. Which MDD specifier may be characterized by motor immobility or stupor and excessive motor activity? a. MDD with psychotic features b. MDD with catatonic features c. MDD with atypical features d. MDD with melancholic features Answers 1. d. Chronic MDD is characterized by the DSM-IV-TR criteria for a major depressive episode having been met continuously for at least the past two years. 2. b. MDD with catatonic features is characterized by at least two of the following symptoms: motor immobility or stupor; excessive motor activity; negativism or mutism; peculiar movements such as stereotyped movements, bizarre posturing, or prominent grimacing or mannerisms; echolalia; or echopraxia.
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Section5:OtherMoodandAnxietyDisorders
There are mood disorders other than depression that are important because they can factor into the diagnosis and/or treatment of a patient. Furthermore, it is important to be familiar with anxiety disorders because their presentation can be confused with depression. Other Mood Disorders[14] Note: Cymbalta is indicated for the treatment of major depressive disorder in adults aged 18 years and older. It is not indicated for the treatment of other mood disorders. The following information is for background purposes only and not for use in discussion with customers. In addition to MDD, there are other mood disorders. Mood disorders are divided into the following categories: depressive disorders bipolar disorders substance-induced mood disorders mood disorders due to a general medical condition mood disorders otherwise not specified. Click the following icon to learn more about these mood disorders, or read a transcript.
Critical Information! Other Mood Disorders
The following table compares the characteristics of MDD and dysthymic disorder:
MDD vs. Dysthymic Disorder
MDD
Dysthymic
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disorder
Consists of at least one major depressive episode. Symptoms can include: Emotional: o Feelings of sadness o Lack of interest o Feelings of guilt o Suicidal thoughts Physical: o Lack of energy o Decreased concentration o Change in appetite o Change in sleep o Change in psychomotor skills Associated: o Brooding o Obsessive rumination o Irritability o Excessive worry over physical health o Complaints of pain Headaches Joint pain Abdominal pain Other pains o Tearfulness o Anxiety or phobias
Severity
Symptoms typically may be less severe and do not meet full criteria for major depressive episode
Chronicity
Usually consists of one or more major depressive episodes that can be distinguished from the person's usual functioning
Characterized by chronic, less severe depressive symptoms that have been present for many years
Persistence
Depressed mood present for most of the day, nearly every day, for at least two weeks
Depressed mood present for more days than not over a period of at
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least two years
Bipolar Disorders
Bipolar disorder is a chronic condition characterized by recurrent episodes of abnormal mood elevation (for example, mania or hypomania) and depression. The following are brief descriptions of mood disorders: Bipolar I disorder Bipolar I disorder is characterized by one or more manic or mixed episodes of mania. Bipolar II disorder Bipolar II disorder is characterized by one or more major depressive episodes and at least one hypomanic episode without a history of mania. Cyclothymic disorder Cyclothymic disorder is characterized by numerous periods with hypomanic symptoms and numerous periods with depressive symptoms over at least a two-year period, without meeting the full criteria for a hypomanic or depressive episode. Bipolar disorder not otherwise specified This disorder is characterized by bipolar features that do not meet the criteria for any specific bipolar disorders.
Anxiety Disorders In addition to mood disorders, there are also anxiety disorders. Differentiating between an anxiety disorder and major depression can be difficult because the two conditions can often coexist.[16, 17] For example, the patient may display the symptoms of anxiety, but the underlying major disorder might be depression, and vice versa. Accurate diagnosis should help guide appropriate treatment selection. Click the following icon to learn more about some anxiety disorders.
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Critical Information! Anxiety Disorders

In addition to mood disorders, there are also anxiety disorders. Differentiating between an anxiety disorder and major depression can be difficult because the two conditions can often coexist.[16, 17] Anxiety Disorders*[18] Generalized anxiety disorder (GAD): Disorder characterized by excessive anxiety, worry (apprehensive expectation) and difficulty controlling worry, occurring more days than not for a period of at least six months, about a number of events or activities; symptoms may include restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension, and disturbed sleep. Panic disorder: (with or without agoraphobia) Disorder characterized by a discrete period of intense fear and discomfort; symptoms may include shortness of breath, palpitations, dizziness, shaking, sweating, and fear of dying or going crazy; agoraphobia anxiety about being in places or situations where escape may be difficult or help may not be available if experiencing a panic attack. Obsessive Compulsive Disorder (OCD): Disorder characterized by recurrent and persistent thoughts, impulses, or images that are intrusive, inappropriate, and cause significant anxiety or distress. The individual recognizes that these are their own thoughts and that they may be excessive. * Not a complete list; see reference for a complete list
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Other Mood Disorders Transcript

Other Mood Disorders[15] The following are brief descriptions of mood disorders: Depressive Disorders
Major depressive disorder MDD, which may also be referred to as unipolar depression, major depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that can have multiple impacts on a person including interference with ability to work, study, eat, sleep, and enjoy activities that were once pleasurable. Dysthymic disorder (also called dysthymia) Dysthymic disorder refers to a chronically depressed mood that occurs for most of the day, more days than not, for at least two years. In comparison to MDD, dysthymic disorder is usually characterized by chronic, less severe depressive symptoms that have been present for many years. The following table compares the characteristics of MDD and dysthymic disorder: MDD vs. Dysthymic Disorder
MDD
Dysthymic disorder
Consists of at least one major depressive episode. Symptoms can include: o o o Emotional: Feelings of sadness Lack of interest Feelings of guilt Suicidal thoughts Physical: Lack of energy Decreased concentration Change in appetite Change in sleep Change in psychomotor skills Associated: Brooding Obsessive rumination Irritability 33 Symptoms typically may be less severe and do not meet full criteria for major depressive episode
Severity
Excessive worry over physical health Complaints of pain Headaches Joint pain Abdominal pain Other pains Tearfulness Anxiety or phobias
Chronicity
Usually consists of one or more major depressive episodes that can be distinguished from the person's usual functioning
Characterize d by chronic, less severe depressive symptoms that have been present for many years
Persistenc e
Depressed mood present for most of the day, nearly every day, for at least two weeks
Depressed mood present for more days than not over a period of at least two years
Depressive disorder not otherwise specified Disorders with depressive features that do not meet criteria for major depressive disorder, dysthymia, or adjustment disorder with depressed or depressed and anxious mood. Examples include minor depressive disorder, premenstrual dysphoric disorder (PMDD), and recurrent brief depressive disorder. Bipolar Disorders
Bipolar disorder is a chronic condition characterized by recurrent episodes of abnormal mood elevation (for example, mania or hypomania) and depression. The following are brief descriptions of mood disorders: Bipolar I disorder Bipolar I disorder is characterized by one or more manic or mixed episodes of mania. 34
Bipolar II disorder Bipolar II disorder is characterized by one or more major depressive episodes and at least one hypomanic episode without a history of mania. Cyclothymic disorder Cyclothymic disorder is characterized by numerous periods with hypomanic symptoms and numerous periods with depressive symptoms over at least a two-year period, without meeting the full criteria for a hypomanic or depressive episode. Bipolar disorder not otherwise specified This disorder is characterized by bipolar features that do not meet the criteria for any specific bipolar disorders. Other Mood Disorders
Substance-induced mood disorder Substance-induced mood disorder is characterized by a prominent and persistent disturbance in mood that is judged to be due to the direct physiological effects of a substance (such as a drug of abuse, a medication, or toxin exposure). Mood disorder due to a general medical condition The primary feature of mood disorder due to a general medical condition is a prominent and persistent disturbance in mood that is judged to be due to the direct physiological effects of a general medical condition (for example, thyroid disease). Mood disorder not otherwise specified This category includes disorders with mood symptoms that do not meet the criteria for any specific mood disorder and in which it is difficult to choose between depressive disorder not otherwise specified and bipolar disorder not otherwise specified.
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Anxiety Disorders
Anxiety Disorders*[18] Generalized anxiety disorder (GAD): Disorder characterized by excessive anxiety, worry (apprehensive expectation) and difficulty controlling worry, occurring more days than not for a period of at least six months, about a number of events or activities; symptoms may include restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension, and disturbed sleep. Panic disorder: (with or without agoraphobia) Disorder characterized by a discrete period of intense fear and discomfort; symptoms may include shortness of breath, palpitations, dizziness, shaking, sweating, and fear of dying or going crazy; agoraphobia anxiety about being in places or situations where escape may be difficult or help may not be available if experiencing a panic attack. Obsessive Compulsive Disorder (OCD): Disorder characterized by recurrent and persistent thoughts, impulses, or images that are intrusive, inappropriate, and cause significant anxiety or distress. The individual recognizes that these are their own thoughts and that they may be excessive. * Not a complete list; see reference for a complete list
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Other Mood and Anxiety Disorders Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Dysthymic disorder differs from depression in terms of: a. Severity and frequency b. Chronicity and complexity c. Persistence and cyclic nature d. Severity, chronicity, and persistence 2. Which type of bipolar disorder is characterized by a history of at least one episode of mania? a. Bipolar I disorder b. Bipolar II disorder c. Cyclothymic disorder d. Bipolar disorder not otherwise specified 3. Which type of bipolar disorder is characterized by numerous periods with hypomanic symptoms and numerous periods with depressive symptoms over at least a two year period? a. Hypomanic bipolar disorder b. Bipolar II disorder c. Cyclothymic disorder d. Bipolar disorder not otherwise specified 4. Which of the following is considered to be an anxiety disorder? a. Dysthymic disorder b. Bipolar disorder c. Obsessive compulsive disorder d. Cyclothymic disorder Answers 1. d. Dysthymic disorder differs from depression in terms of severity, chronicity, and persistence. In comparison to MDD, dysthymic disorder is usually characterized by chronic, less severe depressive symptoms that have been present for many years. 2. a. Bipolar I disorder is characterized by a history of at least one episode of mania. 3. c. Cyclothymic disorder is characterized by numerous periods with hypomanic symptoms and numerous periods with depressive symptoms over at least a two year period. 4. c. Obsessive compulsive disorder (as well as generalized anxiety disorder and panic disorder) is considered to be an anxiety disorder.
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Module1References
1. National Institute of Mental Health publication, Depression: A Treatable Illness. Available at: http://www.nimh.nih.gov/health/publications/depression-a-treatable-illness.shtml. Accessed May 15, 2008. 2. WHO. Depression. Available at http://www.who.int/mental_health/management/depression/en/print.html. Accessed January 7, 2008. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 7. Mitchell AJ, Vase A, et al. Clinical diagnosis of depression in primary care: a meta analysis. The Lancet. 2009: 1-11. They do not list a volume number or actual page numbers, just a DOI:10.1016/S0140-6736(09)60879-5. 8. Munitz H, Valevski A, et al. Recognition and Treatment of Depression in Primary Care Settings in 6 Different Countries: A Restrospective File Analysis by WHO. European Journal of Psychiatry. 2000;14(2): 85-93. 9. Kessler RC, Berglund P, et al. The Epidemiology of Major Depressive Disorder. Result From the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23): 3095-3105. 10. Munitz H, Valevski A, et al. Recognition and Treatment of Depression in Primary Care Settings in 6 Different Countries: A Restrospective File Analysis by WHO. European Journal of Psychiatry. 2000;14(2): 85-93. 11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 13. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 16. The American Psychiatric Publishing Textbook of Psychiatry. 5th Edition. Editors Hales RE, Yudofsky SC, Gabbard GO. 38
17. Kessler RC, et al. The Epidemiology of Major Depressive Disorder: Results From the National Comorbidity Survey Replication (NCS-R) JAMA. 2003;289(23): 3095-3105. 18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:429-484.
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Module2:EpidemiologyofDepression
William is a new Cymbalta MDD sales representative at Lilly. He is learning about the epidemiology of depression to help prepare him for discussions with health care providers treating patients with depression. He knows that he has to be able to talk to health care professionals in their own language and answer their questions intelligentlywhen he makes calls. Click the following icon to listen to William or read a transcript.
William has a number of questions about the epidemiology of depression, including: Which types of health care professionals are involved in evaluating and treating MDD? What is the epidemiology of depression? What is the burden of illness of depression? What are the true costs? What are some common emotional, physical, and associated symptoms of depression? How prevalent are they? Look for answers to these questions as you complete this module.
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Scenario Transcript
William: Ive recently been hired as a Cymbalta MDD sales representative at Lilly. I know that in order to help patients with depression who could benefit from using Cymbalta, I must have credibility with the health care professionals who treat them. And I wont have that credibility unless I understand the epidemiology of major depression and am able to talk about it knowledgeably when needed. If a doctor asks me a question about the prevalence of physical symptoms of depression or about the financial burden of depression in the United States today and I have no response, shell probably end the conversation. I dont think shell give me a chance to explain how Cymbalta might help her patients! So, I need to know not only what happens when people experience depression, but also how depression progresses. Specifically, I need to know the epidemiology of major depression, how significant a problem this is in general, and why it is important to consider a broad range of symptoms presented by patients with depression.
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Module Objectives
Upon completion of this module, you will be able to: Discuss the epidemiology of depression. Describe the burden of illness of depression. Describe the prevalence of painful physical symptoms in depression. Identify that physical symptoms may be reported by patients with depression.
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Section2:Overview
Prevalence A wide range of prevalence rates has been reported in various studies of MDD.[1] However, it is estimated that the lifetime risk for MDD ranges from 10 percent to 25 percent for women and from 5 percent to 12 percent for men.[2] Ethnicity, education,[3] and income[4] do not appear to affect prevalence rates. In the National Comorbidity Survey Replication, the estimated 12-month prevalence rate for MDD was 6.7 percent,[5] while the estimated lifetime prevalence rate for MDD was 16.6 percent.[6]
Critical Information! Prevalence

A wide range of prevalence rates has been reported in various studies of MDD.[1] However, it is estimated that the lifetime risk for MDD ranges from 10 percent to 25 percent for women and from 5 percent to 12 percent for men.[2] Ethnicity, education,[3] and income[4] do not appear to affect prevalence rates.
Gender Features MDD is about twice as common in females as males.[7, 8] Men and women experience a similar amount of stressful life events.[9] However, there is a gender difference in the ways in which the experiences are interpreted. When depressed, men and women may also employ different coping mechanisms. Review the following table for more information.
Women
Men
Precipitating MDD
problems or loss in the social/family network[10, 11] perinatal transitions[12]
physical illness,[13] work problems,[14, 15] separation/divorce[16]
Response to MDD
talk about their feelings,[17] laugh/cry,[18] rely on religion[19, 20]
avoid thinking about it,[21] physical activity, sports, drugs/alcohol[22, 23]
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Gender Features
MDD is about twice as common in females as males.[7, 8]
Age-related Features Some data suggests that the prominence of depressive symptoms may change with age.[24]
The lifetime prevalence estimates for MDD (n=9083) in the total National Comorbidity Survey Replication (NCS-R) sample was 16.2% (95% CI, 15.117.3) of the US population or approximately 32.6 to 35.1 million adults.[25] The median age at onset for mood disorders is 30 years,[26] and the projected lifetime risk of MDD at age 75 is 23.3%
Cultural Features Generally, coping with stress, distress, and "nerves" is viewed as a normal part of life. However, evidence suggests that culture can have a significant influence on the experience and communication of depressive symptoms. In some cultures, depression carries the connotation of a lack of personal strength. This may contribute to the tendency of some ethnic groups, such as African Americans and some Hispanic Americans, to focus on somatic symptoms rather than on the psychological components of their illness.[27] Genetic Features There is an increased frequency of depression in first-degree relatives of patients with depression compared with the general population.[28] One theory suggests that some individuals may have a genetic vulnerability to developing depression.[29]
Critical Information! Genetic Features

There is an increased frequency of depression in first-degree relatives of patients 44
with depression compared with the general population.[28] One theory suggests that some individuals may have a genetic vulnerability to developing depression.[29]
Disease Course Although the onset of MDD may occur at any age, the average age at onset is the mid-20s. The initial episode can often, but does not always, follow a significant psychosocial stressor. Thereafter, the course of recurrent MDD is variable. Isolated episodes may be separated by many years, episodes may occur in clusters, or they may become increasingly frequent with age.[30] Click on the following icon to see definitions of key terms related to the course of MDD.
Critical Information! Disease Course

Although the onset of MDD may occur at any age, the average age at onset is the mid-20s. The initial episode can often, but does not always, follow a significant psychosocial stressor. Thereafter, the course of recurrent MDD is variable. Isolated episodes may be separated by many years, episodes may occur in clusters, or they may become increasingly frequent with age.[30]
Achieving Remission In the past, clinicians have been satisfied with patients feeling better or achieving "response"; however, the goal has shifted to getting patients back to their normal functioning. Remission rather than response should be viewed as the ultimate goal of any therapy.[31] Patients who do not achieve remission, or continue to have residual symptoms despite treatment, have a greater likelihood of relapse.[32] The following stoplight analogy illustrates the difference between response and remission.
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An important clinical aspect of the disease course of MDD is that the number of prior episodes can predict the likelihood of having subsequent episodes. It has been found that: Approximately 60 percent of patients who have a single episode can be expected to have a second episode Patients who have had two episodes have approximately 70 percent chance of having a third episode Patients who have had three episodes have approximately 90 percent chance of having a fourth episode[33] Other aspects associated with poor outcome and/or disease persistence include dysthymic disorder, marked severity of the initial episode, and the presence of some chronic general medical conditions (such as diabetes).[34]
Critical Information! Achieving Remission

In the past, clinicians have been satisfied with patients feeling better or achieving "response"; however, the goal has shifted to getting patients back to their normal functioning. Remission rather than response should be viewed as the ultimate goal of any therapy.[31] Patients who do not achieve remission, or continue to have residual symptoms despite treatment, have a greater likelihood of relapse.[32]
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Key Terminology Regarding the Course of MDD

Episode: A period of depressive symptoms in the course of MDD that may wax and wane in symptomatology. Response: 50% reduction from a baseline score on a standardized scale, such as the HAM-D. Remission: Attainment of a virtually asymptomatic status (euthymia); in clinical trials, commonly defined as HAM-D17 score of 7. Recovery: Remission for a significant time period commonly defined as 6 months. Relapse: Return of symptoms during the same episode of depression before recovery. Recurrence: A new episode of depression occurring after a period of recovery.
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Overview Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. What is the difference in the prevalence of MDD between men and women? a. Men are twice as likely to experience MDD b. Women are twice as likely to experience MDD c. There is no difference between the prevalence of MDD in men and women d. It is impossible to determine gender effects on the prevalence of MDD 2. Which of the following characteristics affect prevalence rates for MDD? a. Ethnicity or culture b. Genetics (family history of depression) c. Socioeconomic status d. Education 3. Remission is defined as: a. Improvement of symptoms in response to treatment ( 50% reduction in HAM-D17 score) b. Attainment of a virtually asymptomatic status (HAM-D17 score of 7) c. A single event of symptoms in the course of a disease that waxes and wanes in symptomatology d. The return of the same episode of depression before complete resolution, as symptoms begin to reappear 4. Recovery is defined as: a. The return of the same episode of depression before complete resolution, as symptoms begin to reappear b. A new episode of depression occurring after a period of moderate asymptomatic living c. Improvement of symptoms in response to treatment ( 50% reduction in HAM-D17 score) d. Remission for a significant time period commonly defined as 6 months 5. Why is the target for MDD treatment remission rather than just response? a. In many patients, remission is easier to achieve than response b. Patients who experience response but dont achieve remission are more likely to relapse c. Response always happens within the first few weeks of treatment, and thats not enough time to claim treatment success d. Remission is always achievable, so it is the obvious primary target Answers 1. b. MDD is about twice as common in females as it is in males. 2. b. There is an increased frequency of depression in first-degree relatives of patients with depression compared with the general population, suggesting that genetics affect prevalence. 3. b. Remission is defined as attainment of a virtually asymptomatic (euthymia). In clinical trials, this is commonly defined as a HAM-D17 score of 7. 4. d. Recovery is defined as remission for a significant time period commonly defined as 6 months. 5. b. Patients who do not achieve remission, or continue to have residual symptoms despite treatment, have a greater likelihood of relapse.
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Find Out More: National Comorbidity Survey Replication (NCS-R)

The NCS-R was a nationally representative face-to-face household survey of 9090 respondents aged 18 years or older conducted between February 2001 and December 2002. Diagnoses were based on DSMIV criteria, and measures included the Composite International Diagnostic Interview (CIDI), Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR), and Sheehan Disability Scale.[35]
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Section3:BurdenofIllness
As stated previously, depression is very common, affecting about 121 million people worldwide.[36] Because depression is associated with significant mortality, morbidity, and direct and indirect financial costs, it is a burden to the patient, the patients family and friends, and society as a whole.[37] Mortality Up to 15 percent of people with MDD die by suicide.[38] Some evidence also suggests that comorbid depression may increase the risk of death from other medical illnesses (such as cancer[39] and cardiovascular disease[40]).
Critical Information! Mortality

Up to 15 percent of people with MDD die by suicide.[38]
Morbidity Depression has a negative impact on occupational, social, or other important areas of functioning.[41] Data analyzed from the WHO World Health Survey (WHS) found that depression produced the greatest decrement in health when compared with the chronic disease angina, arthritis, asthma and diabetes.[42] As previously noted, depression is among the leading causes of disability worldwide and is projected to become the second leading cause of disability by 2020.[43]
Critical Information! Morbidity

Depression has a negative impact on occupational, social, or other important areas of functioning.[41] As previously noted, depression is among the leading causes of disability worldwide and is projected to become the second leading cause of disability by 2020.[43]
Financial Costs In 2000, the total annual estimated cost of depression was approximately $83 billion in the U.S. alone.[44] Estimated Financial Costs of Depression (U.S., 2000)[45] 52
Direct treatment costs include inpatient, outpatient, and pharmaceutical costs. Workplace costs include absenteeism and presenteeism (lost productivity).
Critical Information! Financial Costs

In 2000, the total annual estimated cost of depression was approximately $83 billion in the U.S. alone.[44]
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Burden of Illness Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Approximately how many people with MDD die from suicide? a. Less than 5 percent b. Up to 15 percent c. 50 percent d. 80 percent or more 2. Why are large prevalence rates of MDD an important medical and social concern? a. The cost of treating depression is increasing rapidly, threatening the financial stability of the healthcare system. b. Depressed people are emotionally contagious; they often spread depression among their social groups. c. Depression is the leading cause of emotional and physical illness worldwide. d. Depression has a negative impact on occupational, social, or other important areas of functioning. 3. Estimates of leading causes of disability show that, by 2020, depression is predicted to: a. Rise to second on the list of leading causes of disability worldwide b. Drop to fourth on the list of leading causes of disability worldwide c. Become the third leading cause of disability in North America d. Lead the world in cause of disability, death, and financial burden 4. What was the estimated total financial cost of depression in the U.S. in the year 2000? a. $100 million b. $2.0 billion c. $50 billion d. $83 billion Answers 1. b. Up to 15 percent of people with MDD die by suicide. Some evidence also suggests that comorbid depression increases the risk of death from other medical illnesses (such as cancer and cardiovascular disease). 2. d. Depression has a negative impact on occupational, social, or other important areas of functioning. There is evidence that depression has a greater negative impact on functioning than many other chronic illnesses, such as angina, diabetes, arthritis, and asthma. 3. a. Currently, depression is the fourth leading cause of disability worldwide and is projected to become the second leading cause of disability by 2020. 4. d. The total annual estimated cost of depression was approximately $83 billion in the United States in the year 2000.
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Section4:PatientPresentation
Associated Features Individuals with major depressive episode may present with a broad range of symptoms such as sadness, loss of interest, feelings of guilt, changes in sleep and appetite, lack of energy, irritability, tearfulness, anxiety, excessive worry over physical health, and complaints of pain (such as headaches or joint, abdominal, or other pains).[46] Patients may not present in clinical practice with MDD alone. They may present with a complex mixture of comorbid psychiatric disorders or general medical conditions.[47] In the National Comorbidity Survey Replication (NCS-R), it was found that nearly three-fourths (72.1 percent) of respondents with lifetime MDD also met the criteria for at least one of the other DSM-IV-TR disorders assessed. This included 59.2 percent with an anxiety disorder, 24.0 percent with a substance use disorder, and 30 percent with impulse control disorder.[48]
Critical Information! Associated Features

Individuals with major depressive episode may present with a broad range of symptoms such as sadness, loss of interest, feelings of guilt, changes in sleep and appetite, lack of energy, irritability, tearfulness, anxiety, excessive worry over physical health, and complaints of pain (such as headaches or joint, abdominal, or other pains).[46] Patients may not present in clinical practice with MDD alone. They may present with a complex mixture of comorbid psychiatric disorders or general medical conditions.[47] In the National Comorbidity Survey - Replication (NCS-R), it was found that nearly three-fourths (72.1 percent) of respondents with lifetime MDD also met the criteria for at least one of the other DSM-IV-TR disorders assessed. This included 59.2 percent with an anxiety disorder, 24.0 percent with a substance use disorder, and 30 percent with impulse control disorder.[48]
Prevalence of Physical Symptoms Physical symptoms can commonly occur in patients with depression.[49] In one study, 69 percent of patients diagnosed with depression cited physical symptoms as the reason they visited a primary care physician.[50] Additionally, in a literature review, Bair and colleagues (2003) determined the mean prevalence of pain symptoms in depressed patients was 65 percent.[51]
Critical Information! Prevalence of Physical Symptoms
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Physical symptoms can commonly occur in patients with depression.[49] In one study, 69 percent of patients diagnosed with depression cited physical symptoms as the reason they visited a primary care physician.[50]
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Patient Presentation Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. In the National Comorbidity Survey - Replication (NCS-R), it was found that very few respondents with lifetime MDD also met the criteria for other DSM-IV-TR disorders assessed a. True b. False 2. In one study, 69 percent of patients diagnosed with depression cited what type of symptoms as the reason they visited a primary care physician? a. Psychological b. Physical c. Behavioral d. Emotional 3. Patients with depression may present with symptoms such as sadness, loss of interest, and feelings of guilt. a. True b. False Answers 1. b. In the National Comorbidity Survey - Replication (NCS-R), it was found that nearly threefourths (72.1 percent) of respondents with lifetime MDD also met the criteria for at least one of the other DSM-IV-TR disorders assessed. 2. b. Physical symptoms can commonly occur in patients with depression. In one study, 69 percent of patients diagnosed with depression cited physical symptoms as the reason they visited a primary care physician. 3. a. Individuals with major depressive episode may present with a broad range of symptoms such as sadness, loss of interest, feelings of guilt, changes in sleep and appetite, lack of energy, irritability, tearfulness, anxiety, excessive worry over physical health, and complaints of pain (such as headaches or joint, abdominal, or other pains).
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Module2References
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 4. Kessler RC et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. American Journal of Psychiatry. 2006 Sep;163(9):15611568. 5. Kessler et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry. 2005;62:617-627. 6. Kessler et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602. 7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 8. Kessler RC et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. American Journal of Psychiatry. 2006 Sep;163(9):15611568. 9. Maciejewski PK, Prigerson HG, Mazure CM. Sex differences in event-related risk for major depression. Psychol Med. 2001;31:593-604. 10. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 11. Kendler KS, et al. Am J Psychiatry. 2001;158:587-593. 12. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 13. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 14. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 15. Kendler KS, et al. Am J Psychiatry. 2001;158:587-593. 16. Kendler KS, et al. Am J Psychiatry. 2001;158:587-593. 17. Nolen-Hoeksema S. Psychol Bull. 1987;101:259-282. 18. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 19. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 20. Nolen-Hoeksema S. Psychol Bull. 1987;101:259-282. 58
21. Nolen-Hoeksema S. Psychol Bull. 1987;101:259-282. 22. Angst J, et al. Eur Arch Psychiatry Clin Neurosci. 2002;252:201-209. 23. Nolen-Hoeksema S. Psychol Bull. 1987;101:259-282. 24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 25. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095-3105. 26. Kessler RC, et al. Arch Gen Psychiatry. 2005;62:593-602. 27. Blazer DG, Landerman LR, Hays JC, Simonsick EM, Saunders WB. Symptoms of depression among community-dwelling elderly African-American and white older adults. Psychological Medicine. 1998;28(6):1311-1320. 28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 29. The American Psychiatric Publishing Textbook of Psychiatry. 5th Edition. Editors Hales RE, Yudofsky SC, Gabbard GO. 30. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 31. Ballenger JC. Clinical guidelines for establishing remission in patients with depression and anxiety. J Clin Psychiatry. 1999;60(suppl 22):29-34. 32. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25(6):1171-1180. 33. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 34. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 35. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095-3105. 36. WHO. Depression. Available at http://www.who.int/mental_health/management/depression/en/print.html. Accessed January 7, 2008. 37. Greenberg PE et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-75. 38. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 39. Spiegel D, Giese-Davis J. Depression and Cancer: Mechanisms and Disease Progression. Biol Psych. 2003;54:269-282. 59
40. Carney RM, et al. Depression as a risk factor for cardiac mortality and morbidity. A review of potential mechanisms. J Psychosom Res. 2000;53: 897-902. 41. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 42. Moussavi S, Chatterji S, et al. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. The Lancet. 2007;370: 851-858. 43. Murray CJL, Lopez AD, eds. The Global Burden of Disease; 1996. 44. Greenberg PE et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-75. 45. Greenberg PE et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64(12):1465-75. 46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 47. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 48. Kessler RC, Berglund P, et al. The Epidemiology of Major Depressive Disorder. Results from the National Comorbidity Survey Replication (NCS-R) JAMA. 2003;289(23): 3095-3105. 49. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 50. Simon GE, VonKorff M, Piccinelli M, Fullerton C, Ormel J. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-1335. 51. Bair MJ, Robinson RL, et al. Depression and Pain Comorbidity. Arch Intern Med. 2003;163:24332445.
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Module3:DiagnosingDepression
Victor is a new Cymbalta MDD sales rep at Lilly. He is learning about how health care professionals diagnose depression so that he will be able to talk to them in their own languageand answer their questions intelligentlywhen he makes calls. Click the following icon to listen to Victor or read a transcript.
Victor asks himself the following questions: Which types of health care professionals are involved in evaluating and treating MDD? What are the major symptoms and clinical presentations of MDD? How is MDD evaluated? Look for answers to these questions as you complete this module.
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Scenario Transcript
Victor: Ive recently been hired as a Cymbalta MDD sales rep at Lilly. I want to help patients who could benefit from using Cymbalta to help treat their depression, but I know I cant do that unless I have credibility with doctors and other health care professionals. I have to know which health care professionals diagnose patients with depression, and I have to understand how they diagnose depression so I am able to talk about it knowledgeably when needed. For example, what if a doctor asks me a simple question about a common diagnostic tool used to diagnose MDD or used in one of our efficacy studies, and I have no idea what the doctor is talking about? I dont think that doctor will give me a chance to explain how Cymbalta might help patients! So, I need to know how health care professionals diagnose depression. Specifically, I need to know the major symptoms and clinical presentations of depression and how MDD is evaluated, including a basic understanding of the diagnostic tools commonly used.
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Module Objectives
Upon completion of this module, you will be able to: Identify the common types of health care professionals and treatment settings for patients with MDD. Describe diagnostic approaches to depression, identify diagnostic challenges, and describe potential consequences of delayed or missed diagnosis in patients.
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Section2:HCPsInvolvedinDepression
Treatment Settings There are a variety of settings in which patients with depression may seek evaluation and care. Many patients with depression are seen in primary care settings. However, a patient whose diagnosis or treatment is complexfor example, patients with a comorbid psychiatric disorder or those who have not responded well to treatmentmay be referred to a psychiatrist or other mental health specialist. Patients may also be referred to a psychiatrist if psychotherapy is needed. Patients who are in immediate danger of attempting suicide or have other safety concerns may be hospitalized in a psychiatric hospital or in the psychiatric unit of an acute care hospital. Additionally, patients who are in crisis because of severe depression symptoms may also be seen in emergency room settings or other crisis centers. Patients with depression can also be seen in other settings, including general medical inpatient units and long-term care facilities such as nursing homes.
Critical Information! Treatment Settings

There are a variety of settings in which patients with depression may seek evaluation and care.
Physicians and Other Health Care Professionals The physicians who most commonly diagnose and treat patients with depression are primary care physicians (PCPs) and psychiatrists. PCPs include general practitioners, family practitioners, and internal medicine specialists. Other medical subspecialties (such as OB/GYNs, neurologists) may also diagnose and/or treat depression, but it is not typically a major part of their practices. Other health care providers (HCPs) who may be involved in the diagnosis and/or treatment of patients with depression include: clinical psychologist, psychiatric nurse, nurse practitioner (NP), physician assistant (PA), counselor, social worker, nurse, and pharmacist. Click the following icon to view detailed information on the types of physicians and HCPs involved in diagnosing and treating patients with depression, or read a transcript.
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It is very important to understand that even though some HCPs may not be licensed to prescribe medications, they often see patients under the supervision of another practitioner and help make treatment recommendations. Additionally, many settings involve a multidisciplinary team approach.
Critical Information! Physicians and Other Health Care Professionals

The physicians who most commonly diagnose and treat patients with depression are primary care physicians (PCPs) and psychiatrists. Other health care providers (HCPs) who may be involved in the diagnosis and/or treatment of patients with depression include: clinical psychologist, psychiatric nurse, nurse practitioner (NP), physician assistant (PA), counselor, social worker, nurse, and pharmacist. It is very important to understand that even though some HCPs may not be licensed to prescribe medications, they often see patients under the supervision of another practitioner and help make treatment recommendations. Additionally, many settings involve a multidisciplinary team approach.
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Types of Medical Professionals Who Commonly Diagnose Depression Transcript

Physicians Title General Practitioner (GP) Family Practitioner (FP) Internal Medicine Specialist (IM, internist) Definition A practicing physician who may diagnose and treat a wide variety of medical illnesses A specialist trained to prevent, diagnose, and treat a variety of medical illnesses in patients of all ages Provides long-term, comprehensive care for common illnesses as well as complex health problems, generally in adults and the elderly (though they may treat younger patients as well) A physician who specializes in the diagnosis and treatment of mental health conditions Other HCPs Title Definition A specialist in psychology licensed to practice clinical psychology; unlike a psychiatrist, a psychologist is not a licensed physician and is usually not licensed to write prescriptions in most states A nurse that works mainly in psychiatric settings; duties may include direct nursing care, participation in therapeutic care, and evaluation of patients response to treatment; these professionals are not able to prescribe medication A registered nurse (RN) with at least a master's degree in nursing and additional training in the primary care setting; in many states, NPs can write prescriptions and they usually work in collaboration with a physician Trained, certified, and licensed to perform history taking, physical examination, diagnosis, and treatment of commonly encountered medical problems under the supervision of a licensed physician; may receive additional training and certification to specialize in a particular area; in many states, PAs can write prescriptions Holds a degree in social work, perhaps in psychiatric social work, and may play a supportive role to the psychiatrist or provide patient care on an individual basis, or be an integral part of a larger multidisciplinary care team; social workers are not licensed to write prescriptions 66
Psychiatrist
Clinical Psychologist
Psychiatric Nurse
Nurse Practitioner (NP)
Physician Assistant (PA)
Social Worker
Nurse
A licensed HCP who may have varying levels of general and specialty training; performs a wide range of duties, ranging from direct patient care to supervisory and administrative functions; nurses are not licensed to prescribe medications A licensed HCP trained to prepare and dispense medications; may receive additional training and certification to specialize in a particular area; pharmacists are not licensed to prescribe medications, however, they may change a patients prescribed medication to a generic brand. Consultant pharmacists work in longterm care facilities as well as hospitals and may recommend treatment options to prescribers
Pharmacist
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HCPs Involved in Depression Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Patients with depression are most commonly first seen in which setting? a. Hospital psychiatric wards b. Psychiatrist office c. Primary care physician office d. Hospital emergency room 2. Besides primary care physicians, which type of physician is most likely to diagnose and treat patients with depression? a. Psychiatrist b. Psychologist c. Pediatrician d. Oncologist 3. Which of the following is NOT an example of another type of health care provider who may be involved in the diagnosis and/or treatment of patients with depression? a. Clinical psychologist b. Psychiatric nurse c. Podiatrist d. Social worker 4. Since many non-physician health care providers are not licensed to prescribe medications, they rarely help make treatment recommendations. a. True b. False Answers 1. c. The majority of patients with depression are first seen in primary care physician office settings. 2. a. The physicians who most commonly diagnose and treat patients with depression are primary care physicians and psychiatrists. 3. c. Other health care providers who may be involved in the diagnosis and/or treatment of patients with depression include: clinical psychologist, psychiatric nurse, nurse practitioner (NP), physician assistant (PA), counselor, social worker, nurse, and pharmacist. 4. b. It is very important to understand that even though many HCPs may not be licensed to prescribe medications, they often see patients under the supervision of another practitioner and can help make treatment recommendations.
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Section3:AssessmentandDiagnosticProcedures
Physicians have varying methods for assessing patients and diagnosing depression. Only a healthcare provider can diagnose a psychiatric condition. Click the following icon to view common procedures and tools they may use, or read a transcript.
Once the diagnosis of major depression is made, the physician can focus on treatment.
Critical Information! Assessment and Diagnostic Procedures

Physicians have varying methods for assessing patients and diagnosing depression. Only a healthcare provider can diagnose a psychiatric condition.
Diagnostic Tool/Procedures
Explanation
Clinical interview
The clinical interview involves gathering a detailed history of the patients current symptoms as well as a general medical history. During the interview, the clinician will observe the patients behavior and look for signs indicative of disease.
Mental status examination
The mental status examination is a process of evaluating the patients current mental state.
Depression rating
These are not diagnostic tools but may help patients identify common symptoms of depression and encourage them to begin conversations with their physicians regarding symptoms they are experiencing.
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scales/tools
They may also help exclude other potential psychiatric diagnoses. Medical disorders: Due to the nature of many symptoms of depression, part of the diagnostic process involves ruling out other potential causes of the patients symptoms. Due to similar symptoms patients with other disorders may experience, differential diagnosis for depression involves ruling out numerous medical conditions, including: o endocrinopathies (such as hypothyroidism) o neurologic disorders (such as stroke) o vitamin deficiencies o anemia o some types of cancer (such as pancreatic cancer)
Differential diagnosis
The above list is only a partial list of medical illnesses. Indeed, many medical illnesses may present with depression-like symptoms and can be included in the differential diagnosis. Additionally, the physician must also determine if the patients depressive symptoms are caused by current medications the patient is taking or effects of substance use (such as symptoms of intoxication or withdrawal). Physicians should also try to rule out the presence of bipolar disorder (which may also present with a major depressive episode) because the treatment approaches for bipolar disorder and MDD differ. Psychiatric disorders: In addition to ruling out other medical conditions, medications, and substances of abuse as possible causative factors for the depressive symptoms, physicians must also consider other psychiatric illnesses during their diagnostic evaluation. These include: o Bipolar disorders o Anxiety disorders o Cognitive disorders (such as dementia)
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o o o o
Personality disorders Psychotic disorders (for instance, schizoaffective disorders) Dysthymic disorder Adjustment disorders
Again, it is important to note that the above is only a partial list of psychiatric disorders that one must consider in patients presenting with depressive symptoms.
Monitoring Improvements Physicians may track patient progress using depression rating scales. However, progress is often assessed by clinical interview and patient reporting of symptom improvement, lack of improvement, or overall functioning. It is important to monitor relief of all symptoms, because lingering symptoms may increase the risk of relapse and have been associated with poor psychosocial functioning.[1, 2] Depressed patients who reach full remission after treatment have a better level of functioning and have an improved prognosis compared with patients who are non-remitters.[3, 4]
Critical Information! Monitoring Improvements

Physicians may track patient progress using depression rating scales. However, progress is often assessed by clinical interview and patient reporting of symptom improvement, lack of improvement, or overall functioning. It is important to monitor relief of all symptoms, because lingering symptoms may increase the risk of relapse and have been associated with poor psychosocial functioning.[1, 2]
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Assessment and Diagnostic Procedures Transcript

Diagnostic Tool/Procedures Explanation
Clinical interview
The clinical interview involves gathering a detailed history of the patients current symptoms as well as a general medical history. During the interview, the clinician will observe the patients behavior and look for signs indicative of disease. The clinician will also obtain information regarding family history of psychiatric illness. Comprehensive clinical interviews may include a chief complaint (the sign/symptom that the patient reports as their primary concern or reason for seeking medical evaluation), history of present illness (a review of current signs and symptoms), current and past medical history, current and past psychiatric history (including diagnoses and treatment history), family medical and psychiatric history, developmental history, social history, substance use history, and current medications.
DSM-IV-TR diagnostic criteria
During the clinical interview, the clinician will also be gathering information to determine whether the patients symptoms meet the DSM-IV-TR diagnostic criteria for major depressive disorder or another diagnosis, such as dysthymic disorder. They will also look for the presence of other psychiatric disorders.
Physical examination
A physical examination is generally conducted to assess the patients current health status and rule out a general medical disorder as a cause of symptoms. This exam may include laboratory tests, such as blood tests to check for thyroid dysfunction or other abnormalities.
Mental status examination
The mental status examination is a process of evaluating the patients current mental state. This evaluation may include an assessment of the patients appearance (such as attire, grooming, hygiene), attitude, behavior, motor activity, speech, mood (patients emotional state), affect (the outward appearance of the patients emotional state), perceptions, thought process (such as logic and flow of thoughts), thought content, cognition (such as orientation, attention, concentration, and memory), insight (awareness of the problem), and judgment.
Depression rating scales/tools
Both PCPs and psychiatrists may use depression rating tools to assist in diagnosing depression, gauging its severity, and monitoring symptom change during treatment. Examples of two of the depression rating tools, the HAM-D17 and the Zung Self-
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rating Depression Scale, are linked in the right margin of the online course. There are many depression rating scales including: Beck Depression Inventory (BDI): a patient self-assessment mood scale Zung Self-rating Depression Scale (Zung Scale): a patient self-assessment mood scale Primary Care Evaluation of Mental Disorders (PRIME-MD): a patient questionnaire and structured interview assessment tool designed for use in primary care settings Clinical Global Impression (CGI) Scale: a physician observational rating scale Hamilton Depression Rating Scale (HAM-D): a clinician-administered scale often used in clinical trials; full scale includes 24 items These are not diagnostic tools but may help patients identify common symptoms of depression and encourage them to begin conversations with their physicians regarding symptoms they are experiencing. They may also help exclude other potential psychiatric diagnoses. Physicians must consider a wide variety of disorders in the differential diagnosis of depression, including medical disorders and other psychiatric disorders. Medical disorders: As stated previously, due to the nature of many symptoms of depression, part of the diagnostic process involves ruling out other potential causes of the patients symptoms. Due to similar symptoms patients with other disorders may experience, differential diagnosis for depression involves ruling out numerous medical conditions, including: Differential diagnosis endocrinopathies (such as hypothyroidism) neurologic disorders (such as stroke) vitamin deficiencies anemia some types of cancer (such as pancreatic cancer)
The above list is only a partial list of medical illnesses. Indeed, many medical illnesses may present with depression-like symptoms and can be included in the differential diagnosis. Additionally, the physician must also determine if the patients depressive symptoms are caused by current medications the patient is taking or effects of substance use (such as symptoms of intoxication or withdrawal). Physicians should also try to rule out the presence of bipolar disorder (which may also present with a major depressive episode) because the treatment approaches for bipolar disorder and MDD differ.
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Psychiatric disorders: In addition to ruling out other medical conditions, medications, and substances of abuse as possible causative factors for the depressive symptoms, physicians must also consider other psychiatric illnesses during their diagnostic evaluation. These include: Bipolar disorders Anxiety disorders Cognitive disorders (such as dementia) Personality disorders Psychotic disorders (for instance, schizoaffective disorders) Dysthymic disorder Adjustment disorders
Again, it is important to note that the above is only a partial list of psychiatric disorders that one must consider in patients presenting with depressive symptoms.
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Assessment and Diagnostic Procedures Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Which of the following describes a clinical interview? a. Generally conducted to rule out a general medical disorder as a cause of symptoms. This assessment may include laboratory tests, such as blood tests. b. Gathering information to determine whether the patients symptoms meet the DSM-IV-TR criteria for a major depressive episode or another diagnosis. c. Gathering a detailed history of the patients current symptoms as well as a general medical history. d. A process of estimating psychological and behavioral function by observing the patient, eliciting his or her self-description, and using formal questioning. 2. What other conditions must psychiatrists commonly rule out in the diagnosis of a patient who presents with depressive symptoms? a. The presence of mitigating factors, like high levels of work-related anxiety b. Unexplained and erratic physical symptoms such as rash, headaches, and psychotic delusions c. Medical conditions or other psychiatric illness in people who are closely related to the patient d. Medical conditions (such as diabetes), psychiatric illnesses (such as bipolar disorder), and prescribed medications and substances of abuse 3. Which of the following describes the Hamilton Depression Rating Scale? a. A self-reporting scale developed by the Hamilton clinic b. A physician-administered scale often used in clinical trials c. A physician observational rating scale d. A patient self-assessment mood scale Answers 1. c. The clinical interview involves gathering a detailed history of the patients current symptoms as well as a general medical history. During the interview, the clinician will observe the patients behavior and look for signs indicative of disease. The clinician will also obtain information regarding family history of psychiatric illness, among other things. 2. d. The physician must determine if the patients depressive symptoms are caused by other medical conditions, current medications the patient is taking, or effects of substance use. Additionally, physicians should evaluate patients for the presence of other psychiatric disorders. 3. b. The Hamilton Depression Rating Scale is physician administered scale often used in clinical trials; often referred to in abbreviated form as HAM-D.
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Find Out More: DSM-IV-TR Diagnostic Criteria for a Major Depressive Episode
DSM-IV-TR Diagnostic Criteria for a Major Depressive Episode[5] A major depressive episode is defined in the DSM-IV-TR as the presence of five (or more) of the following symptoms during the same two-week period. These symptoms must be present most of the day, nearly every day and represent a change from previous functioning. At least one of the symptoms is either depressed mood or loss of interest or pleasure. Depressive symptoms can include the following: depressed mood loss of interest or pleasure in usual activities significant change in weight and/or appetite insomnia or hypersomnia psychomotor agitation or retardation fatigue or loss of energy feelings of guilt or worthlessness slowed thinking or impaired concentration suicide attempt or suicidal ideation.
Furthermore, there must be significant distress or impairment in the patients functioning at work, in relationships, or in other important areas of functioning.
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Find Out More: Zung Self-rating Depression Scale
Zung Self-rating Depression Scale1

Patient Name: ____________________________ Date: __________________ Age: _____ Sex: _____ Please check a response for each of the 20 items. None OR a Little of the Time 1 4 1 1 4 4 1 1 1 1 4 4 1 4 1 4 4 4 1 4
Raw Score SDS Index SDS Index Equivalent Clinical Global Impressions Below 50 Within normal range; no psychopathology 5059 Presence of minimal to mild depression 6069 Presence of moderate to marked depression 70 and over Presence of severe to extreme depression Conversion of Raw Scores to SDS Index Raw Score 20 21 22 23 24 25 26 27 28 29 30 31 SDS Index 25 26 28 29 30 31 33 34 35 36 38 39 Raw Score 32 33 34 35 36 37 38 39 40 41 42 43 SDS Index 40 41 43 44 45 46 48 49 50 51 53 54 Raw Score 44 45 46 47 48 49 50 51 52 53 54 55 SDS Index 55 56 58 59 60 61 63 64 65 66 68 69 Raw Score 56 57 58 59 60 61 62 63 64 65 66 67 SDS Index 70 71 73 74 75 76 78 79 80 81 83 84 Raw Score 68 69 70 71 72 73 74 75 76 77 78 79 80 SDS Index 85 86 88 89 90 91 92 94 95 96 98 99 100
2
Some of the Time
Good Part of the Time
Most OR All of the Time
1. I feel downhearted and blue. 2. Morning is when I feel the best. 3. I have crying spells or feel like it. 4. I have trouble sleeping at night. 5. I eat as much as I used to. 6. I still enjoy sex. 7. I notice that I am losing weight. 8. I have trouble with constipation. 9. My heart beats faster than usual. 10. I get tired for no reason. 11. My mind is as clear as it used to be. 12. I find it easy to do the things I used to do. 13. I am restless and cant keep still. 14. I feel hopeful about the future. 15. I am more irritable than usual. 16. I find it easy to make decisions. 17. I feel that I am useful and needed. 18. My life is pretty full. 19. I feel that others would be better off if I were dead. 20. I still enjoy the things I used to.
2 3 2 2 3 3 2 2 2 2 3 3 2 3 2 3 3 3 2 3
3 2 3 3 2 2 3 3 3 3 2 2 3 2 3 2 2 2 3 2
4 1 4 4 1 1 4 4 4 4 1 1 4 1 4 1 1 1 4 1
1 Zung article: Zung WWK. A Self-Rating Depression Scale. Arch Gen Psych. 1965:12: 63-70.
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2 Zung WWK. in Handbook of Psychiatric Measures. American Psychiatric Association 2000 pp. 534-537.
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Find Out More: Hamilton Depression Rating Scale

HAMILTON DEPRESSION SCALE: 17- ITEM SCALE
1. DEPRESSED MOOD: (Sadness, hopeless, helpless, worthless)
Absent 1 These feeling states indicated only on questioning 2 These feeling states spontaneously reported verbally 3 Communicates feeling states nonverbally i.e., through facial expression, posture, voice, and tendency to weep 4 Patient reports VIRTUALLY ONLY these feeling states in his spontaneous verbal and non-verbal communication
0
9. AGITATION
None Fidgetiness 2 "Playing with" hands, hair, etc. 3 Moving about, can't sit still 4 Hand-wringing, nail-biting, hair-pulling, biting of lips
0 1
10. ANXIETY/PSYCHIC
No difficulty Subjective tension and irritability 2 Worrying about minor matters 3 Apprehensive attitude apparent in face or speech 4 Fears expressed without questioning
0 1
2. FEELINGS OF GUILT
Absent Self-reproach, feels he has let people down 2 Ideas of guilt or rumination over past errors or sinful deeds 3 Present illness is a punishment. Delusions of guilt 4 Hears accusatory or denunciatory voices and/or experiences threatening visual hallucinations
0 1
11. ANXIETY (SOMATIC): Physiological concomitants of anxiety, such as: gastrointestinaldry mouth, wind, indigestion, diarrhea, cramps, belching; cardiovascular palpitations, headaches; respiratory hyperventilation, sighing; urinary frequency; sweating.
Absent Mild 2 Moderate 3 Severe 4 Incapacitating
0 1
3. SUICIDE
Absent Feels life is not worth living 2 Wishes he were dead or any thoughts of possible death to self 3 Suicide ideas or gestures 4 Attempts suicide (any serious attempt rates 4)
0 1
12. SOMATIC SYMPTOMS/GASTROINTESTINAL

None Loss of appetite but eating without staff encouragement. Heavy feelings in abdomen 2 Difficulty eating without staff urging. Requests or requires laxatives or medication for bowels or medication for GI symptoms
0 1
4. INSOMNIA EARLY
No difficulty falling asleep Complains of occasional difficulty falling asleep, i.e., more than 1/2 hour 2 Complains of nightly difficulty falling asleep
0 1
13. SOMATIC SYMPTOMS/GENERAL

0 1
5. INSOMNIA MIDDLE
No difficulty Patient complains of being restless and disturbed during the night 2 Waking during the night -- any getting out of bed rates 2 (except for purposes of voiding)
0 1
None Heaviness in limbs, back or head. Backaches, headaches, muscle aches. Loss of energy and fatigability
Any clear-cut symptom rates 2
14. GENITAL SYMPTOMS: Loss of libido, menstrual disturbances

Absent Mild 2 Severe
0 1
6. INSOMNIA LATE 80
No difficulty Waking in early hours of the morning but goes back to sleep 2 Unable to fall asleep again if gets out of bed
0 1
15. HYPOCHONDRIASIS
Not present Self-absorption (bodily) 2 Preoccupation with health 3 Frequent complaints, requests for help, etc. 4 Hypochondriacal delusions
0 1
7. WORK AND ACTIVITIES

No difficulty Thoughts and feelings of incapacity, fatigue, or weakness related to activities, work, or hobbies 2 Loss of interest in activity, hobbies or work -- either directly reported by patient, or indirect in listlessness, indecision and vacillation (feels he has to push self to work or join activities) 3 Decrease in actual time spent in activities or decrease in productivity. In hospital, rate 3 if patient does not spend at least three hours a day in activities (hospital job or hobbies) exclusive of ward chores 4 Stopped working because of present illness. In hospital, rate 4 if patient engages in no activities except ward chores; or if patient fails to perform ward chores unassisted
0 1
ACTUAL WEIGHT CHANGE (since the last visit) 16. LOSS OF WEIGHT
No weight loss or weight loss NOT caused by present illness 1 Weight loss probably caused by present illness 2 Definite weight loss caused by present Illness
0
17. INSIGHT
Acknowledges being depressed and ill Acknowledges illness but attributes cause to bad food, climate, overwork, virus, need for rest, etc. 2 Denies being ill at all
0 1
8. RETARDATION: Slowness of thought and speech; impaired ability to concentrate; decreased motor activity
Normal speech and thought Slight retardation at interview 2 Obvious retardation at interview 3 Interview difficult 4 Complete stupor
0 1
1 Rating Scales In Mental Health. 2 Ed. 2003.
nd
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Section4:DiagnosticChallenges
As stated previously, many individuals with major depression present in the primary care setting. Some studies have found that more than 50 percent of clinically important depression is undiagnosed in primary care settings.[6]
Critical Information! Diagnostic Challenges

Some studies have found that more than 50 percent of clinically important depression is undiagnosed in primary care settings.[6]
Variety of Different Symptoms The patient may present with a broad range of symptoms, and a sad or depressed mood may actually be absent in some patients. One potential reason for the difficulty in recognition is that patients sometimes present with predominantly physical symptoms (such as changes in sleep, lack of energy, decrease concentration, changes in psychomotor skills, and appetite changes) and may complain less of psychological symptoms.[7, 8] This presentation may be due to patients being more comfortable discussing physical symptoms than emotional symptoms.[9] PCPs, therefore, may spend a significant amount of time excluding other conditions. They may also perform extensive medical workups. This may lead to depression being diagnosed after many other conditions are excluded. In many cases, depression may still remain undiagnosed.
Critical Information! Variety of Different Symptoms

The patient may present with a broad range of symptoms, and a sad or depressed mood may actually be absent in some patients. One potential reason for the difficulty in recognition is that patients sometimes present with predominantly physical symptoms (such as changes in sleep, lack of energy, decrease concentration, changes in psychomotor skills, and appetite changes) and may complain less of psychological symptoms.[7, 8] This presentation may be due to patients being more comfortable discussing physical symptoms than emotional symptoms.[9]
Time Constraints and Social Stigma
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It has also been suggested that some reasons for the underdiagnosis of depression in outpatient settings may be related to time and stigmatization.[10] When a patient visits a physician, the time actually spent with the physician may be brief in some instances and not allow for an adequate assessment for a psychiatric disorder. In addition, these visits may be focused on other health issues with which the patient presents. Delays in diagnosis also occur due to time required to rule out other medical disorders, such as an endocrine disorder, malignancy, or injury.[11] As noted previously, the social stigma associated with depression may make the patient reluctant to volunteer depression as a possible cause.
Critical Information! Time Constraints and Social Stigma

Delays in diagnosis also occur due to time required to rule out other medical disorders, such as an endocrine disorder, malignancy, or injury.[11] As noted previously, the social stigma associated with depression may make the patient reluctant to volunteer depression as a possible cause.
Treatment Failure The patient who has been diagnosed as having depression, has received treatment and has failed to receive adequate response may lead the physician to question the original diagnosis and to consider other possible diagnoses. General Medical Conditions and Medication Side Effects Some general medical conditions and medication side effects can cause some of the same symptoms as depression. Once you have completed this section, open the Quick Check and check your understanding of what you have learned or read a transcript.
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Diagnostic Challenges Quick Check Transcript

Read each statement and decide whether it is true or false. Correct answers are revealed at the bottom of the page. 1. Fifty percent or more of significant depression is undiagnosed in primary care settings. 2. The social stigma associated with depression may make patients more eager to volunteer depression as a possible cause of their symptoms. 3. The difficulty in diagnosing depression in primary care settings is sometimes due to patients presenting with predominantly psychological symptoms rather than physical symptoms. 4. The difficulty in diagnosing depression in some patients may be due to the absence of a sad or depressed mood. 5. Delays in diagnosis of depression may also occur due to time required to rule out other medical disorders. Answers 1. True. Fifty percent or more of significant depression is undiagnosed in primary care settings. 2. False. The social stigma associated with depression may make patients more reluctant to volunteer depression as a possible cause of their symptoms. 3. False. The difficulty in diagnosing depression in primary care settings is sometimes due to patients presenting with predominantly physical symptoms rather than psychological symptoms. 4. True. The difficulty in diagnosing depression in some patients may be due to the absence of a sad or depressed mood. 5. True. Delays in diagnosis of depression may also occur due to time required to rule out other medical disorders.
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Module3References
1. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995; 25(6):1171-1180. 2. Fava M. Pharmacological approaches to the treatment of residual symptoms. Journal of Psychopharmacology. 2006;20(3): 29-34. 3. Mendlewicz J. Towards achieving remission in the treatment of depression. Dialogues Clin Neurosicence. 2008;10: 371-375. 4. Trivedi MH, Fava M, et al. Medication Augmentation after the Failure of SSRIs for Depression. NEJM. 2006;354:1243-1252. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Text Revision. 4th ed. Washington, DC: American Psychiatric Association; 2000:345-428. 6. Ani C, et al. Depression symptomatology and diagnosis: discordance between patients and physicians in primary care settings. BMC Family Practice. 2008:9;1. 7. Simon GE, VonKorff M, Piccinelli M, Fullerton C, Ormel J. An international study of the relation between somatic symptoms and depression. N Engl J Med. 1999;341(18):1329-1335. 8. Farah A. Somatization: a survival guide for the primary care physician. Primary Psychiatry. April 1999:86-87, 91, 102. 9. Kroenke K, Jackson JL, Chamberlin J. Depression and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med. 1997;103(5):339-347. 10. Kroenke K, Jackson JL, Chamberlin J. Depression and anxiety disorders in patients presenting with physical complaints: clinical predictors and outcome. Am J Med. 1997;103(5):339-347. 11. Katon W. The epidemiology of depression in medical care. Int J Psychiatry Med. 1987;17(1):93-112.
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Module4:WhatCausesDepression?
Mary is a Lilly sales rep that is new to Cymbalta for MDD. She is learning about some of the possible causes of depression so that when she makes calls she will be able to talk to doctors and other health care professionals about their patients with depression. Click the following icon to listen to Mary or read a transcript.
Mary asks herself the following questions: What are some proposed theories regarding the etiology of MDD? What does neurotransmission have to do with depression? What potential roles do serotonin and norepinephrine play in depression? Look for the answers to these questions as you complete this module.
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Scenario Transcript
Mary: Im a sales rep at Lilly, and Im just starting to sell Cymbalta for major depression. I want to help patients who could benefit from using Cymbalta to help treat their depression, but I know I cant do that unless I have credibility with their doctors and other health care professionals who treat them. And I wont have that credibility unless I understand the proposed causes of depression and am able to talk about them knowledgeably if needed. I would have very little professional credibility with that doctor, and I doubt Id be able to position Cymbalta as a good fit for patients with depression. So, I need to know about the major proposed theories on the causes of depression. Specifically, I need to know the main elements of the biochemical theory of depression and the neurotransmission process in humans, as well as the proposed role of neurotransmitters in causing depression.
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Module Objectives
Upon completion of this module, you will be able to: Identify some theories of the causes of depression. Summarize neurotransmission. Identify some neuroanatomic structures thought to be related to depression. Identify and describe some neurotransmitters thought to play a role in depression. Describe the biochemical theory of depression. Discuss regulation of mood. Discuss the potential roles that serotonin and norepinephrine may play in depression.
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Section2:TheoriesofDepression
The exact cause of depression is unknown. Click the following icon to view a summary of several postulated theories.
These theories are not mutually exclusive, and none have been definitively established as accounting for the etiology of depression. As research in this area progresses, we may develop a much better understanding of the underlying etiology of major depression. Remember that the exact cause of depression is unknown. None of these theories provides a completely satisfactory explanation for the efficacy of antidepressant treatments. However, the proposed mechanisms of action of available antidepressants lend support, in part, to a potential role for neurotransmitters in depression.
Critical Information! Theories of the Cause of Depression

Although the exact cause of depression is unknown, here are some theories on contributing factors: Biochemical theory:[1] Dysfunction of neurotransmitter systems in the brain are thought to be involved in depression. Specifically, neurotransmitters believed to affect mood include dopamine, serotonin, and norepinephrine.[2] Dopamine: Neurotransmitter found in many pathways throughout the central nervous system. Serotonin: Neurotransmitter found in many regions of the brain and other parts of the body. Norepinephrine: Neurotransmitter widely distributed throughout the nervous system; also called noradrenaline. Psychological theory:[3] Issues with attachment, loss, early trauma, unresolved conflicts, and exposure to stress may account for depression. Social theory:[4] Life events and social stressors may lead to depression Heredity/genetic theories:[5] Some evidence suggests that genes might be responsible, at least in part, for making some individuals susceptible to developing depression It is possible that depression involves biological, experiential, and behavioral components; factors such as biological vulnerability and physiological and psychosocial stressors may all contribute to depression.
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Remember that the exact cause of depression is unknown. None of these theories provides a completely satisfactory explanation for the efficacy of antidepressant treatments. However, the proposed mechanisms of action of available antidepressants lend support, in part, to a potential role for neurotransmitters in depression.
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Theories of Depression
Although the exact cause of depression is unknown, here are some theories on contributing factors: Biochemical theory:[1] Dysfunction of neurotransmitter systems in the brain are thought to be involved in depression. Specifically, neurotransmitters believed to affect mood include dopamine, serotonin, and norepinephrine.[2] Dopamine: Neurotransmitter found in many pathways throughout the central nervous system. Serotonin: Neurotransmitter found in many regions of the brain and other parts of the body. Norepinephrine: Neurotransmitter widely distributed throughout the nervous system; also called noradrenaline.
Psychological theory:[3] Issues with attachment, loss, early trauma, unresolved conflicts, and exposure to stress may account for depression. Social theory:[4] Life events and social stressors may lead to depression Heredity/genetic theories:[5] Some evidence suggests that genes might be responsible, at least in part, for making some individuals susceptible to developing depression It is possible that depression involves biological, experiential, and behavioral components; factors such as biological vulnerability and physiological and psychosocial stressors may all contribute to depression.
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Theories of Depression Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. The exact cause of depression is well known. a. True b. False 2. Some theories of depression include: a. Biochemical, psychological, social, and heredity/genetic b. Cognitive, emotional, and physical c. Neurotransmission, psychiatric, and social-clinical d. HAM-D, Beck Depression Inventory, Zung Self-rating, U-Mich checklist 3. The proposed mechanisms of action for most antidepressants lend support to which theory of depression? a. Biochemical b. Genetic c. Psychological d. Social Answers 1. b. The exact cause of depression is unknown. 2. a. Four theories of depression include biochemical, psychological, social, and heredity/genetic. It is possible that depression involves biological, experiential, and behavioral components; factors such as biological vulnerability and physiological and psychosocial stressors may all contribute to depression. 3. a. The proposed mechanisms of action for most antidepressants lend support to the biochemical theory of depression.
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Section3:NeurotransmissionProcess
The Role of Neurotransmitters in Human Health The effect that neurotransmitters have on a person is not restricted to the brain. Click the following icon to learn how neurotransmitters are thought to act on the brain and throughout the body, or read a transcript.
Critical Information! The Role of Neurotransmitters in Human Health

Neurotransmitters are chemical substances that are responsible for transmission of nerve impulses. The central nervous system (CNS) contains a number of neurotransmitters. Key neurotransmitters originate in the midbrain and project to various locations. Projections from the brainstem also descend into the spinal cord, where they can suppress painful input from the body and play a role in other bodily functions. Studies have proposed that the neurotransmitters serotonin (5-HT) and norepinephrine (NE) to be involved in depression and pain among other processes.[6, 7, 8]
The Neurotransmission Process Click the following icon to learn basic information about the neurotransmission process, or read a transcript.
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Neurotransmitters can exert a variety of effects, often depending on the type of receptor to which they bind. Click the link under Find Out More in the margin to learn more about these effects.
Critical Information! The Neurotransmission Process

Neurons are the basic cells of the nervous system. They transmit messages in the form of electrical impulses throughout the CNS. At each gap (synaptic cleft) between neurons, chemical messengers (neurotransmitters) transport this electrical signal from one neuron to the next. This diagram illustrates the structure of a neuron and its communication with a neighboring neuron at the synapse. Neurotransmitters are chemical messengers used to send signals between brain cells, or neurons. Each neuron may send and receive signals to many other neurons. The neurotransmission process consists of the following steps: The electrical signal passes along the nerve to the terminal of a presynaptic neuron. When the signals arrive at the nerves terminal, they stimulate the release of neurotransmitters or chemical messengers from the terminal of the presynaptic neuron into the synapse. The neurotransmitter crosses the synapse to the nerve on the other side of the synapse, or the postsynaptic neuron. Neurotransmitters bind to proteins called receptors on the membrane of the postsynaptic neuron, which receives the message. Once the neurotransmitters are bound, electrochemical changes occur inside the postsynaptic neuron. This transmits the message forward through the neuron. Once the neurotransmitter has passed on the message to the postsynaptic neuron, it detaches from the receptor and returns to the synapse. From there, it is either broken down by enzymes and discarded, or taken up again by the presynaptic neuron and recycled.
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The pump that takes up the free-floating neurotransmitter on the presynaptic neuron is called a reuptake pump.
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The Role of Neurotransmitters in Human Health Transcript

Narrator: Neurotransmitters are chemical substances that are responsible for transmission of nerve impulses. The central nervous system (CNS) contains a number of neurotransmitters. Key neurotransmitters originate in the midbrain and project to various locations. Projections in the brainstem ascend into the brain and mediate numerous emotional functions, some of which may become dysfunctional in patients with depression. Projections from the brainstem also descend into the spinal cord, where they can suppress painful input from the body and play a role in other bodily functions. Neurotransmitters are thought to play a role in a variety of emotional and physiological processes, including, but not limited to: sadness anxiety pain perception irritability vasoconstriction urethral sphincter contractions bladder wall relaxation gastrointestinal motility and pilomotor contraction, commonly known as goose bumps.
Studies have proposed that the neurotransmitters serotonin (5-HT) and norepinephrine (NE) to be involved in depression and pain among other processes.[6, 7, 8] Normally, the sensations associated with the routine functioning of the body, such as digestion in the abdomen, urogenital function, and some inputs to the musculoskeletal system throughout the body, such as pain perception, are suppressed from awareness, so that attention can be paid to more important events outside of the body. Descending serotonergic and noradrenergic pathways help to suppress inputs even when they cause minor discomfort. However, when these neurotransmitter systems malfunction, deficient inhibition from the descending pathways may allow painful stimuli to be felt to a greater degree. Other aspects of human health are impacted by neurotransmitters as well. There are many neurotransmitter receptor sites located in various organs of the body.
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The Neurotransmission Process Transcript

Narrator: Neurons are the basic cells of the nervous system. They transmit messages in the form of electrical impulses throughout the CNS. At each gap (synaptic cleft) between neurons, chemical messengers (neurotransmitters) transport this electrical signal from one neuron to the next. This diagram illustrates the structure of a neuron and its communication with a neighboring neuron at the synapse. Neurotransmitters are chemical messengers used to send signals between brain cells, or neurons. Each neuron may send and receive signals to many other neurons. The neurotransmission process consists of the following steps: The electrical signal passes along the nerve to the terminal of a presynaptic neuron. When the signals arrive at the nerves terminal, they stimulate the release of neurotransmitters or chemical messengers from the terminal of the presynaptic neuron into the synapse. The neurotransmitter crosses the synapse to the nerve on the other side of the synapse, or the postsynaptic neuron. Neurotransmitters bind to proteins called receptors on the membrane of the postsynaptic neuron, which receives the message. Once the neurotransmitters are bound, electrochemical changes occur inside the postsynaptic neuron. This transmits the message forward through the neuron. Once the neurotransmitter has passed on the message to the postsynaptic neuron, it detaches from the receptor and returns to the synapse. From there, it is either broken down by enzymes and discarded, or taken up again by the presynaptic neuron and recycled.
The pump that takes up the free-floating neurotransmitter on the presynaptic neuron is called a reuptake pump.
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Neurotransmission Process Quick Check Transcript

Read each statement and decide whether the it is true or false. Correct answers are revealed at the bottom of the page. 1. Neurotransmitters are electrical impulses that are responsible for the transmission of nerve chemicals between neurons. 2. Key neurotransmitters originate in various locations throughout the body. 3. Neurotransmitters are thought to play a role in a variety of emotional and physiological processes, including, but not limited to: sadness, pain perception, and goose bumps. 4. Multiple studies have proposed that the neurotransmitters serotonin and norepinephrine are not directly involved in depression. 5. In neurotransmission, an electrochemical impulse passes along the nerve to the terminal of a presynaptic neuron and stimulates the release of neurotransmitters from the terminal end of the presynaptic neuron into the synapse. 6. In neurotransmission, a neurotransmitter crosses the synapse from the presynaptic neuron to the postsynaptic neuron on the other side of the synapse, where it binds to proteins, called neurotransmitter receptors, on the membrane of the postsynaptic neuron, to deliver the "message." 7. Once the neurotransmitter has passed on the message to the postsynaptic neuron, it detaches from the receptor and returns to the synapse, where it is taken up again by enzymes for reuse or broken down by a reuptake pump in the presynaptic neuron. Answers 1. False. Neurotransmitters are chemical substances that are responsible for the transmission of nerve impulses. 2. False. Key neurotransmitters originate in the midbrain and project to various locations. 3. True. Neurotransmitters are thought to play a role in a variety of emotional and physiological processes, including, but not limited to: sadness, pain perception, and goose bumps. 4. False. Multiple studies have proposed that the neurotransmitters serotonin and norepinephrine are directly involved in depression and pain. 5. True. In neurotransmission, an electrochemical impulse passes along the nerve to the terminal of a presynaptic neuron and stimulates the release of neurotransmitters from the terminal end of the presynaptic neuron into the synapse. 6. True. The neurotransmitter crosses the synapse to the postsynaptic neuron on the other side of the synapse, where it binds to proteins, called neurotransmitter receptors, on the membrane of the postsynaptic neuron, to deliver the "message." 7. False. Once the neurotransmitter has passed on the message to the postsynaptic neuron, it detaches from the receptor and returns to the synapse, where it is broken down by enzymes or taken up again by a "reuptake pump" in the presynaptic neuron for reuse. 98
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Find Out More: Effects of Neurotransmission

Impairment in neurotransmitter systems can result in a variety of effects. Some types of neurotransmission impairment include the following: deficiency or excess of neurotransmitter(s) upregulation or downregulation of neurotransmitter receptors blockade of neurotransmitter receptors on the postsynaptic neuron blockade of neurotransmitter receptors on the presynaptic neuron interference with neurotransmitter reuptake pumps interference with enzymes that are responsible for breaking down one or more neurotransmitters.
It appears that over time the postsynaptic neurons adjust to the higher levels of neurotransmitter, as receptors on the postsynaptic neuron decrease in number or sensitivity. This adjustment process is called downregulation. It occurs after a few weeks of antidepressant therapy, at about the same time as symptoms of depression improve. However, it is not fully established how downregulation is related to clinical improvement.
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Section4:MoodRegulation
The Biochemical Theory of Depression The biochemical theory posits that depression may be the result of a neurochemical imbalance or a functional deficiency of neurotransmitters, such as 5-HT, NE, and DA. All currently available antidepressants have an impact on one or more of these neurotransmitters. For example, tricyclic antidepressants (TCAs) inhibit the reuptake of serotonin and norepinephrine, in addition to effects on multiple receptors (for example, anticholinergic effects and antihistaminic effects). Serotonin norepinephrine reuptake inhibitors (SNRIs) also inhibit serotonin and norepinephrine reuptake, but generally have less effects at other receptors. Selective serotonin reuptake inhibitors (SSRIs) are largely selective for inhibiting serotonin reuptake. Effects on receptors differ from medication to medication.
Critical Information! The Biochemical Theory of Depression

The biochemical theory posits that depression may be the result of a neurochemical imbalance or a functional deficiency of neurotransmitters, such as 5-HT, NE, and DA. All currently available antidepressants have an impact on one or more of these neurotransmitters.
Serotonin and Norepinephrine Serotonin originates in the nucleus raphe magnus (raphe nuclei), which is located in the midbrain. Norepinephrine originates in the locus ceruleus, also located in the midbrain. Projections from the midbrain go up into some areas of the brain where regulation of mood is thought to occur. Two areas of the brain thought to be involved in depression are the limbic system and the prefrontal cortex. The prefrontal cortex and the limbic system are primarily involved in the regulation of emotion.
Critical Information! Serotonin and Norepinephrine

Serotonin originates in the nucleus raphe magnus (raphe nuclei), which is located in the midbrain. Norepinephrine originates in the locus ceruleus, also located in the midbrain. Projections from the midbrain go up into some areas of the brain where regulation of mood is thought to occur. Two areas of the brain thought to be involved in depression are the limbic system and the prefrontal cortex. The prefrontal cortex and the limbic system are primarily involved in the regulation of emotion.
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Mood Regulation Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. The biochemical theory of depression proposes that: a. Depression is the result of biological or chemical imbalances due to inherited genetic characteristics. b. Biochemical substance abuse plays a role in the development of depression in most, but not all, patients with depression. c. A variety of environmental factors, coupled with genetic tendencies, combine to create the potential for MDD. d. Depression may result from a dysfunction in neurotransmitter systems in the brain. 2. All currently available antidepressants have an impact on one or more of which neurotransmitters? a. Serotonin, norepinephrine, and dopamine b. Serotonin, norepinephrine, and adrenaline c. Dopamine, serotonin, and tryptophan d. Norepinephrine, Dopamine, and Epinephrine 3. Which two regions of the brain are primarily involved in the regulation of emotion? a. Locus ceruleus and nucleus raphe magnus b. Raphe nuclei and prefrontal cortex c. Prefrontal cortex and limbic system d. Limbic system and midbrain 4. In which part of the brain does serotonin (5-HT) originate? a. Locus ceruleus b. Raphe nuclei c. Limbic region d. Prefrontal cortex 5. In which part of the brain does norepinephrine (NE) originate? a. Locus ceruleus b. Raphe nuclei c. Limbic region d. Prefrontal cortex
Answers 1. d. The biochemical theory of depression proposes that depression may result from a dysfunction in neurotransmitter systems in the brain. 2. a. All currently available antidepressants have an impact on one or more of these neurotransmitters: serotonin (5-HT), norepinephrine (NE), and dopamine (DA). 3. c. The prefrontal cortex and the limbic system are primarily involved in the regulation of emotion. 4. b. Serotonin originates in the nucleus raphe magnus (raphe nuclei), which is located in the midbrain. 5. a. Norepinephrine (NE) originates in the nucleus locus ceruleus, which is located in the midbrain.
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Section5:SerotoninandNorepinephrine
Now that you understand how neurotransmitters are transmitted throughout the body, click the following icon to learn about some specific neurotransmitters and their proposed effects, or read a transcript.
Critical Information! Neurotransmitters

Its important to know about three specific neurotransmitters and their potential involvement in depression. These neurotransmitters are: serotonin, or 5-HT norepinephrine, or NE dopamine, or DA. Serotonin, or 5-HT, is found in many regions of the brain and other parts of the body, such as the gastrointestinal tract. 5-HT originates in the nucleus raphe magnus (raphe nuclei), which is located in the midbrain. Projections from the midbrain go up into some areas of the brain where regulation of mood is thought to occur. 5-HT is thought to play a role in the regulation of mood, anxiety, and appetite, among other emotional and physiological processes. Norepinephrine is thought to play a role in depression, concentration, and anxiety, among other emotional and physiological processes. Additionally, some effects associated with NE include anticholinergic-like symptoms, such as: dry mouth blood pressure effects sweating Dopamine is found mainly in the midbrain and is important in the regulation of body motion, muscle coordination, concentration, and sleep, among other emotional and 105
physiological process.
Cross Talk The central nervous system is very complex and interconnected. The neurotransmitters discussed in the animation often have indirect effects on each other that is referred to as "cross talk" within this course. For example, the chemical structures of norepinephrine and dopamine are very similar, and norepinephrine may play a role in modulating activities of dopamine.
Critical Information! Cross Talk

The central nervous system is very complex and interconnected. The neurotransmitters discussed in the animation often have indirect effects on each other that is referred to as "cross talk" within this course. For example, the chemical structures of norepinephrine and dopamine are very similar, and norepinephrine may play a role in modulating activities of dopamine.
Action of Some Currently Available Antidepressants on Monoamine Neurotransmitters The following table lists the neurotransmitter systems affected by selected antidepressant agents. Click the icon to view the table.
Critical Information! Action of Some Currently Available Antidepressants on Monoamine Neurotransmitters
Agent(s)
Neurotransmitter system(s) primarily affected
Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil, Paxil CR), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox)
Serotonin reuptake inhibition
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Duloxetine (Cymbalta), venlafaxine (Effexor, Effexor XR), desvenlafaxine (Pristiq)
Serotonin and norepinephrine reuptake inhibition (effects occur at higher doses)
Mirtazapine (Remeron)
Modulation of norepinephrine and serotonin via inhibition of presynaptic 2 adrenergic autoreceptors
Nefazodone (Serzone)
Serotonin type 2 receptor antagonist; inhibition of serotonin and norepinephrine reuptake
Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL)
Relatively weak norepinephrine and dopamine reuptake inhibition
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Neurotransmitters Transcript
Narrator: Besides knowing how neurotransmitters are transmitted throughout the body, its important to know about three specific neurotransmitters and their potential involvement in depression. These neurotransmitters are: serotonin, or 5-HT norepinephrine, or NE dopamine, or DA.
Serotonin, or 5-HT, is found in many regions of the brain and other parts of the body, such as the gastrointestinal tract. 5-HT originates in the nucleus raphe magnus (raphe nuclei), which is located in the midbrain. Projections from the midbrain go up into some areas of the brain where regulation of mood is thought to occur. 5-HT is thought to play a role in the regulation of mood, anxiety, and appetite, among other emotional and physiological processes. There are also downward projections along the descending pathways through the spinal cord. This is where serotonin acts as a modulator of pain perception. A dysregulation of serotonin is believed to play a role in depression. Several types of serotonin receptors, called serotonergic receptors, have been identified. Potential effects associated with serotonin binding at these receptors include: sexual dysfunction and nausea.
Some Potential Effects Associated with Serotonin Binding at Selected Serotonergic Receptors[9, 10]
Receptor
Potential Associated Effect
5-HT2a
Sexual dysfunction
5-HT3
Nausea
Norepinephrine (NE) is widely distributed throughout the nervous system. NE originates in the locus ceruleus (LC), in the midbrain. Some, but not all, norepinephrine pathways (noradrenergic pathways) project upward to the same areas of the brain where serotonergic pathways project (ascending pathway). 108
Similarly, norepinephrine neurons project to the frontal cortex, the limbic areas, and the hypothalamus. Norepinephrine also projects downward through the descending pathway along the spinal cord. This is where norepinephrine, like serotonin, plays a role in modulating pain perception. Norepinephrine is thought to play a role in depression, concentration, and anxiety, among other emotional and physiological processes. Additionally, some effects associated with NE include anticholinergic-like symptoms, such as: dry mouth blood pressure effects sweating
Dopamine is found mainly in the midbrain and is important in the regulation of body motion, muscle coordination, concentration, and sleep, among other emotional and physiological process. The receptors to which dopamine binds can vary. Researchers have identified several types of dopamine receptors, such as D1, D2, D3, D4, and D5, each of which tends to be more prominent in certain areas of the brain. Different types of receptors also have been found to be involved in different functions.
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Neurotransmitter Systems Affected by Selected Antidepressant Agents

Agent(s) Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil, Paxil CR), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox) Duloxetine (Cymbalta), venlafaxine (Effexor, Effexor XR), desvenlafaxine (Pristiq) Neurotransmitter system(s) primarily affected
Serotonin reuptake inhibition
Serotonin and norepinephrine reuptake inhibition (effects occur at higher doses) Modulation of norepinephrine and serotonin via inhibition of presynaptic 2 adrenergic autoreceptors Serotonin type 2 receptor antagonist; inhibition of serotonin and norepinephrine reuptake Relatively weak norepinephrine and dopamine reuptake inhibition
Mirtazapine (Remeron)
Nefazodone (Serzone)
Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL)
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Serotonin and Norepinephrine Quick Check Transcript

Read each statement and decide whether the statement is true or false. Correct answers are revealed at the bottom of the page. 1. Three neurotransmitters important to the understanding of the treatment of depression are serotonin, norepinephrine, and dopamine. 2. Serotonin is found in one part of the brain and in many other regions of the body. 3. Norepinephrine is found in many regions of the nervous system. 4. Manipulating the level of norepinephrine may lead to unintended effects. 5. Dopamine is found mainly in the prefrontal cortex. 6. Dopamine is important in the regulation of body motion, muscle coordination, concentration, and sleep, among other emotional and physiological processes. Answers 1. True. Three neurotransmitters important to the understanding of the treatment depression are serotonin, norepinephrine, and dopamine. 2. False. Serotonin is found in many regions of the brain and other parts of the body. 3. True. Norepinephrine is found in many regions of the nervous system. 4. True. Manipulating the level of norepinephrine may lead to unintended effects such as dry mouth, blood pressure changes, and sweating. 5. False. Dopamine is found mainly in the midbrain. 6. True. Dopamine is important in the regulation of body motion, muscle coordination, concentration, and sleep, among other emotional and physiological processes.
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Module4References
1. Charney DS, EJ Nestler. Neurobiology of Mental Illness. Oxford University Press, USA; 2008. 2. Women and Depression: Discovering Hope. National Institute of Mental Health Web site. Available at: http://www.nimh.nih.gov/health/publications/women-and-depression-discovering-hope/. Accessed September 15, 2009. 3. Charney DS, EJ Nestler. Neurobiology of Mental Illness. Oxford University Press, USA; 2008. 4. Charney DS, EJ Nestler. Neurobiology of Mental Illness. Oxford University Press, USA; 2008. 5. Charney DS, EJ Nestler. Neurobiology of Mental Illness. Oxford University Press, USA; 2008. 6. Fields H. Neuropsychiatry Neuropsychol Behav Neurol. 1991;4(1):83-92. 7. Verma S, Gallagher RM. Int Rev Psychiatry. 2000;12(2):103-114. 8. Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci. 2001;26(1):37-43. 9. Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, Penn: W.B. Saunders; 2000:701-704. 10. Marieb EN. Human Anatomy & Physiology. 4th ed. Menlo Park, Calif: Benjamin/Cummings Science Publishing; 1998:362-455.
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Module5:TreatingDepression
Sophia has recently been hired as a Cymbalta MDD sales rep at Lilly. She is learning about the treatment of depression so that when she makes calls to health care professionals she will be able to discuss different treatment paths for patients with depression. Click the following icon to listen to Sophia or read a transcript.
Sophia asks herself the following questions: What are the phases and goals for the treatment of depression? Why is it so important to achieve remission? What are some common approaches to the treatment of depression? How are pharmaceuticals thought to work in the treatment of MDD? Look for the answers to these questions as you complete this module.
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Scenario Transcript
Sophia: I've recently been hired as a Cymbalta MDD sales rep at Lilly. I want to help patients who could benefit from using Cymbalta to help treat their depression, but I know I can't do that unless I have credibility with health care professionals involved in treating patients with depression. And I won't have that credibility unless I understand the current approaches to the treatment of depression and I am able to talk about it knowledgeably when I make calls. For example, what if a doctor asks me a simple question related to the initial treatment phase of MDD, and I have no idea what the doctor is talking about? I dont think that doctor will give me a chance to explain how Cymbalta might help his patients! So, I need to know how health care professionals treat depression. Specifically, I need to know the various treatment phases and goals, and why it is so important to achieve remission. I also need to know about a variety of approaches to treating depression, and especially how pharmaceuticals are believed to treat MDD.
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Module Objectives
Upon completion of this module, you will be able to: Identify treatment goals for depression. Discuss the importance of achieving remission. Describe the treatment phases of depression and identify specific goals for each phase. Describe approaches to the treatment of depression. Identify unmet needs in the treatment of depression.
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Section2:TreatmentGoals
Two major treatment goals for depression include but are not limited to: remission functional recovery It is important to note that many patients with depression achieve only a response with treatment. Remission, rather than response, should be the goal of any therapy.[1, 2] Treating a broad range of symptoms of depression may help patients achieve remission.[3] Settling for a response can have negative consequences, such as: poor outcome increased likelihood of relapse[4] increased risk of treatment resistance[5] One study found that of patients who attained remission, 76 percent with residual depressive symptoms relapsed versus 25 percent of patients with no residual symptoms over a 15-month period.[6] Relapse Rates in Patients With and Without Residual Depressive Symptoms[7]
These findings help support the fact that the treatment goal should be remission and physicians should not settle for anything less. Guidelines for the treatment of MDD in clinical practice aim at achieving remission. The trend in psychiatry of shifting the treatment goal from the attainment of response to the achievement of remission raises treatment expectations and applies stricter criteria toward the evaluation of therapeutic options.[8]
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Critical Information! Treatment Goals

Two major treatment goals for depression include but are not limited to: remission functional recovery It is important to note that many patients with depression achieve only a response with treatment. Remission, rather than response, should be the goal of any therapy.[1, 2] Treating a broad range of symptoms of depression may help patients achieve remission.[3] Settling for a response can have negative consequences, such as: poor outcome increased likelihood of relapse[4] increased risk of treatment resistance[5] These findings (Relapse Rates in Patients With and Without Residual Depressive Symptoms) help support the fact that the treatment goal should be remission and physicians should not settle for anything less.
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Treatment Goals Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Two main goals of treatment for depression are: a. Remission and retreat of major symptoms b. Remission and functional recovery c. Response and remission d. Response and recovery 2. Two important consequences of failing to achieve remission are: a. Increased likelihood of relapse and increased risk of treatment resistance b. Increased likelihood of other psychiatric illness and increased risk of treatment resistance c. Increased medical costs over the long term and reduced time to recovery d. Increased likelihood of relapse and reduced risk of treatment relapse 3. Which of the following may help patients achieve remission? a. Focusing treatment on the primary emotional symptom(s) b. Starting treatment slowly to ensure patient stability c. Treating a broad range of symptoms concurrently d. Focusing initial treatment on painful physical symptoms 4. When treating patients for depression, the treatment goal should always be remission; physicians should not settle for anything less. a. True b. False Answers 1. b. The two main goals of treatment for depression are remission and functional recovery. 2. a. Two important consequences of failing to achieve remission are an increased likelihood of relapse and an increased risk of treatment resistance. 3. c. Treating a broad range of symptoms of depression may help patients achieve remission. 4. a. When treating patients for depression, the treatment goal should always be remission; physicians should not settle for anything less.
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Section3:TreatmentPhasesandGoals
Click the following icon to learn about the phases and goals of the treatment of major depression, or read a transcript.
Critical Information! Treatment Phases and Goals

Antidepressant treatment should continue for four to five months after the patients symptoms have responded to treatment to decrease the risk of relapse.[9] There is an increased likelihood that a person will have a subsequent major depressive episode following the initial episode. The likelihood of subsequent episodes increases with each episode that occurs. There are three distinct phases of treatment. These phases are: the acute phase the continuation phase and the maintenance phase The acute phase is the initial period of the treatment of depression symptoms. During the continuation phase, symptoms are in remission, but the patient may not have fully recovered. Recovery is typically defined as a period of sustained remission. The maintenance phase applies to patients at a high risk of subsequent depressive episodes. For these patients, the main goal of therapy is to prevent recurrence.
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Treatment Phases Transcript

Narrator: A study by Dr. David J. Kupfer demonstrated that antidepressant treatment should continue for four to five months after the patients symptoms have responded to treatment to decrease the risk of relapse.[9] Practice guidelines suggest that longer-term treatment with antidepressants may be warranted.[10] There is an increased likelihood that a person will have a subsequent major depressive episode following the initial episode. The likelihood of subsequent episodes increases with each episode that occurs. Kupfers research also outlined three distinct phases of treatment. These phases are: the acute phase the continuation phase and the maintenance phase.
The acute phase is the initial period of the treatment of depression symptoms. The goals of the acute phase are to achieve remission, which is the resolution of most symptoms, and restore functioning to levels prior to the onset of the current major depressive episode.[11] During the continuation phase, symptoms are in remission, but the patient may not have fully recovered. Recovery is typically defined as a period of sustained remission. The primary treatment goal for this phase is to maintain remission. Secondary goals are to prevent relapse and manage symptoms, if they should reoccur. The maintenance phase applies to patients at a high risk of subsequent depressive episodes. For these patients, the main goal of therapy is to prevent recurrence.
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Treatment Phases Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. In order to decrease the risk of relapse, approximately how long after a patients symptoms have responded should antidepressant treatment continue? a. 8 to 10 days b. 4 to 5 weeks c. 4 to 5 months d. 1 to 2 years 2. What effect does the occurrence of a major depressive episode have on the likelihood of subsequent episodes? a. Increases with each episode that occurs b. Decreases with each occurrence that is prevented c. May increase or decrease depending on severity d. There is no predictable effect 3. Which treatment phase is the initial period of treatment? a. Initial phase b. Acute phase c. Continuation phase d. Maintenance phase 4. During which treatment phase are symptoms in remission but the patient has not fully recovered? a. Initial phase b. Acute phase c. Continuation phase d. Maintenance phase 5. What is the main goal of the maintenance phase of treatment? a. Elicit a measured response to therapy and try to avoid early remission b. Reduce residual symptoms to pre-disease levels c. Maintain remission, prevent relapse, and manage relapse if it occurs d. Prevent recurrence Answers 1. c. In order to decrease the risk of relapse, antidepressant treatment should continue for 4 to 5 months after a patients symptoms have responded to treatment. 2. a. There is a strong likelihood that a person will have a subsequent major depressive episode following the initial episode. The likelihood of subsequent episodes increases with each episode that occurs. 3. b. The acute phase is the initial period of treatment. 4. c. During the continuation phase of treatment, symptoms are in remission but the patient has not fully recovered. 5. d. The main goal of the maintenance phase is to prevent recurrence.
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Section4:ApproachestoTreatment
Click the following icon to learn about the treatment approaches of major depression, or read a transcript.
Critical Information! Treatment Approaches

Pharmacotherapy is a widely used treatment for depression. Pharmacotherapy may be either monotherapy, using only one drug, or combination therapy, using two or more drugs. SSRIS, SNRIs and other antidepressants, for example bupropion or mirtazapine, are commonly used as first-line agents. TCAs and MAOIs are effective in alleviating symptoms of depression; however, their current use is generally less common. Nonpharmacologic treatment approaches for depression include: psychotherapy (counseling) electroconvulsive therapy, or ECT vagus nerve stimulation, or VNS or a variety of alternative therapies. The American Psychiatric Association recommends reserving ECT for patients with severe depression, depression with psychotic symptoms, or for situations in which there is a life-threatening aspect to the depression, such as a high risk of suicide, that necessitates a rapid response.[12]
Unmet Needs Despite the availability of numerous treatment options, there are several unmet needs in the treatment of depression. Some of the primary needs are treatments that provide: rapid relief 124
high remission rates good tolerability
Critical Information! Unmet Needs

Some of the primary needs are treatments that provide: rapid relief high remission rates good tolerability
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Treatment Approaches Transcript

Narrator: Pharmacotherapy is a widely used treatment for depression. Pharmacotherapy may be either monotherapy, using only one drug, or combination therapy, using two or more drugs. Monotherapy options include: Selective serotonin reuptake inhibitors, or SSRIs. For example, fluoxetine, paroxetine, sertraline, citalopram, and escitalopram. Serotonin norepinephrine reuptake inhibitors, or SNRIs. For example, duloxetine, venlafaxine, and desvenlafaxine. Antidepressants with other mechanisms of action. For example, bupropion, nefazodone, and mirtazapine. Tricyclic antidepressants, or TCAs. For example, amitriptyline and imipramine. Monoamine oxidase inhibitors, or MAOIs. For example, tranylcypromine.
Although no antidepressant is approved by the FDA specifically for combination therapy, combination therapies that physicians sometimes use include: combinations of two or more antidepressants with different proposed mechanisms of action listed previously, or, the combination of an antidepressant and a non-antidepressant medication such as lithium, thyroid hormone, or an atypical antipsychotic.
SSRIS, SNRIs and other antidepressants, for example bupropion or mirtazapine, are commonly used as first-line agents. Combination therapy with an antidepressant and an augmenting agent is often used for treatmentresistant depression (TRD). TCAs and MAOIs are effective in alleviating symptoms of depression; however, their current use is generally less common. Nonpharmacologic treatment approaches for depression include: psychotherapy (counseling) electroconvulsive therapy, or ECT vagus nerve stimulation, or VNS or a variety of alternative therapies.
Psychotherapy is aimed at improving the patients mental condition through nonpharmacological means. Several forms of psychotherapy may be used in the treatment of major depression, including interpersonal therapy or cognitive-behavioral therapy. Psychotherapy can also be used in conjunction with pharmacological treatment. Electroconvulsive therapy, or ECT, involves the directing of electric stimulus to the brain, in conjunction with the use of anesthetics and muscle relaxants, to induce convulsive seizures. ECT is efficacious.
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The American Psychiatric Association recommends reserving ECT for patients with severe depression, depression with psychotic symptoms, or for situations in which there is a life-threatening aspect to the depression, such as a high risk of suicide, that necessitates a rapid response.[12] Alternative therapies that are sometimes used to treat depression include herbal supplements and acupuncture, though these interventions have not been well-studied and are not specifically approved by the FDA for the treatment of depression.
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Treatment Approaches Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. A pharmacotherapy treatment regimen that uses more than one drug concurrently is called: a. Alternative therapy b. Monotherapy c. Combination therapy d. Experimental treatment 2. Which of the following are common first-line agents in the treatment of major depression? a. Acupuncture b. Unapproved combinations of pain relievers, diuretics, and stimulants c. Herbal remedies d. SSRIs, SNRIs and other antidepressants 3. Which of the following is a nonpharmacologic therapy for depression? a. Psychotherapy b. Psychosurgery to remove the descending neurotransmission pathway c. Alternating hot and cold baths over a multi-day period d. Vagus nervosa electrolysis coupled with daily aspirin 4. Though electroconvulsive therapy (ECT) is efficacious, the American Psychiatric Association recommends reserving ECT for patients who are suicidal and have tried all other reasonable treatment approaches. a. True b. False Answers 1. c. A pharmacotherapy treatment regimen that uses more than one drug concurrently is called combination therapy. 2. d. SSRIS, SNRIs and other antidepressants are commonly used as first-line agents. 3. a. Some non-pharmacologic therapies for depression include psychotherapy, vagus nerve stimulation (VNS), and alternative therapies. ECT is generally reserved for patients with an increasing degree of severity and functional impairment. 4. b. Though electroconvulsive therapy (ECT) is efficacious, the American Psychiatric Association recommends reserving ECT for patients with severe depression, depression with psychotic symptoms, or for situations in which there is a life-threatening aspect to the depression.
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Module5References
1. Thase ME. Defining remission in patients treated with antidepressants. J Clin Psychiatry. 1999;60(suppl 22):35-36. 2. Ballenger JC. Clinical guidelines for establishing remission in patients with depression and anxiety. J Clin Psychiatry. 1999;60(suppl 22):29-34. 3. Keller B. Past, Present, and Future Directions for Defining Optimal Treatment Outcome in Depression. Remission and Beyond. JAMA. 2003;289(23): 3152-3160. 4. Stahl SM. Why settle for silver, when you can go for the gold? Response vs. recovery as the goal of antidepressant therapy. J Clin Psychiatry. 1999;60(4):213-214. 5. Stahl SM. Why settle for silver, when you can go for the gold? Response vs. recovery as the goal of antidepressant therapy. J Clin Psychiatry. 1999;60(4):213-214. 6. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995; 25(6):1171-1180. 7. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995; 25(6):1171-1180. 8. Ferrier IN. Characterizing the ideal antidepressant therapy to achieve remission. J Clin Psychiatry. 2001;62(suppl 26):10-15. 9. Kupfer DJ. Long-term treatment of depression. J Clin Psych. 1991;52(suppl):28-34. 10. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). 2000;157(4 Suppl):1-45. Available at: http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=MDD2e_05-15-06. Accessed April 2, 2008. 11. Kupfer, DJ. The pharmacological management of depression. Dialogues Clin Neurosci. 2005;7(3):191 -205. Available at: http://www.dialogues-cns.org/brochures/26/htm/26_6.asp. Accessed April 2, 2008. 12. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). 2000;157(4 Suppl):1-45. Available at: http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=MDD2e_05-15-06. Accessed April 2, 2008.
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Module6:MarketandCompetition
Molly wants to know more about other pharmaceutical agents used to treat MDD so that she can understand efficacy, tolerability, and safety of these agents. Click the following icon to listen to Molly or read a transcript.
Molly asks herself the following question: What alternatives do physicians and other HCPs currently have available for managing MDD pharmacologically? Look for the answer to this question as you complete this module.
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Scenario Transcript
Molly: Im preparing to start making calls on physicians treating patients with MDD, and I know there are many treatment options they can choose from. I also need to know more about the treatment options physicians sometimes use. What pharmaceuticals are used? How do they compare to Cymbalta? Are they safe and tolerable? If I can prepare myself with answers to these questions, Ill be more successful in making a difference in my market.
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Module Objectives
Upon completion of this module, you will be able to: Describe dosing, safety, and tolerability information for Effexor XR (venlafaxine) and Pristiq (desvenlafaxine). Describe dosing, safety, and tolerability information for Prozac (fluoxetine), Zoloft (sertraline), Paxil CR (paroxetine), Lexapro (escitalopram), and Celexa (citalopram). Describe dosing, safety, and tolerability information for Wellbutrin XL (bupropion).
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Find Out More: Brand Name Table

The following agents are mentioned in this course:
Generic Name
Brand Name Elavil
Manufacturer
Amitriptyline
Etrafon Limbitrol generic Wellbutrin Wellbutrin SR Wellbutrin XL generic Celexa generic Pristiq Cymbalta Prozac generic Luvox generic generic
AstraZeneca Schering ICN Pharmaceuticals various GlaxoSmithKline
Bupropion
various Forest Laboratories, Inc. various Wyeth Eli Lilly and Company Eli Lilly and Company various Solvay Pharmaceuticals Inc. various various Organon various Bristol-Myers Squibb various GlaxoSmithKline 133
Citalopram
Desvenlafaxine Duloxetine
Fluoxetine
Fluvoxamine
Imipramine
Mirtazapine
Remeron generic Serzone generic Paxil
Nefazodone
Paroxetine
Paxil CR generic Reserpine Diutensin-R Zoloft generic Parnate Effexor Effexor XR generic
various Wallace Laboratories Pfizer various GlaxoSmithKline Wyeth-Ayerst various
Sertraline
Tranylcypromine
Venlafaxine
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Find Out More: Pharmacokinetics of Agents

Predicted in vivo inhibition of cytochrome P450 pathways The following table lists the predicted in vivo inhibition of cytochrome P450 pathways by Cymbalta and selected key competitors. Please note that much of the inhibition and induction data is based on in vitro studies. Also, note that the relative strength of antidepressant inhibition of each pathway is denoted as: 0 = negligible, + = low, ++ = moderate, and +++ = high. The table is not meant to serve as an absolute prediction of drug interactions; rather, it is meant to provide a framework in which the learner can begin to conceptualize and appreciate drug interaction potentials. You will not be tested on information on this table. Predicted In Vivo Inhibition of Cytochrome P450 Pathways[1, 2, 3, 4, 5, 6, 7, 8] 1A2 Citalopram Fluoxetine Paroxetine Sertraline Cymbalta Venlafaxine Escitalopram Bupropion + + + + 0 0 0 0 to + 2C9 0 ++ + + 0* 0 0 0 2C19 0 + to ++ + + to ++ 0* 0 0 0 2D6 0 +++ +++ + ++ 0 +/0 0 to + 3A4 0 + + + 0* 0 0 0
*Based on data from in vitro studies; not based on head-to-head studies Note: The relative strength of antidepressant inhibition of each pathway is denoted as: 0 = negligible, + = low, ++ = moderate, and +++ = high.
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Section2:SNRIs
In addition to Cymbalta (duloxetine), the following serotonin-norepinephrine reuptake inhibitors (SNRIs) are used to treat MDD (Note: For complete information, see the Full Prescribing Information for each drug): Effexor XR (venlafaxine)[9] Pristiq (desvenlafaxine)[10] Click each of the following to learn about SNRIs, or read a transcript.
Critical Information! SNRIs
Effexor XR
Indications: Treatment of MDD, GAD, Social Anxiety Disorder (Social Phobia),
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and panic disorder Dosage: Dosage Formulations and Strengths: Oral capsules: 37.5, 75, and 150 mg extended release capsules Dose in MDD: For the initial treatment of MDD, the recommended starting dose of Effexor XR is 75 mg/day administered in a single dose. For some patients, it may be desirable to start at a dose of 37.5 mg/day for 4-7 days. Patients not responding to 75 mg/day may benefit from a dose increase to a maximum of 225 mg/day, made in 75 mg per day increments at intervals of not less than every 4 days. It is not known whether or not the dose of Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Pristiq
Indications: Treatment of MDD Dosage: Dosage Formulations and Strengths: Oral tablets: 50 and 100 mg Dose in MDD: For the initial treatment of MDD, the recommended dose is 50 mg once daily, with or without food. In clinical studies, doses of 50-400 mg/day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg/day and adverse events and discontinuations were more frequent at higher doses.
Once you have completed this section, open the Quick Check and check your understanding of what you have learned, or read a transcript.
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Effexor XR and Pristiq Transcript

Effexor XR
Indications: Treatment of MDD, GAD, Social Anxiety Disorder (Social Phobia), and panic disorder Dosage: Dosage Formulations and Strengths: Oral capsules: 37.5, 75, and 150 mg extended release capsules Dose in MDD: For the initial treatment of MDD, the recommended starting dose of Effexor XR is 75 mg/day administered in a single dose. For some patients, it may be desirable to start at a dose of 37.5 mg/day for 4-7 days. Patients not responding to 75 mg/day may benefit from a dose increase to a maximum of 225 mg/day, made in 75 mg per day increments at intervals of not less than every 4 days. It is not known whether or not the dose of Effexor XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): MDD trials Nausea Dizziness Somnolence Insomnia Abnormal ejaculation Sweating Dry mouth Nervousness Anorexia Abnormal dreams Tremor
Primary Route of Metabolism: CYP450 2D6 Safety: CYP450 Interactions: Weak inhibitor of 2D6 Contraindications: Known Hypersensitivity, concomitant MAOI use Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk 138
Screening patients for bipolar disorder Potential for interaction with monoamine oxidase inhibitors Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Sustained hypertension Elevations in systolic and diastolic blood pressure Discontinuation of treatment (associated adverse events) Insomnia and nervousness Changes in weight Changes in height Changes in appetite Activation of mania/hypomania Hyponatremia Seizures Abnormal bleeding Serum cholesterol elevation Interstitial lung disease and eosinohilic pneumonia Use in patients with concomitant illness Adverse events associated with drug interactions Pristiq
Indications: Treatment of MDD Dosage: Dosage Formulations and Strengths: Oral tablets: 50 and 100 mg Dose in MDD: For the initial treatment of MDD, the recommended dose is 50 mg once daily, with or without food. In clinical studies, doses of 50-400 mg/day were shown to be effective, although no additional benefit was demonstrated at doses greater than 50 mg/day and adverse events and discontinuations were more frequent at higher doses. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): MDD trials: 50 or 100 mg dose groups Nausea Dry mouth Diarrhea Dizziness Headache Insomnia Hyperhidrosis Constipation Somnolence Decreased appetite Anxiety 139
Specific male sexual function disorder Adverse events associated with drug interactions
Primary Route of Metabolism: Primarily by conjugation (via UGT); to a minor extent, 3A4 also involved Safety: CYP450 Interactions: Can result in higher concentrations of drugs metabolized by 2D6 Contraindications: Known hypersensitivity, concomitant MAOI use Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Elevated blood pressure Abnormal bleeding Narrow-angle glaucoma Activation of mania/hypomania Cardiovascular/cerebrovascular disease Serum cholesterol and triglyceride elevation Discontinuation of treatment (associated adverse events) Renal impairment Seizure Hyponatremia Co-administration of drugs containing desvenlafaxine and venlafaxine Interstitial lung disease and eosinophilic pneumonia
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SNRIs Quick Check Transcript

Read each statement and decide if it is true or false. Correct answers are revealed at the bottom of the page. 1. The recommended dose of Pristiq for MDD is 20 mg once daily, with or without food. 2. Effexor XR is indicated for the treatment of MDD, GAD, Social Anxiety Disorder (Social Phobia), and panic disorder.
Answers 1. False. The recommended dose of Pristiq for MDD is 50 mg once daily, with or without food. 2. True. Effexor XR is indicated for the treatment of MDD, GAD, Social Anxiety Disorder (Social Phobia), and panic disorder.
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Find Out More: About Cymbalta

Cymbalta: is a dual reuptake inhibitor that strongly binds to 5-HT and NE reuptake transporters increases serotonergic and noradrenergic neurotransmission by blocking the reuptake of 5HT and NE from the synapse inhibits dopamine (DA) reuptake to a lesser extent
Affinity of Cymbalta for 5-HT and NE Reuptake Transporters The following table shows the affinity of Cymbalta for NE and 5-HT reuptake transporters. The potency is indicated by the Ki value or inhibition constant. Ki is a measure of the tightness of binding to the monoamine transporter, measured in nanoMoles (nM). The lower the number, the higher the affinity or "tighter" the binding. Cymbalta has a low Ki. It is at the low end of the range for both NE and 5-HT transporters, hence it has high affinity or potency for binding to 5-HT and NE reuptake transporters. The ratio of the NE to 5-HT Ki values can be described as within the same order of magnitude, 10 nM or less, which denotes a "relative balance." A ratio value of 1 to 10 is considered in the same order of magnitude. While it is not necessary to remember the specific numbers in the table, it is important to note that: Cymbalta has high affinity for both 5-HT and NE reuptake transporters (it is potent); and Cymbalta has a low NE-to-5-HT ratio (it is balanced; a NE-to-5-HT ratio of around 1 is close to being balanced).
Balance and Potency of Cymbalta for NE and 5-HT Reuptake Transporters[11] (Ki values are in nM)
COMPOUND
NE
5-HT
NE/5-HT Ratio of Ki Values
Cymbalta
7.5 0.3
0.8 0.04
9.4
Results of the in vitro preclinical studies The results of the in vitro preclinical studies have shown that Cymbalta is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.[12] Additionally, Cymbalta has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro.[13, 14] Also, Cymbalta does not inhibit monoamine oxidase (MAO).[15, 16] The clinical effect of the action of Cymbalta on dopamine (DA) is unknown at this time. To summarize, the results of the in vitro preclinical studies showed that Cymbalta: potentiates serotonergic and noradrenergic neurotransmission by blocking the reuptake of 5HT and NE from the synapse 142
inhibits DA reuptake to a lesser extent[17]
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Find Out More: Potential Adverse Events Associated with Blocking Selected Neurotransmitter Transporters and Receptors
The following table lists some adverse events associated with blocking selected neurotransmitter receptors. The cholinergic receptor adverse events are of particular importance to remember because they can resemble noradrenergic adverse events. Adverse Events Associated with Blocking Selected Neurotransmitter Receptors or Reuptake Transporters[18] Postsynaptic receptor Adverse events Dry mouth Blurred vision Constipation Urinary retention Memory disturbances
Cholinergic
Histaminergic
Sedation Weight gain
-Adrenergic
Low blood pressure Dizziness
Reuptake Transporter
Adverse Events Sleep dysfunction Sexual dysfunction Nausea Appetite changes
Serotonin
Norepinephrine
Dry mouth Blood pressure effects Sweating

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Section3:SSRIs
The following selective serotonin reuptake inhibitors (SSRIs) are used to treat MDD (Note: For complete information, see the Full Prescribing Information for each drug): Prozac (fluoxetine)[21] Zoloft (sertraline)[22] Paxil CR (paroxetine)[23] Lexapro (escitalopram)[24] Celexa (citalopram)[25] Click each of the following to learn about SSRIs, or read a transcript.
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Critical Information! SSRIs
Prozac
Indications: Treatment of MDD, obsessive-compulsive disorder (OCD), bulimia nervosa, and panic disorder Dosage: Dosage Formulations and Strengths: Pulvules: 10, 20, and 40 mg; Oral suspension 20 mg/5 mL; Weekly oral capsule: 90 mg Dose in MDD: The recommended initial dose of Prozac is 20 mg/day, administered in the morning. A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a QD (morning) or BID (morning and noon) schedule and should not exceed a maximum dose of 80 mg/day. Zoloft
Indications: Treatment of MDD, OCD, panic disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and SAD Dosage: Dosage Formulations and Strengths: Oral tablets: 25, 50, and 100 mg; Oral concentrate: 20 mg/mL Dose in MDD: For the initial treatment of MDD, the recommended dose is 50 mg QD. It is not known whether the dose of Zoloft needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.
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Paxil CR
Indications: Treatment of MDD, panic disorder, SAD, and PMDD Dosage: Dosage Formulations and Strengths: Oral tablets: 12.5, 25, 37.5 mg Dose in MDD: For the initial treatment of MDD, the recommended initial dose is 25 mg/day, in the morning, with or without food. Some patients may benefit from dose increases, made in 12.5 mg increments. Maximum dose: 62.5 mg/day. Dose changes should occur at intervals of at least 1 week. For the maintenance treatment of MDD, whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Lexapro
Indications: Treatment of MDD and GAD Dosage: Dosage Formulations and Strengths: Oral tablets: 5, 10 and 20 mg; Oral solution: 5 mg/5 mL Dose in MDD: For the initial treatment of MDD, the recommended dose is 10 mg QD, in the morning or evening, with or without food. No greater efficacy was shown at 20 mg QD. Dose increases to 20 mg QD should occur after a minimum of 1 week. Patients should be periodically reassessed to determine the need for maintenance treatment. Celexa
Indications: Treatment of MDD Dosage: Dosage Formulations and Strengths: Oral tablets: 10, 20, and 40 mg; Oral suspension: 10mg/5mL Dose in MDD: For the initial treatment of MDD, the recommended initial dose is 20 mg QD, in the morning or evening, with or without food. Generally, the dose is increase to 40 mg QD, and dose increases should occur in increments of 20 mg and at intervals of no less than 1 week. Some patients may require a dose 147
increase to 60 mg QD. However, the 60 mg QD dose did not demonstrate an advantage over the 40 mg QD dose. During the maintenance treatment of MDD, it is not know whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission.
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Prozac, Zoloft, Paxil CR, Lexapro, and Celexa Transcript

Prozac
Indications: Treatment of MDD, obsessive-compulsive disorder (OCD), bulimia nervosa, and panic disorder Dosage: Dosage Formulations and Strengths: Pulvules: 10, 20, and 40 mg; Oral suspension 20 mg/5 mL; Weekly oral capsule: 90 mg Dose in MDD: The recommended initial dose of Prozac is 20 mg/day, administered in the morning. A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a QD (morning) or BID (morning and noon) schedule and should not exceed a maximum dose of 80 mg/day. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): Nausea Diarrhea Anorexia Dry mouth Insomnia Anxiety Nervousness Somnolence Tremor
Primary Route of Metabolism: CYP450 2D6 Safety: CYP450 Interactions: Inhibitor of 2D6 Contraindications: Known hypersensitivity, concomitant MAOI use, concomitant use with pimozide, concomitant use with thioridazine Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical Worsening and Suicide Risk Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions Allergic Reactions and Rash Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania Seizures Altered Appetite and Weight 149
Abnormal bleeding Hyponatremia Anxiety and insomnia Use in patients with concomitant illness Potential for Cognitive and Motor Impairment Long Elimination Half-Life Discontinuation of treatment (associated adverse events) Altered appetite and weight Activation of mania/hypomania Adverse events associated with drug interactions Zoloft
Indications: Treatment of MDD, OCD, panic disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and SAD Dosage: Dosage Formulations and Strengths: Oral tablets: 25, 50, and 100 mg; Oral concentrate: 20 mg/mL Dose in MDD: For the initial treatment of MDD, the recommended dose is 50 mg QD. It is not known whether the dose of Zoloft needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): Dry mouth Somnolence Tremor Dizziness Fatigue Diarrhea/loose stools Nausea Insomnia
Primary Route of Metabolism (MDD trials): CYP450 2B6, 2C9, 2C19, 3A4 Safety: CYP450 Interactions: Inhibitor of 2D6 (at higher doses) Contraindications: Known hypersensitivity, concomitant MAOI use, concomitant use with pimozide, concomitant use with Antabuse (oral concentrate only) Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults 150
Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Activation of mania/hypomania Weight loss Seizure Discontinuation of treatment (associated adverse events) Abnormal bleeding Weak uricosuric effect Use in patients with concomitant illness Interference with cognitive and motor performance Hyponatremia Platelet function Adverse events associated with drug interactions Paxil CR
Indications: Treatment of MDD, panic disorder, SAD, and PMDD Dosage: Dosage Formulations and Strengths: Oral tablets: 12.5, 25, 37.5 mg Dose in MDD: For the initial treatment of MDD, the recommended initial dose is 25 mg/day, in the morning, with or without food. Some patients may benefit from dose increases, made in 12.5 mg increments. Maximum dose: 62.5 mg/day. Dose changes should occur at intervals of at least 1 week. For the maintenance treatment of MDD, whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): Asthenia Dry mouth Insomnia Abnormal ejaculation Nausea Somnolence Diarrhea Dizziness Constipation Female genital disorder Libido decreased Tremor Sweating Yawn Abnormal vision 151
Trauma
Primary Route of Metabolism (MDD trials): CYP450 2D6 Safety: CYP450 Interactions: Inhibitor of 2D6 Contraindications: Known hypersensitivity, concomitant MAOI use including linezolid, concomitant use with thioridazine, concomitant use with pimozide Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk Screening patients for bipolar disorder Potential for interaction with monoamine oxidase inhibitors Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Usage in pregnancy Activation of mania/hypomania Seizures Discontinuation of treatment (associated adverse events) Akathisia; hyponatremia; abnormal bleeding Use in patients with concomitant illness Adverse events associated with drug interactions Lexapro
Indications: Treatment of MDD and GAD Dosage: Dosage Formulations and Strengths: Oral tablets: 5, 10 and 20 mg; Oral solution: 5 mg/5 mL Dose in MDD: For the initial treatment of MDD, the recommended dose is 10 mg QD, in the morning or evening, with or without food. No greater efficacy was shown at 20 mg QD. Dose increases to 20 mg QD should occur after a minimum of 1 week. Patients should be periodically reassessed to determine the need for maintenance treatment. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): MDD trials Nausea Insomnia 152
Ejaculation disorder Somnolence Fatigue Sweating increased
Primary Route of Metabolism: CYP450 3A4 and 2C19 Safety: CYP450 Interactions: Modest inhibitor of 2D6 Contraindications: Known hypersensitivity to escitalopram or citalopram, concomitant MAOI use, concomitant use with pimozide Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Discontinuation of treatment (associated adverse events) Seizures Activation of mania/hypomania Hyponatremia Abnormal bleeding Interference with cognitive and motor performance Use in patients with concomitant illness Potential for interaction with monoamine oxidase inhibitors Adverse events associated with drug interactions Celexa
Indications: Treatment of MDD Dosage: Dosage Formulations and Strengths: Oral tablets: 10, 20, and 40 mg; Oral suspension: 10mg/5mL Dose in MDD: For the initial treatment of MDD, the recommended initial dose is 20 mg QD, in the morning or evening, with or without food. Generally, the dose is increase to 40 mg QD, and dose increases should occur in increments of 20 mg and at intervals of no less than 1 week. Some patients may require a dose increase to 60 mg QD. However, the 60 mg QD dose did not demonstrate an advantage over the 40 mg QD dose. During the maintenance treatment of MDD, it is not know whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): 153
Ejaculation disorder in male patients Dry mouth Increased sweating Nausea Somnolence Insomnia
Primary Route of Metabolism: CYP450 3A4 and 2C19 Safety: CYP450 Interactions: Weak inhibitor of 1A2, 2D6, & 2C19 Contraindications: Known hypersensitivity to citalopram, concomitant MAOI use, concomitant use with pimozide Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk Screening patients for bipolar disorder Potential for interaction with monoamine oxidase inhibitors Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Discontinuation of treatment (associated adverse events) Abnormal bleeding Hyponatremia Activation of mania/hypomania Seizures Interference with cognitive and motor performance Use in patients with concomitant illness Adverse events associated with drug interactions
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SSRIs Quick Check Transcript

Read each statement and decide if it is true or false. Correct answers are revealed at the bottom of the page. 1. The recommended dose of Zoloft for MDD is 50 mg QD throughout all treatment phases. 2. Paxil CR is indicated for the treatment of MDD, panic disorder, SAD, and PMDD. 3. The recommended dose of Lexapro for MDD is 10 mg QD, in the morning or evening, with or without food. Answers 1. False. The initial recommended dose of Zoloft for MDD is 50 mg QD. Patients should be periodically reassessed to determine the need for maintenance treatment. 2. True. Paxil CR is indicated for the treatment of MDD, panic disorder, SAD, and PMDD. 3. True. The recommended dose of Lexapro for MDD is 10 mg QD, in the morning or evening, with or without food.
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Section4:Bupropion
Wellbutrin XL (bupropion),[26] an atypical antidepressant, is a norepinephrine and dopamine reuptake inhibitor used to treat MDD. (Note: For complete information, see the Full Prescribing Information). Click each of the following to learn about Wellbutrin XL, or read a transcript.
Critical Information! Wellbutrin XL
Wellbutrin XL
Indications: Treatment of MDD and seasonal affective disorder Dosage:
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Dosage Formulations and Strengths: Extended-release tablets: 150 and 300 mg Dose in MDD: For the initial treatment of MDD, initial dosing should begin at 150 mg given once daily in the morning. The target dose is 300 mg given once daily in the morning. If the initial 150 mg/day dose is well tolerated, an increase to the 300 mg/day target dose, given once daily, may be made as early as day 4. There should be an interval of at least 24 hours between successive doses. An increase to the maximum dose of 450 mg/day, given once daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. For the maintenance treatment of MDD, it is not known whether the dose needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
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Wellbutrin XL Transcript
Wellbutrin XL
Indications: Treatment of MDD and seasonal affective disorder Dosage: Dosage Formulations and Strengths: Extended-release tablets: 150 and 300 mg Dose in MDD: For the initial treatment of MDD, initial dosing should begin at 150 mg given once daily in the morning. The target dose is 300 mg given once daily in the morning. If the initial 150 mg/day dose is well tolerated, an increase to the 300 mg/day target dose, given once daily, may be made as early as day 4. There should be an interval of at least 24 hours between successive doses. An increase to the maximum dose of 450 mg/day, given once daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. For the maintenance treatment of MDD, it is not known whether the dose needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Tolerability: Common Adverse Events (This is not an inclusive list. See label for complete information.): MDD trials: in Wellbutrin SR 300 and 400 mg/day Headache Constipation Dry mouth Nausea Insomnia Pharyngitis Dizziness Abdominal pain Agitation Tremor Palpitation Sweating Tinnitus Anxiety Myalgia Rash Anorexia Urinary frequency
Primary Route of Metabolism: CYP450 2B6 Safety: 158
CYP450 Interactions: Potent inhibitor of 2D6 Contraindications: Known hypersensitivity, known seizure disorder, current or prior history of bulimia or anorexia nervosa, concomitant MAOI use, concomitant use of any bupropion formulation, patients undergoing abrupt discontinuation from alcohol or sedatives Boxed Warning: Increased risk of suicidality in children, adolescents, and young adults Warnings and Precautions (see label for complete information): Clinical worsening and suicide risk Screening patients for bipolar disorder Potential for hepatotoxicity Agitation and insomnia Psychosis, confusion, and other neuropsychiatric phenomena Activation of psychosis and/or mania Altered appetite and weight Allergic reactions Cardiovascular effects Hepatic impairment Renal impairment Adverse events associated with drug interactions
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Bupropion Quick Check Transcript

Read each statement and decide if it is true or false. Correct answers are revealed at the bottom of the page. 1. Buproprion is indicated only for the treatment of MDD. 2. For the initial treatment of MDD, initial dosing for Buproprion should begin at 150 mg given once daily in the morning.
Answers 1. False. Buproprion is indicated for the treatment of MDD and seasonal affective disorder. 2. True. For the initial treatment of MDD, initial dosing for Buproprion should begin at 150 mg given once daily in the morning.
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Boxed Warnings
Effexor XR:
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor XR or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Effexor XR is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use)
Pristiq:
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PRISTIQ or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PRISTIQ is not approved for use in pediatric patients [see Warnings and Precautions (5.1), Use in Specific Populations (8.4), and Patient Counseling Information (17.1)].
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Prozac:
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PROZAC or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PROZAC is approved for use in pediatric patients with MDD and Obsessive Compulsive Disorder (OCD) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax.
Zoloft:
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Zoloft is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
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Paxil CR:
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of PAXIL CR or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PAXIL CR is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide)
Lexapro:
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Lexapro or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Lexapro is not approved for use in pediatric patients less than 12 years of age. [See Warnings and Precautions: Clinical Worsening and Suicide Risk (5.1), Patient Counseling Information: Information for Patients (17.1), and Used in Specific Populations: Pediatric Use (8.4)].
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Celexa:
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Celexa or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Celexa is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
Wellbutrin XL:
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of WELLBUTRIN XL or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. WELLBUTRIN XL is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and
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Module6References
1. Greenblatt DJ, et al. Drug interactions with newer antidepressants: role of human cytochrome P450. J Clin Psych. 1998;59(suppl 15):19-27. 2. Ereshefsky L. Antidepressant pharmacodynamics, pharmacokinetics, and drug interactions. Geriatrics. 1998;63(suppl):S22-S33. 3. Ereshefsky L. Drug-drug interaction involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol. 1996;3(suppl):37S-50S. 4. Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry. 1999;60(suppl):20-30. 5. Owen JR, Nemeroff CB. New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone and mirtazapine. Depress Anxiety. 1998;7(suppl):24-32. 6. von Moltke et al. Escitalopram (s-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos. 2001;29(8):1102-1109. 7. Cozza KL, Armstrong SC, Osterheld JR. Concise Guide to drug interaction principles for medical practice: cytochrome P450s, UGTs, P-Glycoproteins. 2nd Edition. Washington, DC. American Psychiatric Publishing, Inc. 2003. 8. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009. 9. Effexor [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; July 2009. 10. Pristiq [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; November 2009. 11. Bymaster FP, et al. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacol. 2001;25:871880. 12. Bymaster FP, et al. The dual transporter inhibitor duloxetine: A review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11:14751493. 13. Bymaster FP, et al. The dual transporter inhibitor duloxetine: A review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11:14751493. 14. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009. 15. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009. 16. Bymaster FP, et al. The dual transporter inhibitor duloxetine: A review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11:14751493. 17. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009. 165
18. Stahl SM. Classical antidepressants, serotonin selective reuptake inhibitors, and noradrenergic reuptake inhibitors. In: Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd ed. Cambridge, UK: Cambridge University Press; 2000:199-242. 19. Bezchlibnyk-Bulter KZ, Jeffries JJ (eds). Clinical Handbook of Psychotropic Drugs. 16th ed. Cambridge, MA: Hogrefe and Huber; 2006:57. 20. Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, Pa: W.B. Saunders; 2000:701-704. 21. Prozac [package insert]. Indianapolis, IN: Eli Lilly & Co; October 2009. 22. Zoloft [package insert]. NY, NY: Roerig, Division of Pfizer Inc.; January 2009. 23. Paxil CR [package insert]. Research Triangle Park, NC: GlaxoSmithKline. August 2009. 24. Lexapro [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc.; January 2009. 25. Celexa [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc.; January 2009. 26. Wellbutrin XL [package insert]. Research Triangle Park, NC: GlaxoSmithKline. December 2008.
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Module7:ClinicalStudies
Elizabeth is a new Lilly sales representative who is learning about the efficacy of Cymbalta for major depressive disorder. She is preparing to call on doctors and has to be prepared to explain the efficacy of Cymbalta for the treatment of MDD when she is asked questions. Listen as Elizabeth describes her concerns and questions, or read a transcript.
Elizabeth has a number of questions about Cymbalta in treating MDD, including: What have research studies shown about the efficacy of Cymbalta in treating MDD? What have research studies shown about the tolerability of Cymbalta? Look for the answers to these questions as you complete this module.
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Scenario Transcript
Elizabeth: I'm preparing to answer questions from health care providers about the efficacy of Cymbalta. I realize that I won't be fully ready to make calls until I can do this confidently. I need to know what studies have shown about the efficacy of Cymbalta for the treatment of MDD. I should also be able to explain the basic design of these studies. I believe that it is also important that I am able to explain the results of studies investigating the tolerability of Cymbalta. I'm looking forward to beginning this sales effort successfully, so that I can help doctors use Cymbalta to treat their patients with major depression.
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Module Objectives
Upon completion of this module, you will be able to: Describe the objectives and study designs of the HMBHa, HMBHb, HMCR, HMFSa, and HMFSb 60 mg once-daily studies. Summarize the outcomes/key results of the HMBHa, HMBHb, HMCR, HMFSa, and HMFSb 60 mg once-daily studies. Summarize efficacy data for the HMBV older patient study. Summarize the study design and key results for the continuation, maintenance, and extended treatment relapse study. Summarize additional adverse event information related to Cymbalta.
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Section2:EfficacyStudyDesigns
Clinical Trials in MDD Prior to Registration[1, 2, 3, 4, 5, 6, 7, 8, 9] There were extensive data at the time of the Cymbalta launch. A total of 2,418 patients were treated with duloxetine in depression trials prior to FDA approval. The safety and efficacy of duloxetine for the treatment of MDD were evaluated in nine phase II and phase III double-blind, placebo-controlled acute trials lasting eight to nine weeks and using doses of 40120 mg/day. The long-term safety of duloxetine for the treatment of MDD was studied in a 52-week, open-label trial.[10] These studies were all performed in adult patients who met DSM-IV criteria for MDD. In several studies, duloxetine was found to have a significantly greater effect on the primary outcome measure compared with placebo. To learn about the results of the clinical trials or the statistical methods used to analyze the data, click the links under Find Out More in the margin.
Critical Information! Clinical Trials in MDD Prior to Registration

There were extensive data at the time of the Cymbalta launch. A total of 2,418 patients were treated with duloxetine in depression trials prior to FDA approval. The safety and efficacy of duloxetine for the treatment of MDD were evaluated in nine phase II and phase III double-blind, placebo-controlled acute trials lasting eight to nine weeks and using doses of 40120 mg/day. The long-term safety of duloxetine for the treatment of MDD was studied in a 52-week, open-label trial.[10] These studies were all performed in adult patients who met DSM-IV criteria for MDD. In several studies, duloxetine was found to have a significantly greater effect on the primary outcome measure compared with placebo.
Additional Clinical Trials Additional clinical studies were conducted to evaluate duloxetine compared to placebo on outcomes important to patient, such as energy and vitality, as measured by both clinician and patient-rated scales in patients with Major Depressive Disorder. These studies evaluated efficacy and safety between duloxetine and placebo in approximately 750 patients (375 patients in each of the two trials) with major depression in two identical multicenter, 9-month, randomized, placebo-controlled, double-blind, trials with 3 study periods. Approximately 50 clinical sites (25 in each of the two trials) with physicians having expertise primarily in psychiatry or experience in Major Depressive Disorder participated in this protocol. These studies will be discussed in more detail in the following sections.
Critical Information! Additional Clinical Trials
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Additional clinical studies were conducted to evaluate duloxetine compared to placebo on outcomes important to patient, such as energy and vitality, as measured by both clinician and patient-rated scales in patients with Major Depressive Disorder. These studies evaluated efficacy and safety between duloxetine and placebo in approximately 750 patients (375 patients in each of the two trials) with major depression in two identical multicenter, 9-month, randomized, placebo-controlled, double-blind, trials with 3 study periods.
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Efficacy Study Designs Quick Check Transcript

Read each statement and decide whether it is true or false. Correct answers are revealed at the bottom of the page. 1. The safety and efficacy of duloxetine for the treatment of MDD were evaluated in 20 phase II and phase III double-blind, placebo-controlled acute trials lasting up to 52 weeks. 2. The safety and efficacy of duloxetine for the treatment of MDD were evaluated in trials using doses of 20 to 60 mg/day. 3. Approximately 2,500 patients were treated with duloxetine in depression trials prior to FDA approval. 4. The long-term safety of duloxetine for the treatment of MDD was studied in a nine-week, openlabel trial. 5. Cymbalta registration studies were all performed in adult patients who met DSM-IV criteria for MDD, bipolar disorder, or another anxiety disorder. 6. In several Cymbalta registration studies, duloxetine was found to have a significantly greater effect on the primary outcome measure compared with placebo. Answers 1. False. The safety and efficacy of duloxetine for the treatment of MDD were evaluated in nine phase II and phase III double-blind, placebo-controlled acute trials lasting eight to nine weeks. 2. False. The safety and efficacy of duloxetine for the treatment of MDD were evaluated in trials using doses of 40 to 120 mg/day. 3. True. A total of 2,418 patients were treated with duloxetine in depression trials prior to FDA approval. 4. False. The long-term safety of duloxetine for the treatment of MDD was studied in a 52-week, open-label trial. 5. False. These studies were all performed in adult patients who met DSM-IV criteria for MDD. 6. True. In several Cymbalta registration studies, duloxetine was found to have a significantly greater effect on the primary outcome measure compared with placebo.
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Find Out More: Results of the Clinical Trials in MDD Prior to Registration
Study Duloxetine Dose Treatment Duration 8 weeks 8 weeks Duloxetine Patients 70 82 Total patients 173 194
Proof of Concept[11] Proof of Concept[12]
2060 mg BID* 2060 mg BID* 20 mg BID 40 mg BID 20 mg BID 40 mg BID 40 mg BID 60 mg BID 40 mg BID 60 mg BID 60 mg QD 60 mg QD 60 mg QD 40 mg BID 60 mg BID
Dose Finding[13]
8 weeks
175
354
Dose Finding[14]
8 weeks
177
353
European registration[15]
8 weeks + 26 weeks 8 weeks + 26 weeks 9 weeks 9 weeks 1226 weeks
188
367
European registration[16]
196
392
60 mg once daily[17] 60 mg once daily[18] Relapse prevention[19] 1-year, open-label safety[20]
123 128 136
245 267 533
52 weeks
1,279
1,279
*Forced titration dosing. Investigators allowed to choose either 40 mg or 60 mg BID dose.
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Find Out More: Statistical Methods Used in Analyzing the Data

Two different statistical methods were used for analyzing the data from Cymbalta clinical studies: Last observation carried forward (LOCF) Mixed-effects model repeated measures (MMRM) Last Observation Carried Forward (LOCF) This is a more traditional statistical method that was used for comparison in Cymbalta clinical studies. In the LOCF method, if a patient drops out of a study before the endpoint, the values on the outcome measures for that patient at the time of discontinuation are carried forward into subsequent analyses. This approach assumes that the patients condition would not have changed had he or she stayed in the study.
Mixed-effects Model Repeated Measures (MMRM)
This method was used for the primary analysis in the Phase 3 Cymbalta studies. MMRM, like LOCF, is a way to account for missing data. MMRM has been shown to better account for patients who drop out of studies early for any reason. These reasons may include adverse events, lack of efficacy, or patient decision. It uses the patients data up to the point of discontinuation, in combination with data from other patients in the same treatment group who continued in the study, to estimate what the values would have been had the patient continued in the study. MMRM has been shown to provide a more accurate estimate of treatment effects than LOCF.
It is important to note that these two analytical approaches produce different results only when some of the data are missing. When no data are missing, MMRM and LOCF yield identical results.
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Section3:OverviewofStudies
Once-Daily Clinical Studies (HMBHa, HMBHb) The primary objective of the HMBHa and HMBHb 60 mg once-daily studies was to assess the efficacy of Cymbalta 60 mg QD compared with placebo in reducing mean total score of the 17-item Hamilton Depression Rating Scale (HAM-D17) in subjects who meet critera for major depressive disorder as defined in the DSM-IV-TR. Click the following icon to see an overview of these studies.
Critical Information! Once-Daily Clinical Studies (HMBHa, HMBHb)

The primary objective of the HMBHa and HMBHb 60 mg once-daily studies was to assess the efficacy of Cymbalta 60 mg QD compared with placebo in reducing mean total score of the 17-item Hamilton Depression Rating Scale (HAM-D17) in subjects who meet critera for major depressive disorder as defined in the DSM-IVTR.
Additional 60 mg Once-Daily Clinical Studies (HMCR, HMFSa, HMFSb) The primary objective of the HMCR 60 mg once-daily non-inferiority study was to compare the onset of antidepressant efficacy for Cymbalta 60 mg once-daily comparedwith escitalopram 10 mg once-daily. The primary objective of the HMFSa,b 60 mg once-daily study was to compare the efficacy of Cymbalta 60 mg once-daily with placebo on improvement in work and activities (HAM-D 24, Item 7) over a 12-week acute treatment phase. Click the following icon to see an overview of the two 60 mg once-daily studies.
Critical Information! Additional 60 mg Once-Daily Clinical Studies (HMCR, HMFSa, HMFSb)

The primary objective of the HMCR 60 mg once-daily non-inferiority study was to
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compare the onset of antidepressant efficacy for Cymbalta 60 mg once-daily with escitalopram 10 mg once-daily. The primary objective of the HMFSa,b 60 mg once-daily study was to compare the efficacy of Cymbalta 60 mg once-daily with placebo on improvement in work and activities (HAM-D 24, Item 7) over a 12-week acute treatment phase.
Inclusion and Exclusion Criteria Across the 60 mg Once-Daily Studies To qualify for the studies, patients had to meet the following key inclusion criteria: be 18 years of age or older DSM-IV criteria for MDD Patients were excluded from the studies if they met any of the following key exclusion criteria: had any current Axis I DSM-IV diagnosis other than MDD Click the link under Find Out More in the margin to learn more about the inclusion and exclusion criteria for participating in the studies.
Critical Information! Inclusion and Exclusion Criteria Across the 60 mg Once-Daily Studies
To qualify for the studies, patients had to meet the following key inclusion criteria: be 18 years of age or older DSM-IV criteria for MDD Patients were excluded from the studies if they met any of the following key exclusion criteria: had any current Axis I DSM-IV diagnosis other than MDD
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Overview of Studies (HMBHa, HMBHb)

HMBHa and HMBHb 60 mg Once-Daily Clinical Studies[21, 22, 23] The primary objective of the HMBHa and HMBHb 60 mg once-daily studies was to assess the efficacy of Cymbalta 60 mg QD compared with placebo in reducing mean total score of the 17-item Hamilton Depression Rating Scale (HAM-D17) in subjects who meet critera for major depressive disorder as defined in the DSM-IVTR. The studies were multicenter, randomized, double blind, placebo-controlled trials. There were variable duration placebo lead-in and lead-out periods to blind the patients and investigators to the start and end of active therapyyet all patients started on treatment during the first week post-randomization. The double-blind study drug periods lasted 9 weeks. Change in 17-item Hamilton Depression Scale (HAM-D17) Total Score Change in: Placebo HMBHa Total: 245 Total number of patients Cymbalta: 123 Placebo: 122 Total: 267 Cymbalta: 128 Placebo: 139 HMBHb Individual HAM-D17 items Visual Analog Scale (VAS) for painful physical symptoms associated with depression HAM-D17 response and remission rates Clinical Global Impressions-Severity scale (CGI-S) Patient Global Impressions-Improvement (PGI-I) Quality of Life in Depression scale (QLDS)
Objective
Study design
Primary outcome measure
Secondary outcome measures
Comparator Baseline Data
Mean baseline HAM-D17 score Mean baseline Clinical Global ImpressionSeverity (CGI-S)
Cymbalta arm: 21.4 Placebo arm: 21.1
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score
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Overview of Additional Studies (HMCR, HMFSa, HMFSb)

HMCR 60 mg Once-Daily Clinical Study[24] The primary objective of the HMCR 60 mg once-daily non-inferiority study was to compare the onset of antidepressant efficacy for Cymbalta 60 mg once-daily with escitalopram 10 mg once-daily. This study was a multicenter, randomized, double-blind, placebo- and active comparator-controlled study. During study period II, the first eight weeks were considered the acute phasea fixed-dose comparison of duloxetine 60 mg QD, escitalopram 10 mg QD, and placebo. After the first eight weeks, patients continued in a flexible-dose extension phase for up to six months, in which duloxetine doses could be increased to 120 mg QD (with 90 mg QD as an intermediate dose), and escitalopram doses could be increased to 20 mg QD. Onset of action, defined as decrease of at least 20 percent from baseline in the Maier subscale of the 17-item Hamilton Depression Rating Scale (HAM-D17) that was maintained or exceeded at all subsequent visits throughout acute treatment Mean changes from baseline in HAM-D17 total score, subscales and individual items (most notably item 1, depressed mood, and item 10, psychic anxiety) Remission rates, as defined by a HAM-D17 total score of = 7 Response rates, as defined by a = 50% change from baseline on the HAMD17 total score Mean changes from baseline on the Hamilton Anxiety Rating Scale total score (HAMA), subscales, and individual items Mean changes from baseline on the Clinical Global Impressions-Severity scale (CGI-S) Patient Global Impressions-Improvement scale (PGI-I)
Objective
Study design
Primary outcome measure
Escitalopram; Placebo HMCR Total: 684
Total number of patients
Cymbalta: 273 Escitalopram: 274 Placebo: 137
HAM-D17 total
Cymbalta arm: 17.6 (4.8) 180
score
Escitalopram arm: 17.8 (5.1) Placebo arm: 17.7 (5.2) Cymbalta arm: 4.2 (0.7) Escitalopram arm: 4.2 (0.7) Placebo arm: 4.2 (0.7) Cymbalta arm: 4.2 (0.7) Escitalopram arm: 4.2 (0.7) Placebo arm: 4.2 (0.7)
Clinical Global ImpressionSeverity (CGI-S) score
HAMA score
HMFSa and HMFSb 60 mg Once-Daily Clinical Study[[25] The primary objective of the HMFSa,b 60 mg once-daily study was to compare the efficacy of Cymbalta 60 mg once-daily with placebo on improvement in work and activities (HAM-D 24, Item 7) over a 3 month acute treatment phase. Study F1J-US-HMFS comprises two identical multicenter, 9-month, randomized, placebo-controlled, double-blind, trials with 3 study periods for the evaluation of efficacy and safety between duloxetine and placebo in approximately 750 patients (375 patients in each of the two trials) with major depression. Study design Approximately 50 clinical sites (25 in each of the two trials) with physicians having expertise primarily in psychiatry or experience in Major Depressive Disorder participated in this protocol. Primary outcome measure HAM-D 24 Item 7 (Work and Activities) Mean changes from baseline in the HAM-D 24 total score, HAM-D17 total score, HAM-D 24 subscales, all HAM-D 24 individual items, the 16-item Quick Inventory of Depressive Symptomatology Self Report (QIDS16 SR), the pain NRS, and the Clinical Global Impression-Severity Scale (CGI-S) Remission rated defined as: o o Placebo HMFSa 181 HMFSb HAM-D17 total score of = 7 QIDS16 SR total score = 5
Objective
Total: 384 Total number of patients Cymbalta: 257 Placebo: 127
Total: 392 Cymbalta: 261 Placebo: 131
Mean HAM-D 24 Item 7 score
Cymbalta arm: 2.9 Placebo arm: 2.8 Cymbalta arm: 22.8 Placebo arm: 22.9
Cymbalta arm: 2.8 Placebo arm: 2.8 Cymbalta arm: 22.9 Placebo arm: 22.8
Mean HAM-D17 score Mean Clinical Global ImpressionSeverity (CGI-S) score Mean Brief Profile of Mood States (BPOMs) V/A score Mean Sheehan Disability Scale (SDS) total score
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Overview of Studies Quick Check Transcript

Read each statement and decide whether it is true or false. Correct answers are revealed at the bottom of the page. 1. The primary objective of the HMBHa and HMBHb 60 mg once-daily studies was to compare the onset of antidepressant efficacy for Cymbalta 60 mg once-daily with escitalopram 10 mg oncedaily. 2. To qualify for the 60 mg once-daily studies, patients had to meet the DSM-IV criteria for MDD. 3. The primary objective of the HMFSa and HMFSb 60 mg once-daily study was to compare the efficacy of Cymbalta 60 mg once-daily with placebo on improvement in work and activities (HAMD 24, Item 7) over a 3 month acute treatment phase. Answers 1. False. TThe primary objective of the HMBHa and HMBHb 60 mg once-daily studies was to to assess the efficacy of Cymbalta 60 mg QD compared with placebo in reducing mean total score of the 17-item Hamilton Depression Rating Scale (HAM-D17). 2. True. To qualify for the 60 mg once-daily studies, patients had to be 18 years of age or older and meet the DSM-IV criteria for MDD. 3. True. The primary objective of the HMFSa and HMFSb 60 mg once-daily study was to compare the efficacy of Cymbalta 60 mg once-daily with placebo on improvement in work and activities (HAM-D 24, Item 7) over a 3 month acute treatment phase.
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Find Out More: Select Inclusion and Exclusion Criteria

HMBH Inclusion: Exclusion: Any current and primary Axis I disorder other than major depressive disorder, including but not limited to dysthymia Any previous diagnosis of bipolar disorders, schizophrenia, or other psychotic disorders HMBV Inclusion: Exclusion: Any current and primary Axis I disorder other than MDD, including but not limited to dysthymia or psychotic depression Any previous diagnosis of bipolar disorders, schizophrenia, or other psychotic disorders Have not had a previous episode of major depression HMCRa Inclusion: Exclusion: Any current primary Axis I disorder other than major depressive disorder (MDD) Any previous diagnosis of bipolar disorders, schizophrenia, or other psychotic disorders Patients judged to be at serious suicidal risk in the opinion of the investigator HMFS Inclusion: 184 Outpatients at least 18 years of age who meet criteria for major depressive disorder (MDD) as defined by the DSM-IV TR MADRS score (greater than or equal to) 22 at Visit 1 and Visit 2 Meet criteria for major depression, as defined by DSM-IV TR HAMD17 total score (greater than or equal to) 18 at Visits 1 and 2 Meet criteria for major depression, as defined by DSM-IV TR HAMD17 total score (greater than or equal to) 15 at Visits 1 and 2
Exclusion: Have any current (within the past 6 months) DSM-IV TR primary Axis I diagnosis other than MDD Outpatients at least 18 years of age who meet criteria for major depressive disorder (MDD) as defined b the DSM-IV TR MADRS score (greater than or equal to) 22 at Visit 1 and Visit 2
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Section4:MeasuresofEfficacy
Key Efficacy Results of 60 mg Once-Daily Studies The data presented in this section are the results from the HMBHa,b two 9-week, randomized, double blind, placebo-controlled studies. The primary outcome in HMBHa,b was mean change in the HAM-D17 scale score. Efficacy data were analyzed for all randomized patients assigned to treatment with Cymbalta or placebo who had post-baseline data: HMBHa: N = 123 Cymbalta- and 122 placebo-treated patients HMBHb: N = 128 Cymbalta- and 139 placebo-treated patients Note that the individual studies were not designed to determine statistical separation on secondary efficacy scalesonly the primary efficacy scale (HAM-D17 Total Score). Click the following icon to learn more about the key results of 60 mg once-daily studies, or read a transcript. Note: Data shown in the following charts comes from HMBHa. Supporting data comes from HMBHb.
No significant effects due to age, gender, or racial origin were seen on any of the outcome measures.
Summary Duloxetine has demonstrated efficacy in the acute treatment of MDD in randomized, controlled clinical trials.
Critical Information! Summary of Key Results

Summary of Key Results[34, 35] Patients treated with Cymbalta had significantly greater improvements on HAM-D17 186
Total Score (primary outcome measure) than placebo. Treatment with Cymbalta 60 mg once-daily showed significant improvement compared to placebo at endpoint on: HAM- D17 Total Score Maier Subscale Retardation Subscale Patients treated with Cymbalta had significantly greater improvements on HAM-D17 Maier subscale than placebo as early as week 2.
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Key Results of 60 mg Once-Daily Studies Transcript

HAM-D17 Total Score and HAM-D17 Subscales Result 1 Primary Outcome Measure HAM-D17 Total Score:[26, 27] Patients treated with Cymbalta had significantly greater improvements on HAM-D17 total score (primary outcome measure) than placebo. HAM-D17 Subscales:[28] Treatment with Cymbalta 60 mg once-daily showed significant improvement compared to placebo at endpoint on: Maier: includes HAM-D17 items of: depressed mood, feelings of guilt, work and activities, psychomotor retardation, agitation and psychic anxiety. Retardation: includes HAM-D17 items: of dysfunction in mood, work, sexual activity, and overall motor retardation. Significant improvement compared to placebo at endpoint
Maier Subscale
Result 2[29, 30] Maier Subscale The subscale removes HAM-D17 items that could be negatively impacted by adverse treatment effects, rather than worsening depression. The subscale also focuses on items that are useful for initial clinical monitoring. The maximum score on the Maier subscale is 24. The data reveals that Cymbalta produced a rapid and significant separation from placebo on the core emotional symptoms of depression. This separation started as early as week 1 and continued throughout the studies.
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Physical Symptoms: Visual Analog Scale (VAS) for Pain
Result 3 Physical Symptoms: Visual Analog Scale (VAS) for Pain[31] The VAS was used as a secondary outcome measure in Cymbalta clinical studies to measure the effect of Cymbalta on painful physical symptoms associated with depression. This scale assess six areas of pain: 1. 2. 3. 4. 5. 6. Overall pain Back pain Shoulder pain Headache Pain while awake Pain interference with daily activities
Patients in these trials were recruited for depression, not for pain. Accordingly, baseline mean Visual Analog Scale (VAS) scores were low. The mean baseline scores of both the Cymbalta and placebo groups were just over 27 (scores range from 0 to 100). Patients were excluded from these trials if they had either chronic use (defined as greater than 50 percent of the days since the last visit) of analgesics including prescription and over-the-counter medications or any narcotic use. In the pooled analysis of the two 60 mg once daily studies (HMBHa and HMBHb) patients receiving Cymbalta showed significant improvement in VAS scores for five of the six areas of painful physical symptoms measured compared to placebo in an analysis of percent mean change in VAS score from baseline looking at the main effect of treatment pooling all visits over nine weeks. Headache did not statistically separate from placebo in this analysis. Note that the trials were not individually powered to identify significant differences in VAS outcomes.
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Figure 5: F1J-MC-HMBH (a,b) VAS Results for Cymbalta and Placebo[32, 33] Summary of Key Results Summary of Key Results[34, 35] Patients treated with Cymbalta had significantly greater improvements on HAM-D17 Total Score (primary outcome measure) than placebo. Treatment with Cymbalta 60 mg once-daily showed significant improvement compared to placebo at endpoint on: HAM- D17 Total Score Maier Subscale Retardation Subscale
Patients treated with Cymbalta had significantly greater improvements on HAM-D17 Maier subscale than placebo as early as week 2.

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Measures of Efficacy Quick Check Transcript

Read each statement and decide whether it is true or false. Correct answers are revealed at the bottom of the page. 1. Patients treated with Cymbalta had significantly greater improvements on HAM-D17 Total Score (primary outcome measure) than placebo. 2. Patients receiving Cymbalta showed no improvement in VAS scores for five of the six areas of painful physical symptoms measured.
Answers 1. True. Patients treated with Cymbalta had significantly greater improvements on HAM-D17 Total Score (primary outcome measure) than placebo. 2. False. Patients receiving Cymbalta showed improvement in VAS scores for five of the six areas of painful physical symptoms measured.
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Section5:OlderPatientStudy
HMBV Study Design[36] An eight-week, multicenter, double-blind, placebo-controlled study was conducted in 311 elderly patients (greater than 65 years of age) who met DSM-IV criteria for MDD and had a HAM-D17 rating scale score of greater than 18 at visits one and two and a Mini-Mental State Exam (MMSE) score of greater than 20 with or without mild dementia. Patients were excluded if they had one of the following: a current primary Axis I diagnosis other than MDD or mild dementia (including dysthymic disorder or psychotic depression); organic mental disorder, moderate to severe dementia, or mental retardation; history of a psychotic disorder, or a serious or unstable medical condition, psychological condition or clinically significant laboratory abnormality that, in the opinion of the investigator, would compromise participation in the study or likely lead to hospitalization during the study; or an alanine transaminase, aspartate transaminase, or gamma glutamyl transferase level greater than 1.5 times the upper limit of normal, based on Eli Lilly reference ranges. The study consisted of a one-week screening period followed by a one-week placebo phase and an eightweek, double-blind treatment phase with Cymbalta 60 mg QD or placebo. A one-week double-blind discontinuation phase was conducted during which patients on Cymbalta tapered to 30 mg QD for four days and then switched to placebo to maintain blinding. Click the following icon to learn about more efficacy studies, or read a transcript.
Critical Information! Focus on Older Patients

For core emotional symptoms of depression in older adults, Cymbalta separated from placebo as early as week 1 on the HAM-D17 Maier Subscale Score.[38]] For mean change from baseline in the HAM-D17 Total Score in older adults, Cymbalta 60 mg/day significantly reduced depressive symptoms vs. placebo as early as week 4 (P<.001).[39]
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Focus on Older Patients Transcript

Core Emotional Symptoms Efficacy Data in Older Patients Reviewing the HMBV Study Design This was a multicenter, parallel, double-blind, placebo-controlled study of 311 MDD patients between the ages of 65 and 89 years, with a median age of 72.[37] After a one-week screening phase and a one-week, double-blind placebo phase, patients were randomized to Cymbalta 60 mg QD (N=207) or placebo (N=104) for 8 weeks, and then entered into a one-week, double-blind discontinuation phase, at which time the dosage of study drug was tapered. Secondary outcome measures included the Geriatric Depression Scale (GDS), HAM-D17, Visual Analog Scale (VAS) for pain, and the Clinical Global Impressions (CGI)-Severity Scale. For core emotional symptoms of depression in older adults, Cymbalta separated from placebo as early as week 1 on the HAM-D17 Maier Subscale Score.[38]] For mean change from baseline in the HAM-D17 Total Score in older adults, Cymbalta 60 mg/day significantly reduced depressive symptoms vs. placebo as early as week 4 (P<.001).[39]
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Older Patients Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Which of the following summarizes a major finding about core emotional symptoms in patients participating in the Cymbalta HMBV study addressing the treatment of MDD in older adults? a. Improvement in core emotional symptoms as early as week one for patients treated with Cymbalta vs. those treated with placebo b. Delayed response (improvement) in core emotional symptoms in Cymbalta vs. placebo c. Delayed response (improvement) in core emotional symptoms in Cymbalta vs. placebo d. Rapid response (improvement) in core emotional symptoms in Cymbalta vs. placebo Answers 1. a. Major findings of the Cymbalta HMBV study addressing the treatment of MDD in older adults include improvement in core emotional symptoms as early as week one in patients treated with Cymbalta vs. those treated with placebo.
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Section6:RelapseStudy
Click the following icon to learn more about continuation, maintenance, and extended treatment data from the efficacy studies, or read a transcript.
Continuation, Maintenance, and Extended Treatment
Study Design
Maintenance Treatment Data[40] To determine the efficacy of duloxetine in preventing relapse of MDD, and to assess its long-term safety and tolerability, a randomized relapse prevention study was conducted. The design was a randomized, active-treatment, lead-in, double-blind, placebo-controlled, multicenter, parallelgroup study of out-patients who met the DSMIV criteria for MDD. Acute phase: All of the participants who met the enrollment criteria received open-label duloxetine (60 mg daily) for 12 weeks. If it was necessary to address problems with regard to tolerability, investigators could reduce the patients daily duloxetine dose to 30 mg until week 4. Continuation phase: Participants were eligible to enter the continuation phase if they met the following key criteria: 17-item Hamilton Depression Rating Scale (HAM-D17 ) score of less than or equal to 9; CGIS score less than or equal to 2; and no longer meeting the DSMIV criteria for MDD in weeks 10 and 12 of the acute phase. Eligible patients were randomized at week 12 to either duloxetine (60 mg daily) or placebo for 26
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weeks. Relapse was defined in the protocol as an increased CGIS score of = 2 points compared with that obtained in week 12, as well as meeting the MINI depression module criteria for MDD at two consecutive visits at least two weeks apart. Time to Relapse Key Result: Time to Relapse[41] Patients who received duloxetine (60 mg daily) during the continuation phase had a significantly delayed time to relapse over 6 months than patients who were on placebo (P=0.004). Estimated Probability of Relapse Key Result: Estimated Probability of Relapse[42] At the end of the continuation phase of the study, the estimated probabilities of relapse were 38.3 percent and 19.7 percent for patients who received placebo and duloxetine (60 mg daily) respectively. Significantly fewer patients who received duloxetine (60 mg daily) relapsed over 6 months compared with patients who received placebo (P = 0.05).
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Continuation, Maintenance, and Extended Treatment Transcript

Study Design Maintenance Treatment Data[40] To determine the efficacy of duloxetine in preventing relapse of MDD, and to assess its long-term safety and tolerability, a randomized relapse prevention study was conducted. It was postulated that MDD patients who showed clinically significant symptom improvement in response to duloxetine (60 mg daily) during 12 weeks of open-label treatment would have a significantly delayed time to relapse when maintained on duloxetine (60 mg daily) compared with patients who were randomized to placebo for six months. The design was a randomized, active-treatment, lead-in, double-blind, placebo-controlled, multicenter, parallel-group study of out-patients who met the DSMIV criteria for MDD. During the initial screening phase and before the second visit (week 0), all participants underwent screening tests in addition to both psychiatric and physical examinations. Acute phase: All of the participants who met the enrollment criteria received open-label duloxetine (60 mg daily) for 12 weeks. If it was necessary to address problems with regard to tolerability, investigators could reduce the patients daily duloxetine dose to 30 mg until week 4. Continuation phase: Participants were eligible to enter the continuation phase if they met the following key criteria: 17-item Hamilton Depression Rating Scale (HAM-D17 ) score of less than or equal to 9; CGIS score less than or equal to 2; and no longer meeting the DSMIV criteria for MDD in weeks 10 and 12 of the acute phase. Eligible patients were randomized at week 12 to either duloxetine (60 mg daily) or placebo for 26 weeks. Patients who were randomized to the placebo arm were tapered with duloxetine (30 mg daily) for one week in a double-blind manner. All continuing participants were assessed during at least nine scheduled visits from week 13 to week 38. Re-emergence of depressive symptoms at any time was defined as an HAM-D17 score of greater than or equal to 12, prompting weekly visits until an HAM-D17 score of less than 12 was obtained or the patient met the criteria for relapse. Relapse was defined in the protocol as an increased CGIS score of = 2 points compared with that obtained in week 12, as well as meeting the MINI depression module criteria for MDD at two consecutive visits at least two weeks apart. Rescue phase: Participants who experienced relapse during the continuation phase were offered the option of entry into the double-blind rescue phase at the investigators discretion. Relapsed patients who had been randomized to placebo were re-initiated on duloxetine (60 mg daily). Relapsed patients who had been randomized to duloxetine (60 mg daily) had their dose of duloxetine increased (to 60 mg twice daily). Follow-up phase: All of the participants entered the follow-up phase after either completing or discontinuing either the continuation phase or the rescue phase. If patients were receiving duloxetine, their duloxetine dose was reduced by 50 percent for three days. Placebo-treated patients continued to receive placebo. In both cases, participants received no study drug after the third day of the follow-up phase. After approximately one week, efficacy and safety data were collected.
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Time to Relapse
Key Result: Time to Relapse[41] Note: Our focus is on results from the continuation phase of the study only. Patients who received duloxetine (60 mg daily) during the continuation phase had a significantly delayed time to relapse over 6 months than patients who were on placebo (P=0.004). The KaplanMeier plot of time to relapse showed that patients on duloxetine separated from those on placebo at endpoint.
Estimated Probability of Relapse
Key Result: Estimated Probability of Relapse[42] At the end of the continuation phase of the study, the estimated probabilities of relapse were 38.3 percent and 19.7 percent for patients who received placebo and duloxetine (60 mg daily) respectively. Significantly fewer patients who received duloxetine (60 mg daily) relapsed over 6 months compared with patients who received placebo (P = 0.05). Relapse Rates for Patients who Received Duloxetine (60 mg daily) vs. Placebo During the Continuation Phase Relapse rate (protocol-defined criteria) n (%) 39 (28.5)
Therapy
Placebo
137
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Duloxetine (60 mg daily)
132
23 (17.4)*
Criteria for relapse: Increased CGI-S score of greater than or equal to two points compared with baseline for two consecutive visits AND meeting MINI criteria for major depressive disorder.
* P less than or equal to 0.05
At the end of the study, the estimated probabilities of being relapse-free at six months in adults with MDD were 61.7 percent and 80.3 percent for patients treated with placebo and Cymbalta (60 mg/day), respectively. Relapse was defined as an increased Clinical Global Impression-Severity (CGI-S) score of 2 points compared with that obtained in week 12, as well as meeting DSM-IV criteria for MDD.
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Relapse Study Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. What was the major finding of the Cymbalta relapse prevention study addressing continuation, maintenance, and extended treatment with respect to time to relapse? a. Reduced time to relapse in Cymbalta over placebo b. Delayed time to relapse in Cymbalta patients over 6 months compared with those treated with placebo c. Reduced effectiveness over time of Cymbalta over placebo d. No significant change in time to relapse in Cymbalta over placebo 2. What were the estimated probabilities of relapse for patients who received placebo and duloxetine (60 mg daily) respectively? a. 13.7 percent and 12.1 percent b. 15 percent and 51.2 percent c. 42.5 percent and 29 percent d. 38.3 percent and 19.7 percent Answers 1. b. One of the major findings of the Cymbalta efficacy study addressing continuation, maintenance, and extended treatment was delayed time to relapse in patients treated with Cymbalta vs. placebo. 2. d. At the end of the continuation phase of the study, the estimated probabilities of relapse were 38.3 percent and 19.7 percent for patients who received placebo and duloxetine (60 mg daily) respectively.
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Section7:AdditionalAdverseEventInformation
Weight Change in Acute Placebo-Controlled Studies in MDD[43] Weight change data in acute placebo-controlled studies of Cymbalta in patients with MDD was analyzed from eight acute placebo-controlled trials lasting up to nine weeks.[44] Analyses were performed using the intent-to-treat principle. Change in weight from baseline to endpoint was compared among treatment groups using a fixed-effects analysis of variance (ANOVA) model. Review the following image to learn more about weight change in acute placebo-controlled studies in MDD.
Patients taking Cymbalta 40-120 mg/day experienced a mean weight loss of approximately 1 lb vs. a mean weight gain of approximately 0.5 lbs in placebo patients.[45] The incidence of potentially clinically significant (PCS) weight gain ( 7%) from baseline to endpoint was not significantly different for patients treated with Cymbalta (0.6%) compared with placebo-treated patients (1.2%).[46] The incidence of potentially clinically significant (PCS) weight loss (> 7%) from baseline to endpoint was significantly greater for patients treated with Cymbalta (1.3%) compared with placebo-treated patients (0.4%).[47] Critical Information!
Weight Change in Acute Placebo-Controlled Studies in MDD

Patients taking Cymbalta 40-120 mg/day experienced a mean weight loss of approximately 1 lb vs. a mean weight gain of approximately 0.5 lbs in placebo patients.[45]
Onset, Duration, and Intensity of Nausea 202
Nausea
Cymbalta 60 mg/day in MDD[48, 49] (N=251)
Cymbalta 40-120 mg/day in MDD[50, 51] and GAD (N=2995)
Incidence
37.8%[52]
24.8%[53]
Severity
Mild 60% Moderate 33.6% Severe 6.3%[54] 0.8%[56]
Mild 46.1% Moderate 44.6% Severe 9.3%[55] 1.9%[57]
Discontinuation Rate Due to Nausea
The incidence of nausea in the analysis of patients with MDD or GAD receiving Cymbalta 40-120 mg/day was 24.8%. The incidence of nausea in the analysis of patients with MDD receiving Cymbalta 60 mg/day was 37.8%.[58, 59] The data from the pooled 60 mg clinical trials for MDD indicated that: 60% of these patients reported nausea to be mild, 33.6% reported their nausea to be moderate and 6.3% of patients rated their nausea to be severe. In the pooled data from the 40-120mg MDD and GAD studies, 46.1% of patients rated their nausea as mild, 44.6% as moderate and 9.3% of patients rated their nausea to be severe.[60, 61] The discontinuation rate due to nausea in the 40-120 mg/day group was 1.9% and for the 60 mg/day group it was 0.8%.[62, 63] Cymbalta 40 to 120 mg/day: Effects on Sexual Functioning (8 Weeks)[64, 65]
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Because sexual adverse events are often underreported in clinical studies, 4 MDD trials for Cymbalta (40 to 120 mg/day) utilized the Arizona Sexual Experience Scale (ASEX) questionnaire to prospectively assess sexual functioning.[66] The results from females (left bar graph) and males (bar graph on right) show mean change in ASEX total scores in four pooled studies of Cymbalta.[67] Overall sexual dysfunction occurred more often in patients treated with Cymbalta than those on placebo.[68] Spontaneously reported adverse events for Cymbalta (40 to 120 mg/day) vs. placebo during acute controlled clinical trials for MDD and GAD included: libido decreased 4% vs. 1%, orgasm abnormal 3% vs. <1%, and for males only: erectile dysfunction 5% vs. 1%, ejaculation delayed 3% vs. <1%. Once you have completed this section, open the Quick Check and check your understanding of what you have learned or read a transcript.
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Additional Adverse Event Information Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. In the pooled analysis of data from 8 acute, placebo-controlled studies lasting up to 9 weeks (Cymbalta 40-120 mg/day), what was the association between weight gain and Cymbalta vs. placebo? a. On average, Cymbalta-treated patients gained approximately 5 lbs; placebo patients did not change weight. b. All Cymbalta patients lost a significant amount of weight (5-10 lbs), while placebo patients gained a small amount of weight (1-2 lbs average). c. On average, Cymbalta patients lost approximately 1 lb; placebo patients gained approximately 0.5 lb. d. There was no significant difference in weight gain or loss between Cymbalta patients and placebo patients. Answers 1. c. Patients taking Cymbalta 40-120 mg/day from 8 pooled acute placebo-controlled studies experienced a mean weight loss of approximately 1 lb vs. a mean weight gain of approximately 0.5 lbs in placebo patients.
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Module7References
1. Goldstein DJ, et al. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. J Clin Psychiatry. 2002;63:225-231. 2. Data on file. Lilly Research Laboratories. CYM20050315L. 3. Nemeroff CB, et al. Duloxetine for the treatment of major depressive disorder. Psychopharmacol Bull. 2002;36:106132. 4. Goldstein DJ, et al. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol. 2004;24:389-399. 5. Detke MJ, et al. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur J Neuropsychopharmacology. 2004;14:457-470. 6. Perahia DG, et al. Duloxetine in the treatment of major depressive disorder: A placebo- and paroxetine-controlled trial. Eur Psychiatry. 2006; 21:367-378. 7. Detke MJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308-315. 8. Detke MJ, et al. Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatr Res. 2002;36:383-390. 9. Perahia DG, et al. Duloxetine in the prevention of relapse of major depressive disorder: doubleblind placebo-controlled study. Br J Psychiatry. 2006;188:346-353. 10. Raskin J, et al. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry. 2003; 64:10. 11. Goldstein DJ, et al. Duloxetine in the treatment of major depressive disorder: a double-blind clinical trial. J Clin Psychiatry. 2002;63:225-231. 12. Data on file. Lilly Research Laboratories. CYM20050315L. 13. Nemeroff CB, et al. Duloxetine for the treatment of major depressive disorder. Psychopharmacol Bull. 2002;36:106-132. 14. Goldstein DJ, et al. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol. 2004;24:389-399. 15. Detke MJ, et al. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur J Neuropsychopharmacology. 2004;14:457-470. 16. Perahia DG, et al. Duloxetine in the treatment of major depressive disorder: A placebo- and paroxetine-controlled trial. Eur Psychiatry. 2006; 21:367-378. 17. Detke MJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308315. 18. Detke MJ, et al. Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatr Res. 2002;36:383390. 206
19. Perahia DG, et al. Duloxetine in the prevention of relapse of major depressive disorder: doubleblind placebo-controlled study. Br J Psychiatry. 2006;188:346-353. 20. Raskin J, et al. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry. 2003; 64:10. 21. Detke MJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308-315 (study A). 22. Detke MJ, et al. . Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression. J Psychiatr Res. 2002;36:383-390 (study B). 23. Data on file, Lilly Research Laboratories. 24. Nierenberg AA, Griest JH, Mallinckrodt CH, et al. Onset of antidepressant action and acute efficacy and safety of duloxetine versus escitalopram and placebo in the treatment of major depressive disorder. Presented at: 44th American College of Neuropsychopharmacology Annual Meeting; December 11-15, 2005; Waikoloa, Hawaii. 25. HMFS protocol. UST Object ID 0900006e820be95b. 26. Data on file, Lilly Research Laboratories. CYM20090505A. 27. Hamilton M. A rating scale for depression. J Neurol Neurosurg Pschyiatry 1960;23:56-62. 28. Data on file, Lilly Research Laboratories: a: CYM20090505A; b: CYM20090505C; c: CYM20090505D; d: CYM20090512A. 29. Data on file, Lilly Research Laboratories: CYM20090505C. 30. Hamilton M. A rating scale for depression. J Neurol Neurosurg Pschyiatry 1960;23:56-62. 31. Data on file, Lilly Research Laboratories: CYM20050315S. 32. Data on file, Lilly Research Laboratories: CYM20050315S. 34. Data on file, Lilly Research Laboratories. CYM20090505A. 35. Data on file, Lilly Research Laboratories: a: CYM20090505A; b: CYM20090505C; c: CYM20090505D; d: CYM20090512A. 36. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo controlled trial. Am J Psychiatry 2007; 164:900-909. 37. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo controlled trial. Am J Psychiatry 2007; 164:900-909. 38. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo controlled trial. Am J Psychiatry 2007; 164:900-909.
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39. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo controlled trial. Am J Psychiatry 2007; 164:900-909. 40. Perahia DG, et al. Duloxetine in the prevention of relapse of major depressive disorder: doubleblind placebo-controlled study. Br J Psychiatry. 2006;188:346353. 41. Perahia DG, et al. Duloxetine in the prevention of relapse of major depressive disorder: doubleblind placebo-controlled study. Br J Psychiatry. 2006;188:346353. 42. Perahia DG, et al. Duloxetine in the prevention of relapse of major depressive disorder: doubleblind placebo-controlled study. Br J Psychiatry. 2006;188:346353. 43. Wise TN, Perahia D, Pangallo BA, et al. Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies. Prim Care Companion J Clin Psychiatry. 2006;8:269-278. 44. Wise TN, Perahia D, Pangallo BA, et al. Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies. Prim Care Companion J Clin Psychiatry. 2006;8:269-278. 45. Data on file, Lilly Research Laboratories: CYM20050315Q. 46. Wise TN, Perahia D, Pangallo BA, et al. Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies. Prim Care Companion J Clin Psychiatry. 2006;8:269-278. 47. Wise TN, Perahia D, Pangallo BA, et al. Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies. Prim Care Companion J Clin Psychiatry. 2006;8:269-278. 48. Greist J, McNamara RK, Mallinckrodt CH, et al. Incidence and duration of antidepressant-induced nausea: duloxetine compared with paroxetine and fluoxetine. J Clin Ther. 2004;26:1446-1455. 49. Data on file, Lilly Research Laboratories: CYM20050315P. 50. Data on file, Lilly Research Laboratories: CYM20100203A. 51. Data on file, Lilly Research Laboratories: CYM20071212A. 52. Greist J, McNamara RK, Mallinckrodt CH, et al. Incidence and duration of antidepressant-induced nausea: duloxetine compared with paroxetine and fluoxetine. J Clin Ther. 2004;26:1446-1455. 53. Data on file, Lilly Research Laboratories: CYM20100203A. 54. Data on file, Lilly Research Laboratories: CYM20050315P. 55. Data on file, Lilly Research Laboratories: CYM20100203A. 56. Data on file, Lilly Research Laboratories: CYM20050315P. 57. Data on file, Lilly Research Laboratories: CYM20071212A. 58. Data on file, Lilly Research Laboratories: CYM20100203A. 59. Data on file, Lilly Research Laboratories: CYM20050315P. 60. Data on file, Lilly Research Laboratories: CYM20100203A. 208
61. Data on file, Lilly Research Laboratories: CYM20050315P 62. Data on file, Lilly Research Laboratories: CYM20071212A. 63. Data on file, Lilly Research Laboratories: CYM20050315P. 64. Hudson JI, Wohlreich MM, Kajdasz DK, et al. Safety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trials. Hum Psychopharm. 2005;20:327-341. 65. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009. 66. Hudson JI, Wohlreich MM, Kajdasz DK, et al. Safety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trials. Hum Psychopharm. 2005;20:327-341. 67. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009. 68. Cymbalta [package insert]. Indianapolis, IN: Eli Lilly & Co; December 2009.
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Module8:CymbaltaPrescribingInformation
This module includes facts contained in the Cymbalta (duloxetine HCI) full Prescribing Information. It is organized to mirror the structure of the prescribing information. Your understanding of this information will help you to effectively answer questions from doctors about Cymbalta. As you read this module, look for the answers to the following questions: What are the key aspects of the Boxed Warning for Cymbalta? What is Cymbalta indicated for? What are key aspects of dosage for Cymbalta? What are the contraindications for Cymbalta? What are the warnings and precautions for Cymbalta? What are the most common adverse reactions to Cymbalta? What are key drug interactions for Cymbalta? Who should not take Cymbalta? What are the signs and symptoms of overdosage? What is the drug class for Cymbalta? What are key aspects of Cymbalta's clinical pharmacology? What are key aspects of the clinical trials that established the efficacy of Cymbalta for each indication?
Note: Unless otherwise referenced, all information in this module comes from the Cymbalta full Prescribing Information (PV6863 AMP)last revised: November 19, 2009. RECENT MAJOR CHANGES
Indications and Usage, General Anxiety Disorder Dosage and Administration, Maintenance/Continuation/Extended Treatment Warnings and Precautions, Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
11/2009 11/2009 01/2009
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Module 8 Objectives
Upon completion of this module, you will be able to: Describe the key aspects of the Boxed Warning for Cymbalta. Describe indications and usage for Cymbalta. Describe dosage and administration for Cymbalta. Describe dosage forms and strengths for Cymbalta. Describe contraindications for Cymbalta. Describe the warnings and precautions for Cymbalta. Describe the adverse reactions for Cymbalta. Describe drug interactions for Cymbalta. Describe considerations for use in specific populations. Describe findings and other considerations regarding drug abuse and dependence. Describe considerations regarding overdosage. Describe the drug class and chemical and physical structure for Cymbalta. Describe the clinical pharmacology for Cymbalta. Describe nonclinical toxicology as it relates to Cymbalta. Describe the clinical studies for Cymbalta. Describe how Cymbalta is supplied and stored. Describe patient counseling information for Cymbalta.
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Section2:IndicationsandUsage
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. [See Warnings and Precautions, Use in Specific Populations, and Information for Patients].
Boxed Warning
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. [See Warnings and Precautions, Use in Specific Populations, and Information for Patients].
1 INDICATIONS AND USAGE 212
Cymbalta is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: Major Depressive Disorder (MDD) Generalized Anxiety Disorder (GAD) Diabetic Peripheral Neuropathic Pain (DPNP) Fibromyalgia (FM) Click each of the following indications to learn more, or read a transcript.
Indications
Cymbalta is indicated for the: treatment of major depressive disorder (MDD) treatment of generalized anxiety disorder (GAD) management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy management of fibromyalgia (FM).
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Indications and Usage Transcript

Major Depressive Disorder Cymbalta is indicated for the treatment of major depressive disorder (MDD). The efficacy of Cymbalta was established in four short-term and one maintenance trial in adults [see Clinical Studies]. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation. Generalized Anxiety Disorder Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of Cymbalta was established in three short-term trials and one maintenance trial in adults [see Clinical Studies]. Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance. Diabetic Peripheral Neuropathic Pain Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy [see Clinical Studies]. Fibromyalgia Cymbalta is indicated for the management of fibromyalgia (FM) [see Clinical Studies].
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Indications and Usage Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy. a. True b. False 2. Which of the following is true regarding the short term studies of antidepressant use addressed in the Boxed Warning about suicidality and antidepressant drugs? a. There was no increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24. b. There was an increase in risk of suicidality with antidepressants compared to placebo in adults aged 65 and older. c. There was no increase in risk of suicidality in children compared to placebo. d. There was no increase in the risk of suicidality compared to placebo in adolescents. 3. Families and caregivers of patients on antidepressant therapy should be advised of what need? a. Development efforts for improved antidepressant and antipsychotic agents. b. Programs that may provide discounted pharmaceuticals. c. Close observation and communication with the prescriber. d. The patient's legal right to refuse the advice of medical professionals. 4. Cymbalta is approved for use in pediatric populations. a. True b. False 5. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. a. True b. False 6. Cymbalta is indicated for the acute treatment of generalized anxiety disorder (GAD). a. True b. False Answers 1. a. Cymbalta is indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy. It is also indicated for the treatment of major depressive disorder (MDD), the treatment of generalized anxiety disorder (GAD), and the management of fibromyalgia (FM). 2. a. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24. 3. c. Families and caregivers should be advised of the need for close observation and communication with the prescriber. 4. b. Cymbalta is NOT approved for use in pediatric populations. 5. a. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 216
6. b. Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD). It is not indicated for the ACUTE treatment of generalized anxiety disorder (GAD).
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Section3:DosageandAdministration
2 DOSAGE AND ADMINISTRATION Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Cymbalta should be given without regard to meals. The following information is from HIGHLIGHTS OF PRESCRIBING INFORMATION. Cymbalta should generally be administered once daily without regard to meals. Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its content be sprinkled on food or mixed with liquids. Starting Dose Maximum Dose
Indication
Target Dose Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day
Major Depressive Disorder
40mg/day to 60mg/day
120 mg/day
Generalized Anxiety Disorder Diabetic Peripheral Neuropathic Pain Fibromyalgia
60 mg/day
60 mg/day (once daily)
120 mg/day
60 mg/day
60 mg/day
30 mg/day
60 mg/day
Some patients may benefit from starting at 30 mg once daily. There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were observed to be dose-dependent. Discontinuing Cymbalta: A gradual dose reduction is recommended. Critical Information!
Highlights of Prescribing Information

The following information is from HIGHLIGHTS OF PRESCRIBING INFORMATION.
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Cymbalta should generally be administered once daily without regard to meals. Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its content be sprinkled on food or mixed with liquids. Starting Dose Maximum Dose
Indication
Target Dose Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day
Major Depressive Disorder
40mg/day to 60mg/day
120 mg/day
Generalized Anxiety Disorder Diabetic Peripheral Neuropathic Pain Fibromyalgia
60 mg/day
120 mg/day
60 mg/day
60 mg/day
30 mg/day
60 mg/day
Some patients may benefit from starting at 30 mg once daily. There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were observed to be dose-dependent. Discontinuing Cymbalta: A gradual dose reduction is recommended.
Click the following icon to learn more about dosage for initial treatment and maintenance/continuous/extended treatment by indication, or read a transcript.
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Dosage for Initial Treatment and Maintenance/Continuous/Extended Treatment
Major Depressive Disorder Initial Treatment Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Generalized Anxiety Disorder Initial Treatment For most patients, the recommended starting dose for Cymbalta is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Maintenance/Continuation/Extended Treatment It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment. Diabetic Peripheral Neuropathic Pain Initial Treatment The recommended dose for Cymbalta is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies]. For patients for whom tolerability is a concern, a 220
lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment. Maintenance/Continuation/Extended Treatment As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials. Fibromyalgia Initial Treatment The recommended dose for Cymbalta is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions. Maintenance/Continuation/Extended Treatment Fibromyalgia is recognized as a chronic condition. The efficacy of Cymbalta in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of Cymbalta was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.
Dosing in Special Populations Hepatic Insufficiency: It is recommended that Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency [see Warnings and Precautions and Use in Specific Populations]. Severe Renal Impairment: Cymbalta is not recommended for patients with end stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see Warnings and Precautions and Use in Specific Populations]. Elderly Patients: No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see Use in Specific Population]. Pregnant Women: There are no adequate and well-controlled studies in pregnant women; therefore, Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations]. Nursing Mothers: Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended [see Use in Specific Populations].
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Dosing in Special Populations

Hepatic Insufficiency: It is recommended that Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency. Severe Renal Impairment: Cymbalta is not recommended for patients with end stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min). Elderly Patients: No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose.
Discontinuing Cymbalta Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions]. Critical Information!
Discontinuing Cymbalta
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
Switching Patients to or from a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI [see Contraindications and Warnings and Precautions]. Critical Information!
Switching Patients to or from a Monoamine Oxidase Inhibitor

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI.
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Dosage Transcript
Major Depressive Disorder Initial Treatment Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated [see Clinical Studies]. Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies]. Generalized Anxiety Disorder Initial Treatment For most patients, the recommended starting dose for Cymbalta is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies]. Maintenance/Continuation/Extended Treatment It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with Cymbalta as monotherapy. Cymbalta should be administered in a dose range of 60-120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies]. Diabetic Peripheral Neuropathic Pain Initial Treatment The recommended dose for Cymbalta is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies]. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see Clinical Pharmacology and Dosage and Administration]. Maintenance/Continuation/Extended Treatment As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials. Fibromyalgia Initial Treatment The recommended dose for Cymbalta is 60 mg administered once daily. Treatment should begin at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence 224
that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies]. Maintenance/Continuation/Extended Treatment Fibromyalgia is recognized as a chronic condition. The efficacy of Cymbalta in the management of fibromyalgia has been demonstrated in placebo-controlled studies up to 3 months. The efficacy of Cymbalta was not demonstrated in longer studies; however, continued treatment should be based on individual patient response.
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Dosage and Administration Quick Check Transcript

Read each statement and decide if it is true or false. Correct answers are revealed at the bottom of the page. 1. The target dose for Cymbalta for the management of DPNP is 60 mg once daily. 2. No dose adjustment for Cymbalta is recommended for elderly patients on the basis of age. 3. Abrupt cessation of Cymbalta is recommended whenever possible. 4. At least 14 days should elapse between discontinuation of Cymbalta and initiation of therapy with an MAOI. 5. Cymbalta should be administered at a total dose of 30 mg once daily for maintenance treatment of MDD. 6. The efficacy of Cymbalta in the management of fibromyalgia has been demonstrated up to 3 months. 7. Maintenance of efficacy in GAD was demonstrated with Cymbalta as combination therapy. Answers 1. True. The target dose for Cymbalta for the management of DPNP is 60 mg once daily. 2. True. No dose adjustment for Cymbalta is recommended for elderly patients on the basis of age. 3. False. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. 4. False. At least five days should be allowed after stopping Cymbalta before starting an MAOI. In addition, at least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. 5. False. Cymbalta should be administered at a total dose of 60 mg once daily for maintenance treatment of MDD. 6. True. The efficacy of Cymbalta in the management of fibromyalgia has been demonstrated up to 3 months.
226
7. False. Maintenance of efficacy in GAD was demonstrated with Cymbalta as monotherapy.
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Section4:DosageFormsandStrengths
DOSAGE FORMS AND STRENGTHS Cymbalta is available as delayed release capsules: 20mg opaque green capsules imprinted with "Lilly 3235 20mg" 30mg opaque white and blue capsules imprinted with "Lilly 3240 30mg" 60mg opaque green and blue capsules imprinted with "Lilly 3237 60mg"
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Section5:Contraindications
4 CONTRAINDICATIONS Monoamine Oxidase Inhibitors: Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions may include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome [see Dosage and Administration and Warnings and Precautions]. Uncontrolled Narrow-Angle Glaucoma: In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrowangle glaucoma [see Warnings and Precautions]. Critical Information!
Contraindications
Monoamine Oxidase Inhibitors: Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. Uncontrolled Narrow-Angle Glaucoma: In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.
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Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Cymbalta is contraindicated in patients taking what medications? a. Antihistamines b. Monoamine oxidase inhibitors (MAOIs) c. Beta blockers d. Non-steroidal anti-inflammatory drugs (NSAIDs) 2. Cymbalta is contraindicated in patients who have been diagnosed with which disease or condition? a. Non-small cell lung cancer (NSCLC) b. Blurred vision and headaches c. Uncontrolled narrow-angle glaucoma d. Controlled narrow-angle glaucoma Answers 1. b. Cymbalta is contraindicated in patients who take a monoamine oxidase inhibitor (MAOI). 2. c. Cymbalta is contraindicated in patients who have uncontrolled narrow-angle glaucoma.
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Section6:WarningsandPrecautions
5 WARNINGS AND PRECAUTIONS Click each of the following to learn more about warnings and precautions for Cymbalta: Clinical worsening and suicide risk Hepatotoxicity Orthostatic hypotension and syncope Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions Abnormal bleeding Discontinuation of treatment with Cymbalta Activation of mania/hypomania Seizures Effect on blood pressure Clinically important drug interactions Hyponatremia Use in patients with concomitant illness Urinary hesitation and retention Laboratory tests Critical Information!
Warnings and Precautions
Clinical worsening and suicide risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric
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disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1
Age Range
Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo
< 18 18 - 24
14 additional cases 5 additional cases Decreases Compared to Placebo
25 - 64 65
1 fewer case 6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebocontrolled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, 232
either increases or decreases. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approved for use in treating bipolar depression. Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (82/27,229) of Cymbalta-treated patients. In these patients, the median time to detection of the transaminase elevation was about two months. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or 233
evidence of chronic liver disease. There is a medical letter available for physicians who request additional information. Orthostatic hypotension and syncope Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy. Serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions The development of a potentially life-threatening serotonin syndrome or NMSlike reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. The concomitant use of Cymbalta with MAOIs intended to treat depression is contraindicated. If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not recommended. Abnormal bleeding SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation. Discontinuation of treatment with Cymbalta Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebocontrolled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, fatigue, paresthesia, vomiting, irritability, nightmares, insomnia, diarrhea,
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anxiety, hyperhidrosis and vertigo. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. Activation of mania/hypomania As with these other agents, Cymbalta should be used cautiously in patients with a history of mania. Seizures Cymbalta should be prescribed with care in patients with a history of a seizure disorder. Effect on blood pressure In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment. Clinically important drug interactions Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potential for Other Drugs to Affect Cymbalta CYP1A2 Inhibitors Co-administration of Cymbalta with potent CYP1A2 inhibitors should be avoided. CYP2D6 Inhibitors Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine. Potential for Cymbalta to Affect Other Drugs Drugs Metabolized by CYP2D6 Co-administration of Cymbalta with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is coadministered with Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma 235
levels of thioridazine, Cymbalta and thioridazine should not be coadministered. Other Clinically Important Drug Interactions Alcohol Use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should ordinarily not be prescribed for patients with substantial alcohol use. CNS Acting Drugs Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action. Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Cymbalta. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Use in patients with concomitant illness Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Hepatic Insufficiency Cymbalta should ordinarily not be used in patients with hepatic insufficiency. Severe Renal Impairment Cymbalta should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis). Controlled Narrow-Angle Glaucoma In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma. Glycemic Control in Patients with Diabetes As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12week acute treatment phase of these studies, Cymbalta was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Cymbalta group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the
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Cymbalta and by 0.2% in the routine care groups. Urinary hesitation and retention Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related. Laboratory tests No specific laboratory tests are recommended.
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Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 18-24 14 additional cases 5 additional cases Decreases Compared to Placebo 25-64 65 1 fewer case 6 fewer cases
Age Range
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial 238
evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration and Warnings and Precautions for descriptions of the risks of discontinuation of Cymbalta]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Cymbalta (duloxetine) is not approved for use in treating bipolar depression.
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Hepatotoxicity
There have been reports of hepatic failure, sometimes fatal, in patients treated with Cymbalta. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Cymbalta increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (82/27,229) of Cymbaltatreated patients. In these patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, elevation of ALT >3 times the upper limit of normal occurred in 1.1% (85/7,632) of Cymbalta-treated patients compared to 0.2% (13/5,578) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
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Orthostatic Hypotension and Syncope

Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions and Drug Interactions] and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.
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Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions

The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Cymbalta with MAOIs intended to treat depression is contraindicated [see Contraindications]. If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Treatment with duloxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
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Abnormal Bleeding
SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
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Discontinuation of Treatment with Cymbalta

Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, fatigue, paresthesia, vomiting, irritability, nightmares, insomnia, diarrhea, anxiety, hyperhidrosis and vertigo. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration].
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Activation of Mania/Hypomania
In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (2/2,489) of duloxetine-treated patients and 0.1% (1/1,625) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, or fibromyalgia placebocontrolled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Cymbalta should be used cautiously in patients with a history of mania.
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Seizures
Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.03% (3/9,445) of patients treated with duloxetine and 0.01% (1/6,770) of patients treated with placebo. Cymbalta should be prescribed with care in patients with a history of a seizure disorder.
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Effect on Blood Pressure

In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions].
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Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potential for Other Drugs to Affect Cymbalta CYP1A2 Inhibitors Co-administration of Cymbalta with potent CYP1A2 inhibitors should be avoided [see Drug Interactions]. CYP2D6 Inhibitors Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see Drug Interactions]. Potential for Cymbalta to Affect Other Drugs Drugs Metabolized by CYP2D6 Co-administration of Cymbalta with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Cymbalta and thioridazine should not be co-administered [see Drug Interactions]. Other Clinically Important Drug Interactions Alcohol Use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should ordinarily not be prescribed for patients with substantial alcohol use [see Warnings and Precautions and Drug Interactions]. CNS Acting Drugs Given the primary CNS effects of Cymbalta, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Warnings and Precautions and Drug Interactions].
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Hyponatremia
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Cymbalta. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when Cymbalta was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations]. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
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Use in Patients with Concomitant Illness

Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Cymbaltas enteric coating. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Cymbalta has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the products premarketing testing. Hepatic Insufficiency Cymbalta should ordinarily not be used in patients with hepatic insufficiency [see Dosage and Administration, Warnings and Precautions, and Use in Specific Populations]. Severe Renal Impairment Cymbalta should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration and Use in Specific Populations]. Controlled Narrow-Angle Glaucoma In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma [see Contraindications]. Glycemic Control in Patients with Diabetes As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, Cymbalta was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Cymbalta group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Cymbalta and by 0.2% in the routine care groups.
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Urinary Hesitation and Retention

Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.
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Laboratory Tests
No specific laboratory tests are recommended.
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Warnings and Precautions Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Cymbalta should ordinarily not be prescribed to which of the following patients? a. Patients with a seizure disorder b. Patients with clinical depression c. Patients with hepatic insufficiency d. Patients with a history of mania 2. Cymbalta was associated with which of the following effects on blood pressure in clinical trials across indications? a. An increase in systolic and decrease in diastolic blood pressure b. A decrease in systolic and increase in diastolic blood pressure c. A decrease in both systolic and diastolic blood pressure d. An increase in both systolic and diastolic blood pressure 3. Following abrupt discontinuation of Cymbalta in the placebo-controlled clinical trials, which of the following symptoms occurred at a rate greater than or equal to 1% and at a significantly higher rate than in the placebo group? a. Dizziness, nausea, and headache b. Nausea, insomnia, and decreased appetite c. Dizziness, somnolence, and nausea d. Nausea, somnolence, and decreased appetite 4. As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. a. True b. False 5. Which of the following is true about Cymbalta and serotonin syndrome or NMS-like reactions? a. Serotonin syndrome or NMS-like reactions do not occur with Cymbalta when used to manage DPNP. b. The risk of serotonin syndrome or NMS-like reactions may be increased by the concomitant use of other drugs that impair serotonin metabolism. c. Concomitant use of serotonergic drugs decreases the risk of serotonin syndrome or NMS-like reactions. d. The concomitant use of Cymbalta with serotonin precursors is recommended. 6. All patients being treated with antidepressants should be monitored for clinical worsening, suicidality, and unusual changes in behavior, especially during: a. A change in the patient's life situation b. An unexpected response to treatment noted by caregivers or a physician c. The abrupt beginning or ending of treatment d. The initial few months of therapy or when dose increases or decreases 7. Why should prescriptions for Cymbalta be written for the smallest quantity of capsules consistent with good patient management? a. To reduce the cost to the patient b. To reduce the risk of overdose c. To meet common health insurance requirements d. To reduce the risk of abuse by minors 8. It is possible that duloxetine and ______________ may interact or cause liver injury. a. Albumin b. Olegin c. Serotonin d. Alcohol 9. Co-administration of Cymbalta with potent CYP1A2 inhibitors should be avoided. a. True 253
b. False 10. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. a. True b. False Answers 1. c. Cymbalta should ordinarily not be prescribed to patients with hepatic insufficiency. Cymbalta should be used cautiously in patients with a history of mania. Cymbalta should be prescribed with care in patients with a history of a seizure disorder. 2. d. In clinical trials across indications, Cymbalta was associated with an increase in both systolic and diastolic blood pressure. 3. a. Following abrupt discontinuation of Cymbalta, dizziness, nausea, and headache occurred at a rate greater than or equal to 1% and at a significantly higher rate than in the placebo group. 4. a. This statement is true. As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes 5. b. The development of a potentially life-threatening serotonin syndrome or NMS-like reactions have been reported with SNRIs and SSRIs alone, including Cymbalta treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs). 6. d. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. 7. b. To reduce the risk of overdose, prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management. 8. d. Because it is possible that Cymbalta and alcohol may interact to cause liver injury or that Cymbalta may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 9. a. This statement is true. Because CYP1A2 is partially responsible for the metabolism of Cymbalta, co-administration of Cymbalta with potent CYP1A2 inhibitors should be avoided. 10. a. This statement is true. Discontinuation of Cymbalta should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
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Section7:AdverseReactions
6 ADVERSE REACTIONS Clinical Trial Data Sources The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2,327), GAD (N=668), DPNP (N=568), and FM (N=876). The population studied was 17 to 89 years of age; 64.8%, 64.7%, 38.7%, and 94.6% female; and 85.5%, 84.6%, 77.6%, and 88% Caucasian for MDD, GAD, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies]. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Click each of the following indications to learn more about adverse reactions reported as reasons for discontinuation of treatment in placebo-controlled trials, or read a transcript.
Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Major Depressive Disorder Approximately 9% (209/2,327) of the patients who received duloxetine in placebocontrolled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1,460) of the patients receiving placebo. Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drugrelated (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a 256
rate of at least twice that of placebo). Generalized Anxiety Disorder Approximately 15.3% (102/668) of the patients who received duloxetine in placebocontrolled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%). Diabetic Peripheral Neuropathic Pain Approximately 14.3% (81/568) of the patients who received duloxetine in placebocontrolled trials for DPNP discontinued treatment due to an adverse reaction, compared with 7.2% (16/223) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) were nausea (duloxetine 3.5%, placebo 0.4%), dizziness (duloxetine 1.6%, placebo 0.4%), somnolence (duloxetine 1.6%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.0%). Fibromyalgia Approximately 19.5% (171/876) of the patients who received duloxetine in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 11.8% (63/535) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 1.9%, placebo 0.7%), somnolence (duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo 0.2%).
Adverse Reactions Occurring at an Incidence of 5% or More and at least Twice Placebo Among Duloxetine-Treated Patients in Placebo-Controlled Trials Pooled Trials for all Approved Indications The most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were: nausea dry mouth constipation somnolence hyperhidrosis decreased appetite In addition to the adverse reactions listed above, DPNP trials also included dizziness and asthenia. Critical Information!
Adverse Reactions Occurring at an Incidence of 5% or More and at

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least Twice Placebo Among Duloxetine-Treated Patients in PlaceboControlled Trials

Pooled Trials for all Approved Indications The most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were: nausea dry mouth constipation somnolence hyperhidrosis decreased appetite In addition to the adverse reactions listed above, DPNP trials also included dizziness and asthenia.
Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Click the following to learn more: Table 2: Treatment-Emergent Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Click each of the following to learn more: Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in MDD and GAD Placebo-Controlled Trials Table 4: Treatment-Emergent Adverse Reactions Incidence of 2% or More in DPNP PlaceboControlled Trials Table 5: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in Fibromyalgia Placebo-Controlled Trials Effects on Male and Female Sexual Function Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo controlled trials. In these trials, as shown in Table 6 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach 258
orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects. Click the following to learn more: Table 6: Mean Change in ASEX Scores By Gender In MDD Placebo-Controlled Trials Critical Information!
Effects on Male and Female Sexual Function

In these trials, as shown in Table 6 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score.
Vital Sign Changes In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions]. Duloxetine treatment, for up to 26 weeks in placebo controlled trials typically caused a small increase in heart rate compared to placebo of up to 3-4 beats per minute. Critical Information!
Vital Sign Changes

In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. Duloxetine treatment, for up to 26 weeks in placebo controlled trials typically caused a small increase in heart rate compared to placebo of up to 3-4 beats per minute.
Weight Changes In placebo controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo treated patients. In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In fibromyalgia studies, 259
patients treated with Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.4 kg compared with a mean weight gain of approximately 0.3 kg in placebo-treated patients. In one longterm fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg. Critical Information!
Weight Changes
In placebo controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo treated patients. In DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebotreated patients. In fibromyalgia studies, patients treated with Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.4 kg compared with a mean weight gain of approximately 0.3 kg in placebo-treated patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg.
Laboratory Changes Cymbalta treatment in placebo-controlled clinical trials, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients [see Warnings and Precautions]. Electrocardiogram Changes Electrocardiograms were obtained from duloxetine treated patients and placebo treated patients in clinical trials lasting up to 13 weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine treated and placebo treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive controlled study in healthy volunteers using duloxetine up to 200 mg twice daily, no prolongation of the corrected QT interval was observed. Critical Information!
Electrocardiogram Changes
Electrocardiograms were obtained from duloxetine treated patients and placebo treated patients in clinical trials lasting up to 13 weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine treated and placebo treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive controlled study in healthy volunteers using duloxetine up to 200 mg twice daily, no prolongation of the corrected QT interval was observed. 260
Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Following is a list of treatment emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 27,229 patients were treated with duloxetine. Of these, 29% (7,886) took duloxetine for at least 6 months, and 13.3% (3,614) for at least one year. The following listing is not intended to include reactions: (1) already listed in previous tables or elsewhere in labeling (2) for which a drug cause was remote (3) which were so general as to be uninformative (4) which were not considered to have significant clinical implications (5) or which occurred at a rate equal to or less than placebo. Click the following to view the list of treatment emergent adverse reactions reported by patients treated with duloxetine in clinical trials: Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Postmarketing Spontaneous Reports The following adverse reactions have been identified during postapproval use of Cymbalta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, erythema multiforme, extrapyramidal disorder, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria. Serious skin reactions including Stevens-Johnson Syndrome that have required drug discontinuation and/or hospitalization have been reported with duloxetine. Once you have completed this section, open the Quick Check and check your understanding of what you have learned, or read a transcript.
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Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Transcript
Major Depressive Disorder Approximately 9% (209/2,327) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1,460) of the patients receiving placebo. Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drugrelated (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder Approximately 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%). Diabetic Peripheral Neuropathic Pain Approximately 14.3% (81/568) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 7.2% (16/223) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) were nausea (duloxetine 3.5%, placebo 0.4%), dizziness (duloxetine 1.6%, placebo 0.4%), somnolence (duloxetine 1.6%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.0%). Fibromyalgia 262
Approximately 19.5% (171/876) of the patients who received duloxetine in 3 to 6 month placebocontrolled trials for FM discontinued treatment due to an adverse reaction, compared with 11.8% (63/535) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 1.9%, placebo 0.7%), somnolence (duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo 0.2%).
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Table 2: Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo.
Percentage of Patients Reporting Reaction Cymbalta (N=4843) 25 16 14 11 11 16 11 11 11 10 8 7 Placebo (N=3048) 9 15 6 6 7 15 6 3 4 7 2 2
Adverse Reaction Nausea Headache Dry Mouth Fatigueb Insomniaa,c Headache Dizziness Somnolencea,d Constipationa Diarrhea Decreased Appetitea,e Hyperhidrosis
a
Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. b Also includes asthenia c Also includes middle insomnia, early morning awakening, and initial insomnia d Also includes hypersomnia and sedation e Also includes anorexia
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Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in MDD and GAD Placebo-Controlled Trials
Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebocontrolled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo.
Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction Cymbalta (N=2995) Cardiac Disorders Palpitations Eye Disorders Vision blurred Gastrointestinal Disorders Nausea Dry mouth Diarrhea Constipationa Abdominal painb Vomiting General Disorders and Administration Site Conditions Fatiguec Investigations Weight decreaseda Metabolism and Nutrition Disorders Decreased appetited Nervous System Disorders Dizziness Somnolencee Tremor Psychiatric Disorders Insomniaf Agitationg 266 Placebo (N=1955)
2 3
2 2
25 15 10 10 4 5
9 6 7 4 4 2
10
<1
10 10 3
6 4 <1
10 5
6 3
Anxiety Libido decreasedh Orgasm abnormali Abnormal dreamsj Reproductive System and Breast Disorders Erectile dysfunctionk Ejaculation delayeda,k Ejaculation disorderk,l Respiratory, Thoracic, and Mediastinal Disorders Yawning Skin and Subcutaneous Tissue Disorders Hyperhidrosis Vascular Disorders Hot flush
a
3 4 3 2
2 1 <1 1
5 3 2
1 <1 <1
<1
<1
Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain c Also includes asthenia d Also includes anorexia e Also includes hypersomnia and sedation f Also includes middle insomnia, early morning awakening, and initial insomnia g Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation h Also includes loss of libido i Also includes anorgasmia j Also includes nightmare k Male patients only l Also includes ejaculation failure and ejaculation dysfunction
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Table 4: Treatment-Emergent Adverse Reactions Incidence of 2% or More in DPNP Placebo-Controlled Trials
Table 4 gives the incidence of treatment emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of DPNP placebo controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo.
Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction Cymbalta 20 mg once daily (N = 115) Cymbalta 60 mg once daily (N = 228) Cymbalta 60 mg twice daily (N = 225) Placebo (N = 223)
Gastrointestinal Disorders Nausea Constipation Diarrhea Dry mouth Vomiting Dyspepsia Loose stools General Disorders and Administration Site Conditions Fatigue Asthenia Pyrexia Infections and Infestations Nasopharyngitis Metabolism and Nutrition Disorders Decreased appetite Anorexia Musculoskeletal and Connective Tissue Disorders Muscle cramp Myalgia Nervous System Disorders Somnolence Headache Dizziness
14 5 13 5 6 4 2
22 11 11 7 5 4 3
30 15 7 12 5 4 2
9 3 6 4 4 3 1
2 2 2
10 4 1
12 8 3
5 1 1
3 3
4 3
11 5
<1 <1
5 3
4 1
4 4
3 <1
7 13 6 268
15 13 14
21 15 17
5 10 6
Tremor Psychiatric Disorders Insomnia Renal and Urinary Disorders Pollakiuria Reproductive System and Breast Disorders Erectile dysfunctiona Respiratory, Thoracic and Mediastinal Disorders Cough Pharyngolaryngeal pain Skin and Subcutaneous Tissue Disorders Hyperhidrosis
a
13
6 3
3 1
5 6
4 1
Male patients only
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Table 5: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in Fibromyalgia Placebo-Controlled Trials
Table 5 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of FM placebo-controlled trials and with an incidence greater than placebo.
Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction Cymbalta (N = 876) Placebo (N = 535)
Cardiac Disorders Palpitations Eye Disorders Vision blurred Gastrointestinal Disorders Nausea Dry mouth Constipation Diarrhea Dyspepsia General Disorders and Administration Site Conditions Fatigueb Immune System Disorders Seasonal allergy Infections and Infestations Upper respiratory tract infection Urinary tract infection Influenza Gastroenteritis viral Investigations Weight increased Metabolism and Nutrition Disorders Decreased appetitec Musculoskeletal and Connective Tissue 270
29 18 15 12 5
11 5 4 8 3
15
7 3 2 2
6 3 2 2
11
Disorders Musculoskeletal pain Muscle spasms Nervous System Disorders Headache Dizziness Somnolencec Tremor Paraesthesia Migraine Dysgeusia Psychiatric Disorders Insomniae Agitationf Sleep disorder Abnormal dreamsg Orgasm abnormalh Libido decreasedi Reproductive System and Breast Disorders Erectile dysfunctiona,j Penis disordera Respiratory, Thoracic, and Mediastinal Disorders Cough Pharyngolaryngeal pain Skin and Subcutaneous Tissue Disorders Hyperhidrosis Rash Pruritis Vascular Disorders Hot flush
a b
5 4
4 3
20 11 11 4 4 3 3
12 7 3 1 4 3 1
16 6 3 3 3 2
10 2 2 1 <1 <1
4 2
0 0
4 3
3 3
7 4 3
1 2 2
Male patients only (N = 46 duloxetine-treated patients versus 26 placebo patients) Also includes asthenia c Also includes anorexia d Also includes hypersomnia and sedation e Also includes middle insomnia, early morning awakening, and initial insomnia f Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation g Also includes nightmare h Also includes anorgasmia i Also includes loss of libido j Also includes ejaculation failure and ejaculation dysfunction
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Table 6: Mean Change in ASEX Scores by Gender in MDD PlaceboControlled Trials

Male Patientsa Cymbalta (n = 175) Placebo (n = 83) Female Patientsa Cymbalta (n = 241) Placebo (n = 126) -1.07 -0.24 -0.18 -0.18 -0.13 -0.17
ASEX Total (Items 1-5) Item 1 Sex Drive Item 2 Arousal Item 3 Ability to achieve erection (men); Lubrication (women) Item 4 Ease of reaching orgasm Item 5 Orgasm satisfaction
a b
0.56b -0.07 0.01 0.03 0.40c 0.09
-1.07 -0.12 -0.26 -0.25 -0.24 -0.13
-1.15 -0.32 -0.21 -0.17 -0.09 -0.11
n = Number of patients with non-missing change score for ASEX total p = 0.013 versus placebo c p < 0.001 versus placebo
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Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine
Adverse Reactions System Organ Class occurring for the first time or worsening while receiving therapy Cardiac Disorders Ear and Labyrinth Disorders Endocrine Disorders Eye Disorders Gastrointestinal Disorders General Disorders and Administration Site Conditions Infections and Infestations Investigations Metabolism and Nutrition Disorders Musculoskeletal and Connective Tissue Disorders Nervous System Disorders musculoskeletal pain weight increased vision blurred flatulence Rare occurring in fewer than 1/1000 patients
Frequent occurring in at least 1/100 patients
Infrequent occurring in 1/100 to 1/1000 patients
palpitations vertigo
myocardial infarction, tachycardia ear pain, tinnitus hypothyroidism diplopia, visual disturbance eructation, gastritis, halitosis, stomatitis feeling abnormal, feeling hot and/or cold, malaise, thirst gastroenteritis, laryngitis blood cholesterol increased dehydration, hyperlipidemia muscle tightness, muscle twitching disturbance in attention, dyskinesia, myoclonus, poor quality sleep apathy, bruxism, disorientation/confusional state, irritability, mood swings, suicide attempt dyslipidemia gastric ulcer, hematochezia, melena gait disturbance
chills/rigors
dysgeusia, lethargy, parasthesia/hypoesthesia
dysarthria
Psychiatric Disorders
abnormal dreams, sleep disorder
completed suicide
274
Renal and Urinary Disorders Reproductive System and Breast Disorders Respiratory, Thoracic and Mediastinal Disorders Skin and Subcutaneous Tissue Disorders Vascular Disorders hot flush anorgasmia/orgasm abnormal
dysuria, micturition urgency, nocturia, polyuria, urine odor abnormal menopausal symptoms, sexual dysfunction
yawning
throat tightness
cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, photosensitivity reaction flushing, orthostatic hypotension, peripheral coldness
ecchymosis
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Adverse Reactions Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Among the patients who received duloxetine in 3 to 6 month placebo-controlled trials for fibromyalgia, nausea was one of the top reasons for discontinuation of Cymbalta. a. True b. False 2. What percent of patients taking Cymbalta in the placebo-controlled clinical trials for DPNP discontinued treatment before the end of the study due to adverse events? a. 7% b. 14% c. 21% d. 28% 3. In the clinical trials for DPNP, what percent of patients in the placebo group discontinued treatment before the end of the study due to adverse events? a. 7% b. 11% c. 14% d. 17% 4. Use of Cymbalta was associated with clinically significant electrocardiogram abnormalities. a. True b. False 5. In pooled trials for all approved indications, the most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, constipation, somnolence, hyperhidrosis, and decreased appetite. a. True b. False 6. In four MDD placebo controlled trials, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. a. True b. False Answers 1. a. Among the patients who received duloxetine in 3 to 6 month placebo-controlled trials for fibromyalgia, common adverse reactions reported as a reason for discontinuation and considered to be drug-related included nausea (duloxetine 1.9%, placebo 0.7%), somnolence (duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo 0.2%). 2. b. Approximately 14.3% (81/568) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction. 3. a. Approximately 7.2% (16/223) of the patients in the placebo group discontinued treatment due to an adverse reaction.
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4. b. Electrocardiograms were obtained from duloxetine-treated patients and placebo-treated patients in clinical trials lasting up to 13 weeks. No clinically significant differences were observed. 5. a. In pooled trials for all approved indications, the most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, constipation, somnolence, hyperhidrosis, and decreased appetite. 6. a. In four MDD placebo controlled trials, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo.
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Find Out More: Arizona Sexual Experience Scale

The ASEX is a patient-rated scale of five questions, with responses measured on a six-point Likert scale. The questions are: Item 1. How strong is your sex drive? Item 2. How easily are you sexually aroused? Item 3. Males Can you easily get and keep an erection? Females How easily does your vagina become moist or wet during sex? Item 4. How easily can you reach an orgasm? Item 5. Are your orgasms satisfying? Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.
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Section8:DrugInteractions
7 DRUG INTERACTIONS Click the following icon to learn more about drug interactions.
Drug Interactions
Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine). Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies. Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3 fold. Drugs Metabolized by CYP2C9 Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit 279
CYP2C19 activity at therapeutic concentrations. Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.
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Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Inhibitors of CYP1A2 When duloxetine 60 mg was co administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6 fold, the Cmax was increased about 2.5 fold, and duloxetine t1/2 was increased approximately 3 fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions]. Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions]. Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the casecontrol and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions]. Lorazepam Under steady state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co administration. Temazepam Under steady state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co administration. Drugs that Affect Gastric Acidity Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH 281
may lead to an earlier release of duloxetine. However, co administration of Cymbalta with aluminum and magnesium containing antacids (51 mEq) or Cymbalta with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions]. Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co administered with duloxetine (60 mg twice daily). Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3 fold [see Warnings and Precautions]. Drugs Metabolized by CYP2C9 Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9 substrates is therefore not anticipated, although clinical studies have not been performed. Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. Monoamine Oxidase Inhibitors [See Dosage and Administration, Contraindications, and Warnings and Precautions]. Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including Cymbalta, and the potential for serotonin syndrome, caution is advised when Cymbalta is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort. The concomitant use of Cymbalta with other SSRIs, SNRIs or tryptophan is not recommended [see Warnings and Precautions].
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Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions]. Alcohol When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol. In the Cymbalta clinical trials database, three Cymbalta treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions]. CNS Drugs [See Warnings and Precautions]. Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.
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Drug Interactions Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Duloxetine is an inhibitor of the _________ isoform in in vitro studies. a. CYP2C19 b. CYP3A4 c. CYP2C9 d. CYP1A2 2. Duloxetine inhibits the in vitro enzyme activity of CYP2C9. a. True b. False 3. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised. a. True b. False 4. Administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. a. True b. False Answers 1. d. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies. 2. b. Duloxetine does not inhibit the in vitro enzyme activity of CYP2C9. 3. a. There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 4. a. Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.
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Section9:UseinSpecificPopulations
8 USE IN SPECIFIC POPULATIONS Click the following icon to learn more about the use of Cymbalta in specific populations.
Use in Specific Populations
Pregnancy There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended.
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Use in Specific Populations

Pregnancy Teratogenic Effects, Pregnancy Category C In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m2 basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m2 basis in rabbit). However, fetal weights were decreased at this dose, with a no effect dose of 10 mg/kg/day (2 times the MRHD and ~1 times the human dose of 120 mg/day on a mg/m2 basis in rat; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester [see Dosage and Administration]. Labor and Delivery The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics. The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine 40 mg twice daily was 286
given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 g/day while on 40 mg BID dosing. The excretion of duloxetine metabolites into breast milk was not examined. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended [see Dosing and Administration]. Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions]. Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need. Geriatric Use Of the 2,418 patients in premarketing clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD, DPNP, and FM studies, no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Cymbalta have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between patient variability. Dosage adjustment based on the age of the patient is not necessary [see Dosage and Administration]. Gender Duloxetines half life is similar in men and women. Dosage adjustment based on gender is not necessary. Smoking Status Duloxetine bioavailability (AUC) appears to be reduced by about one third in smokers. Dosage modifications are not recommended for smokers. Race No specific pharmacokinetic study was conducted to investigate the effects of race. Hepatic Insufficiency Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20 mg dose of Cymbalta, 6 cirrhotic patients with moderate liver impairment (Child Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age and gender matched healthy subjects, with a 5 fold increase in mean exposure (AUC). Although Cmax was similar to 287
normals in the cirrhotic patients, the half life was about 3 times longer [see Dosage and Administration and Warnings and Precautions]. Severe Renal Impairment Limited data are available on the effects of duloxetine in patients with end stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4 hydroxy duloxetine glucuronide and 5 hydroxy, 6 methoxy duloxetine sulfate, largely excreted in urine, were approximately 7 to 9 fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30 80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration and Warnings and Precautions].
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Use in Specific Populations Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. Why should Cymbalta be used during pregnancy only if the potential benefit justifies the potential risk to the fetus? a. There are no adequate and well-controlled studies of Cymbalta use in pregnant women. b. Cymbalta studies in pregnant women have only been conducted during the first two trimesters of pregnancy. c. Most depressive conditions are alleviated when a pregnancy is concluded naturally. d. The major symptoms of depression are often masked or mitigated by the physical and emotional effects of pregnancy. 2. Why is nursing while on Cymbalta not recommended? a. The bioavailability of Cymbalta increases in nursing mothers. b. The safety of duloxetine in nursing infants is not known. c. Nursing mothers are often naturally depressed, so medication may not be required. d. The physical stress of nursing may make a mother excessively tired and weak. Answers 1. a. There are no adequate and well-controlled studies in pregnant women; therefore Cymbalta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 2. b. Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended.
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Section10:DrugandDependence
9 DRUG ABUSE AND DEPENDENCE Abuse In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). Dependence In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.
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Section11:Overdosage
10 OVERDOSAGE Signs and Symptoms In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. Critical Information!
Signs and Symptoms

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.
Management of Overdose There is no specific antidote to Cymbalta, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken Cymbalta and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions and Drug Interactions]. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians Desk Reference (PDR). Once you have completed this section, open the Quick Check and check your understanding of what you have learned, or read a transcript. 291
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Overdosage Quick Check Transcript

Read each statement and decide if it is true or false. Correct answers are revealed at the bottom of the page. 1. Fatal outcomes have been reported for overdoses of Cymbalta in the range of 300-500 mg. 2. In postmarketing experience, some of the signs and symptoms of Cymbalta overdose included somnolence, coma, and serotonin syndrome. Answers 1. False. Fatal outcomes have been reported for acute overdoses of Cymbalta, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. 2. True. In postmarketing experience, signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.
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Section12:Description
11 DESCRIPTION Cymbalta (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-?-(1-naphthyloxy)-2thiophenepropylamine hydrochloride. The empirical formula is C18H19NOSHCl, which corresponds to a molecular weight of 333.88. The structural formula is:
Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water. Each capsule contains enteric coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow.
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Section13:ClinicalPharmacology
12 CLINICAL PHARMACOLOGY Mechanism of Action Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Critical Information!
Mechanism of Action
Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.
Pharmacodynamics Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug related. Critical Information!
Pharmacodynamics
Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).
Pharmacokinetics Duloxetine has an elimination half life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. 295
Absorption and Distribution Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and ?1 acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. Metabolism and Elimination Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4 hydroxy duloxetine glucuronide and 5 hydroxy, 6 methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Critical Information!
Pharmacokinetics
Duloxetine has an elimination half life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Absorption and Distribution Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Duloxetine is highly bound (>90%) to proteins in human plasma. Metabolism and Elimination Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4 hydroxy duloxetine glucuronide and 5 hydroxy, 6 methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the
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major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.
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Clinical Pharmacology Quick Check Transcript

Read each statement and select the best answer from the options given. Correct answers are revealed at the bottom of the page. 1. The antidepressant, central pain inhibitory, and anxiolytic actions of duloxetine in humans are believed to be related to its: a. Psychosomatic reactions to the active ingredients b. Potentiation of serotonergic and noradrenergic activity in the CNS c. Anxiolytic reactions to central pain processing stimuli d. The enteric coating, which controls the absorption of Cymbalta by the CNS 2. Approximately 40% of the duloxetine dose is excreted in the urine. a. True b. False 3. Steady state plasma concentrations of duloxetine are typically achieved after _______ of dosing. a. 3 days b. 10 days c. 3 weeks d. 10 weeks Answers 1. b. The antidepressant, central pain inhibitory, and anxiolytic actions of duloxetine in humans are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. 2. b. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. 3. a. Steady state plasma concentrations of duloxetine are typically achieved after 3 days of dosing.
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Section14:NonclinicalToxicology
13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Duloxetine was administered in the diet to mice and rats for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120 mg/day on a mg/m2 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4 times the human dose of 120 mg/day on a mg/m2 basis). In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and 3 times the human dose of 120 mg/day on a mg/m2 basis) did not increase the incidence of tumors. Mutagenesis Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo. Impairment of Fertility Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60 mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility.
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Section15:ClinicalStudies
14 CLINICAL STUDIES Click following icon to learn more about clinical studies by indication, or read a transcript. Note: The studies presented in this section are included in the Cymbalta full Prescribing Information.
Clinical Studies
Major Depressive Disorder The efficacy of Cymbalta as a treatment for depression was established in 4 randomized, double blind, placebo controlled, fixed dose studies in adult outpatients (18 to 83 years) meeting DSM IV criteria for major depression. Generalized Anxiety Disorder The efficacy of Cymbalta in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed dose randomized, double blind, placebo controlled trial and 2 flexible dose randomized, double blind, placebo controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM IV criteria for GAD. Diabetic Peripheral Neuropathic Pain The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12 week, double blind, placebo controlled, fixed dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Fibromyalgia The efficacy of Cymbalta for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia 300
(a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites).
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Clinical Studies Transcript

Major Depressive Disorder The efficacy of Cymbalta as a treatment for depression was established in 4 randomized, double blind, placebo controlled, fixed dose studies in adult outpatients (18 to 83 years) meeting DSM IV criteria for major depression. In 2 studies, patients were randomized to Cymbalta 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to Cymbalta 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to Cymbalta 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits. In all 4 studies, Cymbalta demonstrated superiority over placebo as measured by improvement in the 17 item Hamilton Depression Rating Scale (HAM-D 17) total score. In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. In another study, 533 patients meeting DSM IV criteria for MDD received Cymbalta 60 mg once daily during an initial 12 week open label treatment phase. Two hundred and seventy eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD 17 total score 9, Clinical Global Impressions of Severity (CGI-S) 2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of Cymbalta at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on Cymbalta experienced a statistically significantly longer time to relapse of depression than did patients on placebo. Relapse was defined as an increase in the CGIS score of 2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of Cymbalta in hospitalized patients with major depressive disorder has not been studied. Generalized Anxiety Disorder The efficacy of Cymbalta in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed dose randomized, double blind, placebo controlled trial and 2 flexible dose randomized, double blind, placebo controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM IV criteria for GAD. In 1 flexible dose study and in the fixed dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily. The 2 flexible dose studies involved dose titration with Cymbalta doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10 week treatment period. The mean dose for completers at endpoint in the flexible dose studies was 104.75 mg/day. The fixed dose study evaluated Cymbalta doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9 week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. In all 3 studies, Cymbalta demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a widely used and well validated scale that measures the extent 302
emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities. In another study, 887 patients meeting DSM-IV-TR criteria for GAD received Cymbalta 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of Cymbalta at the same dose (N = 216) or to placebo (N = 213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score 4 and a MINI (MiniInternational Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking Cymbalta experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. Diabetic Peripheral Neuropathic Pain The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12 week, double blind, placebo controlled, fixed dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study 1 and 2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of 4 on an 11 point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to Cymbalta. Patients recorded their pain daily in a diary. Both studies compared Cymbalta 60 mg once daily or 60 mg twice daily with placebo. Study 1 additionally compared Cymbalta 20 mg with placebo. A total of 457 patients (342 Cymbalta, 115 placebo) were enrolled in Study 1 and a total of 334 patients (226 Cymbalta, 108 placebo) were enrolled in Study 2. Treatment with Cymbalta 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
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Fibromyalgia The efficacy of Cymbalta for the management of fibromyalgia was established in two randomized, doubleblind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study 1 was three months in duration and enrolled female patients only. Study 2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of major depressive disorder (MDD). Study 1 and 2 enrolled a total of 874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain). Both studies compared Cymbalta 60 mg once daily or 120 mg daily (given in divided doses in Study 1 and as a single daily dose in Study 2) with placebo. Study 2 additionally compared Cymbalta 20 mg with placebo during the initial three months of a six-month study. A total of 354 patients (234 Cymbalta, 120 placebo) were enrolled in Study 1 and a total of 520 patients (376 Cymbalta, 144 placebo) were enrolled in Study 2 (5% male, 95% female). Treatment with Cymbalta 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increase the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was associated with more adverse reactions and premature discontinuations of treatment.
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Additionally, the benefit of up-titration in non-responders to Cymbalta at 60 mg/day was evaluated in a separate study. Patients were initially treated with Cymbalta 60 mg once daily for eight weeks in openlabel fashion. Subsequently, completers of this phase were randomized to double-blind treatment with Cymbalta at either 60 mg once daily or 120 mg once daily. Those patients who were considered nonresponders, where response was defined as at least a 30% reduction in pain score from baseline at the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to Cymbalta 120 mg as compared to those who were blindly continued on Cymbalta 60 mg.
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Clinical Studies Quick Check Transcript

Read each statement and decide if it is true or false. Correct answers are revealed at the bottom of the page. 1. The efficacy of Cymbalta for the management of fibromyalgia was established in four randomized, double-blind, placebo-controlled, variable-dose studies. 2. The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebocontrolled, fixed-dose studies.
Answers
1. False. The efficacy of Cymbalta for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies. 2. True. The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebocontrolled, fixed-dose studies.
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Section16:HowSupplied/StorageandHandling
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Cymbalta is available as delayed release capsules in the following strengths, colors, imprints, and presentations:
Strengths Features 20 mga Body color Cap color Cap imprint Body imprint Capsule number Presentations and NDC Codes Opaque green Opaque green Lilly 3235 20mg PU3235 30 mga Opaque white Opaque blue Lilly 3240 30mg PU3240 60 mga Opaque green Opaque blue Lilly 3237 60mg PU3237
Bottles of 30 Bottles of 60 Bottles of 90 Bottles of 1000 Blisters ID100 Blister card of 30

a
NA 0002-3235-60 NA NA NA NA
0002-3240-30 NA 0002-3240-90 0002-3240-04 0002-3240-33 NA
0002-3237-30 NA 0002-3237-90 0002-3237-04 0002-3237-33 0002-3237-34
equivalent to duloxetine base Identi-Dose (unit dose medication, Lilly)
Storage 308
Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].
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Section17:PatientCounselingInformation
17 PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide Information on Medication Guide Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Cymbalta and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Cymbalta. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Cymbalta. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Boxed Warning, and Warnings and Precautions]. Medication Administration Cymbalta should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Continuing the Therapy Prescribed While patients may notice improvement with Cymbalta therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Abnormal Bleeding Patients should be cautioned about the concomitant use of duloxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions]. 310
Concomitant Medications Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [see Dosage and Administration, Contraindications, Warnings and Precautions, and Drug Interactions]. Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cymbalta and triptans, tramadol or other serotonergic agents [see Warnings and Precautions and Drug Interactions]. Pregnancy and Breast Feeding Patients should be advised to notify their physician if they become pregnant during therapy intend to become pregnant during therapy are breast feeding [see Dosage and Administration and Use in Specific Populations]. Alcohol Although Cymbalta does not increase the impairment of mental and motor skills caused by alcohol, use of Cymbalta concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Cymbalta should ordinarily not be prescribed for patients with substantial alcohol use [see Warnings and Precautions and Drug Interactions]. Orthostatic Hypotension and Syncope Patients should be advised of the risk of orthostatic hypotension and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of duloxetine [see Warnings and Precautions]. Interference with Psychomotor Performance Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Cymbalta has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, patients should be cautioned about operating hazardous machinery including automobiles, until they are reasonably certain that Cymbalta therapy does not affect their ability to engage in such activities.
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Find Out More: Medication Guide

Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions[1] Read the Medication Guide that comes with your or your family members antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family members, healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness.
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling very agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent 312
acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood.
What else do I need to know about antidepressant medicines?
Never stop taking an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your childs healthcare provider for more information.
Note: This Medication Guide has been approved by the US Food and Drug Administration for all antidepressants.
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Module8References
1. U.S. Food and Drug Administration, Medication Guide: Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Action. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm100211.pdf.
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CourseCompletion
Before completing the course, you must view all modules and sections. Once completed, you will need to close the course and click on the Get Credit/Take Test link. The automatic path marking (check marks) in this course is solely for your use in keeping track of which sections you have visited. You do not need to have check marks to proceed with course completion.
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StudyGuide
The Study Guide is a document intended to help you note what points to review or what you think you will need to study in the future. You can use the learning objectives as a guide to what you need to know. To save to desktop: 1. Click the workbook link, and then click Save. 2. Select Desktop. 3. Click Save. Download Study Guide (PDF)
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Glossary
adrenergic receptors Receptors that bind the neurotransmitter norepinephrine. anxiety disorders anxiety disorders A group of disorders characterized by significant anxiety as a core feature. Three examples of anxiety disorders are: generalized anxiety disorder (GAD): Disorder characterized by excessive anxiety, worry (apprehensive expectation) and difficulty controlling worry, occurring more days than not for a period of at least six months, about a number of events or activities; symptoms may include restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension, and disturbed sleep. panic disorder: (with or without agoraphobia) Disorder characterized by a discrete period of intense fear and discomfort; symptoms may include shortness of breath, palpitations, dizziness, shaking, sweating, and fear of dying or going crazy; agoraphobia anxiety about being in places or situations where escape may be difficult or help may not be available if experiencing a panic attack. obsessive compulsive disorder (OCD): Disorder characterized by recurrent and persistent thoughts, impulses, or images that are intrusive, inappropriate, and cause significant anxiety or distress. The individual recognizes that these are their own thoughts and that they may be excessive.
ascending pain pathways Set of neurons that convey pain signals from peripheral receptors to higher levels of the central nervous system. BID Abbreviation for twice a day. central nervous system (CNS) The part of the nervous system comprising the brain and spinal cord. cholinergic receptors Receptors that bind the neurotransmitter acetylcholine. class warning Warning not unique to Cymbalta but applies to all other antidepressants in the same class. clinical depression MDD, which may also be referred to as unipolar depression, major depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that interfere with a persons ability to work, study, eat, sleep, and enjoy once pleasurable activities. MDD differs from the normal emotional experiences of sadness, loss, and passing moods in that symptoms of MDD are persistent and severe enough that they can interfere significantly with ones ability to function in everyday life. cognitive disorder Characterized by impairment of mental processes such as comprehension, judgment, memory, and/or reasoning. 317
cytochrome P450 (CYP) enzymes Group of liver enzymes important in metabolizing substances normally present in the body (for example, steroids, fat-soluble vitamins) and in detoxifying numerous environmental pollutants (for example, carcinogens present in tobacco smoke). These enzymes are also responsible for metabolizing medications and other compounds. dementia Cognitive disorders characterized by defects in memory, as well as other cognitive impairment, such as the loss of the ability to use or understand words, inability to carry out motor activities despite intact motor function, and failure to recognize or identify objects. descending pain pathways Processes by which the brain modulates the perception of pain using chemical substances and nerve impulses that travel down to the cells in the spinal cord to counteract pain messages sent up by pain receptors in the periphery. downregulation The process by which a cell decreases the number of a cellular component. DSM-IV-TR Published by the American Psychiatric Association, the Diagnostic and Statistical Manual of Mental Disorders (DSM) is used by mental health professionals as a reference that includes diagnostic criteria for different categories of mental disorders. dysthymic disorder A mood disorder characterized by chronically depressed mood for at least two years in addition to two or more other symptoms, such as: appetite disturbance, sleep disturbance, fatigue, low self esteem, poor concentration, and feelings of hopelessness. endocrinopathies Disease resulting from a disorder of an endocrine gland. episode A period of depressive symptons in the course of MDD that may wax and wane in symptomatology. histaminergic receptors Receptors that bind the neurotransmitter histamine. hyponatremia An electrolyte imbalance characterized by low levels of sodium in the blood. hypothyroidism A condition due to a deficiency of the thyroid secretion, resulting in a lower basal metabolism. locus ceruleus An area of the brain stem with many norepinephrine-containing neurons. major depression Major depression, which may also be referred to as major depressive disorder (MDD), unipolar depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that 318
interfere with a persons ability to work, study, eat, sleep, and enjoy once pleasurable activities. MDD differs from the normal emotional experiences of sadness, loss, and passing moods in that symptoms of MDD are persistent and severe enough that they can interfere significantly with ones ability to function in everyday life. major depressive disorder Major depressive disorder (MDD), which may also be referred to as unipolar depression, major depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that interfere with a persons ability to work, study, eat, sleep, and enjoy once pleasurable activities. MDD differs from the normal emotional experiences of sadness, loss, and passing moods in that symptoms of MDD are persistent and severe enough that they can interfere significantly with ones ability to function in everyday life. major depressive episode Period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly all activities, along with other symptoms and significant distress or impairment in functioning. A major depressive episode is not synonymous with MDD. Major episodes occur in MDD, but can also occur in bipolar disorder. manic episode A distinct period during which there is an abnormal and persistently elevated, expansive, or irritable mood, among other symptoms. mixed episode a period of time (lasting at least 1 week) in which the criteria are met both for a Manic Episode and for a Major Depressive Episode nearly every day (Criterion A). monoamine oxidase inhibitor (MAOI) A class of antidepressant drugs that inhibit the action of monoamine oxidase enzymes, thus decreasing the breakdown of monoamine neurotransmitters. mood disorder Disorders in which mood change or disturbance is the primary manifestation; also called affective disorders.
neurochemical Pertaining to chemicals involved in nervous system function. noradrenergic Using norepinephrine as a neurotransmitter. norepinephrine Neurotransmitter widely distributed throughout the nervous system; also called noradrenaline. nucleus raphe magnus (raphe nuclei) Nucleus (group of cells) in the midbrain whose cells primarily use serotonin as their neurotransmitter. personality disorders Disorders characterized by enduring patterns of perceiving, relating to, and thinking about the 319
environment and oneself that are maladaptive, causing either significant functional impairment or subjective distress. pharmacodynamics The actions of the drug on the bodyfor example, the effects of a drug binding to a receptor site or reuptake transporter. This includes the mechanism of action (MOA) or how a drug works once inside the body. pharmacokinetics The actions of the body on a drugthe absorption, distribution, metabolism, and elimination/excretion (ADME) of pharmacologically active molecules. prefrontal cortex Part of the cerebral cortex at the front of the brain; involved with numerous functions including executive functions (working memory, decision making, planning, and judgment). Pregnancy Category C No adequate human or animal studies; or adverse fetal effects in animal studies, but no available human data. prevalence Number of cases of a disease existing in a given population at a specific period of time or at a particular moment in time. This is different from incidence, which is the rate of occurrence of new patients in a population during a specific period of time. primary care physician (PCP) PCPs include general practitioners (GP), family practitioners (FP), and internal medicine specialists (IM). general practitioner (GP): A practicing physician who may diagnose and treat a wide variety of illnesses. family practitioner (FP): A specialist trained to prevent, diagnose and treat a wide variety of medical illnesses in patients of all ages. internal medicine specialist (IM): Provides comprehensive, long-term care for common illnesses, as well as complex health problems, generally in adults and elderly, although they may treat younger patients as well.
psychiatric disorder Behavioral or psychological disorder that causes significant stress or disability, or a significantly increased risk of suffering, death, pain, or an important loss of freedom. psychiatrist A physician who specializes in the diagnosis and treatment of mental health disorders. psychosocial stressor Stress involving both psychological and social aspects, such as the death of a loved one, loss of a job, etc. psychotic disorder A term generally restricted to mental disorders of such magnitude that there is disintegration and impaired perception of reality.
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recovery Remission for a significant time period commonly defined as 6 months. relapse Return of symptoms during the same episode of depression before recovery. remission Attainment of a virtually asymptomatic status (euthymia); in clinical trials, commonly defined as HAM-D17 score of 7. response Greater than or equal to 50% reduction from a baseline score on a standardized scale, such as the HAMD. serotonergic Using serotonin as a neurotransmitter. serotonin Neurotransmitter found in many regions of the brain and other parts of the body. serotonin syndrome A potentially life-threatening syndrome that may occur when there is too much serotonin activity. The syndrome may occur when drugs that raise the level of serotonin in a patient's nervous system are combined. The combination can result in dangerously high levels of serotonin, which can be potentially fatal. Signs and symptoms may include: mental status changes (such as agitation, hallucinations), autonomic instability (such as increased heart rate, labile blood pressure, increased body temperature), neuromuscular disturbances (such as hyperreflexia, incoordination), and gastrointestinal symptoms (such as nausea, vomiting, and diarrhea). Stevens-Johnson Syndrome A rare skin and mucous membranes disorder that begins with flu-like symptoms and then progresses to inflammation of the mucous membranes that is followed by a painful rash. The rash spreads and blisters and ultimately causes the skin's top layer to die and shred. Though not always apparent, an allergic reaction to medication or infection is usually the cause of the disorder. The disorder is also called erythema multiforme major. substance use disorders Involves the dependence on, or abuse of, alcohol and/or drugs, including the nonmedical use of prescription drugs. trismus Spasms of the muscles used for chewing, resulting in the inability to open the mouth. uncontrolled narrow-angle glaucoma Abnormal condition of elevated pressure within the eye caused by obstruction of the outflow of aqueous humor when the pupil dilates markedly in an eye with a narrow angle between the iris and cornea. unipolar depression Unipolar depression, which may also be referred to as major depressive disorder (MDD), major depression, or clinical depression, is a mood disorder characterized by a combination of symptoms that interfere with a persons ability to work, study, eat, sleep, and enjoy once pleasurable activities. MDD 321
differs from the normal emotional experiences of sadness, loss, and passing moods in that symptoms of MDD are persistent and severe enough that they can interfere significantly with ones ability to function in everyday life. upregulation Increase in receptor number or affinity (chemical attraction). urticaria Acute or chronic skin condition characterized by itchy welts; may be caused by a reaction to a certain type of food, infection, drugs, stress, or contact with certain plants. Also called hives.
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Cymbalta for Major Depressive Disorder (MDD) Online Course Course Content PDF

Course ID: 298603 Course Content PDF

Course Features and Tools Transcript

Critical Information! What are Psychiatric Disorders?

Overview Quick Check Transcript

Critical Information! DSM-IV-TR Criteria for a Major Depressive Episode

Critical Information! Symptoms of Depression

DSM-IV-TR Criteria for a Major Depressive Episode

Symptoms Quick Check Transcript

Find Out More: SIG E CAPS

MDD Specifiers Transcript

MDD with psychotic features (may be referred to as psychotic depression)

Chronic MDD (may be referred to as chronic depression)

MDD with catatonic features (may be referred to as catatonic depression)

MDD with melancholic features (may be referred to as melancholic depression)

MDD with atypical features (may be referred to as atypical depression)

MDD with postpartum onset (may be referred to as postpartum depression)

Onset of major depressive episode within four weeks postpartum

MDD, recurrent, with seasonal pattern

* Not a complete list; see reference for a complete list

MDD Specifiers Quick Check Transcript

Critical Information! Other Mood Disorders

MDD vs. Dysthymic Disorder

least two years

Critical Information! Anxiety Disorders

Other Mood Disorders Transcript

Other Mood and Anxiety Disorders Quick Check Transcript

Critical Information! Prevalence

problems or loss in the social/family network[10, 11] perinatal transitions[12]

physical illness,[13] work problems,[14, 15] separation/divorce[16]

talk about their feelings,[17] laugh/cry,[18] rely on religion[19, 20]

avoid thinking about it,[21] physical activity, sports, drugs/alcohol[22, 23]

Critical Information! Genetic Features

Critical Information! Disease Course

Critical Information! Achieving Remission

Key Terminology Regarding the Course of MDD

Overview Quick Check Transcript

Find Out More: National Comorbidity Survey Replication (NCS-R)

Critical Information! Mortality

Critical Information! Morbidity

Critical Information! Financial Costs

Burden of Illness Quick Check Transcript

Critical Information! Associated Features

Critical Information! Prevalence of Physical Symptoms

Patient Presentation Quick Check Transcript

Critical Information! Treatment Settings

Critical Information! Physicians and Other Health Care Professionals

Types of Medical Professionals Who Commonly Diagnose Depression Transcript

Nurse Practitioner (NP)

Physician Assistant (PA)

HCPs Involved in Depression Quick Check Transcript

Critical Information! Assessment and Diagnostic Procedures

Mental status examination

Critical Information! Monitoring Improvements

Assessment and Diagnostic Procedures Transcript

DSM-IV-TR diagnostic criteria

Mental status examination

Depression rating scales/tools

Assessment and Diagnostic Procedures Quick Check Transcript

Find Out More: Zung Self-rating Depression Scale

Zung Self-rating Depression Scale1

Some of the Time

Good Part of the Time