The Patient Cases: Depression

: s e s a C t n e i t a P e h T Depression The Patient Cases: Depression Every effort has been made in preparing this...

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: s e s a C t n e i t a P e h T Depression

The Patient Cases: Depression

Every effort has been made in preparing this book to provide accurate and upto-date information that is in accord with accepted standards and practice at the time of publication. Nevertheless, the author, editors, and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The author, editors, and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use. PUBLISHED BY NEI PRESS, an imprint of NEUROSCIENCE EDUCATION INSTITUTE Carlsbad, California, United States of America NEUROSCIENCE EDUCATION INSTITUTE 1930 Palomar Point Way, Suite 101 Carlsbad, California 92008 http://www.neiglobal.com Copyright © 2010 Neuroscience Education Institute. All rights reserved. This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Neuroscience Education Institute. Printed in the United States of America First Edition, October 2010 Typeset in Myriad Pro Library of Congress Cataloging-in-Publication Data ISBN 1-4225-0012-8

Table of Contents CME Information................................................................................................. i The Case: 17-Year-Old Girl Admitted for Severe Depression.............. 1 The Case: 24-Year-Old Man With No Antidepressant Response After Two Weeks............................................................................. 11 The Case: 44-Year-Old Woman With Treatment-Resistant Anxious Depression and Comorbid Sleep Disorder.............................. 19 The Case: 30-Year-Old Woman on Antidepressant Treatment Who Wants to Become Pregnant.................................................................. 29 The Case: 72-Year-Old Woman With Severe Depression and Multiple Medical Complications.......................................................... 35 CME Posttest and Activity Evaluation......................................................... 46


CME Information Overview Major depressive disorder is heterogeneous, with differences in both diagnosis and treatment recommendations depending on age, life stage, comorbidities, and unique patient factors. This booklet is a series of five case studies in major depressive disorder, all adapted from real practice, and provides a glimpse into what cases look like after the first consultation, and over time, living through the treatments that work, the treatments that do not work, the mistakes, and the lessons to be learned. Target Audience This activity has been developed for prescribers specializing in psychiatry. There are no prerequisites for this activity. Health care providers in all specialties who are interested in psychopharmacology, especially primary care physicians, nurses, psychologists, and pharmacists, are welcome for advanced study. Statement of Need The following unmet needs regarding depression were revealed following a literature review and through new medical knowledge: • Diagnosing and treating depression across the ages can present with changing challenges, with potentially different treatment guidelines for children, adolescents, pregnant women, and the elderly. • The current care for children and adolescents with depression is not consistent with the available evidence and treatment recommendations, and instead indicates confusion and a lack of awareness of recent data regarding the appropriate use of antidepressants in these patients. • New treatment approaches are constantly being evaluated and can be taken into consideration to optimize treatment. To help fill these unmet needs, quality improvement efforts need to provide education regarding: • Diagnosis of depression and the use of antidepressant medications in specific patient populations, with emphasis on differences related to age and cultural background. • The current labeling of antidepressant medications and how to translate importance into clinical practice. • Evolving evidence and current and novel treatment recommendations and guidelines for depression. Learning Objectives After completing this activity, participants should be better able to: • Identify and diagnose different types and presentations of depression • Make informed decisions regarding the use of antidepressants in the treatment of depression in special populations • Integrate novel treatment approaches into clinical practice • Implement individualized treatment strategies for patients with depression that maximize outcomes Accreditation and Credit Designation Statements The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Neuroscience Education Institute designates this educational activity for a maximum of 3.5 AMA PRA Category 1 Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Also available will be a certificate of participation for completing this activity.

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CME Information

Nurses in most states may claim full credit for activities approved for AMA PRA Category 1 Credits™ (for up to half of their recertification credit requirements). This activity is designated for 3.5 AMA PRA Category 1 Credits. Activity Instructions This CME activity is in the form of a printed monograph and incorporates instructional design to enhance your retention of the information and pharmacological concepts that are being presented. You are advised to go through each case from beginning to end, including the brief tutorial at the end of each case, and then complete the posttest and activity evaluation. The estimated time for completion of this activity is 3.5 hours. Instructions for CME Credit To receive your certificate of CME credit or participation, please complete the posttest (you must score at least 70% to receive credit) and activity evaluation found at the end of the monograph and mail or fax them to the address/number provided. Once received, your posttest will be graded and a certificate sent if a score of 70% or more was attained. Alternatively, you may complete the posttest and activity evaluation online and immediately print your certificate. There is no fee for CME credits for this activity. NEI Disclosure Policy It is the policy of the Neuroscience Education Institute to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. Therefore, all individuals in a position to influence or control content development are required by NEI to disclose any financial relationships or apparent conflicts of interest that may have a direct bearing on the subject matter of the activity. Although potential conflicts of interest are identified and resolved prior to the activity being presented, it remains for the participant to determine whether outside interests reflect a possible bias in either the exposition or the conclusions presented. These materials have been peer-reviewed to ensure the scientific accuracy and medical relevance of information presented and its independence from commercial bias. The Neuroscience Education Institute takes responsibility for the content, quality, and scientific integrity of this CME activity. Individual Disclosure Statements Authors Meghan Grady Director, Content Development, Neuroscience Education Institute, Carlsbad, CA No other financial relationships to disclose. Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine Honorary Visiting Senior Fellow, University of Cambridge, UK Grant/Research: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Dainippon Sumitomo, Forest, Lilly, Lundbeck, Novartis, Pamlab, Pfizer, Pfizer Canada, Pharmasquire, sanofi-aventis, Schering-Plough, Sepracor, Shire, Wyeth Consultant/Advisor: Allergan, Alkermes, Arena, AstraZeneca, BioMarin, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Covance, Cypress Bioscience, Dainippon Sumitomo, Eisai, Forest, GenOmind, GlaxoSmith Kline, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Marinus, MEDACorp/Leerink Swann, Meiji, Merck, Neuronetics, Novartis, Otsuka America, Pamlab, Pfizer, Pfizer Canada, PGxHealth/ Clinical Data, Pierre Fabre, Prexa, Propagate, Rexahn, Royalty, sanofi-aventis, Schering-Plough, Sepracor, Servier, Shire, SK, Sofinnova, Solvay, Vanda, VIVUS, Wyeth Speakers Bureau: Merck, Pfizer, Schering-Plough, Wyeth Peer Reviewer Ronnie Gorman Swift, MD Professor and Associate Chairman, Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla Professor of Clinical Public Health, School of Public Health, New York; New York Medical College, Valhalla Chief of Psychiatry and Associate Medical Director, Metropolitan Hospital Center, New York City No other financial relationships to disclose

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Program Development The following are employed by Neuroscience Education Institute in Carlsbad, CA, and have no other financial relationships to disclose. Rory Daley, MPH, Associate Director, Program Development Steve Smith, President and COO Disclosed financial relationships have been reviewed by the Neuroscience Education Institute CME Advisory Board to resolve any potential conflicts of interest. All faculty and planning committee members have attested that their financial relationships do not affect their ability to present well-balanced, evidence-based content for this activity. Disclosure of Off-Label Use This educational activity may include discussion of products or devices that are not currently labeled for such use by the FDA. Please consult the product prescribing information for full disclosure of labeled uses. Disclaimer The information presented in this educational activity is not meant to define a standard of care, nor is it intended to dictate an exclusive course of patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this educational activity should not be used by clinicians without full evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Primary references and full prescribing information should be consulted. Participants have an implied responsibility to use the newly acquired information from this activity to enhance patient outcomes and their own professional development. The participant should use his/her clinical judgment, knowledge, experience, and diagnostic decision-making before applying any information, whether provided here or by others, for any professional use. Sponsorship Information This activity is sponsored by Neuroscience Education Institute. Support This activity is supported by an educational grant from Lilly USA, LLC. For further information concerning Lilly grant funding visit, www.lillygrantoffice.com. Date of Release/Expiration Release Date: October 1, 2010

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CME Credit Expiration Date: September 30, 2013

The Case: 17-Year-Old Girl Admitted for Severe Depression

The Case: for 17:Year-Old Girl Admitted Severe Depression The Dilemma: Balancing the risks and benefits of treatment for an adolescent patient with depression and risk of suicidality Self-assessment Pretest What type of treatment is recommended first-line for adolescents with severe depression? A. Supportive treatment B. Cognitive behavioral therapy C. Antidepressant D. B or C E. A, B, or C Patient Intake • 17-year-old girl admitted for depression after presenting to the emergency room (ER) with her mother Patient History • • • • • • •

The patient endorses depressive symptoms that include depressed mood, irritability, hyperphagia, hypersomnia, and poor concentration She reports thoughts of death but denies active suicidal ideation She also reports being abused by her stepfather Her mother reports that the patient has been exhibiting agitation, rebelliousness, and belligerent behavior for the past three years and that she recently dropped out of school The patient lost her father four years ago and her mother remarried one year later; the changes in her behavior seem to have originated at about that time She stays to herself and often neglects to care for her activities of daily living She seems to binge eat and has gained about 45 pounds over the past twelve months

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• • • •

In the past two years, she has had four visits to the ER that have led to admission for depression, including two occasions on which she slashed her wrists (superficial cuts requiring stitches) Each of the four previous admissions were brief; she was started on an antidepressant as an inpatient each time (twice on venlafaxine XR, twice on fluoxetine), but she was nonadherent following release There is no known family history of mental illness The patient is not currently on any medications, and her medical history is unremarkable

Question Based on what you have been told so far about this patient’s history and current symptoms, which of the following treatment strategies would you choose? • Medication treatment • Cognitive behavioral therapy (CBT) or interpersonal therapy • Supportive treatment (education, support, and case management) Clinician’s Notes • • • •

Supportive treatment is recommended for adolescents with uncomplicated, mild, or brief depression For adolescents with moderate depression, recommended treatments are either medications [fluoxetine and escitalopram are Food and Drug Administration (FDA) approved], CBT, or interpersonal therapy For adolescents with severe depression and/or risk factors for suicide, recommended treatments are either medication or medication plus CBT Thus, this patient is again prescribed medication to treat her depression

Further Investigation Is there anything else you would especially like to know about this patient? • What was her therapeutic response and side effects during previous medication trials? • She had partial response each time to both fluoxetine and venlafaxine XR • With fluoxetine, she had some anxiety and insomnia • With venlafaxine XR, she had some insomnia and nausea • What reasons did she have for past nonadherence? • She did not believe that the medications would truly help her: “You can’t just fix my life with a pill”

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• Is her binge eating a symptom of depression or of a comorbid eating disorder? • Interview with both the patient and the mother indicates no evidence of self-induced vomiting, misuse of laxatives or diuretics, excessive exercise, or fasting Case Outcome • • • • • •

The patient is prescribed fluoxetine 20 mg/day during her inpatient stay and also receives psychoeducation about the causes of depression and its treatment Department of Social Services is made aware of the abuse allegations against her stepfather After five weeks, she is stabilized and released from the hospital (her stepfather has been arrested) She is referred to a psychiatrist upon discharge from the inpatient unit She shows some improvement in her depressive symptoms but has poor insight and expresses a negative view of herself and the world around her She reports not wanting to wake up, unbelievable tiredness, lack of motivation, and thoughts of death, but she denies suicidal ideation

Question What would you do now? • • • • • • •

Increase fluoxetine dose up to 60 mg/day as tolerated Switch to escitalopram Switch to sertraline Switch to venlafaxine XR Augment with aripiprazole Augment with bupropion Add cognitive behavioral therapy

Clinician’s Notes • • •

Any of these could be a reasonable option Escitalopram is approved to treat major depressive disorder in adolescents Sertraline is not approved to treat major depressive disorder in adolescents, but it is often a preferred treatment in adults for atypical depression (hypersomnia, hyperphagia, low energy), and it may theoretically be preferred in individuals with a history of abuse due to its evidence of efficacy in posttraumatic stress disorder (PTSD)

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• • • • •

Venlafaxine XR is not approved to treat major depressive disorder in adolescents, but like sertraline, it is often preferred for adults with atypical depression Aripiprazole is not approved to treat major depressive disorder in adolescents, but it is approved as an adjunct treatment for depression in adults Bupropion is not approved to treat major depressive disorder in adolescents, but it is often used as an adjunct in adults, particularly to treat symptoms of fatigue and low energy Cognitive behavioral therapy may also be beneficial, particularly considering her history of abuse and loss Given her partial response to fluoxetine, it may be preferable to optimize the dose before switching or adding medications • Although adolescents often receive lower starting doses of antidepressants to avoid unwanted effects, therapeutic doses are similar to those for adults • Fluoxetine is also approved for binge eating in adults, which is a problem for this patient; the therapeutic dose for that indication is 60–80 mg/day

Case Outcomes • • • • • • •

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Fluoxetine dose is titrated gradually to reduce side effects, particularly the activating side effects that can be common with fluoxetine During dose titration, she is carefully monitored for any indications of suicidal behavior • These can include akathisia, irritability, sleep disruption, increased agitation, and induction of mania At 40 mg/day, the patient shows additional improvement; she experiences some jitteriness, but it abates; she does not have any suicidal or parasuicidal behaviors Her dose is ultimately increased to 60 mg/day She has a positive therapeutic alliance with her psychiatrist and is getting along with her mother, although they still have some difficulties with communication She reports improvement in her mood, increased motivation and pleasure, and increased energy • In particular, she expresses interest in going back to school and resuming playing the trumpet Nonetheless, she continues to have a negative view of herself and the world around her; she also exhibits low self-esteem and expresses feelings of guilt


Question What would you do now? • • • •

Add cognitive behavioral therapy Add bupropion Add aripiprazole Add T3 or lithium

Clinician’s Notes • •

Although medication could be added to this patient’s regimen to address ongoing symptoms, it is likely that situational factors (i.e., the abuse she suffered from her stepfather and the untimely death of her father) are playing a significant role in keeping her from remitting Thus, adding cognitive behavioral therapy may be the best treatment option for this patient

Case Debrief • • •

The patient participates in cognitive behavioral therapy and experiences further improvement over time, including improved communication with her mother (who divorces the stepfather) She ultimately graduates from high school and looks forward to college She continues therapy and remains adherent to her medication, with no suicidal or parasuicidal events

Take-Home Points • • • • •

The number one risk factor for suicide across patient populations is untreated depression Additional risk factors in this patient’s history include prior suicide attempts and exposure to abuse Although antidepressants have been associated with an increased risk of suicidality in children and adolescents, a meta-analysis of clinical trials data showed that six times more adolescents would benefit from treatment than would be harmed by it (Bridge et al., 2007) Two antidepressants—fluoxetine and escitalopram—are approved by the FDA for adolescent depression Antidepressants are recommended for adolescents with depression in conjunction with close monitoring, psychoeducation, supportive management, and family and school involvement

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• Monitoring • FDA black box warning suggests weekly face-to-face contact for the first four weeks following antidepressant initiation, followed by biweekly visits for the next four weeks • American Academy of Child and Adolescent Psychiatry recommends telephone contact if face-to-face meetings are not possible • There is no empirical evidence that the particular monitoring schedule proposed by the FDA (or telephone calls) reduces the risk of suicide, but close monitoring in general is particularly important for patients who are at risk for suicide • Psychoeducation and supportive management • Counseling is frequently needed to address self-defeating behavioral patterns, stressful family interactions, and delayed development issues • Psychosocial difficulties often persist following remission of a depressive episode, making it important to continue both antidepressant treatment and treatment that addresses psychosocial issues • Continuation treatment is recommended for 6–12 months and may need to be longer for some patients Performance in Practice Assessment • What could have been done better here? • Should CBT or interpersonal therapy have been started earlier? • Possible action items for improvement in practice • Make sure that options in addition to medication are offered early in treatment • Brief Tutorial: Diagnosis • Common manifestations of depression in adolescents • Irritability (as opposed to sadness) • Mood reactivity (fine with friends, depressed at home or in school) • Low self-esteem • Somatic complaints with no identifiable physiological cause (more so in younger patients) • Change in weight, grades, sleep • Social withdrawal • Medical mimics of depression in adolescents

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Medical cause

Symptoms

Investigations

Hypo/hyperthyroidism

Insomnia, agitation, weight gain/loss

Thyroid function tests

Anemia

Fatigue, hypersomnia

Complete blood count

Sleep disorder

Fatigue, insomnia, snoring

Sleep assessment

Mononucleosis/viral infection

Fatigue, hypersomnia

Epstein-Barr virus test

Steroid medication

Depressed or irritable mood, weight gain, increased appetite

Albuterol sulfate

Irritability, insomnia

Isotretinoin

Depressed mood, suicidality

Medication history, including temporal relationship to symptoms Medication rechallenge test

Brief Tutorial: Developing a Safety Plan • Advise parents to remove lethal means and monitor for risk factors (be explicit, do not rely on “common sense”) • Clean old and unused medications out of medicine cabinet • Severely limit amount of alcohol kept in house • Lock up or remove all weapons • In emergency, call 911 or bring the child to the nearest ER if practical • 1-800-lifenet (give them a card with this number to keep on the refrigerator) • Engage a concerned third party • Establish mutually agreeable emergency contacts in the event of increasing suicidality • Establish clear follow-up • Do not rely on safety contracts • Behavioral warning signs of suicidality • Expressing self-destructive thoughts • Drawing morbid or death-themed pictures • Engaging in death-themed activity (music, video games, books, etc.) • Giving away possessions

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Brief Tutorial: Treatment Tips and Prescribing Pearls

• Medications • Pooled AD trials: NNT=10, NNH=112 • Fluoxetine and escitalopram are approved • Warn patient and family about adverse effects • Signs of switch to mania (excessive spending, risk-taking, needing little sleep, promiscuous behavior, racing thoughts, pressured speech) • Signs of behavioral activation (agitation, hostility, restlessness, suicidal ideation or behavior) • Starting dose is typically lower for adolescents than for adults to avoid unwanted side effects • Develop regular, frequent monitoring schedule

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The Case: 17-Year-Old Girl Admitted for Severe Depression Medication

Dose (mg/day)

Side Effects

Contraindications

Initial

Therapeutic

Maximum

Fluoxetine

10

20

60

Headache, GI, insomnia, agitation

MAOIs, pimozide, thioridazine, tamoxifen

Escitalopram

5

10-20

20

Headache, GI, insomnia

MAOIs, pimozide

Citalopram

10

20

60


MAOIs, pimozide, thioridazine

Duloxetine

40

40-60

120

GI, insomnia, increase in BP, urinary retention

MAOIs, thioridazine, uncontrolled narrow angle-closure glaucoma, substantial alcohol use

Fluvoxamine

25-50

150

300

Headache, GI, sedation

MAOIs, primozide, thioridazine, tizanidine, alosetron, ramelteon

Paroxetine

10

20

60


MAOIs, primozide, thioridazine, tamoxifen

Sertraline

25

100

200


MAOIs, primozide, thioridazine, disulfiram (oral concentrate only)

Venlafaxine XR

37.5

75-225

375

Headache, GI, insomnia, increase in BP

MAOIs, uncontrolled narrow angle-closure glaucoma

• CBT • Typically weekly sessions for 12–16 weeks • Identify self-defeating behaviors • Correct maladaptive thoughts • Encourage participation in pleasurable activities • Develop or reactivate social skills • Develop problem solving strategies • Interpersonal therapy • Typically 12–16 weeks • Addresses relationship difficulties arising from • Grief (loss of someone significant) • Interpersonal disputes (frequent fights with peers or family members) • Role transition (change in school, breakup) • Interpersonal deficits (no significant relationship outside of family)

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Self-assessment Posttest What type of treatment is recommended first-line for adolescents with severe depression? A. Supportive treatment B. Cognitive behavioral therapy C. Antidepressant D. B or C E. A, B, or C (Answer: D. B or C (Cognitive behavioral therapy or Antidepressant)

References American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; 2000. Birmaher B, Brent D, AACAP Work Group on Quality Issues et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 2007;46:1503-26. Bridge JA, Iyengar S, Salary CB et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96. Cheung A, Ewigman B, Zuckerbrot RA, Jensen PS. Adolescent depression: is your young patient suffering in silence? J Fam Pract 2009;58(4):187-92. Goren JL. Antidepressant use in pediatric populations. Expert Opin Drug Saf 2008;7(3):223-5. Stahl SM. Stahl’s essential psychopharmacology: the prescriber’s guide. 3rd ed. New York, NY: Cambridge University Press; 2009. Zuckenbrot RA, Cheung AH, Jensen PS, Stein RE, Laraque D, GLAD-PC Steering Group. Guidelines for adolescent depression in primary care (GLAD-PC): I. identification, assessment, and initial management. Pediatr 2007;120;e1299-e1312.

For Your Patients www.familydoctor.org www.aacap.org www.kidshealth.org www.medlineplus.gov www.suicidehotlines.com

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The Case: 24-Year-Old Man With No ter Antidepressant Response Af Two Weeks Dilemma: Is trying an antidepressant for 6–12 weeks before adjusting treatment the best practice or just the standard practice? Self-assessment Pretest New and ongoing research has the potential to lead to what type of revisions to depression treatment guidelines? A. Increased duration of monotherapy trial B. Decreased duration of monotherapy trial Patient Intake • 24-year-old man with first-episode major depressive disorder The Problem • • • • • • • • • •

The patient is a 24-year-old college graduate with no history of major depressive disorder but a possible history of dysthymia beginning in his early teens He is currently experiencing his first major depressive episode, which is characterized by depressed mood, anhedonia, lack of motivation, poor appetite, weight loss, fatigue, and insomnia He denies suicidal ideation but admits that he thinks about death and sometimes wishes he were dead He is employed as an IT specialist at a large company; lately, he has had to take many sick days, and he is concerned about losing his job He has a girlfriend, who has been supportive of him He does not have any family history of mental illness He began taking sertraline (titrated to 200 mg/day) two weeks ago He initially experienced mild side effects, including headache and nausea, but these have abated; however, he has had no therapeutic response He is particularly bothered by his insomnia and lack of energy; he feels that these symptoms are preventing him from being able to function He has no relevant medical history and does not take any medications other than sertraline 11


Question Which of the following would be your recommended course of action at this point for this patient? • • • • •

Maintain sertraline at current dose for several more weeks Raise the dose of sertraline Switch sertraline to a different antidepressant Augment sertraline with another antidepressant Augment sertraline with a non-antidepressant psychotropic drug

Case Outcome • • • • • • •

Standard practice guidelines state that an adequate trial of antidepressant monotherapy is at least six weeks, after which one should switch (in the event of no response) or augment (in the event of partial response) New data are emerging that suggest that the majority of improvement with antidepressant monotherapy is apparent within the first two weeks; therefore, it may be beneficial to adjust medication treatment at this stage if no response has occurred The data supporting these strategies are preliminary and still under investigation Because he is tolerating sertraline and has only been on it for two weeks, the medication is continued However, because he is particularly bothered by the symptom of insomnia, the sedative hypnotic eszopiclone is added to his sertraline He experiences improvement in his sleep within a few days, and over the course of the next few weeks, he reports some improvement in mood and outlook on life He continues to experience fatigue and lack of motivation, and he is going to maintain his current regimen for another few weeks to see if these symptoms begin to improve

Case Debrief • •

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Recent data show that the majority of improvement with antidepressant monotherapy occurs within the first two weeks of treatment, suggesting that early medication change or early combination may be a better practice than the current standard of maintaining antidepressant monotherapy for at least six weeks in patients who have not responded after two weeks Both of these strategies are currently under investigation; however, as of today, the existing data are preliminary and do not warrant revision to practice guidelines

The Case: 24-Year-Old Man With No Antidepressant Response After Two Weeks

• • • • • •

Nonetheless, there may be individual patients for whom it is preferable to change or augment medication early In this patient’s case, he had no response after two weeks with sertraline and was particularly troubled by his insomnia There are data that support the early combination of an antidepressant with a sedative hypnotic to enhance the likelihood of remission not only through improved insomnia, but also through improvement in other symptoms This patient experienced immediate improvement in insomnia following augmentation of sertraline with eszopiclone, and over the next few weeks, he experienced improvement in some (though not all) of his other symptoms Whether the overall improvement can be attributed to the addition of eszopiclone or simply to more time on sertraline cannot be known for sure Ultimately, getting patients to remission as quickly as possible is key to long-term outcomes

Brief Tutorial: Remission Rates for Major Depressive Disorder

• Approximately one-third of depressed patients will initially remit during treatment with any antidepressant

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• • • • •

Unfortunately for those who fail to remit, the likelihood of remission with another antidepressant monotherapy decreases with each successive trial Thus, after a year of treatment with four sequential antidepressants taken for twelve weeks each, only two-thirds of patients will have achieved remission Relapse rates are significantly less for patients who achieve remission However, there is still a risk of relapse even in remitters, and the likelihood increases with the number of treatments it takes to get the patient to remit Relapse rate at twelve months after one treatment • Nonremitters: 60% Remitters: 33% • Relapse rate at six months after four treatments • Nonremitters: 70% Remitters: 70% Brief Tutorial: Current Practice Guidelines for Major Depressive Disorder

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The Case: 24-Year-Old Man With No Antidepressant Response After Two Weeks

Brief Tutorial: Meta-Analysis Shows That Majority of Improvement Occurs in First Two Weeks of Treatment

• • • • • • • •

This meta-analysis (Posternak and Zimmerman, 2005) showed no evidence of a delayed antidepressant response As shown in the graph, 60.2% of improvement for active and 61.6% for placebo occurred during the first two weeks; additionally, 57% of the drug-placebo difference occurred during the first two weeks Re-analysis showed this could not be accounted for by soporific side effects of antidepressant medications nor by differential attrition rate Only 1 in 5 studies elicited a greater proportion of drug-placebo differences in weeks 3 through 6 versus weeks 1 and 2 Other meta-analyses have also shown results consistent with this one (e.g., Papakostas et al., 2006 and Taylor et al., 2006) The 47 trials included venlafaxine (n=1120), imipramine (n=998), amitriptyline (n=618), fluoxetine (n=511), sertraline (n=444), paroxetine (n=414), doxepin (n=306), zimelidine (n=169), mirtazapine (n=166), nefazodone (n=122), bupropion (n=110), citalopram (n=103), and fluvoxamine (n=77) The Early Medication Change (EMC) trial, which is currently in progress, is a Phase IV, multi-center, multi-step, randomized, observer-blinded, actively controlled, parallel-group clinical trial The EMC trial is the first prospective investigation of whether nonimprovers at 14 days of antidepressant treatment with early medication change are more likely to achieve remission by 56 days than those with treatment as usual

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Brief Tutorial: Several Studies Suggest Enhanced Remission With Early Combination

• •

Ongoing trial: Combining Oral Medications to End Depression (COMED) on the Depression Trials Network COMED is funded by NIMH and compares the potential benefits of combining any two antidepressants at initiation (bupropion, escitalopram, mirtazapine, venlafaxine)

Self-assessment Posttest New and ongoing research has the potential to lead to what type of revisions to depression treatment guidelines? A. Increased duration of monotherapy trial B. Decreased duration of monotherapy trial (Answer: B. Decreased duration of monotherapy trial)

References Cipriani A, Furukawa TA, Salanti G et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373:746-58. Papakostas GI, Perlis RH, Scalia MJ, Peterson TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006;26(1):56-60. Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005;66(2):148-58. Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008.

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The Case: 24-Year-Old Man With No Antidepressant Response After Two Weeks Stahl SM. Stahl’s essential psychopharmacology: the prescriber’s guide. 3rd ed. New York, NY: Cambridge University Press; 2009. Stahl SM. Combining antidepressant therapies from the initiation of treatment: a paradigm shift for major depression. J Clin Psychiatry 2009;70. Tadic A, Gorbulev S, Dahmen N et al. Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder—the EMC trial. Trials 2010;11:21. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006;63:1217-23.

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The Case: Treatment44-Year-Old Woman With n and Resistant Anxious Depressio Comorbid Sleep Disorder The Dilemma: What treatment options are there after antidepressants and ECT fail, and how can treatment for depression be balanced with complex treatment for sleep disorders? Self-assessment Pretest Which of the following are approved treatments for resistant depression? A. Deep brain stimulation B. Transcranial magnetic stimulation C. Vagal nerve stimulation D. A and B E. B and C Patient Intake • 44-year-old woman with a chief complaint of anxiety, depressed mood, and daytime sleepiness Psychiatric History • • • •

The patient had onset of anxiety and depression at about age 15, which she self-medicated with alcohol After graduating from high school, she began college and was about to leave for a study abroad program when she experienced a panic attack, for which she was treated in the emergency room She was then hospitalized and treated for alcohol abuse at age 18; she has remained sober ever since, although she does admit to some possible alprazolam abuse at age 27 as well as one overdose with alprazolam Her history also includes multiple hospitalizations for major depression • Age 19 (approximately one year after her release from the hospital for alcohol abuse), because she became suicidal • Age 24, due to recurrence of depression • Age 26, with an overdose following a divorce and a recurrence of depression • Age 27, due to a recurrence of depression

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• • • •

• Age 29, status post two miscarriages, with a possible postpartum element and some discontinuation of her medications at that time to try to get pregnant • Age 30, when she received electroconvulsive therapy (ECT): 7 sessions as an inpatient and 23 as an outpatient She was much better for several years following her ECT treatment, but she had severe memory impairment She had a recurrence of her depression earlier this year that was characterized by prominent sleepiness, loss of appetite, low motivation, anhedonia, and trouble concentrating She had to go out on disability and then resign from a job that she had enjoyed She continues to be disabled from depression and also has a great deal of anxiety

Additional History • Married since 1996 (second marriage); no children • Medical history • Narcolepsy • Nighttime urinary incontinence possibly related to highly sedating medications • Family history • Grandmother with depression who received ECT with good results • Medication history • Details are unclear from available information and the patient’s memory, but she has taken numerous psychotropic drugs, including antidepressants, antipsychotics, and mood stabilizers, all with poor results • Current medications • Bupropion 450 mg/day (thinks it is helpful as she worsens if she tries to taper) • Ziprasidone 60 mg in the morning and 180 mg at night (unsure if this is helpful) • Lamotrigine 200 mg in the morning and 150 mg at night (thinks it is helpful for her mood) • Gabapentin 300 mg in the morning, 600 mg at noon, and 900 mg at night; occasional 100 mg as needed for breakthrough anxiety (experiences intolerable return of anxiety at much lower doses) • DDAVP 0.4 mg/night for bedwetting • Sodium oxybate 9 ml in one dose at night for narcolepsy and daytime sleepiness

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The Case: 44-Year-Old Woman With Treatment-Resistant Anxious Depression and Comorbid Sleep Disorder

• Methylphenidate extended-release 54 mg/day for daytime sleepiness (thinks it is helpful) Question Based on what you have been told so far about this patient’s history and current symptoms, do you think she falls within the bipolar spectrum? • Yes • No Question Would you continue her “mood-stabilizing” medications? • • • •

Yes, continue both ziprasidone and lamotrigine Continue ziprasidone but discontinue lamotrigine Continue lamotrigine but discontinue ziprasidone No, discontinue both ziprasidone and lamotrigine

Clinician’s Notes • • • •

The nature of several recurrences makes this patient appear to be somewhat unstable; however, she has not shown any overt signs of bipolarity The best diagnosis for this patient may be severe generalized anxiety with major depressive recurrent unipolar disorder Nevertheless, tactics that are useful for bipolar mood disorders may be useful in this patient Continuing ziprasidone and lamotrigine may help mitigate the risk of a future relapse

Further Investigation Is there anything else you would especially like to know about this patient? • What are the details concerning the diagnoses of narcolepsy and restless legs syndrome? What treatments has she been given and what were her responses to them? • •

During the past year, as her depression has recurred and worsened, she has developed excessive daytime sleepiness She had an overnight sleep polysomnogram done in another city that supposedly showed sleep-onset REM periods, but you do not have a copy of the report and do not know if it was done while she was taking medications or after withdrawal of any medications

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Question Based on what you know so far about this patient’s history, current symptoms, and treatment responses, would you continue her sleep disorder medications? • Yes, continue all three (methylphenidate, sodium oxybate, and DDAVP) • No, stop one or more of these Clinician’s Notes • • •

The patient’s complaint of excessive daytime sleepiness can be difficult to assess given all the medications she is taking, especially sodium oxybate and gabapentin, which can cause daytime sleepiness It can also be difficult to determine whether her sleepiness represents narcolepsy or hypersomnia as an associated symptom of depression It is even possible that her sleep disorder treatments are interfering with her treatments for depression and anxiety

Case Outcome • • • • • •

Sodium oxybate is tapered and then DDAVP is discontinued The patient experiences some initial insomnia and restless sleep as sodium oxybate is withdrawn, but this resolves after several days, as does her incontinence Her daytime sleepiness actually improves, but she continues to have problems falling asleep some nights Her daytime gabapentin is then tapered to half-dose, which leads to improvement in daytime sleepiness; but this is only tolerated intermittently due to a reemergence of anxiety She continues to have depression, and her anxiety waxes and wanes throughout the day and night She feels that her results are unsatisfactory overall

Question Considering her former response and side effects with ECT, would you consider using an alternative treatment method for her refractory symptoms? • • • • •

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Yes, consider ECT Yes, consider vagal nerve stimulation Yes, consider transcranial magnetic stimulation Yes, consider deep brain stimulation I would not send her for an experimental protocol



The patient’s prior response to ECT suggests that it or a similar treatment may be beneficial She is hesitant to try ECT again because of the memory loss she sustained, but she may benefit from another alternative treatment strategy Vagal nerve stimulation (approved for treatment-resistant depression) • It involves the surgical implant of a stimulation device in the upper left side of the chest (intended as a permanent implant, although it can be removed) • The pulse generator can be programmed to deliver electrical impulses to the vagus nerve at various durations, frequencies, and currents • Stimulation typically lasts 30 seconds and occurs every five minutes • Transcranial magnetic stimulation (approved for treatment-resistant depression) • Generally done on an outpatient basis • Electromagnetic coil is placed against the scalp near the forehead and is turned off and on repeatedly; a session typically lasts 30–50 minutes • Typical treatment duration is five treatments a week for four to six weeks • Deep brain stimulation (in trials for treatment-resistant depression) • Involves two surgical procedures, one to implant electrodes in the brain and a second to implant a neurostimulator in the chest • Stimulation is generally constant but can be temporarily turned off by holding a hand-held magnetic device over the area of the chest where the neurostimulator is located Would you continue her methylphenidate for daytime sleepiness? • Yes • No Clinician’s Notes • • •

On the one hand, methylphenidate seems to be helpful for her daytime sleepiness and one could even consider raising the dose to try to alleviate her depression On the other hand, this could risk making her anxiety worse and to the extent that daytime sleepiness is related to medication side effects, it may be better to adjust those For now, the patient is unwilling to stop the stimulant, and after a discussion of risks and benefits, methylphenidate is continued

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Would you consider adding any of the following medications to her regimen? • • • • • •

Lithium (to boost mood and mitigate the risk of cycling) Monoamine oxidase inhibitor (MAOI) (to boost mood) Mirtazapine (to boost mood and possibly treat anxiety) Quetiapine (to boost mood and possibly treat anxiety) Aripiprazole (to boost mood) None of these

Clinician’s Notes • Lithium • Could help boost her mood and mitigate the risk of future relapse • If added, it may not be necessary to give her a full dose, as she is already on other mood-stabilizing medications • MAOI • May help boost mood, as this has been effective for patients with anxious depression • However, this could also be activating for some patients and could cause problems with sleep and anxiety • If added, a MAOI would require the discontinuation of bupropion • Transdermal selegiline does not require dietary restriction and may be a preferable formulation • Mirtazapine • May boost mood and potentially treat anxiety • Quetiapine • May boost mood (recently approved for the depressed phase of bipolar disorder and as an adjunct for unipolar depression) • May also be helpful for anxiety (anecdotal reports as adjunct) • If added, it may require careful dosing to avoid daytime sedation • Aripiprazole • May boost mood (recently approved as an adjunct for unipolar depression) • Can be activating and can cause problems with anxiety Case Outcome •

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The patient is encouraged to switch from bupropion to mirtazapine, but she opts instead to try aripiprazole augmentation of her current medications (bupropion, lamotrigine, gabapentin, methylphenidate) while switching off of ziprasidone


• • • • • •

Aripiprazole is titrated from 2 mg/day to 5 mg/day while ziprasidone is discontinued; over the course of one month, there are no changes, good or bad Aripiprazole is increased to 10 mg/day and there is some improvement over the next four weeks After a second month on aripiprazole, there is no further improvement in depression or anxiety and overall results are not satisfactory She is switched from aripiprazole to quetiapine; she does not experience improvement in mood or anxiety, but her sleepiness worsens She is offered a trial of mirtazapine or a MAOI, but she says she would rather consider TMS or another round of ECT Her insurance does not cover TMS, so she will go for another round of ECT and consider a MAOI afterwards

Case Debrief • • • •

The patient has a 25-year history of recurrent anxiety and depression that appears unipolar in nature and has been somewhat responsive to antidepressants and very responsive to ECT in the past Her current relapse is causing her disability and is not fully responsive to the various medication regimens that have been tried Because of her prior response to ECT, she may be an excellent candidate for VNS or TMS, but insurance coverage is preventing the use of these options She may experience benefit from this next course of ECT; additional adjustments to her medications may also be helpful, including trial of a MAOI

Take-Home Points • • •

It can be difficult to determine whether sleep-related problems (insomnia or anxiety at night, daytime sleepiness) are due to a sleep disorder, an anxiety disorder, a mood disorder, or the side effects of medications Simplifying a complicated medication regimen may help determine whether some of the symptoms are due to medications In addition to medications, there are alternative options for patients with resistant depression, but it may be difficult to get insurance approval for some of the more novel approaches

Performance in Practice Assessment • What could have been done better here? • Did it take too long to get to the ECT recommendation?

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• Should she have been pushed harder to try mirtazapine or a MAOI rather than augmentation with atypical antipsychotics? • Possible action items for improvement in practice • Atypical antipsychotics are expensive and can have notable side effects, so make sure that augmentation with these agents is neither the only option offered nor the only option offered early • Despite less robust comparative data, agents such as mirtazapine or MAOIs can be considered earlier in the treatment algorithm Brief Tutorial: Treatment Options for Resistant Depression • •

• • • •

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Lithium augmentation has the best evidence, particularly for patients with suicidality Antidepressant combinations of drugs with different mechanisms are also evidence-based • Reuptake inhibitors plus drugs that block the presynaptic autoreceptor (e.g., mirtazapine, trazodone) may be synergistic combinations Adding thyroid hormone or an atypical antipsychotic is also relatively well evidenced ECT is well established but has cognitive side effects VNS and TMS are approved Investigational options include DBS, ketamine, and others


Brief Tutorial: Sedative Effects of Medications

bupropion escitalopram fluoxetine selegiline sertraline

citalopram desvenlafaxine duloxetine milnacipran venlafaxine

aripiprazole

fluphenazine haloperidol pimozide thiothixene ziprasidone

lamotrigine

oxcarbazepine

amphetamine (d) amphetamine (d,l) lisdexamfetamine methylphenidate (d) methylphenidate (d,l) modafinil

sodium oxybate

Antidepressants

Antipsychotics

Mood stabilizers and anticonvulsants

Sleep disorder treatments

amitriptyline amoxapine clomipramine desipramine doxepin fluvoxamine imipramine isocarboxazid lofepramine maprotiline mirtazapine nefazodone nortriptyline paroxetine phenelzine protriptyline tranylcypromine trazodone trimipramine loxapine mesoridazine molindone olanzapine paliperidone perphenazine risperidone thioridazine trifluoperazine gabapentin levetiracetam lithium pregabalin tiagabine topiramate zonisamide

chlorpromazine clozapine quetiapine

carbamazepine valproate

Sedation scale: unusual = reported in few patients; not unusual = occurs in a significant minority; common = many experience or can be in significant amount; problematic = occurs frequently, can be in a significant amount, and may be a health problem in some patients

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Self-Assessment Posttest Which of the following are approved treatments for resistant depression? A. Deep brain stimulation B. Transcranial magnetic stimulation C. Vagal nerve stimulation D. A and B E. B and C Answer: E. B and C (Transcranial magnetic stimulation and Vagal nerve stimulation)

References Brunoni AR, Teng CT, Correa C et al. Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting. Arq Neuropsiquiatr 2010;68(3):433-51. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a metaanalysis of placebo-controlled randomized trials. Am J Psychiatry 2009;166:980–91. Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008. Stahl SM. Stahl’s essential psychopharmacology: the prescriber’s guide. 3rd ed. New York, NY: Cambridge University Press; 2009.

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The Case: tidepressant 30-Year-Old Woman on An come Treatment Who Wants to Be Pregnant Dilemma: Balancing the risk of treatment to the fetus against the risk of no treatment to the mother Self-assessment Pretest Which of the following is true regarding paroxetine during pregnancy? A. No known risk of fetal toxicity B. Known risk of fetal toxicity at extreme doses only C. Known risk of fetal toxicity at therapeutic doses Patient Intake • 30-year-old woman in remission from depression on paroxetine 40 mg/day The Problem • • • • • • • • •

She experienced her first depressive episode at age 26 She was treated with citalopram and experienced notable improvement in her symptoms after three months After a year of treatment, she decided to discontinue her medication Six months later, she developed another major depressive episode She was first prescribed citalopram but had minimal response after three months She was switched to paroxetine, to which she responded and ultimately remitted The patient has been maintained on paroxetine for over two years, with no recurrence of her depression She and her husband now want to start a family, and she is concerned about the use of her medication during pregnancy She also wants to breastfeed and is concerned about any effects the medication may have on the infant

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Question Which of the following would be your recommended course of action for this patient during her pregnancy? • • • •

Maintain paroxetine at its current dose Reduce the dose of paroxetine Switch to a different antidepressant Discontinue antidepressant medication

Case Outcome • • • • • • • • •

This patient’s history suggests that continued treatment may be important to avoid relapse or recurrence of depression; however, there are risks associated with antidepressant treatment during pregnancy and with paroxetine in particular Epidemiological data have shown an increased risk of cardiovascular malformations (primarily ventricular and atrial septal defects) in infants born to women who took paroxetine during pregnancy Paroxetine use late in pregnancy may be associated with a higher risk of neonatal complications, including respiratory distress Because of the known risks associated with paroxetine, her clinician recommends switching to another antidepressant However, after listening to the risks and benefits of continued treatment, the patient is not comfortable with the potential risks associated with antidepressant treatment during pregnancy, and she decides to discontinue medication In light of this, she is advised to resume antidepressant treatment shortly after giving birth in an effort to mitigate the risk of postpartum depression In addition, she is advised to report the onset of any depression-related symptoms; she has a follow-up appointment scheduled She becomes pregnant three months after discontinuing paroxetine and remains depression-free during her pregnancy She resumes paroxetine treatment after giving birth, with no apparent adverse effects for the infant

Case Debrief •

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There are risks for both antidepressant use during pregnancy and absence of treatment during pregnancy, but there are no randomized controlled trials comparing the effects of antidepressants vs. depression during pregnancy

The Case: 30-Year-Old Woman on Antidepressant Treatment Who Wants to Become Pregnant

• • • • •

Ultimately, one must weigh the risks of treatment against the risk of no treatment and work with the patient and obstetrician to develop the best treatment strategy possible for her unique situation The immediate postpartum period is a high-risk time for depression, especially in women who have had prior depressive episodes; so, if medication is discontinued during pregnancy, it may need to be reinstated late in the third trimester or shortly after childbirth to prevent a recurrence during the postpartum period Again, it is important to work with the patient and pediatrician to develop the best treatment strategy possible For women who take an antidepressant while breastfeeding, it is often recommended to take the medication immediately after breastfeeding and prior to the infant’s sleep time in order to minimize exposure to peak drug concentrations Infants should be monitored for adverse effects, such as sedation, irritability, or change in sleep/feeding patterns

Brief Tutorial: Incidence and Risk of Depression Across Female Life Cycle

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• •

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

Brief Tutorial: Risks of Untreated Depression vs. Antidepressants Antidepressant effects First trimester Impaired feto-placental function Minor physical anomaly Miscarriage Miscarriage Low fetal growth Premature delivery Low birth weight Small gestational age Perinatal complications Septal heart defects Untreated depression

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Third trimester Low birth weight Small gestational age Pulmonary hypertension Gestational hypertension Preeclampsia Neonatal withdrawal (respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, constant crying) Neuropsychological behavioral impairment?

The Case: 30-Year-Old Woman on Antidepressant Treatment Who Wants to Become Pregnant

Brief Tutorial: Antidepressant Use During Pregnancy and Lactation Generic

Pregnancy Risk Category

Amitripyline Bupropion Citalopram Clomipramine Desipramine Doxepin Duloxetine Escitalopram

C C C C C C C C

American Academy of Pediatrics (AAP) Rating Unknown, of concern Unknown, of concern Not available Unknown, of concern Unknown, of concern Unknown, of concern Not available Not available

Fluoxetine

C

Unknown, of concern

Fluvoxamine Imipramine Mirtazapine Nefazodone Nortiptyline Paroxetine Sertraline Trazodone Venlafaxine

C D C C D D C C C

Unknown, of concern Unknown, of concern Not available Not available Unknown, of concern Unknown, of concern Unknown, of concern Unknown, of concern Not available

• • • • •

Lactation Risk Category L2 L3 L3/L3 in older infants L2 L2 L5 Not available L3/L3 in older infants L2 in older infants, L3 if used in neonatal time L2 L2 L3 L4 L2 L2 L2 L2 L3

Pregnancy risk category indicates risk severity Ranked from A–D, X (A = lowest risk, X = highest risk) AAP rating indicates research findings or lack thereof Lactation risk category indicates risks to infant during nursing period The higher the number, the higher the risk

Self-assessment Posttest Which of the following is true regarding paroxetine during pregnancy? A. No known risk of fetal toxicity B. Known risk of fetal toxicity at extreme doses only C. Known risk of fetal toxicity at therapeutic doses (Answer: C. Known risk of fetal toxicity at therapeutic doses)

References Field. T. Prenatal depression and selective serotonin reuptake inhibitors. Int J Neurosci 2010;120:163-67. Gentile S, Galbally M. Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review. J Aff Disord 2010; Epub ahead of print. Payne JL. Antidepressant use in the postpartum period: practical considerations. Am J Psychiatry 2007;164(9):1329-32. Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age. Pediatr 2010;125;e600-e608.

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The Patient Cases: Depression Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008. Stahl SM. Stahl’s essential psychopharmacology: the prescriber’s guide. 3rd ed. New York, NY: Cambridge University Press; 2009.

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The Case: Severe 72-Year-Old Woman With edical Depression and Multiple M Complications The Dilemma: How aggressive should one be with antidepressant treatment in elderly, medically ill patients? Self-assessment Pretest Which of the following is true regarding the use of antidepressants in the elderly? A. B. C.

For most antidepressants, the recommended therapeutic dose is substantially lower in the elderly than it is in younger adults For most antidepressants, the recommended therapeutic dose is the same in the elderly as it is in younger adults, though tolerability may be better at lower doses For most antidepressants, the recommended therapeutic dose is the same in the elderly as it is in younger adults, with no apparent dose-dependent effects on tolerability

Patient Intake • 72-year-old woman with a chief complaint of anxiety Patient History • • • •

She was well until age 32, when she had her first major depressive episode The episode was characterized by depressed mood and loss of appetite, but not anxiety; she was treated with a tricyclic antidepressant and recovered Her second episode was at age 45, after her husband died prematurely; her depression may have been a prolonged grief episode; she was not treated and she ultimately recovered Her third episode was at age 69 and was characterized by severe anxiety and depression; both have continued off and on despite treatment for the past three years • First, she received paroxetine treatment and recovered • She discontinued it after a few months and relapsed • She was retreated with paroxetine and responded again, but then stopped it and relapsed again 35


• Because of severe anxiety, she was given olanzapine 5 mg/day, which helped her anxiety but not her depression • She had no response to nefazodone or desipramine, and venlafaxine made her more anxious • She was then given seven ECT treatments, but her depression did not improve; the ECT treatments caused memory problems • Lithium, cytomel, and perphenazine were not very helpful • She is postmenopausal and is on estrogen/progestin replacement therapy • She has no known family history of mental illness Patient Evaluation • • • • •

She walks into the office with a shuffling gait, masked facies, rigidity, and a tremor She is parsimonious in speech and she appears flat and apathetic; however, she complains of severe anxiety She is not suicidal and her memory is intact She complains of anhedonia, lack of energy, and little motivation and interest while also experiencing anxiety and disrupted sleep She is currently on loxapine and alprazolam

Question Based on what you have been told so far about this patient’s history and current symptoms, what do you think her primary diagnosis is? • • • •

Unipolar major depression with anxiety Nonresponsiveness to antidepressant treatment suggests mixed-state bipolar disorder rather than anxious depression Motor symptoms suggest the depression subtype that is associated with Parkinson’s disease Nonresponsiveness to antidepressant treatment with prominent apathy suggests early dementia

Further Investigation Is there anything else you would especially like to know about this patient? • When did her motor symptoms start? • She is unsure exactly, but she states that it has been several weeks • Has anyone noticed any problems with her memory? • She denies any recent increase in memory problems and says that no one else has mentioned anything to her

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The Case: 72-Year-Old Woman With Severe Depression and Multiple Medical Complications

• She agrees to let you speak with her daughter, who is in the waiting room; the daughter confirms that there do not seem to be any new memory problems or trouble with losing things Question Of the following choices, what would you do? • • • • • • • •

Maintain her current regimen Discontinue the antipsychotic Discontinue the benzodiazepine Switch the antipsychotic Add antidepressant Discontinue antipsychotic and add antidepressant Discontinue antipsychotic and add mood stabilizer Discontinue antipsychotic and benzodiazepine and add antidepressant

Clinician’s Notes • Unipolar major depression with anxiety • This is a reasonable diagnosis for this patient, though it does not account for her motor symptoms • Nonresponsiveness to antidepressant treatment suggests mixed-state bipolar disorder rather than anxious depression • Her history does not suggest nonresponse in general, but rather multiple relapses following treatment discontinuation • Motor symptoms suggest the depression subtype that is associated with Parkinson’s disease • Although it is possible that she has Parkinson’s disease, her depression precedes her motor symptoms by three decades • Nonresponsiveness to antidepressant treatment with prominent apathy suggests early dementia • Although early dementia cannot be ruled out, apathy is also a common manifestation of depression in the elderly • As mentioned before, she does not have a history of nonresponsiveness, but rather lack of response to certain medications and relapse following discontinuation of others • She is diagnosed with unipolar depression with anxiety and drug-induced parkinsonism (not Parkinson’s disease) • The decisions are made to discontinue her antipsychotic, maintain her benzodiazepine, and initiate an antidepressant

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Question Of the following antidepressants, which would you add to her alprazolam? • • • • • • • • •

SSRI (serotonin selective reuptake inhibitor) SNRI (serotonin norepinephrine reuptake inhibitor) NDRI (bupropion; norepinephrine dopamine reuptake inhibitor) NRI (norepinephrine reuptake inhibitor) Mirtazapine Trazodone Tricyclic antidepressant MAO inhibitor I would not give an antidepressant


In general, any of these may be used for this patient Because her main complaint is anxiety, it may not be best to use a NDRI or a NRI, as these agents do not have good evidence of efficacy in anxiety Many elderly patients respond well to mirtazapine, especially those with agitated depression with reduced appetite and weight loss

Case Outcomes • • • •

Loxapine is discontinued; she continues to take alprazolam 0.25 mg three times a day Mirtazapine is initiated at 15 mg/day at bedtime, increasing to 30 mg in a few days based on tolerability Four weeks later, she still has parkinsonism; she and her daughter are concerned that this means she has Parkinson’s disease She is somewhat sleepy during the day, but she wakes up anxious and nervous; her decreased appetite continues and, if anything, her anxiety is worse

Question At this point, which of the following seems most likely with respect to her parkinsonism? • • •

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The diagnosis should be reevaluated because drug-induced parkinsonism should have resolved by now Drug-induced parkinsonism is still the most likely diagnosis because the symptoms would not be expected to resolve for several more weeks Drug-induced parkinsonism is still the most likely diagnosis, but if the symptoms have not resolved by now, it is likely that they never will


Clinician’s Notes • •

Although it is certainly possible that the patient has Parkinson’s disease, four weeks is often insufficient time for dopamine receptors to readapt to normal following antipsychotic washout Waiting 2–6 months is necessary to be sure that the movement symptoms are not due to loxapine

Case Outcomes • • • •

In order to address her daytime sleepiness and ongoing anxiety, mirtazapine is increased to 45 mg at night and alprazolam is adjusted to 0.5 mg at night Eight weeks later, the patient has less depression, worry, and sedation, and her parkinsonism is resolved However, during that time, she had fallen and broken her hip, requiring hip replacement She still has problems coping; so, she is living with her daughter

Question Are you concerned that her fall could have been due to the sedative medications that she is taking? • Yes • No Clinician’s Notes • • • •

Her fall could have been due to sedative medications, especially alprazolam, as benzodiazepines and sedating antidepressants have been reported in some (but not all) studies to increase the risk of falls Parkinsonism—whether drug-induced or Parkinson’s disease—is also associated with falls in the elderly Nevertheless, this patient is not sedated by her medications, and her thinness, frailty, and lack of energy from depression may also have been contributors Thus, it is not clear that her medications led to her fall; on balance, continuing prior medications seems indicated

Case Outcomes • •

She continues mirtazapine 45 mg and alprazolam 0.5 mg at night and is tolerating them well and responding to them; however, she still has ongoing symptoms of anxiety Venlafaxine XR is initiated at 37.5 mg and then increased to 75 mg/day 39


• • • • • •

Eight weeks later, the patient is “not as nervous” She looks lively and spontaneous, and she states that she feels basically well, except that she gets very anxious under stress She is playing bridge and is able to run errands on her own; she is also more confident and is coping better Her daughter corroborates that she seems to be improving She continues on the same medications; three months later, she shows continued improvement and is driving again, but she is still living with her daughter A few months later, she achieves full remission and is lost to follow-up

Question If the patient had not been lost to follow-up and you continued to see her, what adjustments might you make to her medications in the long run? • • • • •

Maintain her medications long term Maintain her medications for 6–12 months, then taper as long as she does not show signs of relapse Maintain her antidepressants, but eventually discontinue the benzodiazepine as long as she does not show signs of relapse Maintain one antidepressant and the benzodiazepine, but eventually discontinue the other antidepressant as long as she does not show signs of relapse Maintain one antidepressant, but eventually discontinue the other two medications as long as she does not show signs of relapse

Case Outcomes • • • • •

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Four years later, the patient is now age 77, and her daughter calls The patient has no depression, no anxiety, and no insomnia However, BUN and creatinine have been rising and creatinine clearance has been falling during the past several months; her primary care provider (PCP) thinks it may be due to venlafaxine and/or mirtazapine, so she has just decreased them to half dose The patient is about to undergo hip surgery on her other hip for bursectomy, and her PCP is considering stopping her medications for surgery and not reinstituting them afterwards The patient is status post-colon resection from colon carcinoma and is presumed cured; she has also had repair of an abdominal hernia


Question What would you be most likely to do in this situation? • • •

Agree with the decision to discontinue the patient’s medications Advise that therapeutic drug levels be obtained before deciding to discontinue the medications entirely Advise that the medications not be discontinued

Case Outcomes • • • • • • • • • • • •

Venlafaxine and mirtazapine are not noted for their ability to cause renal failure/complications; however, for patients with renal impairment from any cause, venlafaxine and mirtazapine doses may need to be lowered by 25%–50% This patient only has borderline to normal renal functioning; she does not have any clear renal impairment Any necessary dosing alterations in her venlafaxine and/or mirtazapine can be determined by getting therapeutic drug levels; if high, oral doses can be reduced Unfortunately, the patient is again lost to follow-up 16 months later, her daughter brings her in for reevaluation Now 79, she is depressed again: “Nothing makes me happy;” she has no enthusiasm, loss of appetite, and ongoing pain from the hip replacement that is not satisfactorily relieved by hydrocodone/acetaminophen The patient’s medication doses were lowered prior to her surgery (to 37.5 mg of venlafaxine XR and 15 mg of mirtazapine); no blood levels were obtained In the meantime, she has had lung resection for stage I lung cancer and is presumed cured Her renal function is now normal She has moved back in with her daughter Her PCP increased her medications back to venlafaxine XR 75 mg and mirtazapine 45 mg two months ago, but there has been no response She continues to take alprazolam 0.5 mg at night

Case Debrief • •

The venlafaxine XR dose is increased to 150 mg; this is ineffective after four weeks, so it is further increased to 225 mg At this dose, she has less daytime hypersomnia, is sleeping better at night, and has better appetite and mood; she considers herself maybe 50% better but not back to her normal self

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• She has some fluctuations in her level of improvement as well • She is facing a second hip replacement in the next month and is advised to await hip replacement and reinstitution of preoperative doses of medications, then return four weeks after surgery • She does well with the surgery, but her mood is still only about 50% better • Advised to increase venlafaxine XR to 300 mg and monitor blood pressure • Four weeks later, there is no further improvement, so venlafaxine XR is increased to 375 mg • Four weeks later, blood pressure is 129/84 and the patient is in remission • Current medications: - venlafaxine XR 375 mg - mirtazapine 45 mg - alprazolam 0.5 mg at night - hydrocodone every 4–6 hours Take-Home Points • • • • • • •

Many elderly patients respond well to mirtazapine, especially those with agitated depression with reduced appetite and weight loss Antipsychotic-induced parkinsonism may take a few months to resolve after discontinuation of drugs, especially in the elderly Sedative antidepressants and benzodiazepines may increase the incidence of falls and hip fractures in the elderly; although this does not preclude their use, caution should be observed Therapeutic drug levels are available for many drugs and can help determine their absorption and dosing; using them here may have prevented an unnecessary dose reduction and a consequent relapse Aggressive antidepressant therapy, such as “California rocket fuel” (i.e., venlafaxine plus mirtazapine), may be necessary even in elderly patients with multiple medical complications This patient had several relapses induced by the discontinuation or reduction of antidepressants, sometimes on the advice of her physicians In retrospect, it may be that many relapses may lead to more difficult-totreat relapses, requiring more aggressive treatment than may have worked in the past for that patient

Performance in Practice Assessment • What could have been done better here? • Should sedative antidepressants and benzodiazepine have been avoided due to an increased risk of falls? • Should her medications have been maintained at their full therapeutic doses?

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• Should communication have been better between the respective care providers? • Possible action items for improvement in practice • Use of sedative antidepressants and benzodiazepines in the elderly may be justified despite the risks, but communication with the patient and the caregivers about the risks should be clear and well documented • Antidepressant treatment may be necessary for a lifetime and without interruption; this seems to be the case for this patient with mood disorder, who continues to need treatment and responds to it well for over 47 years • Good communication among different care providers and better follow-up is also important Brief Tutorial: Diagnosis of Psychiatric Symptoms in the Elderly

• • •

Common symptoms of depression in geriatric patients include fatigue, loss of interest in activities, sleep problems, vague somatic complaints, and complaints of memory problems (vs. a family member complaining) They are less likely to have or complain of overt depressed mood It is important to rule out early dementia, particularly with the symptom of apathy

Brief Tutorial: Use of Antidepressants in the Elderly • Treatment recommendations for elderly patients with depression • Use of validated screening instrument • Individual CBT and/or antidepressant treatment • Patient education • Insufficient evidence • Individual or group psychotherapy • Not recommended for depression • Individual psychotherapy for overall mental health 43


• General education and/or skills training • Geriatric health evaluation and management • Exercise not targeting depression • Rehabilitation and occupational therapy • Pharmacokinetics of antidepressants in the elderly • Absorption is generally complete, but slower • Some medical conditions may reduce the extent of absorption • Elderly have less fluid, so water-soluble medications can reach toxic levels more quickly • Elderly have more adipose tissue, so fat-soluble medications (many psychotropics) are absorbed into less well-vascularized fat stores • Take longer to reach therapeutic level • Take longer to be excreted • Decrease in liver and kidney function also causes longer time to clearance and excretion • Protein malnutrition is common, leaving more freely circulating protein-bound drugs (e.g., warfarin) • Some psychotropics displace highly protein-bound drugs, increasing risk • Antidepressant dosing in the elderly Medication citalopram

Usual adult dose SR: 200–450 mg/d in two doses XL: 150–450 mg/d in one dose 20–60 mg/d

duloxetine

40–60 mg/d

escitalopram

10–20 mg/d

fluoxetine

20–80 mg/d

fluvoxamine

100–200 mg/d

mirtazapine

15–45 mg/d (at night)

paroxetine

IR: 20–50 mg/d CR: 12.5–62.5 mg/d

sertraline

50–200 mg/d

trazodone

150–600 mg/d

bupropion

venlafaxine XR 75–225 mg/d

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Recommended elderly dose Some patients may better tolerate lower dose 20 mg/d (40 mg/d in nonresponders) Some patients may better tolerate lower dose 10 mg/d Some patients may better tolerate lower dose May require lower initial dose and slower titration Some patients may better tolerate lower dose Initial dose 10 mg/d (12.5 mg/d CR) Maximum dose 40 mg/d (50 mg/d CR) Some patients may better tolerate lower dose and slower titration Elderly may be more sensitive to adverse effects and require lower dose Some patients may better tolerate lower dose


Self-assessment Posttest Which of the following is true regarding the use of antidepressants in the elderly? A. B. C.

For most antidepressants, the recommended therapeutic dose is substantially lower in the elderly than it is in younger adults For most antidepressants, the recommended therapeutic dose is the same in the elderly as it is in younger adults, though tolerability may be better at lower doses For most antidepressants, the recommended therapeutic dose is the same in the elderly as it is in younger adults, with no apparent dose-dependent effects on tolerability (Answer: B. For most antidepressants, the recommended therapeutic dose is the same in the elderly as it is in younger adults, though tolerability may be better at lower doses)

References Amella EJ. Presentation of illness in older adults. If you think you know what you’re looking for, think again. Am J Nursing 2006;83(2):372-89. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; 2000. Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge University Press; 2008. Stahl SM. Stahl’s essential psychopharmacology: the prescriber’s guide. 3rd ed. New York, NY: Cambridge University Press; 2009. Steinman LE, Frederick JT, Prohaska T et al. Recommendations for treating depression in communitybased older adults. Am J Prev Med 2007:33(3):175-181.

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n The Patient Cases: Depressio tion Posttest and Activity Evalua Answer Sheet To receive your certificate of CME credit or participation, please complete the posttest (you must score at least 70% to receive credit) and activity evaluation answer sheet found on the last page and return it by mail or fax it to 760-931-8713. Once received, your posttest will be graded and returned to you by mail, along with your certificate (if a score of 70% or more was attained). Alternatively, you may complete these items online and immediately print your certificate at www.neiglobal.com/cme. There is no fee for CME credits for this activity. Please circle the correct answer on the answer sheet provided. 1. The number one risk factor for suicide across patient populations is: A. History of abuse C. Untreated depression B. Multiple psychiatric diagnoses D. History of self-harm 2. What type of treatment is recommended first-line for adolescents with mild depression? A. Supportive treatment B. Cognitive behavioral therapy

C. Interpersonal therapy D. Antidepressant

3. Parkinsonism may be antipsychotic-induced in the elderly but will generally reverse within a week

or two. A. True B. False

4. A 76-year-old man presents with prominent fatigue, apathy, and memory problems. Full interview

and work-up leads to a diagnosis of major depressive disorder. Which of the following is true regarding the pharmacokinetics of antidepressants in elderly patients? A. Absorption is generally incomplete C. Time to excretion is generally longer B. Time to reach therapeutic level is generally shorter 5. Which of the following is/are approved treatment(s) for resistant depression? A. Aripiprazole D. A and B B. Deep brain stimulation E. A and C C. Transcranial magnetic stimulation F. A, B, and C 6. Risk of depression is highest for women during: A. Pregnancy and postpartum B. Postpartum and perimenopause

C. Perimenopause and menopause D. Pregnancy and menopause

7. Alan and Henry are identical twins who both suffer from major depressive disorder. They were both

started on the same antidepressant; Alan achieved remission with this first medication trial, while Henry achieved remission with his third medication trial. What is true regarding the risk of relapse for these two patients? A. Alan has a greater risk of relapse C. Their risk of relapse is the same B. Henry has a greater risk of relapse 8. New and ongoing research has the potential to lead to what type of revisions to depression treatment

guidelines? A. Increased duration of monotherapy trial B. Earlier attempt at combination therapy

46

C. Earlier attempt at using alternative

“stimulation” therapies (VNS, TMS, DBS)

Posttest and Act ivity Evaluation Answ er Sheet, cont’d Please complete the posttest and activity evaluation answer sheet on this page and return by mail or fax. Alternatively, you may complete these items online and immediately print your certificate at www.neiglobal.com/cme. Please circle the correct answer. Posttest Answer Sheet (score of 70% or higher required for CME credit) 1.

A B C D

5.

A B C D E F

2.

A B C D

6.

A B C D

3.

A B

7.

A B C

4.

A B C

8.

A B C

Activity Evaluation: Please rate the following, using a scale of: 1-poor 2-below average 3-average 4-above average

5-excellent

1. The overall quality of the content was…

1 2 3 4 5

2. The overall quality of this activity was…

1 2 3 4 5

3. The relevance of the content to my professional needs was…

1 2 3 4 5

4. The level at which the learning objective was met of teaching me to identify and diagnose different types and presentations of depression:

1 2 3 4 5

5. The level at which the learning objective was met of teaching me to make informed decisions regarding the use of antidepressants in the treatment of depression in special populations:

1 2 3 4 5

6. The level at which the learning objective was met of teaching me to integrate novel treatment approaches into clinical practice:

1 2 3 4 5

7. The level at which the learning objective was met of teaching me to implement individualized 1 2 3 4 5 treatment strategies for patients with depression that maximize outcomes: 8. The level at which this activity was objective, scientifically balanced, and free of commercial bias was…

1 2 3 4 5

9. Based on my experience and knowledge, the level of this activity was… Too Basic Basic Appropriate Complex Too Complex 10. My confidence level in understanding and treating this topic has ___________ as a result of participation in this activity. A. Increased B. Stayed the same C. Decreased 11. Based on the information presented in this activity, I will… A. Change my practice B. Seek additional information on this topic C. Do nothing as current practice reflects activity’s recommendations D. Do nothing as the content was not convincing

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12. What issues/challenges regarding this topic do you confront in your professional practice?

13. What additional information about this topic would you like our CME program to address in future educational activities?

14. What barriers might keep you from implementing changes in your practice you’d like to make as a result of completing this activity? 15. How could this activity have been improved?

16. Number of credits I am claiming, commensurate with the extent of my participation in the activity (maximum of 3.5): _________

Name (print):________________________________________________________ Credentials:___________ Address:_ _______________________________________________________________________________ _______________________________________________________________________________________ City:__________________________________________ State:________________ Zip code:_____________ Phone:_______________________________________ Fax:_________________________ E-mail:____________________________________________________________________ I certify that I completed this CME activity (signature)____________________________________________

Date ______________________________________________

Mail or fax both pages of this form to: Mail: CME Department Neuroscience Education Institute 1930 Palomar Point Way, Ste. 101 Carlsbad, CA 92008

48

Fax: 760-931-8713 Attn: CME Department

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