0108.depression Suppl

SPECIAL SUPPLEMENT TO
Care
New Evidence-Based Treatments for Depression
Proceedings of the Magellan Behavioral Health 2001 Clinical Medical Retreat
HIGHLIGHTS Depressions Ripple Effect on Health Status and Costs Overview of Antidepressant Therapy Antidepressant Drug-Interaction Considerations Using Pharmacoeconomic Data To Compare Antidepressant Therapies The Texas Medication Algorithm Project For Major Depression Roundtable Discussion Efficient, Cost-Effective Therapy: Translating Evidence Into Practice
Continuing medical and pharmacy education sponsored by the University of Arizona Colleges of Medicine and Pharmacy at the Arizona Health Sciences Center
Volume 10, No. 8 August 2001
Care
Editor
INTRODUCTORY MESSAGE
ARON HALFIN, MD Senior Vice President and Chief Medical Officer Health Plan Solutions Group, Magellan Behavioral Health
JOHN A. MARCILLE
Managing Editor
MICHAEL D. DALZELL
Senior Editor
FRANK DIAMOND
Senior Science Editor
Using Evidence To Improve Care For People With Depression

t Magellan Behavioral Healths 2001 Clinical Medical Retreat, New Evidence-Based Treatments for Depression, two outstanding clinicians and researchers presented evidence of treatment options that hold great promise in terms of improving quality of behavioral health care. This meeting was accredited for continuing education by the University of Arizona Colleges of Medicine and Pharmacy at the Arizona Health Sciences Center, and we are grateful for their accreditation support of this publication for continuing medical education and continuing education for pharmacists. Michael E. Thase, MD, professor of psychiatry at the University School of Medicine and the Western Psychiatric Institute and Clinic, addressed current concepts in treatment and management of depression, including a discussion of drug-product selection based on differential efficacy. This valuable information is featured on pages 69. We were fortunate to hear from Larry Ereshefsky, PharmD, professor of pharmacology and psychiatry at the University of Texas Health Science Center, who among other things, presented compelling considerations about medication interactions with respect to antidepressants and an overview of the Texas Medication Algorithm Project for Major Depression. These presentations are abstracted on pages 1013 and 1617, respectively. This publication also includes information that highlights the importance of recognizing depression and its consequences on medical outcomes; pharmacoeconomic data for drug therapy in depression; and concludes with a roundtable discussion of the research presented at the retreat and its relevance to choosing appropriate medical interventions. We encourage you to take advantage of the continuing education that is offered for physicians and pharmacists through this publication. And we hope some of the ideas presented here will be useful to you in your everyday responsibilities.
PAULA SIROIS
Senior Contributing Editor
PATRICK MULLEN
Contributing Editors
BOB CARLSON JOHN CARROLL DAVID COLEMAN, J.D. JEFFREY J. DENNING MIKE FOLIO, J.D. MICHAEL LEVIN-EPSTEIN JACK MCCAIN KAREN TRESPACZ, J.D.
Design Director
PHILIP DENLINGER
Editorial Advisory Board Chairman
ALAN L. HILLMAN, M.D., M.B.A. Senior Fellow Center for Health Policy Leonard Davis Institute of Health Economics University of Pennsylvania, Philadelphia
Group Publisher
TIMOTHY J. STEZZI
Publisher
TIMOTHY P. SEARCH, R.PH.

Midwest Sales Manager
TERRY HICKS
Senior Account Manager
SCOTT MACDONALD
Account Manager
SCOTT OLSON
Director of Production Services
WANETA PEART
MANAGED CARE (ISSN 1062-3388) is published monthly by MediMedia USA Inc. at 275 Phillips Blvd., Trenton, NJ 08618. This is Volume 10, Issue 8. Periodicals postage paid at Trenton, N.J., and at additional mailing offices. POSTMASTER: Send address changes to MANAGED CARE, MediMedia USA, 275 Phillips Blvd., Trenton, NJ 08618. Prices: $10 per copy, $93 per year in the USA; $120 per year elsewhere. Send letters to the editor c/o Frank Diamond, MANAGED CARE, 275 Phillips Blvd., Trenton, NJ 08618. Letters may be edited for length and clarity. E-mail: editors@managedcaremag.com. Phone: (609) 671-2100; fax (609) 882-3213; circulation inquiries, (609) 671-2100. Copyright 2001 MediMedia USA Inc.
SPECIAL SUPPLEMENT
Care
August 2001 New Evidence-Based Treatments for Depression
A continuing education activity Proceedings of the Magellan Behavioral Health 2001 Clinical Medical Retreat
Continuing Education Objectives and Accreditation Statements .............2
HEALTH STATUS OVERVIEW
Depressions Ripple Effect on Health Status and Costs ........4

FACULTY PRESENTATION
Overview of Antidepressant Therapy....................................6

Michael E.Thase, MD FACULTY PRESENTATION
Antidepressant Drug Interaction Considerations ..............10

Larry Ereshefsky, PharmD COST-EFFECTIVENESS ISSUES
Using Pharmacoeconomic Data To Compare Antidepressant Therapies ...............................14

FACULTY PRESENTATION
The Texas Medication Algorithm Project For Major Depression ...........................................................16

Larry Ereshefsky, PharmD ROUNDTABLE DISCUSSION
Cost-Effective Therapy: Translating Evidence Into Practice...........................................................................18

Moderated by Bradley K. Kozar CONTINUING EDUCATION
Physician CME answer sheet and certificate request ...............................23 Pharmacist CE answer sheet and certificate request................................24 Self-test ........................................................................................................25
This supplement is supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories.
SELF-STUDY CONTINUING EDUCATION ACTIVITY

Continuing education is offered to physicians and pharmacists who read this publication, answer the self-test that begins on page 25, and fill out the appropriate evaluation form on either page 23 or 24. ACPE program number: 003-999-01-026-H01. Expiration date: Aug. 31, 2002. actions involving antidepressant medications. Describe the Texas Medication Algorithm Project for Major Depression (T-MAP) and its approaches to treatment resistance in patients with depression. Recognize how pharmacoeconomic data can be used to compare cost-effectiveness of drug therapies. Discuss new evidence on the relative effectiveness and outcomes of different antidepressant medications.
Course description
This activity is designed to educate health care professionals about appropriate medical treatment options for patients with clinical depression.The data and narratives in this publication are derived from information presented at New Evidence-Based Treatments for Depression, a symposium in Las Vegas, Nev., April 30, 2001.The program is directed to managed health care professionals.
Medical accreditation
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Arizona College of Medicine at the Arizona Health Sciences Center and of MediMedia USA.The University of Arizona College of Medicine at the Arizona Health Sciences Center is accredited by ACCME to provide continuing medical education for physicians. The University of Arizona College of Medicine at the Arizona Health Sciences Center designates this education activity for 2 hours in category 1 credit towards AMA Physicians Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Approval for category 1 credit by the University of Arizona College of Medicine should not be construed as endorsement of any product. Release date: September 2001, for a period of one (1) year.
Educational needs assessment

Medical directors, practicing physicians, and pharmacists are seeking treatment approaches for depression that are highly effective, and want to be kept informed of current medical treatments so as to use this knowledge to meet patients needs.The information presented in this publication has been compiled on the basis of faculty perceptions of significant trends and issues related to medical therapies for treatment of depression and cost-effective approaches to managing it.
Planning committee members

Lynne Mascarella, director of continuing education, College of Pharmacy, University of Arizona,Tucson; Kay ONeill, CME coordinator, College of Medicine, University of Arizona,Tucson; Aron Halfin, MD, senior vice president and chief medical officer, Magellan Behavioral Health; Timothy Search, RPh, publisher, MANAGED CARE, a division of MediMedia USA Inc.
PUBLISHERS DISCLAIMER
The opinions expressed herein are those of the symposium participants and faculty, and do not necessarily reflect the views of the University of Arizona Colleges of Medicine and Pharmacy,Wyeth-Ayerst Laboratories, MediMedia USA Inc., or the publisher, editor, or editorial board of MANAGED CARE. Clinical judgment must guide each clinician in weighing the benefits of treatment against the risk of toxicity. Dosages, indications, and methods of use for products referred to in this special supplement may reflect the clinical experience of the authors or may reflect the professional literature or other clinical sources, and may not necessarily be the same as indicated on the approved package insert. Please consult the complete prescribing information on any products mentioned in this special supplement before administering.
Target audiences
Medical directors, chief medical officers, pharmacy directors, and other senior managers in managed health care organizations; primary care physicians; psychiatrists; and pharmacists.
Pharmacy accreditation
The University of Arizona College of Pharmacy is approved by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education.This program is approved for (2) contact hours (0.2 CEU). Credit will be awarded upon completion of registration form, successful completion of assessment questions (70 percent or better) and completion of program evaluation. If a score of 70 percent or better is not achieved, no credit will be awarded and the registrant will be notified.
Educational objectives
After reading this publication, the participant should be able to: Illustrate the extent, as well as the economic and personal consequences, of untreated clinical depression. Identify the most commonly prescribed antidepressant medications and their mechanisms of action. Explain important drug inter-
MANAGED CARE / SUPPLEMENT
ABOUT THIS PUBLICATION

Clinical depression is highly prevalent, underdiagnosed, and undertreated in the United States. This has enormous implications for morbidity, comorbidity, mortality, and economics.When depression is detected, medical treatment often involves random approaches, which can delay remission of illness and incur unnecessary use of health care resources. A systematic methodology, whether based on evidence of drug efficacy or pharmacoeconomic issues, can lessen the morbidity and cost associated with depression and its consequences. Several such strategies are discussed in various sections of this MANAGED CARE continuing education supplement.The information herein was presented at New EvidenceBased Treatments for Depression, a Magellan Behavioral Health symposium in Las Vegas, Nev., April 30, 2001, and attended by managed care medical directors. A crosssection of attendees participated in the roundtable discussion, excerpts from which begin on page 18.
PRIMARY FACULTY
Larry Ereshefsky, PharmD Professor of Pharmacology and Psychiatry University of Texas Health Science Center San Antonio Aron Halfin, MD Senior Vice President and Chief Medical Officer Health Plan Solutions Group Magellan Behavioral Health Alpharetta, Ga. Bradley K. Kozar Group President and CEO MediMedia Managed Care Division Trenton, N.J. Michael E.Thase, MD, FAPA Professor of Psychiatry University of Pittsburgh School of Medicine Western Psychiatric Institute and Clinic Pittsburgh
Conflict of interest policy in continuing medical education

In compliance with this policy, the faculty for this activity has disclosed financial interests, arrangements, and/or affiliations with corporate organizations offering financial support or educational grants for continuing medical education activities, as well as those organizations with a direct interest in the subject matter of this activity.
Disclosures of significant relationships

Michael E.Thase, MD, acknowledges grant and research support from Bristol-Myers Squibb, Merck & Co., Organon Inc., Pharmacia & Upjohn, and Wyeth-Ayerst Laboratories; consulting relationships with the aforementioned companies, as well as Eli Lilly & Co., Forest Laboratories, Glaxo Wellcome Inc./Cerenex, and Pfizer Inc.; and lecture support from Parke Davis, SmithKline Beecham, Solvay Pharmaceuticals, and all of the aforementioned companies except Merck & Co. Larry Ereshefsky, PharmD, acknowledges grant and research support from Bristol-Myers Squibb, Janssen Pharmaceutica, Novartis, Pfizer Inc., Pharmacia & Upjohn, Otsuka, Sanofi~Synthelabo, and Wyeth-Ayerst Laboratories; consulting relationships with AstraZeneca, Janssen, Eli Lilly & Co., Novartis, Pfizer, and Wyeth-Ayerst; and is a major stockholder in Pfizer. The following faculty and roundtable discussion participants have declared they have no financial interest, arrangement, or affiliation that would constitute a conflict of interest concerning this CME activity: Jonathan Book, MD; Kenneth Cohen, MD; Charles Freed, MD; Aron Halfin, MD;Thomas Hamlin, MD; Julie Kessel, MD; Leslie Moldauer, MD; Lawrence Nardozzi, MD; Andrew Rudo, MD.
Content reviewers
Amy Grizzle, PharmD Assistant Director Center for Health Outcomes and PharmacoEconomic Research University of Arizona College of Pharmacy Tucson, Ariz. John J. Misiaszek, MD Associate Professor of Clinical Psychiatry University of Arizona College of Medicine Tucson, Ariz.
SUPPLEMENT / MANAGED CARE
DEPRESSIONS RIPPLE EFFECT ON HEALTH STATUS AND COSTS

epression is one of the most common of all psychiatric disorders;8 to 18 percent of the general population can be expected to experience at least one clinically significant episode during a lifetime (Boyd 1982).The significance of this transcends the debilitating effects of major depression or dysthymia alone; frequently, patients with depression have concomitant major medical conditions thus amplifying the duration, severity, and cost of treatment for those illnesses.While this would suggest that identifying patients for appropriate treatment is an important strategy in keeping overall health care costs down, depression is undertreated in the United States. The following data were presented by Larry Ereshefsky, PharmD, professor of pharmacology and psychiatry at the University of Texas Health Science Center, at the Magellan Behavioral Health Clinical Medical Retreat in Las Vegas, April 30, 2001.
Comorbidity is common and costly

The prevalence of depression in patients with other major illnesses is as high as 60 percent (Figure 2).How its effects on brain chemistry may trigger or exacerbate some illnesses is not understood,but there is evidence that major depression is a bigger risk factor for type 2 diabetes than body mass index,race,or gender (Eaton 1996), and, in late life, depression may be associated with cerebrovascular disease (Steffens 1999). FIGURE 2 Depression and medical illness Studies have estimated the prevalence of depression in people with other conditions.The range of estimates of comorbidity for the six illnesses below varies widely.
Prevalence of depression unrecognized

Depression is underdiagnosed particularly in primary care settings and among the elderly and when it is treated,many patients receive medications that are not fully effective, or in insufficient dosages, or for too short a period to be effective. A Rand Corporation study (Wells 1994) found that of patients whose symptoms would qualify them for a diagnosis of depression, 23 percent were taking antidepressants, and only 14 percent of the whole were receiving the proper dose of medication. Underdiagnosis and undertreatment contribute to the economic impact of depression,which has been estimated in the U.S. at $44 billion annually (Figure 1). FIGURE 1 Economic impact of depression
Mortality Lost wages due to premature death $7.5 billion Direct costs Medications $2.1 billion Medical and psychiatric care $12.4 billion Morbidity Work absence, reduced productivity, increased costs related to other medical 55% illnesses $23.8 billion
Alzheimers disease Cancer Coronary artery disease Diabetes Multiple sclerosis Stroke
15 42 18 26 33 6 30 50
55
60
More than 1 in 7 adults visit the ER each year,and the vast majority of those who visit for any reason present with clinical depression a statistic with implications for cost containment.Depression also tends to increase hospitalization costs significantly, not just for the depression but also for treatment of other medical conditions. In one study of patients over age 60 who had been hospitalized for a medical condition, the top quartile in terms of depressive symptoms incurred 50 percent greater treatment expenses than the lowestquartile group (Table 1). TABLE 1 Health costs based on depressive symptoms Lowestquartile cost (mean) $5,290 $6,395 Highestquartile cost (mean) $9,408 $9,588
17% 5%
Measure Inpatient care Medical/surgical cost after discharge Psychiatric/substanceabuse costs after discharge
SOURCE: DRUSS 1999
23%
$26
$178
SOURCE: GREENBERG 1993
Relapse can be risky for MCOs

Treating patients with the proper medication, at the correct dosage and for an appropriate duration or knowing when to switch to another medication is important, given the probability of relapse. After four weeks, the risk of relapse in patients treated for major depression rises, particularly for those who have a history of multiple depressive episodes (Figure 3). For managed care organizations,identifying this costly subset of patients for adequate treatment is paramount. In many patients with even a single episode of depression, the odds of recurrence are 20 to 30 percent within several years. Incomplete remission where symptoms improve but the patients level of functioning is not normalized increases the odds of relapse (Figure 4).From the standpoints of quality of life and cost-containment, treating patients to full recovery is optimal.
FIGURE 3 Patients with major depression: Cumulative probability of relapse

50
40 % relapsed
3 or more previous episodes
30
20 03 previous episodes 10
0 1 2 4 5 6 7 10 12 Weeks since recovery

SOURCE: KELLER 1998
FIGURE 4 Incomplete remission predicts greater relapse*

100 Probability of remaining symptom-free (%) 80 (Remission)
References
Boyd JH,Weissman MM. Epidemiology. In 60 Paykel ES (ed.) Handbook of Affective Disorders. 1982;109125. New York: (Response) 40 Guilford Press. Druss BG, Rohrbaugh RM, Rosenheck RA. Depressive symptoms and health 20 costs in older medical patients. Am J Psychiatry. 1999 Mar;156(3):477479. 0 Eaton WW, Armenian H, Gallo J, et al. De10 12 0 2 4 6 8 pression and risk for onset of type 2 Months of follow-up diabetes: A prospective populationbased study. Diabetes Care. *After termination of cognitive behavior therapy for depressed patients. 1996;19(10)10971102. SOURCE:THASE 1992 Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER.The economic burden of depression in 1990. J. Clin Psychiatry. 1993 Nov;54(11):425426. Keller MB, Boland RJ. Implications of failing to achieve successful long-term maintenance of recurrent unipolar major depression. Biol Psychiatry. 1998 Sept 1;44(5):348360. Steffens DC, Helms MJ, Krishnan KR, Burke GL. Cerebrovascular disease and depression symptoms in the cardiovascular health study. Stroke. 1999 Oct;30(10):21592166. Thase ME, Simons AD, McGeary J, et al. Relapse after cognitive behavior therapy of depression: potential implications for longer courses of treatment. Am J Psychiatry. 1992 Aug;149(8):10461052. Wells KB, Katon W, Rogers B, Camp P. Use of minor tranquilizers and antidepressant medications by depressed outpatients: results from the medical outcomes study. Am J Psychiatry. 1994 May;151(5):694700.
Overview of Antidepressant Therapy

MICHAEL E. THASE, MD
Professor of Psychiatry, University of Pittsburgh School of Medicine Western Psychiatric Institute and Clinic
the critical shortcoming is that they are potentially lethal epression can be thought of as an extension in overdose with as little as a 10-day supply. of two distressing states that affect all mammals exhaustion in response to sustained Some half truths irresoluble stress and grief. Humans differ with respect to the complexity of intimate attachments It has been stated for years that up to 70 percent of deand social circumstances, as well as the capacity to strucpressed people will respond to the initial course of treatture cognitions about self, world, past, and future. Yet ment with an antidepressant. This is true if the diagnowithin a context of evolutionary survival resis is correct, and if the patient has filled the sponses, humans still have the relatively primiprescription and has taken the medication as tive hard wiring of other mammals. directed for 6 to 8 weeks and if the number These systems were discovered less than 60 of people who have discontinued therapy years ago, and involve two basic monoamine along the way are not counted in the final tally. neurotransmitters: norepinephrine and seroIt also can be shown that 90 percent of detonin. These systems are responsive to acute, pressed people should respond to therapy by life-threatening stress, triggering what is comthe fourth treatment trial. But how often does monly referred to as the fight-or-flight rethis happen in practice? The most recent data sponse. This response is also accompanied by suggest a 33 percent loss of patients with each release of corticotrophin-releasing hormone, Michael Thase, MD treatment trial. The real share of responders which initiates a cascade that results in elemight be in the range of 30 to 50 percent on vated levels of glucocorticoids in the blood and spinal the first trial and 70 to 75 percent by the fourth. fluid. Most norepinephrine in the brain comes from nerve These response rates include people who are somecells in the locus ceruleus. Almost all of the serotonin to what better, but not as well as those who truly are well (rethe brain comes from the dorsal raph nuclei. When a permission). When weighing the pros and cons of various son is distressed or in a threatening situation, both of these antidepressants, it is useful to look for remission, or a renuclei become more active: norepinephrine in an intense, turn to ones usual level of well being, as the strongest inphasic way, serotonin in a more protracted, tonic way. dicator of favorable antidepressant outcomes. Sustained activation of these systems is not healthy There are several compelling clinical reasons to aim for blood pressure increases, immune responses are altered, remission. Response without remission is associated with and cognition becomes less abstract, more focused on a significantly higher risk for relapse. It is also associated survival. If the threat is sustained, brain cells may begin with incomplete normalization of social function. People to shrink or even die. with residual depression, even though they have a reducAn effective antidepressant should dampen the pathotion of depressive symptoms, complain more, decline inlogic activation of stress response. Second, it should envitations, dont return calls, and miss more days from hance behavioral facilitation, because when people are in work. They usually do not function at optimum level. sustained stressful circumstances, they become less active The data in Figure 1 are from a one-year follow-up of and less interested in consuming lifes rewards. Finally, it incompletely remitted patients who had an extra $1,200 should reduce negative affect without changing ones invested in their treatment. These patients received 12 adlevel of consciousness or sense of awareness. ditional sessions of psychotherapy (white dots) at the beToday, there are four types of antidepressants: triginning of the continuation phase, as compared to pacyclics (TCAs), MAO inhibitors, selective serotonin retients randomly assigned to receive straight medication uptake inhibitors (SSRIs), and newer medications that management (black dots). By week 68, patients who reare not in the same class as the other three. Tricyclics and ceived pharmacotherapy alone had an almost 50 percent MAO inhibitors were discovered accidentally, and medirelapse rate. With respect to the main hypothesis, Can cations that are discovered accidentally often carry bagthe risk of an incomplete remission be offset by symptomgage inherent in those compounds. In the case of TCAs, focused psychotherapy, the data suggest a 25 percent ad-
pharmaceutical sales. vantage for the group that received psychotherapy. If One way to resolve the problem of inadequate statisone estimates the costs that were saved by preventing new tical analysis is to use a technique called a meta-analysis, episodes of depression, the psychotherapy, then, esseni.e., an analysis of multiple analyses. However, there are tially paid for itself. inherent difficulties with this approach. A large number Another fact psychiatrists are taught is that all antiof studies is required; not much of a meta-analysis can depressants are comparably effective. Some recent evibe done when there are three relevant controlled studdence suggests that this may not be true, and may never ies. An even greater problem results from the file drawer have been. Some background should be provided on phenomenon. Specifically with a meta-analysis, if half the how clinical trials of antidepressants are conducted and studies are in the file drawer, the analysis will be distorted what kind of results should be expected. by looking only at a subset of the evidence, thus exagIn half of studies of all new antidepressants, the drug gerating the efficacy of the medicine. fails to beat placebo. Moreover, traditionally it has been thought that the average drug-placebo difference is about 33 percent (i.e., 67 FIGURE 1 Relapse-free curves from Cox regression percent responders for active drug and Intention-to-treat analysis of combined major depression and 33 percent for placebo). This probably persistent-system relapse was true in the 1960s, when studies were done in hospitals, where side ef1.0 fects could be managed and patients 0.9 had a higher severity level. Today, the 0.8 average drug-placebo difference is 0.7 about 18 percent (50 versus 32) in am0.6 bulatory studies (Thase 1999). In the science of clinical trials, a 33 0.5 percentage-point difference is a large 0.4 and reliable effect. By contrast, an 180.3 point difference is small.When looking 0.2 Control group for modest or small effects, researchers CT group 0.1 must conduct much larger studies. The antidepressant studies of the 1980s and 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 90s were not designed to find small-toWeeks modest effects. Thus, one reason that antidepressants appear to be equally SOURCE: PAYKEL 1999 effective is that the studies have not had the statistical power to distinguish the good from the better (Thase 1999). For FIGURE 2 Comparison of venlafaxine and SSRI/placebo this purpose, an ideal study would need Remission: HAM-D17 7) to enroll 300 patients in each treatment group, about 3 times larger than the 60 Placebo 55 usual study. Moreover, it is unlikely that * SSRI 50 the difference between a good antiVenlafaxine 45 *, depressant and a better one would 40 be as large as the difference between a 35 30 good antidepressant and placebo. 25 As for the studies that dont distin20 guish drug from placebo, where are 15 10 they? Are they published in major 5 journals, such as Archives of General 0 Psychiatry or American Journal of PsyUS-211 EU-340 EU-347 EU-348 EU-349 CA-360 EU-367 US-372 chiatry? Usually not. Rather, they typi(n=295) (n=67) (n=111) (n=302) (n=155) (n=353) (n=323) (n=439) cally are filed away, unpublished. The *P 0.05 venlafaxine vs SSRIs studies stay in the file drawer because P 0.05 venlafaxine vs placebo theyre not interesting, one or more P 0.05 SSRIs vs placebo flaws are obvious, and, of course, a SOURCE:THASE 2001 negative study does not promote
Remission rate (%) Proportion not relapsing
New standard of therapy
Within several years of the introduction of fluoxetine in the U.S. in 1987, SSRIs had emerged as the standard of antidepressant treatment of ambulatory patients. The SSRIs offered three key advantages in comparison to the older tricyclic drugs that, with respect to public health, were substantial. Importantly, they were the first antidepressants that could be started at a therapeutic dosage for the average patient. They also were more tolerable than TCAs, with the average patient experiencing about one half of the side-effect burden. Six- or eightweek completion rates werent much higher about 10 percent over 6 to 8 weeks but in a population of 10 percent, advantage is important. Finally, psychiatrists
Remission rate (%)
could prescribe a 30-day supply without concern that the patient was putting herself in danger of an overdose. Today, in the U.S., 60 to 70 percent of patients who receive a new prescription antidepressant medication will receive one of four SSRIs: fluoxetine, sertraline, paroxetine, or citalopram. In terms of efficacy, no one SSRI is better than another (Edwards 1999). Pharmacologically, SSRIs have unique and meaningful differences. They are generally comparable to the TCAs in terms of overall efficacy, and they are safer and easier to use. When relevant stress-response systems are modulated directly at the same time, there may be an intensification of effect. The value of this strategy is implicitly reinforced by the fact that it has become state of the art for the skillful psychiatrist to prescribe multiple antidepressants for harder-toFIGURE 3 Pooled analysis of venlafaxine/SSRI/placebo treat patients. The name polypharcomparisons macy, with its negative connotation, 55 Placebo (n=446) ,|| has been replaced by what is now 50 SSRI (n=748) 45 called copharmacy and viewed as a Venlafaxine (n=851) *, 40 good thing.
35 30 25 20 15 10 5 0 *, *, *
Comparisons with SSRIs

SSRIs, which are as the name suggests selective for the reuptake of serotonin, will remain the standard of comparison for the forseeable future. What follows is an overview of the literature and some studies in the file drawer, comparing other antidepressants with SSRIs. Venlafaxine was introduced in the U.S. in 1994. It is a dual reuptake inhibitor, and there was evidence from the first day it came to the U.S. market that it might be a stronger antidepressant than SSRIs (Clerc 1994). However, venlafaxine, in its initial immediate release (IR) formulation, did not compete favorably with SSRIs in a free-market situation. SSRIs held about 70 percent of the market; venlafaxine, about 5 percent, partly because venlafaxine followed three popular drugs onto the market. In addition, the IR form required divided daily dosing, so it was less convenient to the patient. To the clinician, its wide therapeutic range 75 to 375 mg meant more titrations were necessary. More important, initiating therapy with venlafaxine caused more nausea than did SSRIs, and there were concerns about elevated blood pressure. That prompted the manufacturer to
*P0.05 venlafaxine vs SSRI P0.05 venlafaxine vs placebo P0.05 SSRI vs placebo P<0.001 SSRI vs placebo P<0.001 venlafaxine vs SSRI ||P<0.001 venlafaxine vs placebo
Week of treatment
SOURCE:THASE 2001
FIGURE 4 Remission rates, by definition of remission

70 60 Remission rate (%) 50 40 30 20 10
HAM-D17 HAM-D17 HAM-D21 HAM-D21 HAM-D21 HAM-D21 7 10 7 8 10 50% decrease MADRS <10 HAM-D17 10 and CGI = 1
, , , * * * , * , * * , *
Placebo SSRI Venlafaxine , , *
Definition of remission
*P<0.001 SSRI vs placebo P<0.001 venlafaxine vs SSRI P<0.001 venlafaxine vs placebo P<0.05 venlafaxine vs SSRI
SOURCE:THASE 2001
develop an extended-release (XR) form of the drug. This lengthened the time to peak so once-a-day dosing would be possible. The dose for the XR form was capped, meaning the same number of titrations as an SSRI: 75, 150, and 225 mg. In capping the dose, concerns about elevated blood pressure were eliminated. There have been randomized controlled trials comparing this products efficacy with others. Unlike every other newer antidepressant, venlafaxine is defined, in part, by the evidence of comparative efficacy. We received permission to open the file drawer to do a meta-analysis, and we took the first eight comparative studies of either the IR or the XR forms relative to the SSRIs. All eight studies were double-blind randomized. Half used placebo; half didnt. Half used the IR form and half used the new XR form of venlafaxine. Four studies were published (Clerc 1994, Dierick 1996, Silverstone 1998, Rudolph 1999), two were presented as posters and published as abstracts, and two are unpublished and remain on file with the manufacturer. By opening the file drawer and using all the data from all of the patients, we were able to bring the sample up to more than 800 people treated with venlafaxine, more than 700 treated with an SSRI, and more than 400 treated with a placebo. Most importantly, the file drawer was empty. Nothing was left behind. Figures 2, 3, and 4 depict results of the eight studies (venlafaxine IR and XR were combined for this metaanalysis). Figure 2 shows remission rates of venlafaxine and SSRIs. Figure 3 pool the same data across time. Over time, a clear pattern of remission emerges, in which SSRI differentiates from placebo. Notably, at the end of eight weeks of treatment, the magnitude of the venlafaxineSSRI difference is identical to the magnitude of the difference between SSRI and placebo. Figure 4 challenges the assumption that another definition of remission would produce different results; in general, results are consistent, regardless of definition. Since we started this project, 11 other studies have been finished, involving 2,400 more patients. Across the 19 studies, there appears to be a consistent dose-response relationship. In essence, there was no difference at 75 mg of venlafaxine; at 150 mg, a small difference; and at 225 mg and above, there is a difference of 15 or 18 percent. This is important, because the dose-response relationship follows the same relationship evident with blood pressure with this drug. At minimum therapeutic doses, there is no difference relative to placebo. At middle doses, blood pressure increases modestly. At maximum dose, there is a larger effect. Managed care organizations should be prepared to authorize the use of higher than 225 mg, but also should be prepared to measure blood pressure when approving these higher doses. The effects likely will be seen in 10 percent of patients at the doses most likely to show advantages relative to the SSRIs.
Other pharmaceutical comparisons

Bupropion is a weak reuptake inhibitor for norepinephrine and dopamine. We do not know what is in the file drawer for bupropion; the manufacturer has not permitted a pooled analysis. There are four completed published comparisons against SSRIs, and when combined, there is no significant difference in efficacy. It is, however, a different type of antidepressant, with a different structure and different functions, and thus often is prescribed for people who have had negative side effects from SSRIs. Nefazodone is unlike any antidepressant other than trazodone. We do not know what is in the file drawer. There are three published comparisons versus SSRIs; the differences among them are not significant, about 2 percent favoring SSRIs. This does not support a widespread notion among clinicians that this medication is less effective than other newer antidepressants. This stems from the fact that this is the weakest of all the serotonergic reuptake inhibitors. Generally, it is prescribed when stronger serotonergic medications fail meaning it is used in people who are less likely to respond to it. Multiaction antidepressants are more effective when they are comparably tolerable. The tricyclics are not more effective than the SSRIs because they are not comparably tolerable. When a patient is placed in a setting where side effects can be controlled, the tricyclics become more tolerable and the dual reuptake drugs deliver better results. This is similar to what has been seen in ambulatory studies with venlafaxine, because it is more like an SSRI when it comes to tolerability. In summary, the statement that all antidepressants are equally effective has never been true. Among some antidepressants, there are meaningful differences, as evidenced by the meta-analysis data presented in Figures 3 and 4. The main reason that physicians end up with the notion that all things are equal is because they havent been able to appreciate the subtleties between products. Studies that are designed well enough to bring out those subtleties have not been done.
References
Clerc GE, Ruimy P, Verdeau-Pailles J, on behalf of the Venlafaxine French Inpatient Study Group. A double-blind comparison of venlafaxine and fluoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol. 1994;9:139143. Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs. 1999;57(4):507-533. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy. Arch Gen Psychiatry. 1999;56:829835. Thase ME. How should efficacy be evaluated in randomized clinical trials of treatments for depression? J Clin Psychiatry. 1999;60(Supp 4):2331. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001 Mar;178:234241.
Antidepressant Drug Interaction Considerations

LARRY ERESHEFSKY, PHARMD
Professor of Pharmacology and Psychiatry, University of Texas Health Science Center
hree transmitters in the brain (norepinephrine, bolic properties also is important so as to prevent drug serotonin, and dopamine) influence an array of interactions. An emphasis on drug safety was prompted behaviors that are relevant for human funcby the Institute of Medicine in its 1999 report, To Err Is tioning. Antidepressants work on one or more Human: Building a Safer Health System. As translated by of these transmitters. The mechanism of action for some Consumer Reports, the IOM data suggest that a patients medications are different and clinically meaningful. 1-in-500 chance of dying from an unexpected drug reWhen choosing an antidepressant, its imaction in the hospital is far greater than the portant to know the pharmacology of each likelihood of being killed in an auto accident. product. In many cases, trying a drug with a To illustrate a drug interaction using a real different pharmacology is the most rational case: George is a 60-year old male, stable on way to enhance response. Recognize that drugs propranolol and a diuretic for years. He is diwith more than one mechanism of action may agnosed with depression, and a psychiatrist be more effective as first-line therapy. starts him on fluoxetine, 20 mg. His primary The old tricyclic antidepressants (TCAs) care physician follows up a week later, and have a host of side effects that render them unGeorge is tolerating medications fine. But one acceptable as first-line therapies. They can kill month later, George winds up in the ER on overdose, and thus are a tremendous lialethargic, tired, and weak. Hes having nightbility that should be reserved for people who Larry Ereshefsky, mares. He has a resting pulse of 48. PharmD have failed on other therapies. This is a drug interaction occurring not imFigure 1 depicts mechanisms of action for mediately, but a month beyond when one many antidepressants. SSRIs, which generally work the might think about it, because the half-life of fluoxetine same way, are, as the name suggests, serotonergic. Nefazois such that the drug doesnt build up in the body until done and trazodone, which are serotonin 2A receptor the second month of treatment. The higher the blood levblockers, are variations on the serotonin theme. els, the more likely a significant interaction will occur. If Venlafaxine, at lower doses, is a reuptake inhibitor, but things go awry in the second month of therapy, a cliniat dosages above 75150 mg/day, noradrenergic effects cian should consider that a patients level of drug in the begin to become evident. The in-vitro binding at the blood has been building; the right answer may be to retransporter system for norepinephrine, though lower duce the dosage of medication, rather than increase it. than what might be expected to be necessary for a cliniTo continue this example, after Georges ER experical effect, is offset by high central nervous system levels ence, he stops his medications and sees his internist, who of venlafaxine due to its low protein binding. Mirtais managing his blood pressure. This physician has a zapine is a dual-mechanism antidepressant; however, it copy of the ER report, and cuts the previously well-tolworks by blocking noradrenergic and seroadrenergic reerated dosage of propranalol in half. This is, in essence, ceptors. Bupropion is thought to be a weak transporter a reaction to a medical problem that was preventable, inhibitor of both dopamine and norepinephrine, but its given the stability of long-term propranalol therapy. mechanism of action is unknown (Preskorn 1994). There are several antidepressants that likely would not With this array of drugs available, if a patient on an have created this trouble. SSRI has been on an adequate dosage and duration and George then visits his psychiatrist and recounts the does not respond, then instead of trying another SSRI, problems hes had with his other medications. The psyit would make sense to switch to another class. chiatrist realizes that fluoxetine can cause drug interactions, and switches George to sertraline. One month Drug interactions later, George becomes hypertensive. This illustrates the extra health care costs from preUnderstanding mechanism of action is not the only scriptions to hospitalization associated with drug inreason to select an antidepressant; knowledge of its meta-
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teractions. Georges metabolism for propranolol was normal when he was not taking fluoxetine. It was one fifth of normal when taking it (Pritchard 1990 case report). When a patient says to a physician, I feel a lot better since I ran out of those pills you gave me, it can be an indication that something has gone wrong.
Metabolism of drugs
Table 1 lists half-lives of various medications and the time it takes for them to build in the blood before reaching a steady state. Most antidepressants have a short halflife and reach the plateau phase in less than a week; for venlafaxine, this may be three days. Fluoxetine and its metabolite, because of their long half-life, do not reach a steady state until at least 28 days and can continue to build beyond that. Fluoxetine remains in the body for a month after a patient FIGURE 1 Antidepressant mechanisms of action stops taking it (Ereshefsky 1995, 1996). As a result, drug interactions with Antidepressant mechanisms fluoxetine whether coumadin, of action (traditional) codeine, or TCAs can occur for a month after a patient stops taking the drug. This is important for pharmaNE=norepinephrine cists to remember, because once a paSE=serotonin tient has stopped taking the drug and NE SE NE DA SE DA= dopamine the prescription is out of the pharmacys computer system, it wont screen for fluoxetine unless its been 5-HT1A 5-HT2 Sertraline Venlafaxine Reboxetine programmed to remember a drug for Partial Antagonist Fluoxetine (pending?) agonist a month after completion of therapy. Nefazodone Paroxetine Buspirone Trazodone Most drugs are metabolized in the Fluvoxamine Gepirone Citalopram liver by phase I enzymes, a process 2, 5-HT 2, 5-HT 3 that makes them water soluble and ADRs mirtazapine thus more easily excreted. One sub1 Bupropion group of these is the cytochrome P450 (CYP450) enzymes. Among the H1 many CYP450 enzymes, CYP3A4, SOURCE: PRESKORN 1994 CYP2D6, and CYP1A2 metabolize most drugs. Drugs can have any of three metabolic properties: they can TABLE 1 be substrates (when metabolized by a specific enzyme e.g., statins, which Pharmacokinetic profiles of selected antidepressants are metabolized by the CYP3A4 enSertraline Fluoxetine Paroxetine Nefazodone Citalopram* Mirtazapine Venlafaxine* zyme, are CYP3A4 substrates); inhibitors (an agent that decreases an Half-life (h) 24 4872 24 24 35 2040 5 enzymes ability to metabolize a drug Metabolite 2030% Equal No Several No 10% Equal e.g., nefazodone, which suppresses activity activities CYP3A4 metabolism, is a CYP3A4 inhibitor); and inducers (which increase Metabolite metabolic activity). When a substrate half-life (h) 4896 168216 1.518 2040 11 is taken with another drug that inSteady state hibits the same enzyme, a buildup of (d) 714 2842 7 <5 7 7 <5 substrate can occur and cause an adverse drug reaction. *Very low protein binding SOURCE: ERESHEFSKY 1995, 1996 A way to remember interactions be-
tween substrates and inhibitors is to think of receptors and antagonists. A drug interaction occurs when an inhibitor drug competitively antagonizes another drugs access to the active metabolic site. Therefore, the higher the dose of a medication and the more drugs taken, the more likely a drug interaction will occur, because of the number of molecules in the body. The CYP450 enzymes are expressed by genes, with the two alleles defining a patients genotype. This means that genetic mutations and variations found in different racial or cultural populations can cause variability in patients responses to drugs. It can be argued that not only do we as clinicians miss drug interactions, but also that we miss the genetic differences that we know exist in populations and that can lead to drug interactions.
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While software can help clinicians prevent drug interactions, most programs produce potential-interaction lists of drug A to drug B, B to C, C to D and so on. For a patient on five drugs, there could be several pages of drug-interaction output. It is also important to know additive risk something that existing programs do not do. Thats where clinicians and pharmacists come in, trying to add drugs together: A plus B plus C is bad, worse than either A and B together or C and B together.
This is a built-in group of people who need a very different dosage of medication. If a drug-interaction system misses that, then its missing a known quality indicator. One example of how 2D6 inhibitors block substrate action is seen in codeine. Codeine must be converted to morphine by 2D6 to produce an analgesic effect. Poor metabolizers of 2D6 exhibit impaired or no analgesia (Sindrup 1995). To use the group noted above, 7 percent of Caucasians who take acetaminophen with codeine actually are receiving acetaminophen with placebo. From Examples of interactions a standpoint of drug interactions, about half of people Table 2 focuses on the CYP2D6 enzyme. The drugs who take fluoxetine and even more who take paroxmost likely to interact with 2D6 are paroxetine, fluoxeetine have a significant reduction in analgesia potentine, and bupropion. These three agents are highly potent tial from the codeine. As inhibitors, they block codeines in inhibiting 2D6 activity, and are likely to but not alconversion to morphine. To underscore, people who are ways because of variability in patients genetics and the prescribed this drug for migraines or other reasons, and concentration of the inhibitor drug cause drug interwho are told to take it as needed, this is something to look actions with 2D6 substrates. for. It would be natural to ask, How I did miss this in A major interaction can occur when paroxetine or practice? Pain is subjective. Placebo response is real. fluoxetine are added to a patients drug regimen. In one For the CYP1A2 system, the ranking in Table 3 suggests study, 42 percent of extensive metabolizers converted to that fluvoxamine is the most important drug to be conpoor metabolizers after eight days of fluoxetine therapy, cerned about adding to a persons drug regimen. Conwhile 83 percent of extensive metabolizers taking paroxesider, also, a persons consumption of food and nonpretine became poor metabolizers. Venlafaxine and sertrascription medications; caffeine and acetaminophen, for line ran a zero-conversion rate (Lam 1997). instance, are 1A2 substrates. This illustrates a consequence that is avoidable. We This presents a common problem: people who are know that, genetically, 7 percent of Caucasians are poor prescribed fluvoxamine and drink coffee. The half-life for metabolizers of 2D6 (Yue 1998), and so the standard caffeine goes from 5 to 24 hours when fluvoxamine is indosage of an antipsychotic drug can lead to interactions. troduced; half of the cup of coffee consumed one morning is still in the body the next day. At the end of a week, a steady state of TABLE 2 CYP2D6 antidepressant-drug interactions caffeine has been reached, enough to precipitate anxiety reactions and inRelative rank Inhibitors Selected substrates somnia. Some of these people will High Paroxetine Secondary TCAs then be prescribed benzodiapines. Fluoxetine Beta blockers (older, lipophilic) Simply decaffeinating people on SSRIs Bupropion Codeine/hydrocodone should be the first step in managing Dextromethorphan insomnia, agitation, and jitteriness for Moderate TCAs Amphetamines the first week on fluvoxamine. Phenothiazines Concluding with the CYP3A4 sysLow High dosages of: Haloperidol tem, Table 4 indicates that nefazodone Sertraline >150 Flurazepam is a significant risk for serious or lethal Citalopram Quazepam drug interaction with such 3A4 subFlecainide strates as cisapride, carbamazepine, Minimal Fluvoxamine Chlorpheniramine cyclosporine, and some statins. It also Mirtazapine* Venlafaxine alters the risk for many other drug inNefazodone Fluoxetine teractions, because 3A4 is the bodys Venlafaxine Paroxetine most common enzyme and is a safety Propafenone net. If 2D6 metabolism is blocked, Other Thioridazine Nefazodone (m-CPP) blood levels of 2D6 substrates reach a inhibitors Haloperidol Tramadol new steady state of 4- or 5-fold higher. Some of the drug goes through 3A4. If 3A4 is blocked, 2D6 and 1A2 inter* in-vitro data only SOURCE: ERESHEFSKY 1995 actions become more dangerous. In
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considering new-product applications, the U.S. Food and Drug Administration takes a firm stance in terms of protecting the 3A4 system. While fluoxetine has a moderate to low risk, higher dosages (>40 mg/day) can inhibit the 1A2 system. Those at greatest risk for interactions include those who receive drugs with narrow therapeutic indices; people on multiple drug regimens at high dosages; and people who receive potent inhibitors, such as paroxetine, fluoxetine, and quinidine (Gregg 1999).
TABLE 3
High
CYP1A2 antidepressant-drug interactions

Inhibitors Fluvoxamine High dosages of: Paroxetine Fluoxetine Sertaline Nefazodone Bupropion Mirtazapine* Citalopram Venlafaxine Fluoroquinolones Grapefruit
*in-vitro data only
Relative rank
Substrates Caffeine Haloperidol Clozapine Olanzapine Theophylline Tacrine Tertiary TCAs Phenothiazines Beta blockers Acetaminophen
Moderate to Low Low to minimal
References
Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6. Clin Pharmacokinet. 1995;29 Suppl 1:1018. Ereshefsky L. Drug-drug interactions involving antidepressants: focus on venlafaxine. J Clin Psychopharmacol. 1996 Jun;16(3 Suppl 2):37S50S. Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry. 1996;57 Suppl 11:1225. Ereshefsky L, Riesenman C, Lam YW. Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. J Clin Psychiatry. 1996;57 Suppl 8:1724. Gregg CR. Drug interactions and antiinfective therapies. Am J Med. 1999 Feb;106(2):227237. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington: Institute of Medicine, 1999. Lam YW, Alfaro, Ereshefsky L. Antidepressant crossover study: conversion EM to PMs (abstract). American Psychiatric Association Annual Meeting 1997. Preskorn SH. Antidepressant drug selection: criteria and options. J Clin Psychiatry. 1994 Sep;55 Suppl A:622. Sindrup SH, Hofmann U, Asmussen J, et al. Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake. Eur J Clin Pharmacol. 1996;49(6):503509. Yue QY, Zhong ZH, Tybring G, et al. Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther. 1998 Oct;64(4):384390.
Other inhibitors
SOURCE: ERESHEFSKY 1996
TABLE 4
CYP3A4 antidepressant-drug interactions

Inhibitors Nefazodone Fluvoxamine TCAs Fluoxetine 20 mg Mirtazapine* Paroxetine Sertraline Venlafaxine Citalopram Grapefruit Protease inhibitor Antifungals Ca+2 blockers Erythromycin Clarithromycin Substrates Cisapride Ketoconazole Itraconazole Alprazolam Triazolam Estazolam Clonazepam Midazolam Verapamil Nifedipine Diltiazam Carbamazepine Cyclosporine Quetiapine Ziprasidone Corticosteroids Sex hormones Tamoxifen Erythromycin Quinidine Lovastatin/other statins Protease inhibitors increase efficacy
Relative rank High Moderate
Low to minimal (unlikely) Other inhibitors
SOURCE: ERESHEFSKY 1996
* in-vitro data only
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USING PHARMACOECONOMIC DATA TO COMPARE ANTIDEPRESSANT THERAPIES

ncreasingly, health care systems are looking for cost-effective,not just inexpensive,treatment options; similarly, pharmacy & therapeutics committees are seeking greater proof of a products pharmacoeconomic impact when making formulary decisions.Larry Ereshefsky,PharmD,professor of pharmacology and psychiatry at the University of Texas Health Science Center,presented various types of pharmacoeconomic data designed to produce outcomes information. An important consideration when reviewing the results of any pharmacoeconomic model is that the results are influenced by assumptions that are built into them; thus, Ereshefsky stressed the importance of adapting pharmacoeconomic models to account for influencing factors present in a population or health care delivery system. After doing this, the model will produce outcomes data that can allow the user to draw more accurate conclusions about any interventions that may be suggested by the results.
among 2.3 million covered lives between 1994 and 1999. Patients were followed for six months. A pattern was noticed that at the time of diagnosis, patients given the serotonin norepinephrine reuptake inhibitors (SNRI) venlafaxine IR and venlafaxine XR generally had more frequent medical (nonmental health-related) illnesses and a greater number of mental health-related hospitalizations than patients given SSRIs (fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine).At the end of six months, inpatient nonmental health-related hospitalization expenses were significantly lower for the venlafaxine IR/XR group compared with the SSRI group, while there were virtually no differences in antidepressant medication costs between the venlafaxine IR/XR and SSRI groups (Figure 1). Adherence to antidepressant therapy was similar in patients treated with venlafaxine XR compared to SSRIs.The upshot is that use of venlafaxine to treat depression can influence total medication costs in patients with concomitant illness.
Retrospective analysis
A retrospective analysis of the Medstat MarketScan database examined the effects on all health care costs after prescribing various antidepressant medications to patients newly diagnosed with depression with or without anxiety. The researchers examined new episodes of depressive illness with or without anxiety
Decision-analytic model
A second analysis presented was a classic pharmacoeconomic model using a decision-analytic approach. It is useful in developing budget-impact data when specific clinical pathways are followed and associated health outcomes are compared with treatment costs. Ereshefsky presented data using a model developed by Einarson (1997) and based on inpatient data from 14 studies and outpatient data from 51 FIGURE 1 6-month retrospective studies of all health care costs among patients expenditure analysis, SNRI vs. SSRI with depression taking either venlafaxine,SSRIs, P <0.01 $600 s SNRI (n=468) or TCAs (Table 1).This mathematical model was s SSRI (n=8,625) $526 customized by running data from five MCOs 500 (independent practice associations and P = 0.50 network-model HMOs),each accounting for its 400 $352 $360 own drug and health care resource costs, de300 mographic information,and physician-practice patterns (Arikian 2000). The model assumed 200 $177 equal adherence rates among medications. Medication-cost differences were generally 100 negligible between the venlafaxine XR and SSRI 0 groups. Over 6 months, inpatient and outAntidepressant Nonmental healthpatient costs in the venlafaxine XR group were medication treatment related hospitalization about $1,500 less than the SSRI or TCA groups, cost per patient cost per patient with an average per-member, per-month cost SNRI = Venlafaxine IR/XR; SSRI = Fluoxetine, Paroxetine, Sertraline, Citalopram, Fluvoxamine. 19941999 MarketScan data,The MEDSTAT Group, Inc. savings of about 15 cents (Figure 2). Overall MarketScan is a registered trademark of the MEDSTAT Group, Ann Arbor, Mich. success rates,defined as a minimum 50-percent SOURCE:WAN GJ, CROWN WH, BERNDT ER, FINKELSTEIN SN, LING D. ARE VENLAFAXINE reduction in depression scores on the Hamilton AND VENLAFAXINE XR ASSOCIATED WITH LOWER HOSPITALIZATION COSTS IN DEPRESSED PATIENTS WITH OR WITHOUT ANXIETY COMPARED TO SSRIs? 2001. WORLD Depression Rating Scale (HAM-D 17 ), were ASSEMBLY FOR MENTAL HEALTH, VANCOUVER, CANADA: POSTER PRESENTATION. higher for venlafaxine XR patients.The analysis
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concluded that in all systems combined, each 1 percentage point of patients switched from other antidepressant drugs to venlafaxine XR would represent about $16,000 in savings per year. Potential savings are based on the differences in expected costs per successfully treated patient, though this research does not specifically target where these savings occur.
TABLE 1 Study basis for meta-analysis Venlafaxine IR Inpatient data from 3 studies, 164 patients Venlafaxine XR Outpatient data from 5 studies, 324 patients SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) Inpatient data from 3 studies, 84 patients Outpatient data from 28 studies, 2,496 patients TCAs (amitriptyline, imipramine, desipramine, nortriptyline) Inpatient data from 8 studies, 325 patients Outpatient data from 18 studies, 727 patients
Depression-free day analysis

The third presentation was an analysis of pooled data from eight clinical trials (the same trials used for Michael Thase, MDs, meta-analysis detailed on pages 69) comparing venlafaxine, SSRIs, and placebo.This analysis used the pooled data to develop depression-free days as a measure of the approximate time patients spent in remission of their depression symptoms following 8 weeks of acute treatment. The construct, applied by Mallick (2001) and based on previous literature,ascribes maximum depressionfree time to patients who achieve and maintain a fully asymptomatic state (a score of <7 on the HAM-D17) and minimum or zero depressionfree days to those patients who are continuously in a state of fully symptomatic depression (HAM-D17 >15). Over the 8-week period,the number of depression-free days for each patient could, theoretically, range from 0 to 56. Patients who received venlafaxine were associated with median 18.8 depression-free days, compared to median 13.6 depression-free days for patients receiving SSRIs and median 7.4 depressionfree days for those who received placebo ( Table 2). All differences were statistically significant.Further, as expected,this was consistent with similar differences across groups relative to the proportion of patients in each group who achieved sustained remission due to treatment and the duration for which they remained in sustained remission.
FIGURE 2 Average treatment costs per patient

$16,546 $14,846 $0.69 $16,695 $0.84
Annual ($) PMPM $0.84
Venlafaxine XR
SSRI
TCA
BASED ON EINARSON T.PHARMACEUTICAL APPLICATIONS OF META-ANALYSIS.CLIN THER.1997:19(3); 559569.DATA SOURCE:ARIKIAN S,CASCIANO J,KANG-CIPOLLA L,VODOOR M,GRUBIN M,CLARK D, WAUGH W,KELSEY J,OSBORN LW.THE MANAGEMENT OF DEPRESSION:IMPLICATIONS FOR MANAGED CARE ROUNDTABLE DISCUSSION,PART 2.MANAGED CARE INTERFACE. 2000; SUPPL B:1925,32.
TABLE 2 Depression-free days (DFDs) by treatment group Treatment group Venlafaxine (n=864) Mean DFDs (SD) Median DFDs (IQ range) % of patients with >41 DFDs 19.8 (16.7) 18.8 (0.935.0) 12.3 SSRI (n=756) 17.3 (15.9) 13.6 (030.4) 7.8 Placebo (n=450) 14.1 (15.4) 7.4 (026.2) 6.0 P values 0.0022* <0.0001 0.0007 0.0041* <0.0001 0.0005 0.003* 0.0003 0.2499
* Venlafaxine vs. SSRI. Venlafaxine vs. placebo. SSRI vs. placebo.

SOURCE: MALLICK R, ENTSUAH R, CHEN J. DEPRESSION-FREE DAYS AND CGI-S: A POOLED COMPARISON OF VENLAFAXINE, SSRIs, AND PLACEBO. 2001. PROCEEDINGS OF THE AMERICAN PSYCHIATRIC ASSOCIATION NEW ORLEANS: POSTER PRESENTATION.
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The Texas Medication Algorithm Project For Major Depression

LARRY ERESHEFSKY, PHARMD
Professor of Pharmacology and Psychiatry, University of Texas Health Science Center
he Texas Medication Algorithm Project (TMAP) for major depression started in our state mental health system as a way to encourage evidence-based practice in a wide array of environments. These algorithms (Crismon 1999) illustrate strategies and for the treatment of major depression in nonpsychotic (Figure 1) and psychotic (not shown) patients and those with bipolar illness (not shown). Moving toward evidence-based practice means developing not only an algorithm, but a culture that integrates monitoring and education, and uses evidencebased practice when making drug-treatment decisions. What has made TMAP work is a culture shift not simply,Heres a blueprint. Follow it. It was designed to use a best-practices approach to treatment resistance, while being flexible: A particular stage of the TMAP algorithm can be modified or ignored by any clinician at any time. The only thing we ask clinicians who stray from the algorithms to do is to document why. Documentation improves evidence-based practice because it forces people to articulate a reason for what they do. TMAP is being computerized and will become a system that gives automatic feedback. When available on disk, TMAP will prompt users to adhere to best practices: They will be warned when departing the algorithm. It wont force anyone to use a particular drug, but it will require documentation for deviations from this standard. A user can download physician training manuals and implementation guides at http://www.mhmr.state. tx.ux/centraloffice/medicaldirector/tmap.html.
TMAP algorithms
The antidepressants listed in the algorithms include the SSRIs as a class, nefazodone, bupropion SR, venlafaxine XR, mirtazapine, TCAs, and MAO inhibitors. Stage 1 is when the clinician believes monotherapy is appropriate for a new diagnosis of depression. One can choose from a variety of drugs, except for TCAs which we dont believe are front-line therapies for depression. The user progresses through strategies illustrated in the algorithm. There are also tactical steps decision points to consider when the patient does not respond to the treatment given at each stage, such as: Do you
bump up the dose after 4 weeks of therapy? Do you augment? Do you switch? This is illustrated as stage 1A. If this fails, go to stage 2: Switch to a different drug. Although a patient who failed on an SSRI at stage 1 can be switched to another, its recommended that this be done only for side-effect intolerance, rather than for lack of efficacy. Augmentation the best data suggest lithium or thyroid supplementation can be tried for partial responders here (stage 2A) or at any stage. Stage 3 again is monotherapy, but the clinician must use a different class of medication. If, for instance, there is a history of treatment resistance to paroxetine and fluoxetine, then the patient should be switched from SSRIs to a different class. Stage 4 adds lithium augmentation, if not already used, because it has the best data for augmentation and has been shown to have fast response. Stage 5 involves use of combination antidepressants. At this stage, if not already tried as augmentation, the addition of a TCA to a serotonergic agent has the most evidence to support its use. However, combinations of bupropion, venlafaxine, and mirtazapine with other antidepressants are considered the most potent strategies. There is no correct way to switch patients from one therapy to another. Most physicians overlap taper the first drug, while increasing the dosage of the second product. Some will stop one drug and switch, especially within the same class. In this case, there are no consensus guidelines except that abruptly stopping a drug and doing nothing else is known to be harmful. With SSRIs, a serotonin-discontinuation syndrome is seen; the SSRI with fewest discontinuation problems is fluoxetine, because of its buildup in a patients system.
Outcomes
In analyzed results presented at the American College of Neuropsychopharmacology and the Texas Society of Health-System Pharmacists, for people treated using the TMAP algorithm, there is a 20 percent better response rate in patients who are more severely depressed than in those whose treatment did not follow TMAP protocols. In summary, when managing patients with limited response, first maximize the dose and administer the
16
medication for an adequate duration. If this fails to produce a response, switch classes. Thereafter, a pharmacologically different agent should be tried. When switching classes, consider a broad-spectrum antidepressant that affects more than one neurotransmitter system, or affects the system differently from the one already used. TMAP
gives clinicians a sense of how to combine drugs rationally after monotherapy has been tried.
Reference
Crismon ML, Trevedi M, Piggot TA, et al. The Texas medical algorithm report. J Clin Psychiatry. 1999;60:142156.
FIGURE 1 Strategy for treatment of nonpsychotic major depression

Monotherapy Stage 1
SSRI, bupropion, nefazodone, venlafaxineXR, or mirtazapine
Any stages(s) can be skipped depending on the clinical picture. Partial response Partial response or nonresponse
Response
Stage 1A Augmentation** Response
Continuation
Monotherapy Stage 2
SSRI, bupropion, nefazodone, venlafaxineXR, mirtazapine, or TCA
Partial response or nonresponse
Response
Partial response Partial response or nonresponse Stage 2A Augmentation** Response
Continuation
Monotherapy Stage 3
SSRI, bupropion, nefazodone, venlafaxineXR , mirtazapine,TCA, or MAOI* A class other than used in Stage 1 or 2
Partial response Partial response or nonresponse
Stage 3A Augmentation**
Response
Continuation
Stage 4
Lithium augmentation***
Response
Continuation
Combination antidepressants: Stage 5

TCA+SSRI bupropion+SSRI nefaz+SSRI bupropion+nefaz Partial response or nonresponse
Response
Continuation
Stage 6
ECT Response Other

* Consider TCA/venlafax if not tried ** Lithium, thyroid, buspirone *** Skip if lithium augmentation has already failed Most studied combination SSRI = Fluox, Sert, Parox, Cital
Continuation Maintenance phase when indicated
Stage 7
E.g., lamotrigine, fluvoxamine, mirtazapine+bupropion, olanzapine, etc. (provide rationale)
SOURCE: Crismon 1999
17
ROUNDTABLE DISCUSSION
Efficient, Cost-Effective Therapy: Translating Evidence Into Practice
ollowing the presentations by Lawrence Ereshefsky, PharmD, and Michael Thase, MD, a group of behavioral health medical directors were invited to share their impressions. The panelists discussed the comparative data that had been presented about the effectiveness of various antidepressant medications, and their relevance to clinical practice that is, how the data can be made meaningful to primary care physicians when making prescribing decisions. The following pages include excerpts from this discussion, moderated by Bradley Kozar, group president and CEO of MediMedia Managed Care, a division of Vivendi Universal Health. Attendees
The days faculty included: Jonathan D. Book, MD Executive Vice President and Chief Medical Officer Magellan Behavioral Health Columbia, Md. Kenneth H. Cohen, MD Medical Director Green Spring Health Services (Portland) Maine Regional Service Center Charles Freed Jr., MD, MHA Divisional Medical Director Health Plan Solutions Group Magellan Behavioral Health Chattanooga,Tenn. Aron Halfin, MD Senior Vice President and Chief Medical Officer Health Plan Solutions Group Magellan Behavioral Health Alpharetta, Ga. Thomas A. Hamlin, MD Vice President, Medical Services Magellan Behavioral Health Dallas Regional Service Center Julie B. Kessel, MD Medical Director and Vice President, Medical Services Magellan Behavioral Health of Eastern Pennsylvania Philadelphia Leslie Moldauer, MD Divisional Medical Director Magellan Behavioral Health Greenwood Village, Colo. Lawrence J. Nardozzi, MD, FAPA Vice President, Medical Services Magellan Behavioral Health King of Prussia (Pa.) Regional Service Center Andrew Rudo, MD Senior Vice President, Medical Services Magellan Behavioral Health Columbia, Md.
18
The group began by evaluating the information presented by the days speakers about therapeutic options for patients with depression. Several panelists agreed that while the comparative data were well substantiated, the key to affecting patient care lies in translating those data into useful information at the clinical level. The participants determined that favorable outcomes data, and not just information about a drugs acquisition cost, are needed to influence formulary decisions.
BRADLEY K. KOZAR: Of the themes touched on during
todays presentations outcomes, drug interactions, the Texas treatment algorithms (TMAP), relative-effectiveness data, remission data, pharmacoeconomics which of these data were compelling or of value to you? KENNETH H. COHEN, MD: The clarification between drug response and remission was important. Often, the two are taken as synonymous. There is a difference, and this should be considered. JULIE B. KESSEL, MD: Michael Thases presentation on the way you look at What do MCOs expect from managed data was outstanding. It helps people behavioral health organizations incorporate the literature, which is (MBHOs) with which they contract? The critical to clinicians who make their panelists indicated its important for an own determinations when evaluatMBHO to demonstrate the value of thering drugs. apy in terms of reducing overall cost of Andrew Rudo, MD LESLIE MOLDAUER, MD: The TMAP algocare and improving a patients level of rithm was fascinating. I would like to functioning. It was suggested that an MBHO could focus on high-risk groups of patients for have seen how its used on a day-to-day, real-life MCOs seeking to educate primary care physicians about basis. the effective treatment options for depression. This, in KOZAR: Do you have algorithms that are similar, at least turn, can influence physicians prescribing habits. in concept, to TMAP? ANDREW RUDO, MD: We have a multidisciplinary medicalpractice guidelines committee that looks at the KOZAR: Ultimately, are MCOs expectations that you simguidelines available and [considers] what would best ply reduce costs? Or is it about outcomes, getting pasuit our purposes either adopting existing guidetients well and back to work? lines or drafting them. We dont have an algorithmARON HALFIN, MD: Cost is one dimension, but its neither type guideline, although that was an interesting prethe only nor the main one. I think the expectations sentation to me, too. are really that members receive appropriate care in CHARLES FREED JR., MD, MHA: For me, the most comthe most expeditious way, and that patients get well. pelling information was the pharmacoeconomic MOLDAUER: Theres also an issue of short-term versus data, especially when you consider that plans inlong-term cost. Sometimes you dont see the results creasingly use tiers for medications to offset costs to of an intervention you put in today for four to five the plan. The question often arises: Which tier years. I think thats why were there, as physicians, to should an agent be placed on? know what a patients treatment course should be COHEN: I think P&T committees want corroborating over a five-year period, then measure the effect of that data. Theyre concerned about getting objective data. intervention. LAWRENCE J. NARDOZZI, MD: Weve been involved in a HALFIN: One advantage we have is our size and scope. collaborative effort with Aetna regarding education More likely than not, if an individual is with health and training of primary care physicians, so that they plan A today and health plan B tomorrow, well still can recognize depression and become better capable be managing that persons care by virtue of the scope
of treating it. Not much of the empirical data presented today would be useful to primary care physicians. Whats important is better recognition of depression and then having an agent that physicians are comfortable prescribing, based on a patients disease severity and on an understanding of its side effects. As we all know, the vast majority of mood disorders are not treated by psychiatrists. THOMAS A. HAMLIN, MD: I think information about the integration of psychiatry into primary care would have been pertinent. The evidence presented today about increased incidence of depression among patients with diabetes, heart disease, and other illnesses was very helpful to me. JONATHAN D. BOOK, MD: What I found interesting was the increased information available to guide rational prescribing practices away from the notion that an antidepressant is an antidepressant. Why shouldnt the decision on a first-line drug be a rational pick? Most patients couldnt differentiate why we would start with one antidepressant versus another.
19
of our relationships. So that puts us in a better position to do some of the longer-term interventions that Leslie Moldauer was talking about. FREED: The health plans I work with are sensitive to costs, but the concept of value has more meaning to them. Ken Cohen made a good point when he said we need quantified information. The problem is that theres not always one resource you can go to for this information. I wonder what other people do to get information that would be helpful to P&T committees in understanding that this is beyond cost. KOZAR: Are your health plans asking for data from you? FREED: Well, in P&T committees, when were asked why a more expensive agent should remain on tier 1, thats when we need that information. KOZAR: One of the things Dr. Ereshefsky presented is that the actual cost of these medications rose only about 4.7 percent. MOLDAUER: However, last year alone, there was a 22 percent increase [in the drug spend]. Its the increase that health plans tend to look at. BOOK: One of the things that could use more thoughtful analysis is the combination of prescription drugs and other modalities of care, such as cognitive behavior therapy. Our customers look for us to provide fairly sophisticated exploration of the role of specialty behavior health services. Not just prescription medications, but also in the application of psychosocial intervention, therapy, and the like and how that as a whole affects the health of their members and medical costs. RUDO: Thinking about the wealth of information were exposed to, and using that to try to influence primary care physicians who prescribe antidepressants, its a massive task. Health plans are looking for us to help in manageable bits. An example of what we can do: Take not the whole depressed population, but just the highest-risk populations such as those with chronic medical illnesses and then collaborate, as the experts in behavioral health care, with health plans to create programs and partner with organizations to create programs. Then we can focus on education, like what we heard today about the advantages of newer agents. KOZAR: It requires integration between you and your health plans, as well as between psychiatrists, psychologists, and primary care providers. That gets to provider education. What types of things do you need to help educate primary care physicians? HAMLIN: Theres some debate as to whether education alone can affect primary care physicians prescribing practices. You might need an integrated effort with the health plan, and it is pharmacy because education alone wont do it. COHEN: Theres another level: plans integrating with other
plans. Typically, one primary care provider works with multiple health plans. NARDOZZI: We emphasize communication between the primary care physician and therapist. Its critical that information flows freely. So the challenge to us in medicine is to have physicians practice more on the basis of knowledge. When we talk to physicians, thats what we hear: I like this drug because it works more. It happens to be the most novel agent, and so people rush to use it. This is a particular challenge in behavioral health, where the complexity of the brain is so enormous that our understanding of it is relatively less than comparable recognition of how the body functions in other fields of medicine. HAMLIN: Giving primary care physicians readily digestible, easily understood pieces of information, as opposed to multiple bar graphs and tables with lots of numbers on them, is critical. MOLDAUER: Presentations like todays reinforce the need to disseminate credible, research-based data, and hopefully that will have an effect on prescribing patterns. I think what we saw today might lead us to a different conclusion about therapeutic options than we might have had if we spoke with our colleagues or friends and had only anecdotal information. The panel discussed how pharmaceutical companies can help to educate primary care physicians about effective therapeutic options. Many were concerned that primary care doctors, who are more apt than psychiatrists to prescribe SSRIs exclusively as opposed to considering whether another class of antidepressant might be more effective for certain patients, are influenced by SSRI marketing. A suggestion for getting the message about a drugs effectiveness to these physicians was that pharmaceutical companies demonstrate the impact a medication can have on a patients overall medical condition.
KOZAR: How can pharmaceutical manufacturers help
with provider education and integration with health plans and the psychiatrist? KESSEL: I really think a focus on disease management and outcomes, and a direct comparison to medical illness, is important. In psychiatry, were struggling to establish ourselves as a medical discipline before our medical colleagues. A focus on the same principles that guide medical management of major illnesses that cost a great deal of money would be useful. COHEN: Pharmaceutical companies marketing has been very effective, as evidenced by the number of prescriptions written for SSRIs. Most health plans will indicate that SSRIs are among their top four medications. And because 70 to 75 percent of SSRIs are written by nonpsychiatric physicians, that has a major impact.
20
KOZAR: SSRIs get higher support from primary care
physicians than non-SSRIs, such as venlafaxine, nefazodone, or bupropion. How many of you currently use SSRIs as first-line therapy? Or do you consider alternatives as first-line agents? Health plans almost make you go to an SSRI first. BOOK: A large proportion of antidepressants is prescribed by primary care physicians. Im not a primary care physician, but it begins with having to ask the question: Is the prescription really being written because we have a patient with major depressive disorder? I think theres good reason to believe the answer is often no. Studies show how underdiagnosed major depression is, despite how well prescribed antidepressants are. Whats the matter with this picture? One way of thinking about that: Antidepressants are prescribed, in some notso-small way, for vague complaints. Primary care doctors have learned that fluoxetine and other SSRIs have been effective for a breadth of nonspecific symptoms that fall below the threshold of a major depressive diagnosis. One challenge for any new anti- Kenneth H. Cohen, MD depressant is to get past that, to define its niche in the way primary physicians use antidepressants. KOZAR: I saw a lot of nodding in agreement when I asked whether psychiatrists would think of non-SSRIs as first line. However, primary care physicians tend to prescribe the SSRI. So when a psychiatrist sees a patient who has been initiated on an SSRI and isnt getting better, what do you do? Do you increase the dose or augment therapy, as suggested in stage 1A of the TMAP presentation? Do you try another SSRI, which the data presented today suggest may make little clinical difference? Or, would you change to a different class, as we saw in TMAP, stage 2? HAMLIN: The important thing is, first, to determine the dose strength of the initial prescription and whether there are any compliance issues. At that point, I would recommend increasing the dose if the patient is compliant. Then, if the patient is on a sufficient dose of an SSRI for a sufficient length of time but shows no effect, I generally would switch to another class of antidepressant. The importance of cohesion among and between providers and/or health plans was again highlighted by medications comparative data about remission. Psychiatrists, the panel agreed, are trained to look for remission
of mental illness, not just symptom improvement, while primary care physicians who tend to focus on a patients entire medical health might not push as hard for full remission.
KOZAR: Have you thought about the agents comparatively
with remission as the end point?

HAMLIN: I always measure remission by evaluation of a
patients level of functioning prior to the advent of the illness. A lot of patients we see have suffered major depressive disorder so long that they dont know their true potential. They might have developed the illness as a child or an adolescent, resulting in developmental delays. Generally, we want to get them back to a high level of functionality. MOLDAUER: Health plans make you look at it differently, to be aware of the comparative differences in remission between drugs. FREED: The difference is largely due to the variation in training and skill sets between psychiatrists and primary care physicians. Psychiatrists are much more likely to take into consideration remission, versus just improvement. I dont think primary care physicians have been trained in that fashion, and so they are less likely to ask patients questions that would elicit this kind of information. RUDO: Its also a matter of focus. A primary care physicians focus necessarily needs to be on the persons entire medical-surgical health. And like with any physician, there is only a limited amount of time to do that. So he may not push as aggressively about full remission if he has to cover a bunch of other issues in that same session. I still see patients and from a psychiatrists perspective, if theyre not all the way in remission, I want to know why. Ill keep driving for that. KOZAR: How many of you were aware that, comparatively, venlafaxine has better remission data than SSRIs? KESSEL: Im aware of that data for major depressive disorder that is moderate to severe without comorbid illness. I think theres a basic issue about diagnosis in primary care, even though I happen to be one of the people who thinks primary care doctors do a decent job treating depression, because most patients are adequately satisfied and recovered not that they couldnt do better. I do think, however, that primary care physicians and psychiatrists alike suffer from an inability to diagnose specific syndromes and choose medications based on those syndromes.
21
The panel concluded with a discussion about how to promote consideration of non-SSRIs as first-line therapy if data support them as effective therapeutic options and for whom this would be appropriate.
KOZAR: Thats another way to or look at it: If Im a pri-
mary care physician, for whom should I consider venlafaxine or other non-SSRIs, as opposed to fluoxetine, paroxetine, sertraline, or citalopram? KOZAR: Most of you seem to agree that nonKESSEL: Patients with weight loss and SSRIs, such as nefazodone, venlafaxine, anhedonia, decreased activities of bupropion, or others can be first-line daily living, or who are brought in by agents, yet recognize that primary care a family member and impaired. physicians tend to go to the SSRIs. It COHEN: I can speak only from my own seems that the remission data for more clinical experience, but some of the severe patients favors venlafaxine. Why more anxious and somatic complaints arent these drugs first line among priof patients seem to have responded mary care physicians? And how can this better to venlafaxine than SSRIs. information be disseminated? HAMLIN: First-line use would be adRUDO: One thing that occurs to me about visable for the patient who suffered primary care application efforts is that Leslie Moldauer, MD, left, and previous side effects from an SSRI. we could help [focus that discussion]. Charles Freed Jr., MD, MHA Major side effects, whether sexual, Often the depression talks are an hour, shakiness, or disturbing side effects and try to cover A to Z about depression as opthat prevent the patient from returning to the work posed to focusing on one or two aspects that would force, would be the indicator for a different first-line be most pertinent to primary care physicians. One of approach. those things could be differences demonstrated by KOZAR: If Im treating a drug-nave patient, when should the literature among antidepressants. I use SSRIs versus non-SSRIs? KESSEL: I think it would be beneficial for primary care NARDOZZI: If I were a primary care physician, what I physicians to focus on patients who are most relevant need [to know about a product] is its tolerability, efto them: the share who are high utilizers, hypoficacy, and its drug-interaction profile. Give me that chondriacs, somatic, and have mixed anxiety and information, and in all likelihood, it would be more depression. Those are their problem patients. So if probable that Id prescribe it as a first-line agent, as [the manufacturer of] venlafaxine was able to gather opposed to [another drug that I already know is] safe. information about that group and its effectiveness COHEN: Single-dosing of the SSRIs is a clear advantage. I with that group, I think that could be useful to prithink the XR experience [of venlafaxine] needs to be mary care physicians. shared.
22
CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUEST
CE Credit for PHYSICIANS

Sponsored by the University of Arizona College of Medicine at the Arizona Health Sciences Center
Name _________________________________________
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Title __________________________________________ Specialty_______________________________________ Address _______________________________________ City ___________________________________________ State ___________________________ ZIP ___________ Daytime telephone ______________________________
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PROGRAM EVALUATION In order to assess the value of this self-study program,we ask that you fill out this evaluation form. Overall activity rating Excellent Very good 5 4 Good 3 Fair 2 Poor 1 Not at all 1
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CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUEST
CE Credit for PHARMACISTS

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24
CONTINUING EDUCATION QUESTIONS

Directions: Please tear out the combined answer sheet/assessment form on Page 23 (physicians) or 24 (pharmacists). On the answer sheet, place an X through the box of the letter corresponding with the correct response for each question.
1. When weighing the effectiveness of an antidepressant, it is most useful to consider: A. Remission of illness. B. Improvement of symptoms. C. Missed work days. D. Cost of treatment. 2. What percentage of patients with symptoms that would qualify for a diagnosis of depression are taking antidepressants? A. 77 percent. B. 44 percent. C. 23 percent. D. 14 percent. 3. Which drug takes at least 28 days to reach steady state in the body? A. Fluoxetine. B. Fluvoxamine. C.Venlafaxine. D. Caffeine. 4. The Texas Medical Algorithm Project (TMAP) for Major Depression was an effort to: A. Encourage evidence-based practice. B. Increase the share of people with depression on antidepressants. C. Force clinicians to follow set guidelines for treatment of depression. D. Reduce the number of people in state mental hospitals. 5. Of the four types of antidepressants, which is potentially lethal in overdose? A. MAO inhibitors. B. Selective serotonin reuptake inhibitors (SSRIs). C.Tricyclics (TCAs). D. Other medications that are not in any of the above classes. 6. From a metabolic standpoint, what is a substrate? A. A drug that suppresses metabolic activity. B. A drug that induces metabolic activity. C. An enzyme that metabolizes drugs in the body. D. A drug that is metabolized by a specific enzyme. 7. Venlafaxine employs what mechanism of action? A. It is noradrenergic. B. It is serotonergic. C. Both A and B. D. It blocks noradrenergic and seroadrenergic receptors. 8. When considering pharmacoeconomic data: A. General retrospective database analyses are more useful than experience reflecting a health systems use of specific clinical pathways. B. It is important to consider that outcomes are influenced by assumptions built into the input data. C. Drug-cost differences are the primary influencing factor in outcomes. D. Recall that no one model can be customized to a health systems practice model. 9. The CYP3A4 metabolic enzyme is notable because: A. It is the bodys safety net. B. It can metabolize some drugs when other enzymes are inhibited. C.The U.S. Food and Drug Administration pays close attention to an agents effect on CYP3A4 when considering new-drug applications. D. All of the above. 10. After four weeks of drug treatment, the risk of relapse in patients treated for major depression is greatest among those who have had ____ previous episodes. A. 3 or more. B. 2. C. 1. D. 0. 11. Which drugs are variations on SSRIs, in that they are serotonin II blockers? A.Venlafaxine and nefazodone. B. Nefazodone and trazodone. C. Mirtazapine and bupropion. D. All drugs in answers A and C. 12. On average, results of modern clinical studies peg the drug/placebo difference, in terms of effectiveness, at: A. 67 to 33 percent. B. 60 to 35 percent. C. 50 to 32 percent. D. 50 to 50 percent. 13. Under TMAP, it is suggested that another class of antidepressant be tried if there is no response after which stage? A. Stage 1. B. Stage 1A. C. Stage 2. D. Stage 2A. 14. The following patients are at greatest risk for drug interactions: A.Those receiving drugs with narrow therapeutic indices. B. People on multiple drug regimens at high doses. C. Patients prescribed potent inhibitors. D. All of the above.
25

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SPECIAL SUPPLEMENT TO

Volume 10, No. 8 August 2001

Using Evidence To Improve Care For People With Depression

TIMOTHY P. SEARCH, R.PH.

HEALTH STATUS OVERVIEW

Depressions Ripple Effect on Health Status and Costs ........4

Overview of Antidepressant Therapy....................................6

Antidepressant Drug Interaction Considerations ..............10

Using Pharmacoeconomic Data To Compare Antidepressant Therapies ...............................14

The Texas Medication Algorithm Project For Major Depression ...........................................................16

Cost-Effective Therapy: Translating Evidence Into Practice...........................................................................18

This supplement is supported by an unrestricted educational grant from Wyeth-Ayerst Laboratories.

SELF-STUDY CONTINUING EDUCATION ACTIVITY

Educational needs assessment

Planning committee members

MANAGED CARE / SUPPLEMENT

ABOUT THIS PUBLICATION

Conflict of interest policy in continuing medical education

Disclosures of significant relationships

SUPPLEMENT / MANAGED CARE

DEPRESSIONS RIPPLE EFFECT ON HEALTH STATUS AND COSTS

Comorbidity is common and costly

Prevalence of depression unrecognized

SOURCE: GREENBERG 1993

MANAGED CARE / SUPPLEMENT

Relapse can be risky for MCOs

FIGURE 3 Patients with major depression: Cumulative probability of relapse

3 or more previous episodes

0 1 2 4 5 6 7 10 12 Weeks since recovery

FIGURE 4 Incomplete remission predicts greater relapse*

SUPPLEMENT / MANAGED CARE

Overview of Antidepressant Therapy

MANAGED CARE / SUPPLEMENT

SUPPLEMENT / MANAGED CARE

New standard of therapy

Remission rate (%)

Comparisons with SSRIs

FIGURE 4 Remission rates, by definition of remission

Placebo SSRI Venlafaxine , , *

MANAGED CARE / SUPPLEMENT

Other pharmaceutical comparisons

SUPPLEMENT / MANAGED CARE

Antidepressant Drug Interaction Considerations

MANAGED CARE / SUPPLEMENT

SUPPLEMENT / MANAGED CARE

MANAGED CARE / SUPPLEMENT

CYP1A2 antidepressant-drug interactions

Moderate to Low Low to minimal

CYP3A4 antidepressant-drug interactions

Relative rank High Moderate

Low to minimal (unlikely) Other inhibitors

SOURCE: ERESHEFSKY 1996

* in-vitro data only

SUPPLEMENT / MANAGED CARE

USING PHARMACOECONOMIC DATA TO COMPARE ANTIDEPRESSANT THERAPIES

MANAGED CARE / SUPPLEMENT

Depression-free day analysis

FIGURE 2 Average treatment costs per patient

Annual ($) PMPM $0.84

* Venlafaxine vs. SSRI. Venlafaxine vs. placebo. SSRI vs. placebo.

SUPPLEMENT / MANAGED CARE

The Texas Medication Algorithm Project For Major Depression