0108.Depression Suppl

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M A N A G E D

SPECIAL SUPPLEMENT TO

New Evidence-BasedTreatments for DepressionProceedings of the Magellan Behavioral Health2001 Clinical Medical Retreat

HIGHLIGHTS

Depressions Ripple Effect on Health Status and Costs

Overview of Antidepressant Therapy

Antidepressant Drug-Interaction Considerations

Using Pharmacoeconomic DataTo Compare Antidepressant Therapies

The Texas Medication Algorithm ProjectFor Major Depression

Roundtable Discussion Efficient, Cost-Effective Therapy:Translating Evidence Into Practice

Continuing medical and pharmacy educationsponsored by the University of ArizonaColleges of Medicine and Pharmacyat the Arizona Health Sciences Center

CareCare

Volume 10, No.8

August 2001


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I N T R O D U C T O R Y M E S S A G E

Using Evidence To Improve CareFor People With Depression

At Magellan Behavioral Healths 2001 Clinical Medical Retreat,

New Evidence-Based Treatments for Depression, two outstand-ing clinicians and researchers presented evidence of treat-

ment options that hold great promise in terms of improving qualityof behavioral health care. This meeting was accredited for continu-ing education by the University of Arizona Colleges of Medicine and

Pharmacy at the Arizona Health Sciences Center, and we are grate-ful for their accreditation support of this publication for continuingmedical education and continuing education for pharmacists.

Michael E. Thase, MD, professor of psychiatry at the UniversitySchool of Medicine and the Western Psychiatric Institute and Clinic,addressed current concepts in treatment and management of de-pression, including a discussion of drug-product selection based ondifferential efficacy. This valuable information is featured on pages69.

We were fortunate to hear from Larry Ereshefsky, PharmD, pro-fessor of pharmacology and psychiatry at the University of TexasHealth Science Center, who among other things, presented com-pelling considerations about medication interactions with respect toantidepressants and an overview of the Texas Medication AlgorithmProject for Major Depression. These presentations are abstracted onpages 1013 and 1617, respectively.

This publication also includes information that highlights the im-portance of recognizing depression and its consequences on medicaloutcomes; pharmacoeconomic data for drug therapy in depression;and concludes with a roundtable discussion of the research pre-sented at the retreat and its relevance to choosing appropriate medi-cal interventions.

We encourage you to take advantage of the continuing educationthat is offered for physicians and pharmacists through this publica-tion. And we hope some of the ideas presented here will be useful to

you in your everyday responsibilities.

A R ON H A L FIN, MD

Senior Vice President and Chief Medical Officer

Health Plan Solutions Group, Magellan Behavioral HealthEditor

JOHN A. MARCILLE

Managing EditorMICHAEL D. DALZELL

Senior EditorFRANK DIAMOND

Senior Science EditorPAULA SIROIS

Senior Contributing EditorPATRICK MULLEN

Contributing EditorsBOB CARLSONJOHN CARROLL

DAVID

COLEMAN

, J.D.JEFFREY J. DENNINGMIKE FOLIO, J.D.MICHAEL LEVIN-EPSTEINJACK MCCAINKAREN TRESPACZ, J.D.

Design DirectorPHILIP DENLINGER

Editorial Advisory Board ChairmanALAN L. HILLMAN, M.D., M.B.A.Senior FellowCenter for Health PolicyLeonard Davis Institute

of Health EconomicsUniversity of Pennsylvania, Philadelphia

Group PublisherTIMOTHY J. STEZZI

PublisherTIMOTHY P. SEARCH,R.PH.

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Account ManagerSCOTT OLSON

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MANAGED CARE (ISSN 1062-3388) is published monthly byMediMedia 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 addresschanges 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 FrankDiamond, MANAGED CARE, 275 Phillips Blvd., Trenton,NJ 08618.Letters may be edited for length and clarity.E-mail: [email protected]: (609) 671-2100;fax (609) 882-3213; circulation inquiries,(609) 671-2100.Copyright 2001 MediMedia USA Inc.

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Continuing education is offeredto physicians and pharmacists whoread this publication,answer theself-test that begins on page 25, andfill out the appropriate evaluation

form on either page 23 or 24.

Medical accreditationThis activity has been planned

and implemented in accordancewith the Essential Areas and Policiesof the Accreditation Council for Con-tinuing Medical Education (ACCME)through the joint sponsorship of theUniversity of Arizona College ofMedicine at the Arizona Health Sci-ences Center and of MediMediaUSA.The University of Arizona Col-

lege of Medicine at the ArizonaHealth Sciences Center is accreditedby ACCME to provide continuingmedical education for physicians.

The University of Arizona Collegeof Medicine at the Arizona HealthSciences Center designates this edu-cation activity for 2 hours in cate-gory 1 credit towards AMA Physi-cians Recognition Award.Eachphysician should claim only thosehours of credit that he/she actuallyspent in the educational activity.

Approval for category 1 credit bythe University of Arizona College ofMedicine should not be construedas endorsement of any product.

Release date:September 2001,for a period of one (1) year.

Pharmacy accreditationThe University of ArizonaCollege of Pharmacy is ap-proved by the American

Council on Pharmaceutical Educa-tion as a provider of continuingpharmaceutical education.This pro-gram is approved for (2) contacthours (0.2 CEU).Credit will beawarded upon completion of regis-tration form,successful completionof assessment questions (70 percentor better) and completion of pro-gram evaluation. If a score of 70 per-cent or better is not achieved,nocredit will be awarded and the regis-trant will be notified.

ACPE program number:003-999-01-026-H01.Expiration date:Aug.31, 2002.

Course description

This activity is designed to edu-cate health care professionals aboutappropriate medical treatment op-tions for patients with clinical de-pression.The data and narratives inthis publication are derived frominformation presented at NewEvidence-Based Treatments forDepression, a symposium in LasVegas, Nev., April 30, 2001.The pro-gram is directed to managed healthcare professionals.

Educationalneeds assessmentMedical directors,practicing

physicians,and pharmacists areseeking treatment approaches fordepression that are highly effective,and want to be kept informed ofcurrent medical treatments so as touse this knowledge to meet pa-tientsneeds.The information pre-sented in this publication has beencompiled on the basis of faculty per-ceptions of significant trends and

issues related to medical therapiesfor treatment of depression andcost-effective approaches to man-aging it.

Target audiencesMedical directors, chief medical

officers, pharmacy directors, andother senior managers in managedhealth care organizations;primarycare physicians;psychiatrists;andpharmacists.

Educational objectivesAfter reading this publication, the

participant should be able to: Illustrate the extent,as well as the

economic and personal conse-quences,of untreated clinical de-pression.

Identify the most commonly pre-scribed antidepressant medi-cations and their mechanisms ofaction.

Explain important drug inter-

actions involving antidepressantmedications.

Describe the Texas Medication Al-gorithm Project for Major Depres-sion (T-MAP) and its approaches

to treatment resistance in pa-tients with depression.

Recognize how pharmaco-economic data can be used tocompare cost-effectiveness ofdrug therapies.

Discuss new evidence on the rela-tive effectiveness and outcomesof different antidepressant medi-cations.

Planning committeemembers

Lynne Mascarella,director of con-tinuing education, College of Phar-macy, University of Arizona,Tucson;Kay ONeill,CME coordinator,Col-lege of Medicine,University of Ari-zona,Tucson; Aron Halfin,MD,seniorvice president and chief medical of-ficer, Magellan Behavioral Health;

Timothy Search,RPh,publisher, MAN-AGED CARE, a division of MediMediaUSA Inc.

PUBLISHERS DISCLAIMER

The opinions expressed hereinare those of the symposium partici-pants and faculty, and do not neces-sarily reflect the views of the Univer-sity of Arizona Colleges of Medicineand Pharmacy,Wyeth-Ayerst Labo-ratories, MediMedia USA Inc.,or thepublisher, editor, or editorial boardof MANAGED CARE.

Clinical judgment must guideeach clinician in weighing the bene-fits of treatment against the risk oftoxicity. Dosages,indications,andmethods of use for products re-ferred to in this special supplementmay reflect the clinical experience ofthe authors or may reflect the pro-fessional literature or other clinicalsources,and may not necessarily bethe same as indicated on the ap-proved package insert. Please con-sult the complete prescribing infor-mation on any products mentionedin this special supplement beforeadministering.

2 MANAGED CARE / SUPPLEMENT

SELF-STUDY CONTINUING EDUCATION ACTIVITY


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Clinical depression is highlyprevalent, underdiagnosed,andundertreated in the United States.

This has enormous implications formorbidity, comorbidity,mortality,

and economics.When depression isdetected, medical treatment ofteninvolves random approaches, whichcan delay remission of illness andincur unnecessary use of health careresources. A systematic methodol-ogy, whether based on evidence ofdrug efficacy or pharmacoeconomicissues,can lessen the morbidity andcost associated with depression andits consequences.

Several such strategies are dis-cussed in various sections of this

MANAGED CARE continuing educationsupplement.The information hereinwas presented at New Evidence-Based Treatments for Depression, aMagellan Behavioral Health sympo-sium in Las Vegas,Nev., April 30,2001,and attended by managedcare medical directors.A cross-section of attendees participated inthe roundtable discussion,excerptsfrom which begin on page 18.

PRIMARY FACULTY

Larry Ereshefsky, PharmDProfessor of Pharmacology

and Psychiatry

University of TexasHealth Science Center

San Antonio

Aron Halfin,MDSenior Vice President

and Chief Medical OfficerHealth Plan Solutions GroupMagellan Behavioral Health

Alpharetta,Ga.

Bradley K. KozarGroup President and CEO

MediMedia Managed Care DivisionTrenton, N.J.

Michael E.Thase,MD,FAPAProfessor of PsychiatryUniversity of Pittsburgh School

of MedicineWestern Psychiatric Institute

and ClinicPittsburgh

Content reviewers

Amy Grizzle,PharmDAssistant DirectorCenter for Health Outcomes

and PharmacoEconomic ResearchUniversity of Arizona

College of PharmacyTucson,Ariz.

John J.Misiaszek, MDAssociate Professor

of Clinical PsychiatryUniversity of Arizona

College of Medicine

Tucson,Ariz.

Conflict of interest policyin continuing medicaleducation

In compliance with this policy, thefaculty for this activity has disclosed

financial interests, arrangements,and/or affiliations with corporate or-ganizations offering financial sup-port or educational grants for con-tinuing medical education activities,as well as those organizations with adirect interest in the subject matter

of this activity.

Disclosures of significantrelationships

Michael E.Thase, MD,acknowl-edges grant and research support

from Bristol-Myers Squibb,Merck &Co.,Organon Inc., Pharmacia & Up-

john,and Wyeth-Ayerst Laborato-ries;consulting relationships withthe aforementioned companies,aswell as Eli Lilly & Co., Forest Labora-tories, Glaxo Wellcome Inc./Cerenex,and Pfizer Inc.;and lecture supportfrom Parke Davis,SmithKlineBeecham,Solvay Pharmaceuticals,and all of the aforementioned com-panies except Merck & Co.

Larry Ereshefsky, PharmD, ac-

knowledges grant and research sup-port from Bristol-Myers Squibb,Janssen Pharmaceutica,Novartis,Pfizer Inc., Pharmacia & Upjohn,Ot-suka, Sanofi~Synthelabo,andWyeth-Ayerst Laboratories; consult-ing relationships with AstraZeneca,Janssen,Eli Lilly & Co.,Novartis,Pfizer, and Wyeth-Ayerst; and is amajor stockholder in Pfizer.

The following faculty and round-table discussion participants havedeclared they have no financial in-

terest,arrangement,or affiliationthat would constitute a conflict ofinterest concerning this CME activ-ity:Jonathan Book,MD; KennethCohen,MD; Charles Freed, MD;AronHalfin,MD; Thomas Hamlin,MD; JulieKessel,MD; Leslie Moldauer, MD;Lawrence Nardozzi, MD; AndrewRudo,MD.

SUPPLEMENT /MANAGED CARE 3

ABOUT THIS PUBLICATION


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DEPRESSIONS RIPPLE EFFECT ON HEALTH STATUS AND COSTS

Depression is one of the most common of allpsychiatric disorders;8 to 18 percent of thegeneral population can be expected to ex-perience at least one clinically significant

episode during a lifetime (Boyd 1982).The significanceof this transcends the debilitating effects of major de-pression or dysthymia alone; frequently,patients withdepression have concomitant major medical condi-tions thus amplifying the duration, severity, andcost of treatment for those illnesses.While this wouldsuggest that identifying patients for appropriate treat-ment is an important strategy in keeping overall healthcare costs down, depression is undertreated in theUnited States.

The following data were presented by Larry Ereshef-sky,PharmD,professor of pharmacology and psychia-

try at the University of Texas Health Science Center,atthe Magellan Behavioral Health Clinical Medical Retreatin Las Vegas,April 30, 2001.

Prevalence of depression unrecognizedDepression is underdiagnosed particularly in pri-

mary care settings and among the elderly and whenit is treated,many patients receive medications that arenot fully effective,or in insufficient dosages,or for tooshort a period to be effective. A Rand Corporationstudy (Wells 1994) found that of patients whose symp-toms would qualify them for a diagnosis of depression,23 percent were taking antidepressants, and only 14percent of the whole were receiving the proper doseof medication.

Underdiagnosis and undertreatment contribute tothe economic impact of depression,which has been es-timated in the U.S.at $44 billion annually (Figure 1).

FIGURE 1 Economic impact of depression

Comorbidity is common and costlyThe prevalence of depression in patients with othermajor illnesses is as high as 60 percent (Figure 2).Howits effects on brain chemistry may trigger or exacerbatesome illnesses is not understood,but there is evidencethat major depression is a bigger risk factor for type 2diabetes than body mass index,race,or gender (Eaton1996), and, in late life, depression may be associatedwith cerebrovascular disease (Steffens 1999).

FIGURE 2 Depression and medical illnessStudies have estimated the prevalence of depression inpeople with other conditions.The range of estimates ofcomorbidity for the six illnesses below varies widely.

More than 1 in 7 adults visit the ER each year,and thevast majority of those who visit for any reason presentwith clinical depression a statistic with implicationsfor cost containment.Depression also tends to increasehospitalization costs significantly, not just for the de-pression but also for treatment of other medical con-ditions. In one study of patients over age 60 who hadbeen hospitalized for a medical condition, the topquartile in terms of depressive symptoms incurred 50percent greater treatment expenses than the lowest-quartile group (Table 1).

TABLE 1Health costs based on depressive symptoms

Lowest- Highest-quartile quartile

Measure cost (mean) cost (mean)

Inpatient care $5,290 $9,408Medical/surgical

cost after discharge $6,395 $9,588Psychiatric/substance-

abuse costsafter discharge $26 $178

SOURCE: DRUSS 1999

Coronary arterydisease 26

Diabetes 33

Multiplesclerosis

60

Stroke 50

Cancer 42

Alzheimersdisease 5515

18

6

30

Work absence,reduced

productivity,increasedcosts relatedto othermedicalillnesses

$23.8 billion

Lost wages dueto prematuredeath

$7.5 billion

Direct costs

MorbidityMortality

Medications$2.1 billion 55%

23%

5%

17%

Medical andpsychiatric care$12.4 billion

SOURCE:GREENBERG 1993


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Relapse can be risky for MCOsTreating patients with the proper

medication, at the correct dosageand for an appropriate duration or knowing when to switch to an-other medication is important,

given the probability of relapse.After four weeks, the risk of relapsein patients treated for major de-pression rises,particularly for thosewho have a history of multiple de-pressive episodes (Figure 3). Formanaged care organizations,identi-fying this costly subset of patientsfor adequate treatment is para-mount.

In many patients with even a sin-gle episode of depression,the oddsof recurrence are 20 to 30 percent

within several years. Incomplete re-mission where symptoms im-prove but the patients level offunctioning is not normalized in-creases the odds of relapse (Figure4).From the standpoints of quality oflife and cost-containment, treatingpatients to full recovery is optimal.

ReferencesBoyd JH,Weissman MM.Epidemiology.In

Paykel ES (ed.) Handbook of AffectiveDisorders. 1982;109125.New York:

Guilford Press.Druss BG,Rohrbaugh RM, Rosenheck RA.

Depressive symptoms and healthcosts in older medical patients.Am JPsychiatry.1999 Mar;156(3):477479.

Eaton WW, Armenian H,Gallo J, et al. De-pression and risk for onset of type 2diabetes:A prospective population-based study. Diabetes Care.1996;19(10)10971102.

Greenberg PE, Stiglin LE,Finkelstein SN,Berndt ER.The economic burden ofdepression in 1990.J. Clin Psychiatry.1993 Nov;54(11):425426.

Keller MB,Boland RJ. Implications of failing to achieve success-

ful long-term maintenance of recurrent unipolar majordepression.Biol Psychiatry. 1998 Sept 1;44(5):348360.Steffens DC, Helms MJ, Krishnan KR,Burke GL. Cerebrovascular

disease and depression symptoms in the cardiovascularhealth study. Stroke.1999 Oct;30(10):21592166.

Thase ME,Simons AD, McGeary J, et al. Relapse after cognitivebehavior therapy of depression:potential implicationsfor longer courses of treatment.Am J Psychiatry.1992Aug;149(8):10461052.

Wells KB, Katon W, Rogers B,Camp P. Use of minor tranquilizersand antidepressant medications by depressed out-patients: results from the medical outcomes study.Am JPsychiatry.1994 May;151(5):694700.


%r

elapsed

Weeks since recovery

0

10

20

30

40

50

1 2 4 5 6 7 10 12

FIGURE 3 Patients with major depression: Cumulativeprobability of relapse

SOURCE:KELLER 1998

Probabilityofremaining

symp

tom-free(%)

0 2 4 6 8 10 12

Months of follow-up

(Remission)

(Response)

100

80

60

40

20

0

FIGURE 4 Incomplete remission predicts greaterrelapse*

SOURCE:THASE 1992

3 or more previous episodes

03 previous episodes

*After termination of cognitive behavior therapy for depressed patients.


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Overview of Antidepressant TherapyMICHAEL E. THASE, MD

Professor of Psychiatry, University of Pittsburgh School of MedicineWestern Psychiatric Institute and Clinic

Depression can be thought of as an extensionof two distressing states that affect all mam-mals exhaustion in response to sustainedirresoluble stress and grief. Humans differ

with respect to the complexity of intimate attachmentsand social circumstances,as well as the capacity to struc-ture cognitions about self, world, past, and future. Yetwithin a context of evolutionary survival re-sponses,humans still have the relatively primi-

tive hard wiringof other mammals.These systems were discovered less than 60

years ago, and involve two basic monoamineneurotransmitters: norepinephrine and sero-tonin. These systems are responsive to acute,life-threatening stress,triggering what is com-monly referred to as the fight-or-flight re-sponse. This response is also accompanied byrelease of corticotrophin-releasing hormone,which initiates a cascade that results in ele-vated levels of glucocorticoids in the blood and spinalfluid.Most norepinephrine in the brain comes from nervecells in the locus ceruleus. Almost all of the serotonin tothe brain comes from the dorsal raph nuclei.When a per-son is distressed or in a threatening situation,both of thesenuclei become more active: norepinephrine in an intense,phasic way, serotonin in a more protracted, tonic way.

Sustained activation of these systems is not healthy blood pressure increases, immune responses are altered,and cognition becomes less abstract, more focused onsurvival. If the threat is sustained, brain cells may beginto shrink or even die.

An effective antidepressant should dampen the patho-logic activation of stress response. Second, it should en-hance behavioral facilitation, because when people are in

sustained stressful circumstances, they become less activeand less interested in consuming lifes rewards.Finally, itshould reduce negative affect without changing oneslevel of consciousness or sense of awareness.

Today, there are four types of antidepressants: tri-cyclics (TCAs), MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), and newer medications thatare not in the same class as the other three. Tricyclics andMAO inhibitors were discovered accidentally,and medi-cations that are discovered accidentally often carry bag-gage inherent in those compounds. In the case of TCAs,

the critical shortcoming is that they are potentially lethalin overdose with as little as a 10-day supply.

Some half truthsIt has been stated for years that up to 70 percent of de-

pressed people will respond to the initial course of treat-ment with an antidepressant. This is true if the diagno-

sis is correct, and if the patient has filled theprescription and has taken the medication as

directed for 6 to 8 weeks and if the numberof people who have discontinued therapyalong the way are not counted in the final tally.

It also can be shown that 90 percent of de-pressed people should respond to therapy bythe fourth treatment trial.But how often doesthis happen in practice? The most recent datasuggest a 33 percent loss of patients with eachtreatment trial. The real share of respondersmight be in the range of 30 to 50 percent on

the first trial and 70 to 75 percent by the fourth.These response rates include people who are some-

what better, but not as well as those who truly are well (re-mission). When weighing the pros and cons of variousantidepressants, it is useful to look for remission, or a re-turn to ones usual level of well being,as the strongest in-dicator of favorable antidepressant outcomes.

There are several compelling clinical reasons to aim forremission.Response without remission is associated witha significantly higher risk for relapse. It is also associatedwith incomplete normalization of social function.Peoplewith residual depression, even though they have a reduc-tion of depressive symptoms,complain more,decline in-vitations, dont return calls, and miss more days fromwork. They usually do not function at optimum level.

The data in Figure 1 are from a one-year follow-up ofincompletely remitted patients who had an extra $1,200invested in their treatment.These patients received 12 ad-ditional sessions of psychotherapy (white dots) at the be-ginning of the continuation phase, as compared to pa-tients randomly assigned to receive straight medicationmanagement (black dots).By week 68, patients who re-ceived pharmacotherapy alone had an almost 50 percentrelapse rate. With respect to the main hypothesis, Canthe risk of an incomplete remission be offset by symptom-focused psychotherapy, the data suggest a 25 percent ad-

Michael Thase, MD


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vantage for the group that received psychotherapy. Ifone estimates the costs that were saved by preventing newepisodes of depression, the psychotherapy, then, essen-tially paid for itself.

Another factpsychiatrists are taught is that all anti-depressants are comparably effective. Some recent evi-dence suggests that this may not be true, and may neverhave been. Some background should be provided onhow clinical trials of antidepressants are conducted andwhat kind of results should be expected.

In half of studies of all new antidepressants, the drugfails to beat placebo. Moreover, traditionally it has beenthought that the average drug-placebodifference is about 33 percent (i.e.,67percent responders for active drug and33 percent for placebo). This probablywas true in the 1960s, when studieswere done in hospitals, where side ef-fects could be managed and patients

had a higher severity level. Today, theaverage drug-placebo difference isabout 18 percent (50 versus 32) in am-bulatory studies (Thase 1999).

In the science of clinical trials, a 33percentage-point difference is a largeand reliable effect. By contrast, an 18-point difference is small.When lookingfor modest or small effects,researchersmust conduct much larger studies.Theantidepressant studies of the 1980s and90s were not designed to find small-to-modest effects. Thus, one reason thatantidepressants appear to be equallyeffective is that the studies have not hadthe statistical power to distinguish thegood from the better (Thase 1999).Forthis purpose,an ideal study would needto enroll 300 patients in each treatmentgroup, about 3 times larger than theusual study.Moreover,it is unlikely thatthe difference between a good anti-depressant and a better one wouldbe as large as the difference between agoodantidepressant and placebo.

As for the studies that dont distin-guish drug from placebo, where arethey? Are they published in majorjournals, such as Archives of GeneralPsychiatryor American Journal of Psy-chiatry? Usually not.Rather, they typi-cally are filed away, unpublished.Thestudies stay in the file drawer becausetheyre not interesting, one or moreflaws are obvious, and, of course, anegative study does not promote

pharmaceutical sales.One way to resolve the problem of inadequate statis-

tical analysis is to use a technique called a meta-analysis,i.e., an analysis of multiple analyses. However, there areinherent difficulties with this approach.A large numberof studies is required; not much of a meta-analysis canbe done when there are three relevant controlled stud-ies. An even greater problem results from the file drawerphenomenon. Specifically with a meta-analysis, if half thestudies are in the file drawer, the analysis will be distortedby looking only at a subset of the evidence, thus exag-gerating the efficacy of the medicine.


FIGURE 1 Relapse-free curves from Cox regressionIntention-to-treat analysis of combined major depression and

persistent-system relapse

PlaceboSSRIVenlafaxine

*

*,

US-211 EU-340 EU-347 EU-348 EU-349 CA-360 EU-367 US-372(n=295) (n=67) (n=111) (n=302) (n=155) (n=353) (n=323) (n=439)

FIGURE 2 Comparison of venlafaxine and SSRI/placebo

SOURCE:THASE 2001

SOURCE:PAYKEL 1999

*P 0.05 venlafaxine vs SSRIsP 0.05 venlafaxine vs placeboP 0.05 SSRIs vs placebo

Remissionrate(%)

Remission:HAM-D177)

6055504540353025201510

50

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 4

Control group

CT group

8 12 16 20 24

Weeks

Proportionnotrelapsing

28 32 36 40 44 48 52 56 60 64 68


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11/27

develop an extended-release (XR) form of the drug.Thislengthened the time to peak so once-a-day dosing wouldbe possible.The dose for the XR form was capped,mean-ing the same number of titrations as an SSRI: 75,150,and225 mg. In capping the dose, concerns about elevatedblood pressure were eliminated.

There have been randomized controlled trials com-paring this products efficacy with others. Unlike everyother newer antidepressant, venlafaxine is defined, inpart, by the evidence of comparative efficacy.

We received permission to open the file drawer to doa meta-analysis,and we took the first eight comparativestudies of either the IR or the XR forms relative to theSSRIs.All eight studies were double-blind randomized.Half used placebo;half didnt.Half used the IR form andhalf used the new XR form of venlafaxine. Four studieswere published (Clerc 1994, Dierick 1996, Silverstone1998,Rudolph 1999), two were presented as posters andpublished as abstracts,and two are unpublished and re-

main on file with the manufacturer. By opening the filedrawer and using all the data from all of the patients,wewere able to bring the sample up to more than 800 peo-ple treated with venlafaxine, more than 700 treated withan SSRI, and more than 400 treated with a placebo.

Most importantly,the file drawer was empty.Nothingwas left behind.

Figures 2, 3, and 4 depict results of the eight studies(venlafaxine IR and XR were combined for this meta-analysis). Figure 2 shows remission rates of venlafaxineand SSRIs. Figure 3 pool the same data across time. Overtime,a clear pattern of remission emerges, in which SSRIdifferentiates from placebo. Notably,at the end of eightweeks of treatment, the magnitude of the venlafaxine-SSRI difference is identical to the magnitude of the dif-ference between SSRI and placebo. Figure 4 challengesthe assumption that another definition of remissionwould produce different results; in general, results areconsistent, regardless of definition.

Since we started this project, 11 other studies havebeen finished, involving 2,400 more patients.Across the19 studies, there appears to be a consistent dose-responserelationship.In essence,there was no difference at 75 mgof venlafaxine; at 150 mg, a small difference; and at 225mg and above, there is a difference of 15 or 18 percent.

This is important, because the dose-response rela-tionship follows the same relationship evident with bloodpressure 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 shouldbe prepared to authorize the use of higher than 225 mg,but also should be prepared to measure blood pressurewhen approving these higher doses.The effects likely willbe seen in 10 percent of patients at the doses most likelyto show advantages relative to the SSRIs.

Other pharmaceutical comparisonsBupropion is a weak reuptake inhibitor for norepine-

phrine and dopamine. We do not know what is in the filedrawer for bupropion; the manufacturer has not per-mitted a pooled analysis. There are four completed pub-lished comparisons against SSRIs, and when combined,there is no significant difference in efficacy.It is,however,a different type of antidepressant, with a different struc-ture and different functions, and thus often is prescribedfor people who have had negative side effects from SSRIs.

Nefazodone is unlike any antidepressant other thantrazodone. We do not know what is in the file drawer.There are three published comparisons versus SSRIs; thedifferences among them are not significant, about 2percent favoring SSRIs. This does not support a wide-spread notion among clinicians that this medication isless effective than other newer antidepressants. This stemsfrom the fact that this is the weakest of all the serotoner-gic reuptake inhibitors. Generally, it is prescribed when

stronger serotonergic medications fail meaning it isused in people who are less likely to respond to it.

Multiaction antidepressants are more effective whenthey are comparably tolerable. The tricyclics are notmore effective than the SSRIs because they are not com-parably tolerable. When a patient is placed in a settingwhere side effects can be controlled, the tricyclics becomemore tolerable and the dual reuptake drugs deliver bet-ter results. This is similar to what has been seen in am-bulatory studies with venlafaxine,because it is more likean SSRI when it comes to tolerability.

In summary, the statement that all antidepressantsare equally effective has never been true. Among someantidepressants,there are meaningful differences, as ev-idenced by the meta-analysis data presented in Figures3 and 4.The main reason that physicians end up with thenotion that all things are equal is because they haventbeen able to appreciate the subtleties between products.Studies that are designed well enough to bring out thosesubtleties have not been done.

ReferencesClerc GE, Ruimy P, Verdeau-Pailles J, on behalf of the Venlafax-

ine French Inpatient Study Group. A double-blind compar-ison of venlafaxine and fluoxetine in patients hospitalizedfor major depression and melancholia. Int Clin Psychophar-

macol. 1994;9:139143.Edwards JG, Anderson I. Systematic review and guide to selec-

tion of selective serotonin reuptake inhibitors. Drugs.1999;57(4):507-533.

Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse inresidual depression by cognitive therapy. Arch Gen Psychia-try. 1999;56:829835.

Thase ME. How should efficacy be evaluated in randomizedclinical trials of treatments for depression?J Clin Psychiatry.1999;60(Supp 4):2331.

Thase ME, Entsuah AR, Rudolph RL. Remission rates duringtreatment with venlafaxine or selective serotonin reuptakeinhibitors. Br J Psychiatry. 2001 Mar;178:234241.



12/27

bolic properties also is important so as to prevent druginteractions.An emphasis on drug safety was promptedby the Institute of Medicine in its 1999 report, To Err IsHuman: Building a Safer Health System. As translated byConsumer Reports, the IOM data suggest that a patients1-in-500 chance of dying from an unexpected drug re-

action in the hospital is far greater than thelikelihood of being killed in an auto accident.

To illustrate a drug interaction using a realcase: George is a 60-year old male, stable onpropranolol and a diuretic for years. He is di-agnosed with depression, and a psychiatriststarts him on fluoxetine, 20 mg. His primarycare physician follows up a week later, andGeorge is tolerating medications fine.But onemonth later, George winds up in the ER lethargic, tired, and weak. Hes having night-mares. He has a resting pulse of 48.

This is a drug interaction occurring not im-mediately, but a month beyond when one

might think about it, because the half-life of fluoxetineis such that the drug doesnt build up in the body untilthe second month of treatment.The higher the blood lev-els, the more likely a significant interaction will occur. Ifthings go awry in the second month of therapy, a clini-cian should consider that a patients level of drug in theblood has been building; the right answer may be to re-duce the dosage of medication, rather than increase it.

To continue this example, after Georges ER experi-ence,he stops his medications and sees his internist,whois managing his blood pressure. This physician has acopy of the ER report, and cuts the previously well-tol-erated dosage of propranalol in half. This is, in essence,

a reaction to a medical problem that was preventable,given the stability of long-term propranalol therapy.There are several antidepressants that likely would nothave created this trouble.

George then visits his psychiatrist and recounts theproblems hes had with his other medications. The psy-chiatrist realizes that fluoxetine can cause drug inter-actions, and switches George to sertraline. One monthlater, George becomes hypertensive.

This illustrates the extra health care costs from pre-scriptions to hospitalization associated with drug in-


Antidepressant Drug InteractionConsiderationsLARRY ERESHEFSKY, PHARMD

Professor of Pharmacology and Psychiatry, University of Texas Health Science Center

Three transmitters in the brain (norepinephrine,serotonin,and dopamine) influence an array ofbehaviors that are relevant for human func-tioning.Antidepressants work on one or more

of these transmitters. The mechanism of action for somemedications are different and clinically meaningful.

When choosing an antidepressant, its im-portant to know the pharmacology of each

product. In many cases, trying a drug with adifferent pharmacology is the most rationalway to enhance response.Recognize that drugswith more than one mechanism of action maybe more effective as first-line therapy.

The old tricyclic antidepressants (TCAs)have a host of side effects that render them un-acceptable as first-line therapies.They can killon overdose, and thus are a tremendous lia-bility that should be reserved for people whohave failed on other therapies.

Figure 1 depicts mechanisms of action formany antidepressants. SSRIs, which generally work thesame way,are,as the name suggests, serotonergic.Nefazo-done and trazodone, which are serotonin 2A receptorblockers, are variations on the serotonin theme.

Venlafaxine, at lower doses, is a reuptake inhibitor, butat dosages above 75150 mg/day, noradrenergic effectsbegin to become evident. The in-vitro binding at thetransporter system for norepinephrine, though lowerthan what might be expected to be necessary for a clini-cal effect, is offset by high central nervous system levelsof venlafaxine due to its low protein binding. Mirta-zapine is a dual-mechanism antidepressant; however, itworks by blocking noradrenergic and seroadrenergic re-

ceptors. Bupropion is thought to be a weak transporterinhibitor of both dopamine and norepinephrine,but itsmechanism of action is unknown (Preskorn 1994).

With this array of drugs available, if a patient on anSSRI has been on an adequate dosage and duration anddoes not respond, then instead of trying another SSRI,it would make sense to switch to another class.

Drug interactionsUnderstanding mechanism of action is not the only

reason to select an antidepressant; knowledge of its meta-

Larry Ereshefsky,PharmD


13/27


tween substrates and inhibitors is to think of receptorsand antagonists.A drug interaction occurs when an in-hibitor drug competitively antagonizes another drugs ac-cess to the active metabolic site.Therefore, the higher thedose of a medication and the more drugs taken, the morelikely a drug interaction will occur, because of the num-ber of molecules in the body.

The CYP450 enzymes are expressed by genes, withthe two alleles defining a patients genotype. This meansthat genetic mutations and variations found in differentracial or cultural populations can cause variability inpatients responses to drugs. It can be argued that notonly do we as clinicians miss drug interactions,but alsothat we miss the genetic differences that we know existin populations and that can lead to drug interactions.

teractions.Georges metabolism for propranolol was nor-mal when he was not taking fluoxetine. It was one fifth ofnormal when taking it (Pritchard 1990 case report).

When a patient says to a physician, I feel a lot bettersince I ran out of those pills you gave me, it can be anindication that something has gone wrong.

Metabolism of drugsTable 1 lists half-lives of various medications and the

time it takes for them to build in the blood before reach-ing a steady state.Most antidepressants have a short half-life and reach the plateau phase in less than a week; forvenlafaxine, this may be three days. Fluoxetine and itsmetabolite, because of their long half-life, do not reach asteady state until at least 28 days and can continue tobuild beyond that.Fluoxetine remainsin the body for a month after a patientstops taking it (Ereshefsky 1995,1996).

As a result, drug interactions with

fluoxetine whether coumadin,codeine, or TCAs can occur for amonth after a patient stops taking thedrug. This is important for pharma-cists to remember, because once a pa-tient has stopped taking the drug andthe prescription is out of the phar-macys computer system, it wontscreen for fluoxetine unless its beenprogrammed to remember a drug fora month after completion of therapy.

Most drugs are metabolized in theliver by phase I enzymes, a processthat makes them water soluble andthus more easily excreted. One sub-group of these is the cytochrome P-450 (CYP450) enzymes. Among themany CYP450 enzymes, CYP3A4,CYP2D6, and CYP1A2 metabolizemost drugs. Drugs can have any ofthree metabolic properties: they canbe substrates (when metabolized by aspecific enzyme e.g., statins,whichare metabolized by the CYP3A4 en-zyme, are CYP3A4 substrates); in-

hibitors (an agent that decreases anenzymes ability to metabolize a drug e.g.,nefazodone, which suppressesCYP3A4 metabolism,is a CYP3A4 in-hibitor); and inducers (which increasemetabolic activity).When a substrateis taken with another drug that in-hibits the same enzyme, a buildup ofsubstrate can occur and cause an ad-verse drug reaction.

A way to remember interactions be-

Antidepressant mechanismsof action (traditional)

Venlafaxine

DA SENESENE

Reboxetine

(pending?)

Sertraline

Fluoxetine

Paroxetine

Fluvoxamine

Citalopram

5-HT2Antagonist

Nefazodone

Trazodone

5-HT1APartial

agonist

Buspirone

Gepirone

2, 5-HT2, 5-HT3mirtazapine

H1

1

ADRs

Bupropion

FIGURE 1 Antidepressant mechanisms of action

SOURCE:PRESKORN 1994

TABLE 1Pharmacokinetic profiles of selected antidepressants

SOURCE:ERESHEFSKY 1995, 1996

Sertraline Fluoxetine Paroxetine Nefazodone Citalopram* Mirtazapine Venlafaxine*

Half-life (h) 24 4872 24 24 35 2040 5

Metabolite 2030% Equal No Several No 10% Equal

activity activities

Metabolite

half-life (h) 4896 168216 1.518 2040 11

Steady state

(d) 714 2842 7


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While software can help clinicians prevent drug inter-actions, most programs produce potential-interactionlists of drug A to drug B,B to C,C to D and so on. For apatient on five drugs, there could be several pages ofdrug-interaction output. It is also important to knowadditive risk something that existing programs donot 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.

Examples of interactionsTable 2 focuses on the CYP2D6 enzyme. The drugs

most likely to interact with 2D6 are paroxetine, fluoxe-tine, and bupropion.These three agents are highly potentin inhibiting 2D6 activity,and are likely to but not al-ways because of variability in patients genetics and theconcentration of the inhibitor drug cause drug inter-actions with 2D6 substrates.

A major interaction can occur when paroxetine orfluoxetine are added to a patients drug regimen. In onestudy, 42 percent of extensive metabolizers converted topoor metabolizers after eight days of fluoxetine therapy,while 83 percent of extensive metabolizers taking paroxe-tine became poor metabolizers. Venlafaxine and sertra-line ran a zero-conversion rate (Lam 1997).

This illustrates a consequence that is avoidable. Weknow that, genetically, 7 percent of Caucasians are poormetabolizers of 2D6 (Yue 1998), and so the standarddosage of an antipsychotic drug can lead to interactions.

This is a built-in group of people who need a very dif-ferent dosage of medication.If a drug-interaction systemmisses that, then its missing a known quality indicator.

One example of how 2D6 inhibitors block substrateaction is seen in codeine. Codeine must be converted tomorphine by 2D6 to produce an analgesic effect. Poormetabolizers of 2D6 exhibit impaired or no analgesia(Sindrup 1995).To use the group noted above, 7 percentof Caucasians who take acetaminophen with codeineactually are receiving acetaminophen with placebo. Froma standpoint of drug interactions, about half of peoplewho take fluoxetine and even more who take parox-etine have a significant reduction in analgesia poten-tial from the codeine. As inhibitors,they block codeinesconversion to morphine. To underscore,people who areprescribed this drug for migraines or other reasons, andwho are told to take it as needed,this is something to lookfor. It would be natural to ask, How I did miss this in

practice? Pain is subjective. Placebo response is real.For the CYP1A2 system,the ranking in Table 3 suggests

that fluvoxamine is the most important drug to be con-cerned about adding to a persons drug regimen. Con-sider, also, a persons consumption of food and nonpre-scription medications; caffeine and acetaminophen, forinstance, are 1A2 substrates.

This presents a common problem: people who areprescribed fluvoxamine and drink coffee.The half-life forcaffeine goes from 5 to 24 hours when fluvoxamine is in-troduced; half of the cup of coffee consumed one morn-

ing is still in the body the next day.Atthe end of a week, a steady state ofcaffeine has been reached, enough toprecipitate anxiety reactions and in-somnia. Some of these people willthen be prescribed benzodiapines.Simply decaffeinating people on SSRIsshould be the first step in managinginsomnia,agitation, and jitteriness forthe first week on fluvoxamine.

Concluding with the CYP3A4 sys-tem, Table 4 indicates that nefazodoneis a significant risk for serious or lethaldrug interaction with such 3A4 sub-

strates as cisapride, carbamazepine,cyclosporine,and some statins.It alsoalters the risk for many other drug in-teractions, because 3A4 is the bodysmost common enzyme and is a safetynet. If 2D6 metabolism is blocked,blood levels of 2D6 substrates reach anew steady state of 4- or 5-fold higher.Some of the drug goes through 3A4. If3A4 is blocked, 2D6 and 1A2 inter-actions become more dangerous. In


TABLE 2 CYP2D6 antidepressant-drug interactions

* in-vitro data onlySOURCE:ERESHEFSKY 1995

Selected substrates

Secondary TCAsBeta blockers (older,lipophilic)Codeine/hydrocodoneDextromethorphanAmphetaminesPhenothiazinesHaloperidolFlurazepamQuazepamFlecainideChlorpheniramineVenlafaxineFluoxetineParoxetinePropafenoneNefazodone (m-CPP)Tramadol

Relative rank

High

Moderate

Low

Minimal

Otherinhibitors

Inhibitors

ParoxetineFluoxetineBupropion

TCAs

High dosages of:Sertraline >150Citalopram

FluvoxamineMirtazapine*NefazodoneVenlafaxine

ThioridazineHaloperidol


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considering new-product applica-tions, the U.S. Food and Drug Ad-ministration takes a firm stance interms of protecting the 3A4 system.

While fluoxetine has a moderate tolow risk,higher dosages (>40 mg/day)can inhibit the 1A2 system.

Those at greatest risk for interac-tions include those who receive drugswith narrow therapeutic indices; peo-ple on multiple drug regimens at highdosages; and people who receive po-tent inhibitors, such as paroxetine, flu-oxetine, and quinidine (Gregg 1999).

References

Ereshefsky L, Riesenman C, Lam YW. Anti-depressant drug interactions and the

cytochrome P450 system. The role ofcytochrome P450 2D6. Clin Pharma-cokinet. 1995;29 Suppl 1:1018.

Ereshefsky L. Drug-drug interactions in-volving antidepressants: focus on ven-lafaxine.J Clin Psychopharmacol. 1996Jun;16(3 Suppl 2):37S50S.

Ereshefsky L. Pharmacokinetics and druginteractions: update for new antipsy-chotics.J Clin Psychiatry. 1996;57Suppl 11:1225.

Ereshefsky L, Riesenman C, Lam YW. Sero-tonin selective reuptake inhibitor druginteractions and the cytochrome P450system.J Clin Psychiatry. 1996;57

Suppl 8:1724.Gregg CR. Drug interactions and anti-

infective therapies. Am J Med. 1999Feb;106(2):227237.

Kohn LT, Corrigan JM, Donaldson MS, eds.To Err Is Human: Building a SaferHealth System. Washington: Instituteof Medicine, 1999.

Lam YW, Alfaro, Ereshefsky L. Anti-depressant crossover study: conver-sion EM to PMs (abstract).AmericanPsychiatric Association Annual Meet-ing 1997.

Preskorn SH.Antidepressant drug selec-tion: criteria and options.J Clin Psy-

chiatry. 1994 Sep;55 Suppl A:622.Sindrup SH, Hofmann U,Asmussen J, et al.

Impact of quinidine on plasma andcerebrospinal fluid concentrations ofcodeine and morphine after codeineintake. Eur J Clin Pharmacol.1996;49(6):503509.

Yue QY, Zhong ZH, Tybring G, et al. Phar-macokinetics of nortriptyline and its10-hydroxy metabolite in Chinesesubjects of different CYP2D6 geno-types. Clin Pharmacol Ther. 1998Oct;64(4):384390.


TABLE 3 CYP1A2 antidepressant-drug interactions

SOURCE: ERESHEFSKY 1996 *in-vitro data only

TABLE 4 CYP3A4 antidepressant-drug interactions

SOURCE:ERESHEFSKY 1996 * in-vitro data only

Substrates

CaffeineHaloperidolClozapineOlanzapineTheophyllineTacrineTertiary TCAsPhenothiazinesBeta blockersAcetaminophen

Relative rank

High

ModeratetoLow

Low tominimal

Other

inhibitors

Inhibitors

Fluvoxamine

High dosages of:ParoxetineFluoxetineSertaline

NefazodoneBupropionMirtazapine*CitalopramVenlafaxine

Fluoroquinolones

Grapefruit

Substrates

CisaprideKetoconazoleItraconazoleAlprazolam

TriazolamEstazolamClonazepamMidazolamVerapamilNifedipineDiltiazamCarbamazepineCyclosporineQuetiapineZiprasidoneCorticosteroids

Sex hormonesTamoxifenErythromycinQuinidineLovastatin/other statins

Protease inhibitorsincrease efficacy

Relative rank

High

Moderate

Low tominimal

(unlikely)

Otherinhibitors

Inhibitors

Nefazodone

FluvoxamineTCAs

Fluoxetine 20 mgMirtazapine*ParoxetineSertralineVenlafaxineCitalopram

GrapefruitProtease

inhibitorAntifungals

Ca+2 blockersErythromycinClarithromycin


16/27


among 2.3 million covered lives between 1994 and1999. Patients were followed for six months.

A pattern was noticed that at the time of diagnosis,patients given the serotonin norepinephrine reuptakeinhibitors (SNRI) venlafaxine IR and venlafaxine XRgenerally had more frequent medical (nonmentalhealth-related) illnesses and a greater number of men-tal health-related hospitalizations than patients givenSSRIs (fluoxetine, paroxetine, sertraline,citalopram,orfluvoxamine).At the end of six months, inpatient non-mental health-related hospitalization expenses weresignificantly lower for the venlafaxine IR/XR groupcompared with the SSRI group, while there were vir-tually no differences in antidepressant medicationcosts between the venlafaxine IR/XR and SSRI groups

(Figure 1). Adherence to antidepressant therapy wassimilar in patients treated with venlafaxine XR com-pared to SSRIs.The upshot is that use of venlafaxine totreat depression can influence total medication costsin patients with concomitant illness.

Decision-analytic modelA second analysis presented was a classic pharmaco-

economic model using a decision-analytic approach.It is useful in developing budget-impact data whenspecific clinical pathways are followed and associatedhealth outcomes are compared with treatment costs.

Ereshefsky presented data using a model developedby Einarson (1997) and based on inpatient datafrom 14 studies and outpatient data from 51studies of all health care costs among patientswith depression taking either venlafaxine,SSRIs,or TCAs (Table 1).This mathematical model wascustomized by running data from five MCOs(independent practice associations andnetwork-model HMOs),each accounting for itsown drug and health care resource costs, de-mographic information,and physician-practicepatterns (Arikian 2000). The model assumedequal adherence rates among medications.

Medication-cost differences were generallynegligible between the venlafaxine XR and SSRIgroups. Over 6 months, inpatient and out-patient costs in the venlafaxine XR group wereabout $1,500 less than the SSRI or TCA groups,with an average per-member, per-month costsavings of about 15 cents (Figure 2). Overallsuccess rates,defined as a minimum 50-percentreduction in depression scores on the HamiltonDepression Rating Scale (HAM-D

17) , were

higher for venlafaxine XR patients.The analysis

I

ncreasingly, health care systems are looking forcost-effective,not just inexpensive,treatment op-tions; similarly, pharmacy & therapeutics com-mittees are seeking greater proof of a products

pharmacoeconomic impact when making formularydecisions.Larry Ereshefsky,PharmD,professor of phar-macology and psychiatry at the University of TexasHealth Science Center,presented various types of phar-macoeconomic data designed to produce outcomesinformation.

An important consideration when reviewing the re-sults of any pharmacoeconomic model is that the re-sults are influenced by assumptions that are built intothem; thus, Ereshefsky stressed the importance ofadapting pharmacoeconomic models to account for

influencing factors present in a population or healthcare delivery system. After doing this, the model willproduce outcomes data that can allow the user todraw more accurate conclusions about any interven-tions that may be suggested by the results.

Retrospective analysisA retrospective analysis of the Medstat MarketScan

database examined the effects on all health care costsafter prescribing various antidepressant medicationsto patients newly diagnosed with depression with orwithout anxiety.The researchers examined new epi-sodes of depressive illness with or without anxiety

USING PHARMACOECONOMIC DATATO COMPARE ANTIDEPRESSANT THERAPIES

0

100

200

300

400

500

$352 $360

$177

$526

$600

FIGURE 1 6-month retrospectiveexpenditure analysis,SNRI vs.SSRI

SNRI = Venlafaxine IR/XR;SSRI = Fluoxetine, Paroxetine,Sertraline,Citalopram,

Fluvoxamine. 19941999 MarketScan data,The MEDSTAT Group,Inc.MarketScan is a registered trademark of the MEDSTAT Group,Ann Arbor,Mich.

SOURCE:WAN GJ,CROWN WH,BERNDT ER,FINKELSTEIN SN, LING D.ARE VENLAFAXINE

AND VENLAFAXINE XR ASSOCIATED WITH LOWER HOSPITALIZATION COSTS IN DE-PRESSED PATIENTS WITH OR WITHOUT ANXIETY COMPARED TO SSRIs? 2001. WORLD

ASSEMBLY FOR MENTAL HEALTH,VANCOUVER,CANADA: POSTER PRESENTATION.

Nonmental health-

related hospitalizationcost per patient

Antidepressant

medication treatmentcost per patient

P= 0.50

P


17/27


concluded that in all systems com-bined, each 1 percentage point ofpatients switched from other anti-depressant drugs to venlafaxine XRwould represent about $16,000 insavings per year. Potential savingsare based on the differences in ex-pected costs per successfully treatedpatient, though this research doesnot specifically target where thesesavings occur.

Depression-free day analysisThe third presentation was an

analysis of pooled data from eightclinical trials (the same trials used forMichael Thase, MDs, meta-analysisdetailed on pages 69) comparing

venlafaxine, SSRIs, and placebo.Thisanalysis used the pooled data to de-velop depression-free days as a mea-sure of the approximate time pa-tients spent in remission of theirdepression symptoms following 8weeks of acute treatment.

The construct, applied by Mallick(2001) and based on previous litera-ture,ascribes maximum depression-free time to patients who achieveand maintain a fully asymptomaticstate (a score of 15).

Over the 8-week period,the num-ber of depression-free days for eachpatient could, theoretically, rangefrom 0 to 56. Patients who receivedvenlafaxine were associated withmedian 18.8 depression-free days,compared to median 13.6 depres-sion-free days for patients receiving

SSRIs and median 7.4 depression-free days for those who receivedplacebo (Table 2). All differenceswere statistically significant.Further,as expected,this was consistent withsimilar differences across groups rel-ative to the proportion of patientsin each group who achieved sus-tained remission due to treatmentand the duration for which they re-mained in sustained remission.

SSRI TCA

$0.69

$0.84 $0.84

Venlafaxine XR

$14,846

$16,546 $16,695

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 1Study 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

TABLE 2Depression-free days (DFDs) by treatment group

Treatment group

Venlafaxine SSRI Placebo(n=864) (n=756) (n=450) Pvalues

Mean DFDs 19.8 17.3 14.1 0.0022*(SD) (16.7) (15.9) (15.4)


18/27


bump up the dose after 4 weeks of therapy? Do you aug-ment? Do you switch? This is illustrated as stage 1A.

If this fails, go to stage 2:Switch to a different drug.Al-though a patient who failed on an SSRI at stage 1 can beswitched to another, its recommended that this be doneonly for side-effect intolerance,rather than for lack of ef-ficacy.Augmentation the best data suggest lithium or

thyroid supplementation can be tried for partial re-sponders here (stage 2A) or at any stage.

Stage 3 again is monotherapy, but the clinician mustuse a different class of medication. If, for instance, thereis a history of treatment resistance to paroxetine andfluoxetine, then the patient should be switched fromSSRIs to a different class.

Stage 4 adds lithium augmentation, if not alreadyused, because it has the best data for augmentation andhas been shown to have fast response.

Stage 5 involves use of combination antidepressants.Atthis stage, if not already tried as augmentation, the addi-tion of a TCA to a serotonergic agent has the most evi-dence to support its use. However, combinations ofbupropion,venlafaxine,and mirtazapine with other anti-depressants are considered the most potent strategies.

There is no correct way to switch patients from onetherapy to another. Most physicians overlap taperthe first drug,while increasing the dosage of the secondproduct. Some will stop one drug and switch, especiallywithin the same class. In this case, there are no consen-sus guidelines except that abruptly stopping a drug anddoing nothing else is known to be harmful.With SSRIs,a serotonin-discontinuation syndrome is seen; the SSRIwith fewest discontinuation problems is fluoxetine, be-

cause of its buildup in a patients system.

OutcomesIn analyzed results presented at the American College

of Neuropsychopharmacology and the Texas Society ofHealth-System Pharmacists, for people treated using theTMAP algorithm, there is a 20 percent better responserate in patients who are more severely depressed than inthose whose treatment did not follow TMAP protocols.

In summary, when managing patients with limitedresponse, first maximize the dose and administer the

The Texas Medication Algorithm ProjectFor Major DepressionLARRY ERESHEFSKY, PHARMD

Professor of Pharmacology and Psychiatry, University of Texas Health Science Center

The Texas Medication Algorithm Project(TMAP) for major depression started in ourstate mental health system as a way to encour-age evidence-based practice in a wide array of

environments. These algorithms (Crismon 1999) illus-trate strategies and for the treatment of major depressionin nonpsychotic (Figure 1) and psychotic (not shown)

patients and those with bipolar illness (not shown).Moving toward evidence-based practice means de-

veloping not only an algorithm, but a culture that inte-grates monitoring and education, and uses evidence-based practice when making drug-treatment decisions.

What has made TMAP work is a culture shift notsimply,Heres a blueprint.Follow it. It was designed touse a best-practices approach to treatment resistance,while being flexible: A particular stage of the TMAP al-gorithm can be modified or ignored by any clinician atany time. The only thing we ask clinicians who strayfrom the algorithms to do is to document why. Docu-mentation improves evidence-based practice because itforces people to articulate a reason for what they do.

TMAP is being computerized and will become a sys-tem that gives automatic feedback. When available ondisk,TMAP will prompt users to adhere to best practices:They will be warned when departing the algorithm. Itwont force anyone to use a particular drug, but it will re-quire documentation for deviations from this standard.

A user can download physician training manuals andimplementation guides at http://www.mhmr.state.tx.ux/centraloffice/medicaldirector/tmap.html.

TMAP algorithms

The antidepressants listed in the algorithms includethe SSRIs as a class, nefazodone, bupropion SR, venla-faxine XR, mirtazapine, TCAs, and MAO inhibitors.

Stage 1 is when the clinician believes monotherapy isappropriate for a new diagnosis of depression. One canchoose from a variety of drugs,except for TCAs whichwe dont believe are front-line therapies for depression.

The user progresses through strategies illustrated inthe algorithm. There are also tactical steps decisionpoints to consider when the patient does not respondto the treatment given at each stage, such as: Do you


19/27


medication for an adequate duration.If this fails to pro-duce a response, switch classes. Thereafter, a pharmaco-logically different agent should be tried. When switchingclasses,consider a broad-spectrum antidepressant that af-fects more than one neurotransmitter system, or affectsthe system differently from the one already used. TMAP

gives clinicians a sense of how to combine drugs ratio-nally after monotherapy has been tried.

Reference

Crismon ML, Trevedi M, Piggot TA, et al. The Texas medical al-

gorithm report.J Clin Psychiatry. 1999;60:142156.

Response

Response

Response

Partial responseor nonresponse







Any stages(s) can be skippeddepending on the clinical picture.

Partial response

Partial response

Partial response



Response

Response

Response

Response

Response

* Consider TCA/venlafax if not tried** Lithium,thyroid, buspirone*** Skip if lithium augmentation

has already failed Most studied combination SSRI = Fluox,Sert, Parox, Cital

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Stage 6

Stage 7

MonotherapySSRI, bupropion,nefazodone,venlafaxineXR,or mirtazapine

Monotherapy

SSRI, bupropion,nefazodone,venlafaxineXR,mirtazapine,or TCA

MonotherapySSRI, bupropion,nefazodone,venlafaxineXR ,

mirtazapine,TCA,or MAOI*A class other than used in Stage 1 or 2

Lithium augmentation***

Combination antidepressants: TCA+SSRI bupropion+SSRI nefaz+SSRI bupropion+nefaz

ECT

OtherE.g., lamotrigine, fluvoxamine,

mirtazapine+bupropion,olanzapine, etc.(provide rationale)

Stage 1A

Augmentation**

Stage 2A

Augmentation**

Stage 3A

Augmentation**

Maintenancephase when

indicated

Continuation

Continuation

Continuation

Continuation

Continuation

Continuation

FIGURE 1 Strategy for treatment of nonpsychotic major depression

SOURCE:Crismon 1999


20/27


21/27

of treating it. Not much of the empirical data pre-sented today would be useful to primary care physi-cians. Whats important is better recognition of de-pression and then having an agent that physicians arecomfortable prescribing, based on a patients dis-ease severity and on an understanding of its side ef-fects. As we all know, the vast majority of mooddisorders are not treated by psychiatrists.

THOMAS A. HAMLIN, MD: I think information about the in-tegration of psychiatry into primary care would havebeen pertinent. The evidence presented today aboutincreased incidence of depression among patients

with diabetes, heart disease, and other ill-nesses was very helpful to me.JONATHAN D. BOOK,MD: What I found in-teresting was the increased informationavailable to guide rational prescribingpractices away from the notion that anantidepressant is an antidepressant.Why

shouldnt the decision on a first-line drugbe a rational pick? Most patients couldntdifferentiate why we would start with oneantidepressant versus another.

What do MCOs expect from managedbehavioral health organizations(MBHOs) with which they contract? Thepanelists indicated its important for anMBHO to demonstrate the value of ther-apy in terms of reducing overall cost ofcare and improving a patients level offunctioning. It was suggested that an

MBHO could focus on high-risk groups of patients forMCOs seeking to educate primary care physicians aboutthe effective treatment options for depression. This, inturn, can influence physicians prescribing habits.

KOZAR: Ultimately,are MCOsexpectations that you sim-ply reduce costs? Or is it about outcomes,getting pa-tients well and back to work?

ARON HALFIN, MD: Cost is one dimension,but its neitherthe only nor the main one. I think the expectationsare really that members receive appropriate care inthe most expeditious way, and that patients get well.

MOLDAUER: Theres also an issue of short-term versuslong-term cost. Sometimes you dont see the resultsof an intervention you put in today for four to fiveyears. I think thats why were there, as physicians, toknow what a patients treatment course should beover a five-year period,then measure the effect of thatintervention.

HALFIN: One advantage we have is our size and scope.More likely than not, if an individual is with healthplan A today and health plan B tomorrow, well stillbe managing that persons care by virtue of the scope


The group began by evaluating the information pre-sented by the days speakers about therapeutic options forpatients with depression. Several panelists agreed thatwhile the comparative data were well substantiated, thekey to affecting patient care lies in translating those datainto useful information at the clinical level. The partici-pants determined that favorable outcomes data, and notjust information about a drugs acquisition cost, areneeded to influence formulary decisions.

BRADLEY K. KOZAR: Of the themes touched on duringtodays presentations outcomes, drug interac-tions, the Texas treatment algorithms(TMAP), relative-effectiveness data,remission data, pharmacoeconom-ics which of these data were com-pelling or of value to you?

KENNETH H. COHEN,MD: The clarificationbetween drug response and remis-

sion was important. Often, the twoare taken as synonymous. There is adifference, and this should be con-sidered.

JULIE B. KESSEL, MD: Michael Thasespresentation on the way you look atdata was outstanding. It helps peopleincorporate the literature, which iscritical to clinicians who make theirown determinations when evaluat-ing drugs.

LESLIE MOLDAUER, MD: The TMAP algo-rithm was fascinating. I would like tohave seen how its used on a day-to-day, real-lifebasis.

KOZAR: Do you have algorithms that are similar,at leastin concept, to TMAP?

ANDREW RUDO, MD: We have a multidisciplinary medical-practice guidelines committee that looks at theguidelines available and [considers] what would bestsuit our purposes either adopting existing guide-lines or drafting them. We dont have an algorithm-type guideline,although that was an interesting pre-sentation to me, too.

CHARLES FREED JR., MD, MHA: For me, the most com-

pelling information was the pharmacoeconomicdata, especially when you consider that plans in-creasingly use tiers for medications to offset costs tothe plan. The question often arises: Which tiershould an agent be placed on?

COHEN: I think P&T committees want corroboratingdata.Theyre concerned about getting objective data.

LAWRENCE J. NARDOZZI, MD: Weve been involved in acollaborative effort with Aetna regarding educationand training of primary care physicians, so that theycan recognize depression and become better capable

Andrew Rudo,MD


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KOZAR: SSRIs get higher support from primary carephysicians than non-SSRIs, such as venlafaxine,ne-fazodone,or bupropion.How many of you currentlyuse SSRIs as first-line therapy? Or do you consideralternatives as first-line agents? Health plans almostmake you go to an SSRI first.

BOOK: A large proportion of antidepressants is prescribedby primary care physicians. Im not a primary carephysician,but it begins with having to ask the ques-tion: Is the prescription really being written becausewe have a patient with major depressive disorder? Ithink theres good reason to believe the answer isoften no. Studies show how underdiagnosed majordepression is,despite how wellprescribed antidepressants are.Whats the matter with thispicture? One way of thinkingabout that: Antidepressantsare prescribed, in some not-

so-small way, for vague com-plaints. Primary care doctorshave learned that fluoxetineand other SSRIs have been ef-fective for a breadth of non-specific symptoms that fallbelow the threshold of a majordepressive diagnosis. Onechallenge for any new anti-depressant is to get past that,todefine its niche in the way primary physicians useantidepressants.

KOZAR: I saw a lot of nodding in agreement when I askedwhether psychiatrists would think of non-SSRIs asfirst line. However, primary care physicians tend toprescribe the SSRI.So when a psychiatrist sees a pa-tient who has been initiated on an SSRI and isnt get-ting better,what do you do? Do you increase the doseor augment therapy, as suggested in stage 1A of theTMAP presentation? Do you try another SSRI,whichthe data presented today suggest may make littleclinical difference? Or, would you change to a dif-ferent class, as we saw in TMAP, stage 2?

HAMLIN: The important thing is, first, to determine thedose strength of the initial prescription and whether

there are any compliance issues. At that point, Iwould recommend increasing the dose if the patientis compliant. Then, if the patient is on a sufficientdose of an SSRI for a sufficient length of time butshows no effect, I generally would switch to anotherclass of antidepressant.

The importance of cohesion among and betweenproviders and/or health plans was again highlighted bymedications comparative data about remission. Psychia-trists, the panel agreed, are trained to look for remission

of mental illness, not just symptom improvement, whileprimary care physicians who tend to focus on a pa-tients entire medical health might not push as hardfor full remission.

KOZAR: Have you thought about the agents comparatively with remission as the end point?

HAMLIN: I always measure remission by evaluation of apatients level of functioning prior to the advent ofthe illness. A lot of patients we see have sufferedmajor depressive disorder so long that they dontknow their true potential. They might have devel-oped the illness as a child or an adolescent, resulting

in developmental delays. Gener-ally, we want to get them back to ahigh level of functionality.MOLDAUER: Health plans make youlook at it differently,to be aware ofthe comparative differences in re-

mission between drugs.FREED: The difference is largelydue to the variation in trainingand skill sets between psychia-trists and primary care physi-cians. Psychiatrists are muchmore likely to take into consider-ation remission, versus just im-provement.I dont think primarycare physicians have been trained

in that fashion, and so they are less likely to askpatients questions that would elicit this kind ofinformation.

RUDO: Its also a matter of focus. A primary care physi-cians focus necessarily needs to be on the persons en-tire medical-surgical health. And like with any physi-cian,there is only a limited amount of time to do that.So he may not push as aggressively about full remis-sion if he has to cover a bunch of other issues in thatsame session. I still see patients and from a psy-chiatrists perspective,if theyre not all the way in re-mission, I want to know why. Ill keep driving forthat.

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 dis-order that is moderate to severe without comorbidillness. I think theres a basic issue about diagnosis inprimary care,even though I happen to be one of thepeople who thinks primary care doctors do a decentjob treating depression, because most patients areadequately satisfied and recovered not that theycouldnt do better.I do think,however, that primarycare physicians and psychiatrists alike suffer from aninability to diagnose specific syndromes and choosemedications based on those syndromes.

Kenneth H. Cohen,MD


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The panel concluded with a discussion about how topromote consideration of non-SSRIs as first-line therapyif data support them as effective therapeutic options and for whom this would be appropriate.

KOZAR: Most of you seem to agree that non-SSRIs, such as nefazodone, venlafaxine,bupropion, or others can be first-lineagents, yet recognize that primary carephysicians tend to go to the SSRIs. Itseems that the remission data for moresevere patients favors venlafaxine. Whyarent these drugs first line among pri-mary care physicians? And how can thisinformation be disseminated?

RUDO: One thing that occurs to me aboutprimary care application efforts is thatwe could help [focus that discussion].Often the depression talks are an hour,

and try to cover A to Z about depression as op-posed to focusing on one or two aspects that wouldbe most pertinent to primary care physicians. One ofthose things could be differences demonstrated bythe literature among antidepressants.

KESSEL: I think it would be beneficial for primary carephysicians to focus on patients who are most relevantto them: the share who are high utilizers, hypo-chondriacs, somatic, and have mixed anxiety anddepression. Those are their problem patients. So if[the manufacturer of] venlafaxine was able to gatherinformation about that group and its effectivenesswith that group, I think that could be useful to pri-mary care physicians.

KOZAR: Thats another way to or look at it: If Im a pri-mary care physician, for whom should I considervenlafaxine or other non-SSRIs, as opposed to flu-

oxetine, paroxetine, sertraline, orcitalopram?KESSEL: Patients with weight loss andanhedonia, decreased activities ofdaily living, or who are brought in bya family member and impaired.COHEN: I can speak only from my ownclinical experience, but some of themore anxious and somatic complaintsof patients seem to have respondedbetter to venlafaxine than SSRIs.HAMLIN: First-line use would be ad-visable for the patient who sufferedprevious side effects from an SSRI.Major side effects, whether sexual,shakiness, or disturbing side effects

that prevent the patient from returning to the workforce,would be the indicator for a different first-lineapproach.

KOZAR: If Im treating a drug-nave patient,when shouldI use SSRIs versus non-SSRIs?

NARDOZZI: If I were a primary care physician, what Ineed [to know about a product] is its tolerability, ef-ficacy, and its drug-interaction profile.Give me thatinformation, and in all likelihood, it would be moreprobable that Id prescribe it as a first-line agent, asopposed to [another drug that I already know is] safe.

COHEN: Single-dosing of the SSRIs is a clear advantage. Ithink the XR experience [of venlafaxine] needs to beshared.

Leslie Moldauer, MD,left, andCharles Freed Jr., MD,MHA


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CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUEST

New Evidence-Based Treatments for Depression

Sponsored by the University of Arizona

College of Medicineat the Arizona Health Sciences Center

Name _________________________________________FIRST MI LAST

Title __________________________________________

Specialty_______________________________________

Address _______________________________________

City ___________________________________________

State ___________________________ ZIP ___________

Daytime telephone ______________________________

Physician Maximum of 2 hours in category 1credit.This learning module may be used forcategory 1 credit through Sept. 30, 2002.

Complete answer sheet/evaluation form and mail to:

Continuing Medical EducationUniversity of Arizona College of MedicinePO Box 245121

Tucson,AZ 85724-5121

Alternately, you may fax this completed sheet to:(520) 626-2427.

Credit will be awarded upon successful completionof assessment questions (80 percent or better) andcompletion of program evaluation. If a score of 80percent or better is not achieved,no credit will be

awarded and the registrant will be notified.

Please allow up to six weeks for processing.

The cost of this activity is provided at no chargeto the participant through an unrestricted educa-tional grant by Wyeth-Ayerst Laboratories.

EXAMINATION: Place an X through the box of the let-

ter that represents the best answer to each question onpage 25. There is only ONE answer per question. Placeall answers on this answer form:

A. B. C. D.1. s s s s2. s s s s3. s s s s4. s s s s5. s s s s6. s s s s7. s s s s8. s s s s9. s s s s

10. s s s s11. s s s s12. s s s s13. s s s s14. s s s s

PROGRAM EVALUATIONIn order to assess the value of this self-study program,weask that you fill out this evaluation form.

Overall activity ratingExcellent Very good Good Fair Poor

5 4 3 2 1

Were the educational objectives met?A great deal Not at all

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Rate how the activity will benefit you and improvepatient care.

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What other topics would you like to see addressed?________________________________________________________________________________________________________________________________________________

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If yes,please explain: ________________________________________________________________________________________________________________________________________________________________________________

CE Credit for PHYSICIANS See page 24 for answer sheet for pharmacists


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CONTINUING EDUCATION ANSWER SHEET/CERTIFICATE REQUEST

New Evidence-Based Treatments for Depression

Sponsored by the University of Arizona

College of Pharmacyat the Arizona Health Sciences Center

Name _________________________________________FIRST MI LAST

Specialty_______________________________________

Address _______________________________________

______________________________________________

City ___________________________________________

State ___________________________ ZIP ___________

Daytime telephone ______________________________

Pharmacist This program is approved for2 contact hours (0.2 CEU).

ACPE program number: 003-999-01-026-H01.Expiration date:Aug. 31, 2002.

Complete answer sheet/evaluation form and mail to:

Office of Continuing EducationUniversity of Arizona College of PharmacyPO Box 210207

Tucson,AZ 85721-0207

Alternately, you may fax this completed sheet to(520) 626-2023.

Credit will be awarded upon successful completionof assessment questions (70 percent or better) and

completion of program evaluation. If a score of 70percent or better is not achieved,no credit will beawarded and the registrant will be notified.

Please allow up to six weeks for processing.

The cost of this activity is provided at no chargeto the participant through an unrestricted educa-tional grant by Wyeth-Ayerst Laboratories.

CE Credit for PHARMACISTS

EXAMINATION: Place an X through the box of the let-

ter that represents the best answer to each question onpage 25. There is only ONE answer per question. Placeall answers on this answer form:

A. B. C. D.1. s s s s2. s s s s3. s s s s4. s s s s5. s s s s6. s s s s7. s s s s8. s s s s9. s s s s

10. s s s s11. s s s s12. s s s s13. s s s s14. s s s s

PROGRAM EVALUATIONTo receive pharmacy credit,please answer all informationrequested below.This will assure prompt and accurateissuance of your continuing education certificate.

Please rate this program as follows:

VeryExcellent good Good Fair Poor

Overall quality of program 5 4 3 2 1Content 5 4 3 2 1Relevance of content

to objectives 5 4 3 2 1Effectiveness of this

format for learning 5 4 3 2 1Value to me in my

daily responsibilities 5 4 3 2 1

How long did it take you to complete this continuingeducation activity?

hours _____ minutes ______

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See page 23 for answer sheet for physicians


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Documents

0108.Depression Suppl