differences in medication adherence and healthcare resource utilization patterns

CNS Drugs 2008; 22 (11): 963-973ORIGINAL RESEARCH ARTICLE 1172-7047/08/0011-0963/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Differences in MedicationAdherence and HealthcareResource Utilization PatternsOlder versus Newer Antidepressant Agents in Patientswith Depression and/or Anxiety Disorders

David V. Sheehan,1 Matthew S. Keene,2 Michael Eaddy,3 Stan Krulewicz,4John E. Kraus5 and David J. Carpenter6

1 University of South Florida College of Medicine, Tampa, Florida, USA2 Medco Health Solutions, Franklin Lakes, New Jersey, USA3 Xcenda, Palm Harbor, Florida, USA4 Neurosciences Medicines Development Center, Clinical Psychiatry North America,

GlaxoSmithKline, King of Prussia, Pennsylvania, USA5 Neurosciences Medicines Development Center, GlaxoSmithKline, Research Triangle Park,

North Carolina, USA6 Psychiatry Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania, USA

Background: Given the number of antidepressants available and their risingAbstractcosts, healthcare payers have initiated restrictive reimbursement policies fornewer antidepressants, without consideration for differences in their effectivenessor tolerability.Objective: The objective of this study was to comprehensively compare med-ication adherence rates and associated healthcare utilization costs for patientsusing later-generation versus earlier-generation antidepressants in a managed caresetting. Antidepressants launched after 2002 were deemed third-generation anti-depressants, while antidepressants available prior to 2002 were deemed first-generation (TCAs and MAOIs) and second-generation (serotonin and noradrena-line [norepinephrine]-dopamine reuptake inhibitors).Study design: Retrospective database analysis using medical and pharmacy datafrom over 75 managed care plans covering 55 million lives.Setting/patients: All patients receiving an antidepressant between 1 January 2002and 30 September 2004 were identified. The index date for patients was the dateof their first antidepressant prescription within this time period. Patients had to(i) have a diagnosis of depression or anxiety disorder, or depression and anxietydisorder within 6 months prior to or 30 days after their index prescription; (ii) be atleast 18 years of age, without having taken antidepressant therapy for 6 monthsprior to their index date; and (iii) be continuously eligible for 6 months prior totheir index date and during their 6-month follow-up period. Patients were exclud-ed if they had a diagnosis of psychosis-related disease, Alzheimer’s or Parkin-son’s disease, or were initiated on psychosis-related medications.

964 Sheehan et al.

Intervention/main outcome measure: Patients meeting selection criteria werefollowed for 6 months to assess rates of antidepressant adherence, therapy changerates and medical healthcare costs.Results: Study population: A total of 266 665 patients met the study criteria.Approximately 66% were female, with a mean age of 39 years. About 63% had adiagnosis of depression, 31% had an anxiety disorder diagnosis and 6% haddiagnoses for both an anxiety disorder and depression.Therapy change: Therapy change within 6 months occurred in 18% of patientsreceiving third-generation agents compared with 21% and 40% for second- andfirst-generation agents, respectively. The odds of a therapy change were signifi-cantly lower with third-generation antidepressants compared with both olderagent cohorts.Adherence: Of patients receiving third-generation antidepressants, 33.6% wereadherent compared with 29.3% and 12.4% of patients receiving second- and first-generation antidepressants, respectively. Newer agents also had better adherencerates across all diagnostic cohorts. After adjusting for baseline differences, theodds of being adherent to therapy were significantly lower for those takingsecond- and first-generation agents versus newer antidepressants. Among thenewer agents, the proportion of patients adherent to their therapy was: venlafaxineextended release 38%, paroxetine controlled release (CR) 35%, escitalopram34%, duloxetine 32% and bupropion extended release (XL) 31%.Healthcare utilization: Of the patients taking older antidepressants, 13% (secondgeneration) and 21% (first generation) were hospitalized at least once for anyreason compared with 12% of patients taking newer agents. Overall, the odds ofall-cause hospitalization within 6 months of therapy initiation were significantlyhigher for patients taking older antidepressants. Among the newer agents, hospi-talization rates ranged from 15.9% for duloxetine to 12.5% for paroxetine CR andbupropion XL. The unadjusted 6-month total medical costs (not includingpharmacy costs) per patient were $US3514 for second-generation, $US5744 forfirst-generation and $US3284 for newer antidepressants. After controlling forbaseline differences, patients receiving second- and first-generation antidepres-sants incurred 12% and 44% higher costs, respectively. The unadjusted 6-monthmedical costs for the newer agents ranged from $US2715 for paroxetine CR to$US6042 for duloxetine.Conclusion: The results of this study provide essential information for healthcaredecision makers about the potential advantages of newer generation antidepres-sants versus older generation antidepressants, as well as the differences betweenthe specific newer agents, with respect to improved rates of adherence and therapychange, reduced hospitalizations and healthcare costs.

Background experiencing an anxiety disorder in their lifetime.[1,2]

These disorders, alone or in combination, are disa-In the US, depression and anxiety disorders are bling, with considerable co-morbidity, risk of sui-

among the most common psychiatric conditions, cide, social consequences and enormous healthcarewith 16.2% of the population experiencing a major expenditures causing a major public health issue indepressive disorder and at least one in four persons industrialized nations.[3-5]

© 2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (11)

Adherence and Utilization: Older versus Newer Antidepressants 965

The general treatment approach towards depres- the primary objective of this study was to comparepatient adherence rates and associated healthcaresion and anxiety disorders consists of specific typesutilization costs for the newer agents (launched onof psychotherapy, pharmacotherapy or both.[6] In theor after 1 January 2002) with older antidepressantsUS, medications approved for treating depression(available before 1 January 2002) in a real-worldinclude SSRIs, selective noradrenaline reuptake in-managed care setting.hibitors (SNRIs), TCAs and MAOIs. TCAs were

considered the gold standard for treating depressionMaterials and Methodsand anxiety for almost 30 years. However, the intro-

duction of SSRIs has provided physicians with atreatment option that has the same efficacy as TCAs Data Sourcebut greater safety and tolerability with long-termuse, thereby making SSRIs the preferred first-line Medical and pharmacy data were extracted fromagents for depression and anxiety disorders.[7-11] The the Pharmetrics® Integrated Outcomes Databasewidespread physician acceptance of SSRIs has re- (Watertown, MA, USA). The Pharmetrics Databasesulted in this class becoming the most commonly represents approximately 75 managed care organi-prescribed antidepressant medications, with total zations covering 55 million lives and over 2 billion

claims.annual US sales exceeding $US10 billion in2004.[12]

Sample SelectionGiven the rising cost of antidepressants and themany treatment options that are available, health- All patients receiving an antidepressant listed incare payers have initiated restricted formularies, ge- table I between 1 January 2002 and 30 Septemberneric step-edits and prior authorization requirements 2004 were identified in the database. The index datefor newer antidepressants. This approach assumes for patients was the date of their first antidepressantno difference in the effectiveness or tolerability of prescription within this time period. To be includednewer antidepressants. However, research has deter- in the study, patients had to have a diagnosis ofmined that the tolerability and subsequent adherence depression or anxiety disorder, or depression andamong SSRIs, even those with the same chemical anxiety disorder within 6 months prior to or 30 daysentity, are not equivalent, with differences in adher- after the index prescription. Patients with anxietyence across the entire SSRI portfolio being observ- were included in this study given the co-morbided.[13-16] Although studies highlighting adherence nature of depression and anxiety. Patients had to beand resource differences are available for most of at least 18 years of age, without having taken antide-the SSRIs, these data do not include newer agents pressant therapy for 6 months prior to their indexsuch as escitalopram and duloxetine, attenuating the date, and continuously eligible for 6 months prior tousefulness of these studies in making formulary their index date and during their 6-month follow-updecisions. In fact, since 2002, a number of newer period. The diagnoses of anxiety disorder or depres-antidepressants have become available in the US, in- sion were determined using the International Classi-cluding escitalopram, venlafaxine extended-release fication of Diseases, Ninth Revision, Clinical Modi-(XR), duloxetine, and bupropion extended-release fication (ICD-9-CM) codes (table II).[22] Patients(XL). These agents have been specifically designed were excluded if they had a diagnosis of psychosis-to have improved tolerability or administration related disease, Alzheimer’s or Parkinson’s disease,schedules compared with existing antidepressants or or were initiated on psychosis-related medicationstheir precedent compounds.[17-21] However, there are (table III). Patients meeting all the selection criteriano studies that compare adherence and outcomes for were then followed for 6 months after their indexthe newer antidepressants against traditional antide- date to assess adherence rates, hospitalization ratespressant agents in a naturalistic setting. Therefore, and total healthcare charges.


966 Sheehan et al.

before 1 January 2002 were classified as older, andstratified as first- and second-generation agents, asshown in table I. Antidepressants classified assecond-generation differed from those classified asfirst-generation in that the second-generation agentsare considered to be more selective (serotonin, nor-adrenaline) and better tolerated.

Measurement of Adherence

Adherence with antidepressant medication wasmeasured by initially calculating a medication pos-session ratio (MPR), using the continuous, multipleinterval medications available (CMA) method asdescribed by Steiner and Prochazka.[23] Accordingto the CMA method, MPR is calculated as the sumof the days’ supply of all antidepressant prescrip-tions in a specific time period divided by the totaldays during the specified time period, and rangesfrom 0%, indicating no adherence, to 100%, indicat-ing perfect adherence. Patients were assumed tohave consumed all the medications acquired duringthe study period. When there was an overlap ofprescriptions (i.e. a patient received an additionalprescription before the ending date of the precedingprescription), residual days were added to the end-ing date of the next prescription; therefore, somepatients could have had MPR values >100%, whichwere truncated to 100%. Patients were consideredadherent if they had an MPR of ≥80% during thefirst 6 months (180 days) of follow-up, without a30-day gap in therapy during the first 90 days.[24]

Patients were deemed not adherent if their MPR was<80% or if they had evidence of a 30-day gap inprescriptions.

Co-Morbidity Assessment

To assess co-morbidities across the medicationcohorts, the Charlson index with Dartmouth-Mani-

Table I. List of antidepressants included in the study

Drug Therapeutic class

First-generation agents (older)

Amitriptyline TCA

Amoxapine TCA

Clomipramine TCA

Desipramine TCA

Doxepin TCA

Imipramine TCA

Nortriptyline TCA

Protriptyline TCA

Trimipramine TCA

Isocarboxazid MAOI

Phenelzine MAOI

Tranylcypromine MAOI

Maprotiline Tetracyclic

Mirtazapine Noradrenergic and specific serotonergicantidepressant

Nefazodone Blocks post-synaptic serotonin 5-HT2A

receptors

Trazodone Blocks post-synaptic serotonin 5-HT2A

receptors

Second-generation agents (older)

Bupropion Noradrenaline (norepinephrine)-dopaminereuptake inhibitor

Bupropion SR Noradrenaline-dopamine reuptakeinhibitor

Citalopram SSRI

Fluoxetine SSRI

Fluoxetine weekly SSRI

Fluvoxamine SSRI

Paroxetine SSRI

Sertraline SSRI

Venlafaxine SNRI

Third-generation agents (newer)

Bupropion XL Noradrenaline-dopamine reuptakeinhibitor

Duloxetine SNRI

Venlafaxine XR SNRI

Escitalopram SSRI

Paroxetine CR SSRICR = controlled release; SNRI = selective noradrenaline reuptakeinhibitors; SR = sustained release; XL and XR = extended release.

toba and Deyo modification was utilized.[25,26] TheAntidepressants were categorized as third-gener- Charlson co-morbidity index predicts the 1-year

ation agents if they were launched on or after 1 Janu- mortality for a patient who may have a range of co-ary 2002. The 2002 cut-off point was selected as all morbid conditions. The index contains 19 condi-products available prior to 2002 are now available tions, each assigned with a score of 1, 2, 3 or 6generically in the US, whereas products launched on depending on the risk of dying associated with theor after 1 January 2002 are not. Agents available condition. The scores are summed to give a total



hospitalizations, outpatient hospital care, emergencydepartment visits and other services, includingmental health specialty care. Pharmacy costs werenot included in the definition of medical healthcarecosts. Descriptive analyses were conducted to des-cribe the differences in the principle variables acrossthe three diagnostic cohorts of depression, anxietydisorder and anxiety/depression (dual diagnosis ofdepression and anxiety disorder).

Inferential differences in rates were assessed us-ing logistic regression models, controlling for differ-ences in age, sex, co-morbidities, overall diseaseand medication burden, healthcare costs during the6-month pre-period, and insurance type (healthmaintenance organization, preferred provider organ-ization, point of service plan). Differences inmedical costs were assessed using semi-log ordinaryleast square models. The α level of significance waspreset at 0.05.

Table II. International Classification of Diseases, 9th Revision,Clinical Modification[22] codes for study inclusion

Indication Inclusion diagnoses Code

Anxiety disorders Panic disorder without agoraphobia 300.01

Panic disorder with agoraphobia 300.21

Agoraphobia without a history of 300.22panic disorder

Social phobia (social anxiety 300.23disorder)

Obsessive-compulsive disorder 300.3

Post-traumatic stress disorder 309.81

Acute stress disorder 308.3

Generalized anxiety disorder 300.02

Anxiety disorder not otherwise 300.00specified

Depression Major depressive disorder, single 296.2episode

Major depressive disorders, 296.3recurrent episode

Neurotic depression 300.4

Depressive disorder not classified 311elsewhere

Resultsscore. This overall co-morbidity score, ranging from0 to 32, reflects the cumulative increased likelihoodof 1-year mortality; the higher the score, the more Study Populationsevere the burden of co-morbidity. The Deyo modi-fication is an adaptation of the Charlson index for A total of 266 665 patients met the study inclu-use with ICD-9-CM diagnosis codes. Charlson in- sion and exclusion criteria. Approximately 66%dex scores were derived from the presence of vari-ous ICD-9-CM codes in the 6-month period beforeeach patient’s index date.

In addition to the Charlson co-morbidity index,disease co-morbidity and patient severity was as-sessed by evaluating the number of unique classes ofdrugs a patient received, the number of unique diag-nosis codes, diagnosis type (anxiety, depression orboth) and all-cause medical costs prior to initiatingantidepressant therapy.

Analysis of Outcomes

The principle variables of interest were rates ofantidepressant adherence, therapy change rates andmedical healthcare costs. Therapy change was de-fined as a change in antidepressant medication fromthe index prescription within 180 days of initiatingtreatment. Medical healthcare costs included thetotal amount charged for physician visits, inpatient

Table III. International Classification of Diseases, 9th Revision,Clinical Modification[22] codes for study exclusion

Indication Exclusion diagnoses Code

Schizophrenia Schizophrenic disorders 295.xx

Bipolar disorder Manic disorder, single episode 296.0x

Bipolar affective disorder, manic 296.4x

Bipolar affective disorder, mixed 296.6x

Bipolar affective disorder, 296.5xdepressed

Bipolar affective disorder, 296.7unspecified

Manic-depressive psychosis, 296.89other

Affective personality disorder, 301.13cyclothymic disorder

Manic-depressive psychosis, 296.80unspecified

Organic affective syndrome 293.83

Unspecified affective psychosis 296.90

Parkinson’s disease 332.xx

Alzheimer’s disease 331.0


968 Sheehan et al.

Table IV. Baseline demographic characteristics

Parameter Overall Third-generation Second-generation First-generation

No. of patients 266 665 83 800 161 166 21 699

Age in years [mean (SD)]a 39.1 (12.7) 38.9 (12.1) 38.8 (12.8) 41.9 (13.1)

Female (%)a 66.41 65.04 67.49 63.67

Charlson Index score [mean (SD)]a 0.363 (1.04) 0.328 (0.94) 0.356 (1.04) 0.555 (1.36)

No. of unique drugs [mean (SD)]a 3.08 (3.31) 3.07 (3.21) 2.96 (3.24) 4.01 (4.03)

No. of unique drug classes [mean (SD)]a 2.90 (3.00) 2.89 (2.93) 2.79 (2.94) 3.69 (3.56)

No. of unique diagnosis codes, excluding 5.50 (5.35) 5.42 (5.00) 5.33 (5.27) 7.08 (6.81)depression and anxiety [mean (SD)]a

Diagnosis type (%)a

depression 62.72 59.69 64.92 58.08

anxiety 30.93 33.10 29.11 36.04

anxiety/depression 6.35 7.21 5.97 5.88

Medical costs in the 6 months before 4941 (25 930) 4418 (21 770) 4653 (24 511) 9100 (44 175)antidepressant prescription ($US; 2005 costings)[mean (SD)]

Insurance type (%)a

HMO 43.43 37.70 46.52 42.64

indemnity plan 4.29 4.54 4.14 4.43

PPO 28.38 35.21 24.81 28.51

POS 16.58 15.03 17.42 16.33

other 7.31 7.51 7.11 8.10

a Differences between cohorts statistically different (p < 0.05).

HMO = health maintenance organization; POS = point of service; PPO = preferred provider organization.

(n = 177 066) of the study sample was female, with a first-generation agents, respectively (figure 1). Themean age of 39 years. About 63% (n = 167 255) had odds of a therapy change were significantly lowera diagnosis of depression, 31% (n = 82 477) had an with newer agents than either older cohort (second-anxiety disorder diagnosis and 6% (n = 16 933) had

generation, odds ratio [OR] = 1.19; 95% CI 1.16,an anxiety disorder diagnosis and a diagnosis of1.21; p < 0.001, and first-generation, OR = 3.02;depression. The mean Charlson co-morbidity index

score was 0.36 (SD = 1.04), indicating a low overall 95% CI 2.92, 3.12; p < 0.001) [figure 2].burden of co-morbidity, as the range for the index is0–32. The demographic characteristics of the groupsreceiving newer versus older agents are given intable IV.

The average medical costs in the pre-indexperiod were higher for patients receiving olderagents. Patients receiving second-generation agentshad a higher rate of depression diagnosis than pa-tients receiving first- or third-generation agents.

Patterns and Rates of Therapy Change

Overall therapy change within 6 months occurredin 18% of patients receiving newer agents comparedwith 21% and 40% of patients receiving second- and

6-M

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apy

chan

ge r

ates

(% o

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ient

s)

50

40

30

20

10

0Overall Depression Anxiety Depression/

anxiety

Third-generationSecond-generationFirst-generation

17.6

20.4

39.5

18.6

21.1

43.0

15.8

18.5

32.7

17.8

22.9

46.2

*

*

*

*

*

*

*

*

Fig. 1. 6-Month therapy change rates for antidepressant drug cate-gories by diagnostic cohort. * p < 0.001 compared with third-gener-ation agents.



third-generation agents (figure 5). Overall, the oddsof all-cause hospitalization within 6 months of ther-apy initiation was significantly higher for patientstaking second- (OR = 1.11; 95% CI 1.08, 1.15;p < 0.001) or first-generation (OR = 1.39; 95% CI1.30, 1.46; p < 0.001) antidepressants than thosetaking newer agents (figure 6). Among the neweragents, hospitalization rates ranged from 15.9% forduloxetine to 12.5% for paroxetine CR andbuproprion XL (figure 7).

As shown in figure 8, the unadjusted 6-monthtotal medical costs per patient were $US3514 forthose receiving second-generation agents and$US5744 for those receiving first-generation agentsversus $US3284 for patients receiving a newer anti-

5.00

4.00

3.00

2.00

1.00

0.00

Odd

s ra

tio o

f the

rapy

cha

nge

rate

s

First-generation

First-generation

First-generation

First-generation

Second-generation

Second-generation

Second-generation

Second-generation

Overall Depression Anxiety Depression/anxiety

3.023.25

2.50

3.86

1.361.211.161.19

Fig. 2. Odds ratio of therapy change rates for antidepressant drugcategories by diagnostic cohort (reference group: third-generationagents). All comparisons are significant at p < 0.001.

depressant. After controlling for baseline differ-ences, patients receiving older antidepressants in-Patients having a therapy change were excludedcurred significantly higher medical costs (excludingfrom subsequent analyses.pharmacy costs), with those receiving second-gener-

Patterns of Adherence ation agents having 12% higher costs and thosereceiving first-generation agents having 44% higher

Overall, in the 6 months after the index prescrip-costs than those receiving third-generation agents.

tion, 33.6% of patients receiving third-generationThe unadjusted 6-month medical costs for patients

antidepressants versus 29.3% and 12.4% of patientsreceiving the newer agents ranged from $US2715

receiving second- and first-generation antidepres-for paroxetine CR to $US6042 for duloxetine (figure

sants, respectively, were found to be adherent.9).

For each diagnostic cohort, the newer agents hadbetter adherence rates than the two older cohorts Discussion(figure 3). After adjusting for baseline differences,the odds of being adherent to therapy was signifi- The primary purpose of this study was to com-cantly lower for those taking second-generation pare rates of medication adherence, therapy change(OR = 0.82; 95% CI 0.80, 0.84; p < 0.001) and first- rates, and medical healthcare utilization and costsgeneration (OR = 0.26; CI 0.25, 0.28; p < 0.001)agents versus the newer, third-generation antide-pressants (figure 4). Among the newer agents, theproportion of patients adherent to their therapy was:venlafaxine XR (38%), paroxetine CR (35%), esci-talopram (34%), duloxetine (32%) and bupropionXL (31%).

Patterns of Healthcare Utilization

In terms of healthcare utilization, patients takingsecond- and first-generation antidepressants weremore likely to be hospitalized for any reason within6 months of therapy initiation; 13% and 21%, re-spectively, compared with 12% of patients receiving

Adh

eren

ce r

ates

(%

of p

atie

nts) 40

35

30

25

20

15

10

5

0



33.6

33.8

* *

* *

* *

33.6

32.4

* *

29.3

12.4

13.5

11.2

9.9

29.7

29.1

29.7

Fig. 3. Medication adherence rates for antidepressant drug catego-ries by diagnostic cohort. * p < 0.001 compared with third-genera-tion agents.


970 Sheehan et al.

of care, measured by hospitalizations and costs, maybe better with later generation antidepressants.

The results of this study are germane for man-aged care decision makers who make formularydecisions based predominantly on clinical trial data,which may not always reflect real-world treatmentpatterns and outcomes. Typically, health plan andpharmacy benefit management decision makers mayopt to include antidepressants that are genericallyavailable on their formulary solely on the basis ofdrug cost. However, this strategy neglects to consid-er differences in outcomes and medical costs thatmay be attributed to differences in adherence, rates


Odd

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tio o

f med

icat

ion

adhe

renc

e

First-generation

First-generation First-

generationFirst-

generation

Second-generationSecond-

generationSecond-generation

Second-generation

0.82 0.81 0.83 0.89

0.220.240.290.26

1.00

0.00

0.20

0.40

0.60

0.80

Fig. 4. Odds ratio of medication adherence for antidepressant drugcategories by diagnostic cohort (reference group: third-generationagents). All comparisons are significant at p < 0.001. of therapy change and, subsequently, reduced effec-

tiveness. Managed care organizations that automati-among early- and late-generation antidepressants for cally place newer antidepressant agents on higherthe treatment of depression and/or an anxiety disor- tiers or implement a ‘generics first’ strategy may

ultimately incur higher overall costs from more hos-der in a managed care setting. The results show thatpitalizations and other resource use.at ‘real-world’ treatment doses, <50% of patients are

adherent to their antidepressant therapy over a For decision makers who are looking to differ-6-month period. However, adherence rates were sig- entiate among the newer antidepressants, a couple of

trends must be noted. First, adherence was highestnificantly higher for those taking newer antidepres-in patients taking venlafaxine XR and paroxetinesants compared with those taking early-generationCR. Linking this finding with observations fromagents. Patients receiving newer antidepressantsprevious work,[15,24,27] one may surmise that thesealso had a lower likelihood of therapy change, in-agents would also have (i) the lowest hospitalizationcurred lower resource utilization and were less like-rates (figure 7); and (ii) the lowest healthcare costsly to be hospitalized than those receiving older(figure 9). Although these characteristics are sup-agents over a 6-month period. These results supportported for patients receiving paroxetine CR, theprevious work suggesting that higher adherencepremise is not supported for patients receiving ven-

rates are associated with lower resource utilizationlafaxine XR. Patients taking venlafaxine XR ranked

and hospitalizations,[24,27] and may also indicate that third in hospitalization rates and healthcare costsnewer agents could be better tolerated than olderantidepressants.

The improved tolerability premise for newer anti-depressants is further supported by higher rates oftherapy change with older antidepressants. Previousstudies have suggested that high rates of therapychange are associated with a lack of efficacy, thepresence of adverse events, or poor patient adher-ence with a treatment regimen.[28] While this studycannot determine if lower therapy change rates arethe result of better adherence, efficacy or tolerabili-ty, it is reasonable to conclude that inherent differ-ences exist between these agents and that outcomes

6-M

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s (%

of p

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nts)

25.0

20.0

15.0

10.0

5.0

0.0Overall Depression Anxiety Depression/

anxiety


12.1

13.2

21.0

13.1

14.0

22.5

10.8

12.2

19.4

9.9

10.1

16.6

*

*

*

*

*

*

*

*

Fig. 5. 6-Month hospitalization rates after therapy initiation for anti-depressant drug categories by diagnostic cohort. * p < 0.001 com-pared with third-generation agents.



lowest costs. Further research is needed to moredistinctly answer this question.

Although the results of this study highlight thepotential benefits of later generation antidepressantsversus older agents, there are some limitations thatneed to be discussed. Patients in this study were notrandomized to treatment; therefore, it is possiblethat differences in outcomes may be due to factorsthat cannot be controlled in a retrospective analysis(such as physician preference, severity of illness andprevious episodes of depression or anxiety). Differ-ences in severity were thought to be controlledthrough the inclusion of background and demo-graphic co-variates. Although statistical differenceswere observed across almost all demographic vari-

2.00

1.75

1.50

1.25

1.00

0.75

Odd

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tio o

f hos

pita

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s

First-generation*

First-generation*

First-generation*

First-generation***

Second-generation*

Second-generation*

Second-generation* Second-

generation**


1.11

1.391.43

1.11

1.28

1.13

1.29

1.03

Fig. 6. Odds ratio of hospitalization rates within 6 months aftertherapy initiation for antidepressant drug categories by diagnosticcohort (reference group: third-generation agents). * p < 0.001,** p = 0.649, *** p = 0.052.

ables, most of these differences were not likelyclinically meaningful, with the exception of medical

(figures 7 and 9) even though they were the most costs and rates of depression and/or anxiety diagno-adherent cohort and faired well in terms of therapy ses.change. This finding suggests that adherence may

Gaps in medication adherence may also occur asnot always be the overriding factor in terms of lowera result of medication sampling or intentional cessa-costs and hospitalizations, and brings to questiontion of therapy. It was assumed that the latter woulddifferences in effectiveness at real-world doses.be equal across cohorts, and that medication sam-Since depression is generally managed by primarypling would negatively bias the results for newercare physicians, the real-world doses of antidepres-agents, since the majority of these agents are brand-sants are usually on the lower end of the dosageed and thus more likely to have sampling, whichspectrum, as primary care physicians do not push thewould result in lower adherence rates. Also, thishigher limit of doses commonly seen within clinicalstudy did not directly evaluate symptoms of depres-trials. This use of lower doses may adversely affectsion or depression-specific clinical measures. Asproducts that are thought to be more effective atsuch, one cannot conclude superiority of any classeshigher doses, such as venlafaxine XR, which has

been shown to affect multiple receptors at higherdoses. This low-dose, low-effectiveness premisewas supported in a post hoc analysis, where patientstaking venlafaxine XR had an average daily dose of86.2 mg, a dose much lower than the dose at whichmultiple receptors are affected. Based on previouswork,[29] this dose may not be sufficient to adequate-ly improve the symptoms of depression and/or ananxiety disorder. If this dose is subtherapeutic, pa-tients may experience fewer adverse effects, result-ing in better adherence, but outcomes of care maynot be as high as with other agents. Effectivenessmay also explain why bupropion XL had the lowestrates of adherence among the newer agents, but alsohad the lowest rates of hospitalizations and second

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18

16

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12

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8

6

4

2

0

Venla

faxine

XR

Bupro

pion

XL

Duloxe

tine

Escita

lopra

m

Parox

etine

CR

13.712.5

15.9

13.912.5

Fig. 7. 6-Month hospitalization rates for newer (third-generation)antidepressants. CR = controlled release; XL and XR = extendedrelease.


972 Sheehan et al.

clinical and economic benefits highlighted in thisstudy.

Acknowledgements

This study was supported by a Collaborative ResearchGrant from GlaxoSmithKline. Management of the study, dataanalysis and interpretation were conducted by Dr Sheehan,and Dr Eaddy and his team at Xcenda, independent of thefunding source. Mr Krulewicz, Dr Kraus and Dr Carpenter,employees of GlaxoSmithKline, participated in the studydesign and in the review of the manuscript. Dr Sheehan hasworked, on a contractual basis, as a consultant to Xcenda and

7000

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Fig. 8. Total unadjusted medical costs for 6 months for antidepres-sant drug categories by diagnostic cohort. to GlaxoSmithKline. He received an honorarium from

Xcenda for his consulting work on this study. He has receivedthree grants for clinical trials through the University of Southor products within this study. Lastly, the costs ofFlorida from GlaxoSmithKline over the past 5 years. Drantidepressant prescriptions were not included inKeene has worked, on a contractual basis, as a consultant to

this assessment. One must evaluate the medical cost Xcenda. He received an honorarium from Xcenda for hisdifferences seen within the analysis with the incre- consulting work on this study. Dr Eaddy is an employee of

Xcenda. Xcenda provides consulting services to GlaxoSmith-mental pharmacy costs.Kline on a contractual basis. Mr Krulewicz and Dr Carpenterown stock and/or options in GlaxoSmithKline. In addition toConclusionDr Eaddy, the Xcenda team included: Timothy S. Regan,RPh, CPh, research design and manuscript review; AnupritaWith an understanding of these limitations, thePatkar, PhD, research design and database analysis; Anna

results of this study provide essential information D’Souza, PhD, database analysis and manuscript preparation;for healthcare decision makers about the potential and Amy L. Grabowski, study management and manuscript

preparation.advantages of later generation antidepressants withrespect to improved rates of medication adherenceand therapy change rates, along with a reduction in References

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Fig. 9. 6-Month medical costs for newer (third-generation) antide-pressants. CR = controlled release; XL and XR = extended re-lease.



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conventional serotonin reuptake inhibitors and venlafaxineinhibitor treatment in the UK: risk of relapse or recurrence ofXR: a meta-analysis. J Psychiatry Neurosci 2006; 31 (2): 122-depression. Br J Psychiatry 2000; 177: 163-831

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tended-release versus conventional antidepressants in the re-mission of depressive disorders after previous antidepressant

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