RESEARCH. What is already known about this subject

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1 RESEARCH Comparative Assessment of Adherene Measures and Resoure Use in SSRI/SNRI-Treated Patients with Depression Using Seond-Generation Antipsyhotis or L-Methylfolate as Adjuntive Therapy Rolin L. Wade, RPh, MS; Sylvia L. Kindermann, MPH; Qingjiang Hou, MS; and Mihael E. Thase, MD ABSTRACT BACKGROUND: Antidepressant monotherapy is effetive in ahieving treatment remission in only approximately one third of patients with depression, and even swithing to a seond antidepressant brings the umulative remission rate to only 50%-55%. This has led to an interest in augmentation therapy for the management of treatment-resistant depression. OBJECTIVES: To assess (a) seletive serotonin reuptake inhibitor/seletive norepinephrine reuptake inhibitor (SSRI/SNRI) adherene when augmented with seond-generation atypial antipsyhotis (SGAs) or L-methylfolate using a modified appliation of the Healthare Effetiveness Data and Information Set (HEDIS) aute mediation management (AMM) measures at the time of augmentation, and (b) the depression-speifi and total health are ost, omparing the 2 forms of augmentation therapy in the treatment of depressive disorder. METHODS: Patients with a diagnosis of depression and a pharmay laim for an SSRI/SNRI between January 1, 2006, and Deember 31, 2009 (index date), and reeiving onomitant augmentation therapy with either an SGA or L-methylfolate (augmentation date), were identified in the MarketSan database and followed for 231 days (follow-up). Patients were exluded for having any pharmay laim for an antidepressant or SGA 90 days pre-index; having an L-methylfolate laim 6 months pre-index; age < 18 years on the index date; or a diagnosis of pregnany, dementia, psyhoti-related mental disorders, Alzheimer s disease, or Parkinson s disease in the 12-month preindex period. Propensity sore mathing (3:1 ratio, atypial antipsyhoti to L-methylfolate) was used to selet the final study ohorts, using ovariates of age, gender, omorbidities, index SSRI/SNRI, and index SSRI/SNRI dose. Adherene to antidepressant therapy was measured from the augmentation date and inluded a modified appliation of the HEDIS (mhedis) AMM aute and hroni phase measures as well as the 6-month mediation possession ratio. Health are utilization and ost were measured for the 6-month postaugmentation period and inluded both total as well as depressionrelated utilization/ost. Comparisons between the losely mathed SGA and L-methylfolate-augmented ohorts were made using hi-square tests for binary measures and t-tests for ontinuous measures. RESULTS: Following propensity sore mathing, 4,053 SGA and 1,351 L-methylfolate patients were found to have augmentation of the index SSRI/ SNRI within 12 months of the index date. The omparison groups were well mathed on age, gender, omorbidities, and the type and dose of the SSRI/ SNRI being augmented. The most ommon antidepressants augmented in both groups were esitalopram, duloxetine, and venlafaxine. Mean (standard deviation [SD]) time from index to augmentation was 73.5 [96.7] days for SGA and [108.7] days for L-methylfolate (P < 0.001). The most ommon SGAs utilized for augmentation were quetiapine, aripiprazole, and risperidone. L-methylfolate was primarily dosed at 7.5 mg/day. The mhedis AMM aute phase measure was met by 68.7% of the SGA ohort and 78.7% of the L-methylfolate ohort (P < 0.001). The mhedis ontinuation phase measure was met by 50.3% of the SGA ohort and 62.1% of the L-methylfolate ohort (P < 0.001) following augmentation. Medial utilization (inpatient, emergeny department, and outpatient) was signifiantly higher for the SGA group, while total presription utilization was signifiantly higher in the L-methylfolate group. Mean [SD] total 6-month postaugmentation osts for the SGA group was $8,499 [$13,585] and $7,371 [$12,404] for the L-methylfolate group (P = 0.005), and 6-month depression-related osts were $2,688 [$4,201] for the SGA group and $1,613 [$2,315] for the L-methylfolate group (P < 0.001). CONCLUSIONS: Patients who augmented SSRI/SNRI therapy with SGA or L-methylfolate ahieved mhedis AMM aute phase and ontinuation phase adherene sores of 69%-79% and 50%-62%, respetively. These modified sores exeeded the 2012 national median benhmarks for unmodified HEDIS AMM measures for ommerial health plans. In this study, augmentation with L-methylfolate was assoiated with signifiantly higher adherene measures ompared with augmentation with SGA. In addition, health are utilization and total health are osts, as well as depression-related osts, were signifiantly lower in the L-methylfolate augmentation group ompared with augmentation with SGA. J Manag Care Pharm. 2014;20(1):76-85 Copyright 2014, Aademy of Managed Care Pharmay. All rights reserved. What is already known about this subjet A large perentage of patients with depressive disorder fail to ahieve remission using antidepressant monotherapy even after swithing antidepressant mediation. The STAR*D trial failed to demonstrate the superiority of any individual antidepressant option and reported a remission rate of only 50%-55% following a seond-step treatment attempt. This has led to an interest in augmentation of antidepressant therapy, in whih evidene is building that augmentation may be an effetive strategy in treatment-resistant depression. 76 Journal of Managed Care Pharmay JMCP January 2014 Vol. 20, No. 1

2 What is already known about this subjet (ontinued) The effetiveness of seond-generation atypial antipsyhotis (SGA) augmentation in depression has been well studied, and several agents now arry approved labeling for suh use. There is a neurophysiologial rationale for folate augmentation of antidepressant therapy involving both biohemial and geneti fators, and this strategy has been studied for more than 30 years. Reent linial trial evidene suggests that L-methylfolate, whih is FDA-labeled as a presription medial food and is available as a pharmay benefit in some health plans, may be effetive as an adjuntive therapy for treatment-resistant depression. Despite evidene of effetiveness, little is known about antidepressant adherene rates or osts in patient populations utilizing SGA or L-methylfolate augmentation therapy. What this study adds Patients who augmented seletive serotonin reuptake inhibitor/ seletive norepinephrine reuptake inhibitor therapy with SGA or L-methylfolate ahieved antidepressant mediation management (AMM) aute phase and ontinuation phase adherene sores of 69%-79% and 50%-62%, respetively, using a modified National Committee for Quality Assurane s Healthare Effetiveness Data and Information Set (mhedis) AMM sore. The modified sores represent AMM HEDIS measures sored following augmentation rather than being sored upon antidepressant initiation. These modified sores exeeded the 2012 national median benhmarks for unmodified HEDIS AMM measures for ommerial health plans. Adherene sores following L-methylfolate augmentation were signifiantly higher than those for SGAs. Patients reeiving augmentation of antidepressant therapy with L-methylfolate demonstrated lower health are utilization, lower all-ause osts, and lower depression-related osts than patients augmenting with SGA for depression. Major depressive disorder (MDD) is a ommon, highly reurrent, and potentially fatal illness and has a lifetime prevalene in the United States of approximately 16%. 1 It is estimated that the soietal osts of depression, inluding those resulting from lost earnings, premature death, and treatment osts, translate into a eonomi burden of more than $83 billion. 2 Patients with MDD have inreased rates of morbidity and mortality, funtional impairment, redued quality of life, and inreased risk of suiide. 3 Studies have shown that despite a wide range of options for treating MDD, up to 40% of patients fail to respond to treatment, even after fourth-line therapy, based on a validated self-report sale. 4 Patients who do not respond to antidepressants onsume a disproportionally larger share of health are resoures and have lower work produtivity than patients that respond to treat- ment. 2 As even sequential monotherapy with antidepressants fails to produe an adequate response to treatment for a large proportion of patients, augmentation of antidepressant therapy with a seond antidepressant, atypial antipsyhotis, lithium salts, or other agents has been suggested as a solution when traditional therapy fails. 5,6 Evidene is aumulating showing that ombination therapy in treatment of MDD may produe higher remission rates and lower relapse rates than traditional monotherapy, 6 either as an initial treatment plan or as a strategy for nonresponse to initial treatment. 7 However, many of the ommonly used augmentation strategies are assoiated with an inrease in ost burden as well as higher rates of adverse events, both of whih may lead to poor adherene to treatment. The use of antipsyhotis to augment antidepressants for the treatment of depression has been reported sine the 1960s. 8 Conventional antipsyhotis have largely been replaed by seond-generation antipsyhotis (SGAs), perhaps primarily beause the newer drugs are assoiated with fewer extrapyramidal side effets, suh as restlessness and repetitive involuntary musle movements, and have a lower risk for ausing tardive dyskinesia than the older agents. Meta-analyses and both the 2006 and 2011 Ageny for Healthare Researh and Quality reviews of the effiay of SGAs onfirmed that at least 4 of the SGAs were effiaious when added to seletive serotonin reuptake inhibitors/seletive norepinephrine reuptake inhibitors (SSRIs/SNRIs) in studies of patients with MDD Moreover, 3 SGAs (aripiprazole, quetiapine, and olanzapine speifially in ombination with fluoxetine) have been approved by the U.S. Food and Drug Administration for this indiation. While effetive, adjuntive therapy with SGAs has some limitations and disadvantages, inluding the high ost of many agents and the risks of weight gain and other metaboli ompliations (e.g., dyslipidemia, hypertriglyeridemia, gluose dysregulation, diabetes mellitus, and hyperprolatinemia), as well as less ommon risks suh as tardive dyskinesia, neurolepti malignant syndrome, and QT prolongation. 7,12,13 In ontrast, folate and related ompounds, whose role in depression has been reognized for over 20 years, are not assoiated with the metaboli ompliations observed with SGAs The folate yle plays a entral role in the prodution of ateholamine neurotransmitters, and inreasing the synapti onentration of these transmitters are believed to be one mehanism of ation for many antidepressants. 18 Rather than bloking ateholamine reuptake as with the SSRI/SNRI lass of ompounds, folate works at the presynapti level to support ateholamine prodution. 17 A meta-analysis of 11 studies with more than 15,000 partiipants found a signifiant relationship between low folate status and depression (pooled adjusted odds ratio 1.42, 95% onfidene interval ). 19 Foli aid must undergo enzymati redution by methyltetrahydrofolate redutase (MTHFR) to beome biologially ative. 20 The heterozygous polymorphism of MTHFR has been found in 47% Vol. 20, No. 1 January 2014 JMCP Journal of Managed Care Pharmay 77

3 of the normal population and the homozygous polymorphism in 11% of the population. These polymorphisms are known to ause a redution in MTHFR ativity of 34% and 71%, respetively. 19,21,22 Folate defiieny an also be aused by drugs (suh as antionvulsants, antibiotis, and oral ontraeptives), malabsorption syndromes, hroni diseases, and alohol use. 23 Depression is often assoiated with weight flutuation, inluding anorexia and weight loss, whih suggests that low folate levels ould be both a ause and a onsequene of depression. 24 Low folate blood levels have been assoiated with poorer or slower response to fluoxetine for MDD, 25,26 and higher folate levels have been assoiated with better response to antidepressants. 27 Folate has been studied as an adjuntive treatment with fluoxetine, with signifiantly greater improvement in those reeiving folate espeially among female patients. 28 L-methylfolate is the primary biologially ative isomer of folate, does not require MTHFR for biologial ativity, and is the form of folate that is transported aross the blood-brain barrier. The 2010 Amerian Psyhiatri Assoiation guidelines state, Considering the modest evidene that supports folate as an augmentation strategy and its attrative risk-benefit profile, folate an be reommended as a reasonable adjuntive strategy for major depressive disorder that arries little risk. 7 From a regulatory perspetive, L-methylfolate is lassified as a medial food that differs from dietary supplements in that medial foods are presribed and are intended for dietary management of a disease or ondition for whih nutritional requirements are established. The ompound is only available as a presription produt in the United States and is indiated for the distint nutritional requirements of individuals who have suboptimal L-methylfolate levels in the erebrospinal fluid, plasma, and/or red blood ells and have MDD, with partiular emphasis as adjuntive support for individuals who are on an antidepressant. 29 While some U.S. payers do not inlude medial foods as a overed benefit, those that do over them as a pharmay benefit in a manner similar to other presription produts. Several studies have demonstrated greater effiay of SSRI/SNRI therapy in MDD when ombined with L-methylfolate, providing a more rapid improvement in symptoms and higher remission rates. 15,16,30 A reent doubleblind, plaebo-ontrolled trial using a sequential parallel group design demonstrated the linial effetiveness of L-methylfolate in patients with SSRI-resistant depression, with a signifiant differene in both response rate and degree of improvement in the L-methylfolate group ompared with plaebo. 31 Another important fator that moderates the effetiveness of treatments for MDD is the likelihood of adherene to therapy. The importane of mediation adherene is mentioned often in the Amerian Psyhiatri Assoiation guidelines, 7 and the National Committee for Quality Assurane (NCQA) Healthare Effetiveness Data and Information Set (HEDIS) Antidepressant Mediation Management (AMM) measures utilize adherene to antidepressant therapy as a key measure. 32 There is evidene that health are resoures and osts are lower in patients who maintain ontinuous therapy with antidepressants ompared with those who disontinue early, 33,34 although not all studies are in agreement, as an administrative laims study found that osts were higher in NCQA guideline-adherent patients in the 6 months following initiation of therapy. 35 There is very little published information regarding the impat of augmentation therapy on adherene to antidepressant mediation or the impat augmentation may have on health are resoure utilization. With the inreased interest in adjunts to SSRI/ SNRI therapy in MDD, in partiular with inreasing SGA use and reent linial trials examining L-methylfolate, we sought to examine the adherene rates, using a modified appliation of the NCQA HEDIS AMM measures, and 6-month health are resoure osts in patients with MDD augmenting SSRI/ SNRI therapy with 1 of these 2 augmentation strategies. We hypothesized that adjuntive therapy with both SGAs and L-methylfolate would result in aute phase and ontinuation phase adherene rates that exeed the 2012 median HEDIS benhmarks and thresholds. We also hypothesized that we would observe differenes in the 6-month health are resoure utilization between the 2 augmentation strategies, prediting that the lower ingredient ost during the study period, as well as the lower side effet burden of L-methylfolate (in ontrast to SGAs), would result in lower overall utilization of health are resoures. This study desribes the demographi, linial, and treatment harateristis of patients with depression who first initiated therapy with an SSRI/SNRI and subsequently were presribed adjuntive therapy with either an SGA or L-methylfolate. Sine our dataset does not inlude validated indies of symptomati outome, our primary interest was in assessing antidepressant adherene outomes using a modified appliation of the NCQA AMM measures, and the seondary objetive was to assess resoure utilization and osts aross the 2 populations. Methods This retrospetive ohort study utilized the Truven Health Analytis MarketSan Commerial Claims and Enounter and the Mediare Supplemental databases, whih apture patientlevel demographi and linial harateristis, medial and pharmay utilization, and expenditures aross a large U.S. population. The study data extrat period was January 1, 2006, to Deember 31, The intake patient identifiation period was January 1, 2007, to Deember 31, 2009, thereby allowing 12-month pre- and post-index periods to apture pre-existing omorbidities, outomes of interest, and exlusionary riteria. Patients were inluded in the study if they had a pharmay laim for an SSRI or SNRI, as well as at least 1 medial laim indiating a linial visit oded for depression (International 78 Journal of Managed Care Pharmay JMCP January 2014 Vol. 20, No. 1

4 TABLE 1 Age at index, years Demographis: Pre- and Post-Propensity Sore Mathing Prior to PS Mathing LM n = 1,351 Mean [SD] [12.91] SGA n = 11,161 Mean [SD] [15.80] LM n = 1,351 Mean [SD] [12.91] PS Mathed Groups SGA n = 4,053 Mean [SD] [13.98] P Value a Gender n % n % n % n % Male , , Female 1, , , , Pre-index omorbidities n % n % n % n % Caner (solid tumor exluding skin other than melanoma) Hematologi malignany Diabetes, any Dyslipidemia Obesity Hypertension Coronary and peripheral artery disease Cerebrovasular disease Heart failure Atrial fibrillation Asthma Chroni obstrutive pulmonary disease/bronhietasis Chroni liver disease and irrhosis Pepti/upper GI uler Inflammatory bowel disease Chroni kidney disease ESRD Dialysis HIV/AIDS Arthriti onditions Fibromyalgia Chroni fatigue Episodi mood disorders (bipolar disorders) Anxiety disorders Alohol or drug abuse , Insomnia disorders a PS mathed groups. ESRD = end stage renal disease; GI = gastrointestinal; HIV/AIDS = human immunodefiieny virus/aquired immunodefiieny syndrome; LM = L-methylfolate; PS = propensity sore; SD = standard deviation; SGA = seond-generation antipsyhoti Classifiation of Diseases, Ninth Revision, Clinial Modifiation [ICD-9-CM] odes 296.2x, 296.3x, 300.4, 309.1, 311) in either the primary or seondary position within the intake period. The patients first SSRI/SNRI laim during the identifiation intake period served as their study index date. Due to the observed differenes in dispensed days supply for the various study agents (SGAs are ommonly dispensed in a 30-day supply and L-methylfolate in a 100-day supply), to serve as a washout period, patients with 1 or more presription laims for an antidepressant of any type or for an SGA in the 90 days prior to the index date, or with 1 or more presription laims for L-methylfolate in the 6 months preeding the index date, were exluded from the analysis. Additional exlusions were pregnany 12 months pre- or post-index; lak of ontinuous health plan enrollment 12 months prior to and following the index date; age < 18 years on the index date; or a primary diagnosis of dementia, psyhoti-related mental disorders, Alzheimer s disease, or Parkinson s disease (ICD-9-CM odes 290.xx, 295.xx, 297.xx, 298.xx, 331.x, 332.x, 345.xx) in the 12-month pre-index period. Finally, patients required augmentation with either an SGA (aripiprazole, lozapine, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) or L-methylfolate within 12 months of the index date, as well as at least 231 days of ontinuous eligibility following the augmentation date. Patients reeiving augmentation with both SGA and L-methylfolate in the 12-month post-index period were exluded. Vol. 20, No. 1 January 2014 JMCP Journal of Managed Care Pharmay 79

5 FIGURE 1 Seletion of Members for the SGA and L-Methylfolate Augmented Comparison Groups Members with at least 1 pharmay laim for an SSRI/SNRI during the intake period January 1, 2007, through Deember 31, 2009 n = 1,103,424 Members with at least 1 medial visit ontaining a primary or seondary diagnosis of depression during the intake period January 1, 2007, through Deember 31, 2009 n = 250,715 Members after exlusions due to pre-index utilization of antidepressants, seond-generation antipsyhotis, L-methylfolate; diagnosis of pregnany, dementia, psyhosis, or Parkinson s; less than age 18 on index date; or with at least 12 months pre-index and 231 days post-index ontinous eligibility n = 220,827 Members with augmentation with SGA or L-methylfolate within 1 year of the index date and within 1.25x days supply of an SSRI/SNRI n = 12,763 Members with at least 231 days postaugmentation eligibility n = 12,512 Premath augmentation with SGA n = 11,161 Premath augmentation with L-methylfolate n = 1,351 Propensity sore mathed augmentation with SGA n = 4,053 Propensity sore mathed augmentation with L-methylfolate n = 1,351 SGA = seond-generation atypial antipsyhoti; SSRI/SNRI = seletive serotonin reuptake inhibitor/seletive norepinephrine reuptake inhibitor. Augmentation with an SGA or L-methylfolate was defined as at least 1 presription laim for either agent, the first laim ourring within 12 months following the index date and within 1.25x the days supply period of an SSRI/SNRI laim (either index date laim or a subsequent laim), supporting that adjuntive therapy overlapped with SSRI/SNRI therapy, while allowing for an adherene rate for the SSRI/SNRI of between 80%-100%. The date of the first laim for the SSRI/SNRI agent used in ombination with an SGA or L-methylfolate is the augmentation date. Propensity sore (PS) mathing was utilized for seletion of the final SGA and L-methylfolate ohorts. A 3:1 (SGA:Lmethylfolate) PS model was adopted using a greedy mathing algorithm and nearest neighbor approah. 36,37 Propensity sores were assigned utilizing ovariates of age, gender, and omorbidities (Table 1) where the harateristis had a differene between the L-methylfolate and SGA groups of P Comorbidities were seleted from those ommonly observed in populations with depression. 38 Additional variables fored into the PS model inluded speifi SSRI/SNRI types and the index SSRI/SNRI dose (as defined by prespeified dose ut points, see Appendix [available in online artile]). A flowhart of the population seletion proess is shown in Figure 1. AMM outome measures were modified from NCQA definitions and inluded (a) aute phase, the perentage of eligible members who remained on antidepressant mediation ontinuously for 3 months as determined by at least 84 days supply of antidepressant drugs during the first 114 days following reeipt of the index antidepressant, and (b) ontinuation phase, the perentage of eligible members who remained on antidepressant mediation ontinuously for 6 months as determined by at least 180 days supply of antidepressants during the first 231 days following reeipt of the augmented antidepressant. It is important to note that the HEDIS measure speifiations start with the first antidepressant presription start date, and 80 Journal of Managed Care Pharmay JMCP January 2014 Vol. 20, No. 1

6 TABLE 2 SSRI/SNRI Utilization Patterns, Propensity Sore Mathed Groups LM, n = 1,351 SGA, n = 4,053 P Value a AD (on augmentation date) n % n % Desvenlafaxine Duloxetine Citalopram Esitalopram Fluoxetine Venlafaxine Fluvoxamine Paroxetine Sertraline Dose hange in AD, index to augmentation No hange 1, , Higher Lower Patients exeeding AD high-dose ut point (on augmentation date) , AD swith, index date to augmentation Time to augmentation date, days, mean [SD] [108.7] 73.5 [96.7] < b aby Pearson hi-square test. By t-test. AD = antidepressant; LM = L-methylfolate; SD = standard deviation; SGA = seond-generation antipsyhoti; SSRI/SNRI = seletive serotonin reuptake inhibitor/seletive norepinephrine reuptake inhibitor. for purposes of this study, the HEDIS measures were applied to the antidepressant augmentation date, sine the outome of interest was adherene assoiated with treatment augmentation. Thus, we refer to these measures as a modified appliation of the HEDIS AMM measures, or mhedis. Mediation possession ratio (MPR) was alulated as the sum of patients days supply/183 days following the SSRI/SNRI augmentation date to provide a ontinuous measure of adherene for the 6-month period postaugmentation date. 39 MPR was apped at 100%, and days supply that extended past the 183-day measurement window was trunated. All-ause and depression-related utilization and osts were assessed for the 6-month period following the augmentation date. Costs inluded plan paid amount without member ost share and were adjusted to 2010 dollars using the medial Consumer Prie Index. Total utilization and ost estimates inluded all medial and presription laims without regard to diagnosis or drug type, while depression-related utilization and osts inluded only those medial laims with a primary or seondary diagnosis of depression and pharmay laims for SSRI/SNRI antidepressants, SGAs, and L-methylfolate. Costs were further ategorized as inpatient, emergeny department, outpatient, or presription omponents based on the soure of the laim (medial or pharmay). Comparisons between the PS-mathed SGA and L-methylfolate ohorts were made using desriptive statistis. Differenes in the binary and ategorial measures suh as omorbidities, type of antidepressant, and AMM measures between the groups were evaluated using hi-square tests, while the differenes in ontinuous measures inluding time to augmentation, MPR, resoure use, and ost were evaluated using t-tests. For ost outomes, a generalized linear model with log link and gamma distribution was used as a sensitivity analysis to test the ost results. Results Of patients reeiving SSRI/SNRI therapy, 11,161 reeived SGA, and 1,351 reeived L-methylfolate augmentation within 12 months of the index date. The PS math of 3:1 (SGA to L-methylfolate) provided 4,053 SGA and 1,351 L-methylfolateaugmented patients for analysis in the final study ohort. Table 1 presents the pre- and postmath study group harateristis. PS mathing eliminated signifiant age, gender, and omorbidity differenes (with the exeption of hroni obstrutive pulmonary disease/bronhietasis) between the ohorts and produed omparison groups that were equivalent with respet to the type and dose of the SSRI/SNRI being augmented (Table 2). The most ommonly augmented antidepressants among the SGA and L-methylfolate groups, respetively, were the following: duloxetine (23%-24%), esitalopram (23%), and venlafaxine (15%-14%). In the SGA-augmented group, 37.1% of the patients exeeded the high-ut point for SSRI/SNRI therapy, while 34.5% of the L-methylfolate-augmented group exeeded the high-ut point for SSRI/SNRI therapy (Table 2). An equivalent perentage of patients in both groups swithed to a different antidepressant from the index date to augmentation, and there were equivalent perentages in both groups that either Vol. 20, No. 1 January 2014 JMCP Journal of Managed Care Pharmay 81

7 TABLE 3 Mediation Adherene Outomes: Propensity Sore Mathed Groups LM, n = 1,351 SGA, n = 4,053 n % n % P Value a mhedis Met aute phase AMM 1, , < Met ontinuation phase AMM , < month AD therapy MPR Mean [SD] Mean [SD] [0.2501] [0.2980] < a By Pearson hi-square test. AD = antidepressant; AMM = Antidepressant Mediation Management; LM = L-methylfolate; mhedis = Healthare Effetiveness Data and Information Set (modified appliation); MPR = mediation possession ratio; SD = standard deviation; SGA = seond-generation antipsyhoti. inreased or dereased the dose of SSRI/SNRI from index date to augmentation (Table 2). Small differenes (5% or less in absolute terms) were observed in the utilization of other drug therapy in the preaugmentation period when omparing the SGA and L-methylfolate ohorts, inluding (SGA, L-methylfolate, respetively): bupropion (10.0% vs. 13.6%, P = ); stimulants (8.3% vs. 13.3%, P < ); thyroid supplementation (9.7% vs. 13.3%, P = ); estrogen and oral ontraeptives (15.1% vs. 18.4%, P = ); nonsteroidal anti-inflammatory drugs, inluding COX-2 (16.0% vs. 20.4%, P = ); opioids (26.8% vs. 32.8%, P < ); and beta blokers (7.8% vs. 10.4%, P = ). The most ommon adjuntive SGAs and their mean daily doses were as follows: quetiapine 39.1% (109.1 milligrams per day [mg/d]), aripiprazole 29.5% (6.4 mg/d), and risperidone 13.7% (1.14 mg/d). The SGA-augmented group had a mean [SD] time to augmentation of 73.5 [96.7] days; 52.0% augmented in < 30 days, 32% in days, and 15.9% in days. The vast majority of patients (96.5%) presribed adjuntive L-methylfolate reeived a dose of 7.5 mg/day. The mean [SD] time to augmentation for the L-methylfolate group was [108.7] days, with 36.9% augmenting in < 30 days, 37.8% in days, and 25.2% in days. There was a signifiant differene between the time to augmentation for SGA ompared with L-methylfolate (P < 0.001), indiating that L-methylfolate was typially used later in a treatment episode than SGAs. Evaluation of the mhedis AMM measures following augmentation found that 68.7% of the SGA-augmented ohort and 78.7% of the L-methylfolate ohort met the aute phase measures (P < 0.001). For the mhedis ontinuation phase measures, 50.3% of the SGA-augmented ohort and 62.1% of the L-methylfolate ohort met the measures (P < 0.001). In addition, the mean 6-month antidepressant therapy MPR was signifiantly higher in the L-methylfolate group ompared with the SGA-augmented group (Table 3). Cost and utilization data are presented in Table 4. Allause 6-month utilization ount, inluding mean inpatient, emergeny department, and outpatient visits, were higher in the SGA-augmented ohort ompared with those augmented with L-methylfolate. All-ause 6-month mean presription ount was higher in the L-methylfolate ohort ompared with the SGA-augmented ohort. Depression-related utilization followed the same pattern, with the exeption that 6-month depression-related presription utilization was equivalent between the 2 groups. Mean all-ause 6-month ost in the SGA-augmented group was approximately $1,100 higher than the L-methylfolate group ($8,499 vs. $7,372, P = 0.005). The ost differene was refleted in higher 6-month mean osts for inpatient, emergeny department, and outpatient visits, as well as presription osts. Depression-related osts followed the same patterns, with 6-month depression-related osts in the SGA-augmented group being approximately $1,000 higher than in the L-methylfolate ohort, refleting higher osts aross all ategories ($2,689 vs. $1,613, P < 0.001). Table 4 also reports signifiant differenes in the omponent osts for outpatient osts and pharmay osts for both all-ause and depressionrelated osts. Robust statistial differenes within the inpatient and emergeny department omponent osts ould not be established due to the exess zero response variables within these omponents. Multivariate adjustment is ommonly applied in these types of studies. In this study, a generalized linear model with log link and gamma distribution was onstruted to test the ost results. As the study group mathing resulted in losely mathed populations, very few variables entered the model and had no influene on the results, with the exeption of dereasing the P values for some of the ost differenes. We therefore report only the more onservative t-test for the ost outomes. Disussion The use of adjuntive antidepressant therapies has grown dramatially over the past deade. The prinipal objetive of this study was to ompare the impat on SSRI/SNRI adherene and health are utilization between 2 adjuntive strategies, SGA and L-methylfolate, following the initiation of antidepressant monotherapy. In this large administrative laims database, we found that MDD patients were 8 times more likely to reeive adjuntive therapy within 1 year with 1 of the SGAs than they were to reeive L-methylfolate. We also observed that a large proportion of patients in both groups were augmented within a short time (< 30 days) of initiating antidepressant therapy, suggesting that in pratie, liniians are augmenting therapy before establishing the effetiveness of antidepressant monotherapy, as is reommended in pratie guidelines suh as those published by the Amerian Psyhiatri Assoiation. Thus, results from this study indiate that using ombination therapy as an initial or early strategy in the treatment of depression 82 Journal of Managed Care Pharmay JMCP January 2014 Vol. 20, No. 1

8 TABLE 4 All-Cause Costs a and Utilization Costs and Utilization Outomes: Propensity Sore Mathed Groups LM, n = 1,351 SGA, n = 4,053 Mean [SD] Median Mean [SD] Median P Value b Total osts 7, [12,403.60] 4, , [13,585.01] 4, Inpatient omponent 1, [9,635.56] 0 2, [10,512.57] 0 Outpatient omponent 3, [5,558.66] 1, , [5,853.52] 1, ED omponent [680.03] [917.91] 0 Pharmay omponent 2, [2,823.33] 1, , [2,673.62] 1, Visit ounts Inpatient 0.63 [2.94] [5.85] 0 ED 0.16 [1.42] [2.28] 0 Outpatient [18.12] [22.15] 15 < Depression-Related Costs and Utilization Total osts 1, [2,314.81] 1, , [4,201.08] 1, < Inpatient omponent [1,123.90] [2,618.09] 0 Outpatient omponent [1,230.62] [2,214.15] < ED omponent 8.80 [121.79] [218.77] 0 Pharmay omponent [816.64] , [1,412.58] 1,053 < Visit ounts Inpatient 0.22 [1.43] [4.33] 0 ED [0.487] [1.107] 0 Outpatient 6.03 [10.10] [12.16] a In 2010 USD. b P values are based on t-tests with log transformed response variables, whih takes the form of log [x i + α] where x i represents the observed value for the i th subjet and α is a small numerial onstant that auses the log transformed value to be nonmissing if x i is zero. Data ontains exess zero response variables and thus are unable to provide a robust log transformed t-test ED = emergeny department; LM = L-methylfolate; SD = standard deviation; SGA = seond-generation antipsyhoti; USD = U.S. dollars. may be ommon in the real-world setting. After equating the groups on relevant demographi and linial measures using a propensity mathing strategy, it was still observed that the patients who were presribed L-methylfolate were more likely to have reeived other adjuntive therapies suh as thyroid hormone or bupropion. This may explain why L-methylfolate was found to be presribed later in treatment episodes than the SGAs inluded in this report. Despite these differenes, we found that patients who reeived adjuntive therapy were above the 2012 median HEDIS benhmarks and thresholds (66% for aute phase and 53% for ontinuation phase) 40 for adherene to therapy (SGA 69% and 50%, L-methylfolate 79% and 62%, respetively) when measured at the time of augmentation. With respet to outomes, the group that reeived L-methylfolate showed greater adherene to therapy using both the binary mhedis AMM as well as the ontinuous MPR measures when ompared with the group that reeived adjuntive therapy, whih was predominately quetiapine, aripiprazole, and risperidone. As the study groups were well mathed based on over 20 onfounders onsidered, the auses for adherene differenes between the groups is not likely explained by some of the patient-level reasons for nonadherene with mediation in patients with depression, suh as younger age, substane abuse, ardiovasular morbidity, or use of first-generation agents. 41 The groups were also well mathed on type and dose of SSRI/SNRI, so the differenes in adherene are likely aused by the differene in augmentation agents, whih inlude the ost of SGAs at the time of the study and the prevalene and type of adverse events. There is a lak of literature regarding the effet of augmentation on SSRI/SNRI adherene, so these are the first results we are aware of that report on this phenomena. We also observed that patients reeiving adjuntive L-methylfolate showed lower overall and depression-speifi ost of treatment than did the group reeiving an adjuntive SGA. The differene in ost of treatment was not simply attributable to the higher overall presription osts in the SGA group ompared with the L-methylfolate group, sine the medial ost ategories were also found to be higher in the SGA group for all-ause as well as depression-related osts. The adverse effets of SGAs, suh as sedation, sexual dysfuntion, gluose abnormalities, and weight gain, whih are not assoiated with L-methylfolate, may have ontributed to the additional medial utilization in the SGA group. It is noteworthy that the majority of patients who reeived L-methylfolate utilized 7.5 mg/day, a dose that has not been shown to have signifiant adjuntive effiay in randomized ontrolled trials. Sine a reent trial has shown that 15 mg/ day of L-methylfolate for adjuntive therapy of diffiult-to-treat MDD is effetive, 31 it is possible that the findings of the urrent analysis underestimate the potential utility of this strategy. For Vol. 20, No. 1 January 2014 JMCP Journal of Managed Care Pharmay 83

9 omparison, the doses of aripiprazole, risperidone, and quetiapine were also used at doses muh lower than the usual daily dosage of these ompounds for antipsyhoti therapy. 42 Limitations Several limitations to this study should be noted. First, due to the observational design of the study, assoiations an be identified, but ausality annot be established. The PS mathing design ontrols for the measured onfounders in the 2 study groups, but unmeasured differenes between the groups likely remained. In partiular, this study was unable to ontrol for disease severity or duration, sine suh data are unavailable in the database. The SGA group was augmented signifiantly earlier in the post-index period, an effet that may point to unmeasured onfounders, and may have ontributed to the higher pharmay omponent osts seen in the SGA-augmented group. There were unexplained omorbidity differenes between the study groups before mathing, with the SGA group generally showing a higher level of omorbidities, whih may indiate a treatment seletion bias between SGA and L-methylfolate. This may in turn suggest these results may be limited to populations that are similar to the postmathed groups, whih following PS mathing was quite similar in measured omorbidities. As is true of all retrospetive studies where ohort identifiation is based on the use of ICD-9-CM diagnosti oding, we have to onsider the possibility that there was inauray in the oding, but we have no reason to believe there was any systemati bias in diagnosti oding between the study groups. The generalizability of these results is limited to a ommerially insured population and may not be appliable to other populations suh as the Mediaid or traditional fee-for-servie Mediare populations. We also note that many of the SGAs in this study were available only as branded produts during the study period, and while the differenes in pharmay osts between the SGA and L-methylfolate groups may be mitigated as generi versions of SGAs replae the branded versions, the differenes in side effets and metaboli effets between SGAs and L-methylfolate will remain. The individual antipsyhoti agents may have resulted in different outomes for eah agent, but our study was not designed to examine individual agents, whih may be of interest for future study. Finally, the use of speialty psyhiatri are was not taken into aount, sine no information was available as to whether any patient was enrolled in a health plan with a psyhiatri arve-out. Conlusions In this study, patients reeiving augmentation of antidepressant therapy with L-methylfolate ompared with SGA for depression demonstrated lower health are utilization, lower all-ause osts, and lower depression-related osts. Further, patient populations using augmentation therapy with L-methylfolate had signifiantly higher mhedis sores than the SGA group in both aute and ontinuing phase AMM measures. While further study of the effet of augmentation therapy in MDD is warranted, a benefit design that inludes L-methylfolate should be onsidered among the options available as augmentation therapy to SSRI/SNRI treatment in depression, given the neurohemial basis for ativity, reent trials demonstrating linial effetiveness, and the relatively low ost and adverse event profile. Authors ROLIN L. WADE, RPh, MS, is Prinipal, Health Eonomis and Outomes Researh, Real World Evidene Solutions, IMS Health, Parsippany, New Jersey; SYLVIA L. KINDERMANN, MPH, is Sientist, and QINGJIANG HOU, MS, is Sientist/Biostatistiian, Cerner Researh, Culver City, California; and MICHAEL E. THASE, MD, is Professor of Psyhiatry, Perelman Shool of Mediine, University of Pennsylvania, Philadelphia, Pennsylvania. AUTHOR CORRESPONDENCE: Rolin Wade, RPh, MS, IMS Health, 11 Waterfront Blvd., Parsippany, NJ Tel.: ; rwade@imshealth.om. DISCLOSURES The work presented in this manusript was supported by Nestlé Health Siene-Pamlab, In. Kindermann and Hou are employees of Cerner Researh, who ontrated with the sponsor to ondut the projet. At the time of this study, Wade was an employee of Cerner Researh. Thase has been a member of advisory boards and has onsulted for Pamlab, Astra Zenea, Bristol-Myers Squibb, and Eli Lilly and Company. Study onept and design were ontributed by Wade, Kindermann, and Thase, with assistane from Hou. Hou was primarily responsible for data olletion, with assistane from Wade. Wade, Kindermann, and Thase were responsible for data interpretation, with assistane from Hou. Kindermann, Wade, and Thase wrote the manusript, with assistane from Hou, and Lisa Kaspin was primarily responsible for revisions along with Wade and with assistane from Kindermann, Hou, and Thase. ACKNOWLEDGMENTS The authors would like to aknowledge Lisa Kaspin, PhD, for her assistane in editing the final manusript. Referenes 1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Repliation (NCS-R). JAMA. 2003;289(23): Greenberg PE, Kessler RC, Birnbaum HG, et al. The eonomi burden of depression in the United States: how did it hange between 1990 and 2000? J Clin Psyhiatry. 2003;64(12): Greden F. The burden of disease for treatment-resistant depression. J Clin Psyhiatry. 2001; 62(Suppl 16): Rush AJ, Trivedi MH, Wisniewski SR, et al. Aute and longer-term outomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psyhiatry. 2006; 163(11): Journal of Managed Care Pharmay JMCP January 2014 Vol. 20, No. 1

10 5. Alexopoulos GS. Pharmaotherapy for late-life depression. J Clin Psyhiatry. 2011; 72(1):e Stahl SM. Combining antidepressant therapies from the initiation of treatment: a paradigm shift for major depression. J Clin Psyhiatry. 2009; 70(11): Amerian Psyhiatri Assoiation. Pratie Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. Arlington, VA: Amerian Psyhiatri Assoiation; Cowen PJ. Revisiting pharmaologial management of treatment-resistant depression. Advanes in Psyhiatri Treatment. 2005;11: Shekelle P, Maglione M, Bagley S, et al. Comparative effetiveness of offlabel use of atypial antipsyhotis. Comparative Effetiveness Review No. 6. (Prepared by the Southern California/RAND Evidene-based Pratie Center under Contrat No ) Rokville, MD: Ageny for Healthare Researh and Quality. January Available at: gov/books/nbk43235/pdf/toc.pdf. Aessed November 5, Maglione M, Ruelaz Maher A, Hu J, et al. Off-label use of atypial antipsyhotis: an update. Comparative Effetiveness Review No. 43. (Prepared by the Southern California Evidene-based Pratie Center under Contrat No. HHSA ) Rokville, MD: Ageny for Healthare Researh and Quality. September Available at: LabelAntipsyhotis_ pdf. Aessed November 5, Nelson JC, Papakostas GI. Atypial antipsyhoti augmentation in major depressive disorder: a meta-analysis of plaebo-ontrolled randomized trials. Am J Psyhiatry. 2009;166(9): Wright BM, Eiland EH, 3rd, Lorenz R. Augmentation with atypial antipsyhotis for depression: a review of evidene-based support from the medial literature. Pharmaotherapy. 2013; 33(3): Newomer JW. Seond-generation (atypial) antipsyhotis and metaboli effets: a omprehensive literature review. CNS Drugs. 2005;19 (Suppl 1):S1-S Fava M, Mishoulon D. Folate in depression: effiay, safety, differenes in formulations, and linial issues. J Clin Psyhiatry. 2009;70(Suppl 5):S12-S Godfrey PS, Toone BK, Carney MW, et al. Enhanement of reovery from psyhiatri illness by methylfolate. Lanet. 1990;336(8712): Proter A. Enhanement of reovery from psyhiatri illness by methylfolate. Br J Psyhiatry. 1991;159: Stahl SM. Novel therapeutis for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spetr. 2007;12(10): Westenberg HG. Pharmaology of antidepressants: seletivity or multipliity? J Clin Psyhiatry. 1999;60(Suppl 17):S4-S Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk fator for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007;61(7): Bottiglieri T. Homoysteine and folate metabolism in depression. Prog Neuropsyhopharmaol Biol Psyhiatry. 2005;29(7): de Bree A, Vershuren WM, Bjorke-Monsen AL, et al. Effet of the methylenetetrahydrofolate redutase 677C-->T mutation on the relations among folate intake and plasma folate and homoysteine onentrations in a general population sample. Am J Clin Nutr. 2003;77(3): Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Shouten EG. MTHFR 677C-->T polymorphism and risk of oronary heart disease: a meta-analysis. JAMA. 2002;288(16): Alpert JE, Mishoulon D, Nierenberg AA, Fava M. Nutrition and depression: fous on folate. Nutrition. 2000;16(7-8): Nelson JC. The evolving story of folate in depression and the therapeuti potential of l-methylfolate. Am J Psyhiatry. 2012;169(12): Papakostas GI, Petersen T, Mishoulon D, et al. Serum folate, vitamin B12, and homoysteine in major depressive disorder, Part 1: preditors of linial response in fluoxetine-resistant depression. J Clin Psyhiatry. 2004;65(8): Papakostas GI, Petersen T, Lebowitz BD, et al. The relationship between serum folate, vitamin B12, and homoysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsyhopharmaol. 2005;8(4): Alpert M, Silva RR, Pouget ER. Predition of treatment response in geriatri depression from baseline folate level: interation with an SSRI or a triyli antidepressant. J Clin Psyhopharmaol. 2003;23(3): Coppen A, Bailey J. Enhanement of the antidepressant ation of fluoxetine by foli aid: a randomised, plaebo ontrolled trial. J Affet Disord. 2000;60(2): Deplin pakage insert. Pamlab LLC. Available at: om/request-pakage-insert/. Aessed Deember 3, Fava M, Rush AJ. Current status of augmentation and ombination treatments for major depressive disorder: a literature review and a proposal for a novel approah to improve pratie. Psyhother Psyhosom. 2006;75(3): Papakostas GI, Shelton RC, Zajeka JM, et al. L-Methylfolate as adjuntive trherapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psyhiatry. 2012;169(12): National Committee for Quality Assurane. The state of health are quality Available at: Aessed November 5, Eaddy MT, Druss BG, Sarnes MW, Regan TS, Frankum LE. Relationship of total health are harges to seletive serotonin reuptake inhibitor utilization patterns inluding the length of antidepressant therapy results from a managed are administrative laims database. J Manag Care Pharm. 2005;11(2): Available at: aspx?id= Thompson D, Bueshing D, Gregor KJ, Oster G. Patterns of antidepressant use and their relation to osts of are. Am J Manag Care. 1996;2: Robinson RL, Long SR, Chang S, et al. Higher osts and therapeuti fators assoiated with adherene to NCQA HEDIS antidepressant mediation management measures: analysis of administrative laims. J Manag Care Pharm. 2006;12(1): Available at: DownloadAsset.aspx?id= Rosenbaum PR, Rubin DB. The entral role of the propensity sore in observational studies for ausal effets. Biometrika. 1983;70(1): Rosenbaum PR, Rubin DB. Construting a ontrol group using multivatiate mathed sampling methods that inorporate the propensity sore. The Amerian Statiian. 1985;39(1): Caughey GE, Roughead EE, Shakib S, MDermott RA, Vitry AI, Gilbert AL. Comorbidity of hroni disease and potential treatment onflits in older people dispensed antidepressants. Age Ageing. 2010;39(4): Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherene in pharmay administrative databases: a proposal for standard definitions and preferred measures. Ann Pharmaother. 2006;40(7-8): National Committee for Quality Assurane. Benhmarks and thresholds: 2012 areditation. August 1, Available at: tabid/422/default.aspx. Aessed November 5, Akinigil A, Bowblis JR, Levin C, Walkup JT, Jan S, Crystal S. Adherene to antidepressant treatment among privately insured patients diagnosed with depression. Med Care. 2007;45(4): Muenh J, Hamer AM. Adverse effets of antipsyhoti mediations. Am Fam Physiian. 2010;81(5): Vol. 20, No. 1 January 2014 JMCP Journal of Managed Care Pharmay 85