The Texas Medication Algorithm Project: Clinical Results for Schizophrenia

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1 The Texas Medicatin Algrithm Prject: Clinical Results fr Schizphrenia by Alexander L. Miller, M. Lynn Crismn, A. Jhn Rush, Jhn Chiles, T. Michael Kashner, Marcia Tprac, Thmas Carmdy, Melanie Biggs, Kathy ShreS'Wilsn, Judith Chiles, Brad Witte, Christine BW'Thmas, Dawn I. Velligan, Madhukar Trivedi, Trisha Suppes, and Steven Shrt Abstract In the Texas Medicatin Algrithm Prject (TMAP), patients were given algrithm-guided treatment () r treatment as usual (). The interventin included a clinical crdinatr t assist the physicians and administer a patient and family educatin prgram. The primary cmparisn in the schizphrenia mdule f TMAP was between patients seen in clinics in which was used (n = 165) and patients seen in clinics in which n algrithms were used (n = 144). A third grup f patients, seen in clinics using an algrithm fr biplar r majr depressive disrder but nt fr schizphrenia, was als studied (n = 156). The grup had mdestly greater imprvement in symptms (Brief Psychiatric Rating Scale) during the first quarter f treatment The grup caught up by the end f 12 mnths. Cgnitive functins were mre imprved in than in at 3 mnths, and this difference was greater at 9 mnths (the final cgnitive assessment). In secndary cmparisns f with the secnd grup, the greater imprvement in cgnitive functining was again nted, but the initial symptm difference was nt significant Keywrds: Algrithm, guideline, medicatin, schizphrenia, symptms. Schizphrenia Bulletin, 30(3): ,2004. A number f studies have fund that the use f medicatins in utpatients with schizphrenia frequently des nt cnfrm t expert recmmendatins (Lehman and Steinwachs 1998; Buchanan et al. 2002) and is ften subptimal r prly dcumented (Yung et al. 1998; Cradck et al. 2001). These findings have given added impetus t effrts t develp medicatin guidelines and algrithms, based n the premise that they will reduce variability in medicatin practices, imprve quality f care, and lead t better patient utcmes. Cnsiderable evidence, hwever, indicates that, in the absence f specific measures t prmte physician adherence t the guideline r algrithm, actual practice behavirs are little affected by the adptin f guidelines r algrithms by behaviral health care rganizatins (see literature reviews in Gilbert et al. 1998; Rush et al. 1999; Bauer 2002). The Texas Medicatin Algrithm Prject (TMAP) examined the effects f using medicatin algrithms fr schizphrenia, biplar disrder, and majr depressive disrder under cnditins in which implementatin f the algrithms was aided by prvisin f a clinical crdinatr (CC) t wrk with physicians and t administer an educatinal prgram t patients and their families. The ratinale and general utline f the prject have been described previusly (Gilbert et al. 1998; Rush et al. 1999). The results presented here are the clinical utcmes fr patients with schizphrenia ver their first 12 mnths f treatment. As detailed belw (Methds) and elsewhere (Rush et al. 2003), TMAP cnsisted f a package f interventins that included treatment manuals, CCs, expert cnsultatins thrugh cnference calls and site visits, and an extensive multistep patient and family educatin prgram (Tprac et al. 2000). The principal analyses are f the effects f this package f interventins cmpared with treatment as usual (). The duratin f patient enrllment was 13 mnths. Fllwing enrllment, patients participated in the study fr 1 t 2 years, depending n when they enrlled. Because all patients ptentially had at least 1 year f participatin, the analyses fcus n the clinical utcmes ver the first 12 mnths fllwing study entry. In keeping with usual clinical practice, the main fcus f algrithm-guided treatment () was n Send reprint requests t Dr. A.L. Miller, Department f Psychiatry, MS 7792, University f Texas Health Science Center at San Antini, 7703 Flyd Curl Drive, San Antni, TX ; millera@uthscsa.edu. 627

2 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. symptm imprvement. Fr schizphrenia, bth psitive and negative symptms were clinically mnitred, because imprvement in these symptms with antipsychtic treatment has been mst extensively evaluated (Miller et al. 1999). Because impairments in cgnitive functining have been shwn t be very strngly related t pr adaptatin and rle functining in schizphrenia (Green 1996; Velligan et al. 1997), we als included a brief battery f cgnitive functin tests. Participating clinicians were given specific guidance and prmpting with regard t medicatin use and assessment f symptms and side effects at each clinic visit. They were, hwever, free t exercise their wn clinical judgment and t deviate frm algrithm recmmendatins if they felt that this was clinically indicated. The results presented here, therefre, reflect the effects f as it was actually implemented. The medicatin algrithms develped fr the treatment f schizphrenia and related disrders have been detailed elsewhere (Miller et al. 1999). They were based in large part n the American Psychiatric Assciatin guidelines (APA 1997) and the first versin f the Expert Cnsensus Guidelines (Frances et al. 1996) fr schizphrenia. The antipsychtic algrithm was subsequently mdified t incrprate recmmendatins fr use f lanzapine and quetiapine when these antipsychtics were apprved by the U.S. Fd and Drug Administratin. Because evidence was, and still is, lacking n respnse rates t trials f subsequent atypical antipsychtics after ne has failed, the antipsychtic algrithm gave clinicians the ptin f trying each agent r skipping ahead t clzapine, depending n clinical judgment. Methds Study Design. This multisite trial cmpared with fr schizphrenia and schizaffective disrder (excluding biplar type). Physicians in fur clinics used, while physicians in eight matched clinics used. Fur clinics used n algrithms fr any disrder and had n augmentatin f their clinical staff. The ther fur clinics used algrithms and had CCs t assist in administering the interventin packages fr depressin r biplar disrder but nt schizphrenia (-AC, treatment as usual in an algrithm clinic). Study assignment t r was by clinic rather than by physician r patient. Study assignment (e.g., randmizatin) by patient rather than by clinic wuld have required physicians t fllw with sme patients but nt thers with the same diagnsis. Assignment by physician wuld have required sme physicians in the same clinic t use while thers wuld deliver. This methd wuld require that physicians avid sharing experiences with ne anther and nt cver fr each ther t avid cntaminating with ("water cler" effect). A limited number f clinics were available fr study participatin, and t reflect the gegraphic and demgraphic diversity f Texas, the clinics were chsen t be diverse by design. Given these factrs, study cell assignments by clinic were matched rather than randmized. When pssible, clinics were matched in rder t have an clinic and a clinic fr the same disrder within the same lcal mental health authrity. This was ften nt pssible fr rural authrities with limited numbers f clinics. In such cases, we attempted t match an clinic with a similar-type clinic (e.g., rural with rural ). Finally, we tried t match a given clinic with a clinic that was similar in ethnic cmpsitin. The primary test f the effects f versus was the cmparisn between the grup and the grup seen in clinics in which n algrithms were being used. The -AC grup prvides an indicatin f the pssible impact f using an algrithm fr ne disrder n fr anther disrder. The study was cnducted in accrdance with internatinal guidelines fr gd clinical practice and the Declaratin f Helsinki. It was apprved by the Institutinal Review Bards f the University f Texas Suthwestern Medical Center at Dallas and the University f Texas at Austin. After entry int the study, symptms, functin, quality f life, side effect severity and burden, and utilizatin f health care and ther public and private services were evaluated at baseline and quarterly fr at least a 12-mnth perid in all available participants. Patient participants gave written infrmed cnsent fr the research ratings and fr access t their medical and administrative recrds. Fr, patient cnsent was btained at the time f the decisin t change antipsychtic medicatin. The medicatin decisins were nt cntingent upn agreement t participate in the study. Ptential patients were identified as described belw. Individuals meeting eligibility criteria were apprached by a research crdinatr t btain written infrmed cnsent t the research prcedures. Clinic persnnel were nt asked t give infrmed cnsent. All were vluntary participants in the prject. Interventin. The primary gal f the interventin was t ptimize pharmactherapy and imprve clinical utcmes. Multiple tls were prvided fr the physicians and the treatment team t enhance their adherence t the algrithm. The primary aim f pharma- 628

3 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 ctherapy was remissin f symptms. Each physician implemented the interventin in clse cllabratin with a CC, wh assisted the physician by btaining symptm and side effect measures at each visit, by prviding patient and family educatin, and by reminding the physicians f the guidelines. The CCs were mental health prfessinals (nurses, scial wrkers, psychlgists, cunselrs) with at least 2 years f experience. They and the physicians received 2 days f training n the interventins at the utset f the prject, and nging cnsultatins frm investigatrs (A.L.M., J.C, and M.L.C.) and the crdinatr (Ju.C). Additinally, the CCs were trained n the brief rating scales f psitive and negative symptms initially, with quarterly retraining n standardized tapes. The antipsychtic algrithm and algrithms fr side effects and assciated symptms have been described elsewhere (Miller et al. 1999). Figure 1 shws the antipsychtic algrithm used during the study. A clinical prcedures manual was the basis fr training and nging guidance f the physicians and CCs. The manual cntained specific recmmendatins fr mnitring symptms and side effect burden t infrm medicatin decisins at clinic visits. Critical decisin pints were described in the manual fr each medicatin step in rder t define recmmended minimum and maximum trial lengths. The manuals included recmmended dse ranges and criteria fr adequacy f treatment f psitive and negative symptms. Psitive and negative symptms were assessed at each clinic visit in with brief anchred rating scales using items taken frm the Brief Psychiatric Rating Scale (BPRS; Ventura et al. 1993) r derived frm the Scale fr the Assessment f Negative Symptms (SANS; Andreasen 1982) and the Negative Symptm Assessment (Alphs et al. 1989). The respnse criteria are discussed in Miller et al. (1999). The gal was t achieve a virtual absence f psitive symptms and, n average, n greater than mild negative symptms. If these gals were nt achieved after a medicatin trial f reasnable dse and duratin, a medicatin change, based n the sequence in the algrithm, was recmmended. In additin, patients were evaluated fr verall side effect burden, cre symptm severity, assciated symptm severity, and level f functining by the CC and physician befre a decisin was made t maintain r change the medicatin regimen at each clinic visit. Each patient als received a multistep educatin prgram that prvided infrmatin abut the disease and its treatment (Tprac et al. 2000). There was n cmparable prgram fr patients. The patient educatin package encuraged patient participatin in treatment decisins and treatment adherence. patients had an average f 4.9 visits (range 0-18) at which they received elements f the psycheducatin prgram. The basic educatinal materials were usually cvered in the first three t six visits. Subsequently, patients had the ptin f participating in educatinal grup discussins abut their illness and its treatment. Patient Selectin. Male and female utpatients 18 years r lder with a clinical diagnsis, by their treating physicians, f schizphrenia r schizaffective disrder (unless specifically f the biplar subtype) were included in the study in either the grup r the grup based n their clinic assignments. Patients with clinical diagnses f schizaffective disrder, biplar type, were excluded, based n the likelihd that their treatment wuld include lng-term use f md stabilizers and be mre like that recmmended in the biplar algrithm (Suppesetal. 2001). Patients entered the grup if their treating physician decided that an antipsychtic medicatin change was warranted because f lack f efficacy r because f side effects. Initially, patients were t be selected fr inclusin in the same manner as patients; that is, thse patients with a diagnsis f schizphrenia wh had a change in antipsychtic medicatin by their physician were eligible fr enrllment in the study. Hwever, it sn became apparent that it was uncmmn fr patients t have a change in their antipsychtic medicatin and that an additinal methd wuld need t be used t define study eligibility if we were t meet enrllment gals fr the grup. Therefre, patients were als recruited in an additinal manner. If a patient's mst recent rutine clinic 24-item Brief Psychiatric Rating Scale (BPRS 24 ) scre was greater than the median fr that mental health center, then the patient was eligible fr screening fr the study. An alphabetical list f patients meeting this criterin during the prir 6 mnths was given t the research crdinatrs, wh then cntacted patients n the list, starting with thse seen mre recently. If the patient was willing t be evaluated fr the study, the research crdinatr did a screening BPRS 24 - If the patient's scre n this BPRS was higher than ne standard deviatin (SD) belw the mean fr the grup, then the patient was eligible fr entry int the grup. Only thse individuals meeting these criteria and prviding written infrmed cnsent were entered int the grup. There were minimal exclusin criteria fr study entry. Patients were excluded if they were unable r unwilling t give vluntary infrmed cnsent t the research evaluatins, r if they had grss intxicatin due t substance abuse at the initial visit. They were nt, hwever, excluded n the basis f a histry f substance abuse r dependence. 629

4 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. Figure 1. Antipsychtic algrithm L Stage 1 W Histry f Typical Antipsychtic Failure Olanzapine r Quetlapine r Rispertdne (Any stagefs) can be skipped depending n the clinical picture.) Acute Exacerbatin First presentatin r nt nn-respnder t lanzapine, quetlapine r rispertdne Histry f Typical Antipsychtic Failure Olanzapine r Queti spine r Rlsperidne Stage 2 Use Anther Nn-respnse t ne Halperidl Decanate r Flupbenazine Decanate Nncmpliance Nncmpliance 1 Use Anther Nn-respnse t ne Nn-respnder t One L Stage 3 Nn-respnder t Tw Use the Third Nn-respnse t tw Nn-respnse t three Use the Third Nn-respnse Nn-respnse Use the Third Nn-respnse t tw Nn-respnse t three Stage 4 Typical Antipsychtic Y Nn-respnse 1 Stage 5 Ctzapine Stage 5a Partial w Respnse Cizapine + Augmenting Agent (Typical r atypical antipsychtic, md stabilizer, ECT. antidepressant) Nn-respnse Nn-respnse r cizapine refusal Stages Atypical + Typical Cmbinatin f Atypicats, Typical r Atypical + ECT Nte. ECT " electrcnvulslve therapy. 630

5 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 Study Prcedures. Study participants prvided baseline demgraphic and medical histry. They underwent a cmplete evaluatin at the baseline visit with a research crdinatr. The evaluatin battery included symptm testing with the 24-item BPRS (Ventura et al. 1993), the Scale fr the Assessment f Negative Symptms (SANS; Andreasen 1982), and the Calgary Depressin Scale (Addingtn et al. 1993); functin testing with the Shrt Frm Health Survey (SF-12) mental and physical (Ware et al. 1996); and cgnitive testing with Trails A and B, Verbal Fluency (categries and letters), and the Hpkins Verbal Learning Test (Reitan 1955, 1958; Lezak 1995; Benedict et al. 1998; Cadle et al. 2002). These assessments were repeated quarterly fr at least 12 mnths, except fr the cgnitive tests, which were administered at baseline, 3 mnths, and 9 mnths. Subjects were als asked abut the burden f side effects frm medicatin during the past mnth that "bthered r interfered with daily functining." Respndents were cnsidered t have n significant side effects if they reprted "n side effects" r "nly mild side effects, nt really significant," and t have significant side effects when they reprted that side effects "bthered me, but culd tlerate them," "really bthered me, I either need t change my medicatin r take smething fr the side effects," r "were s severe I had t be hspitalized." Demgraphic infrmatin was btained frm a patient questinnaire administered during the face-t-face baseline interview. Alchl use and drug use were assessed quarterly using the Drug Abuse Screening Test (Skinner 1982) (> 5 indicates drug abuse) and the Michigan Alchlism Screening Test (Selzer 1971) (S 5 indicates alchl abuse). The Patient Perceptin f Benefits is a 10-item self-reprt develped fr this study, ranging frm 10 (belief) t 50 (disbelief) that the patient will see imprved functining if he r she gets needed care. Research Assessments. The research assessments (see Study Prcedures) were cnducted ver a maximum perid f 18 mnths. Because the enrllment perid was 13 mnths and the fllwup perid was 12 mnths, all patients had the pprtunity t participate fr 12 mnths, whereas nly earlier enrllees had the pprtunity t participate fr lnger perids. Because the number f participants fell markedly beynd 12 mnths, nly results frm the first 12 mnths are reprted here, althugh data frm beynd 12 mnths, when available, were used in the statistical mdeling prcedures. The assessrs were initially trained in each f the assessments and had quarterly retraining n the structured clinical interviews. The assessrs cntacted and assessed and patients independently f the patients' clinical prviders. Outcmes. The primary research utcme measure was the 18-item BPRS (Overall and Grham 1962), extracted frm the 24-item BPRS. Secndary symptm measures included the SANS (Andreasen 1982) and the Calgary Depressin Scale (Addingtn et al. 1993). Tests f cgnitive functining included Trails A and B (Reitan 1955, 1958), Verbal Fluency (categries and letters) (Lezak 1995), and the Hpkins Verbal Learning Test (Benedict et al. 1998). Functinal utcmes were measured with the SF-12 (Ware et al. 1996). The ppulatin fr the analysis f efficacy included all patients wh were enrlled and had cmplete 18-item BPRS data n at least ne pstbaseline quarterly assessment. Adherence Variables. Charts were reviewed and data extracted fr medicatins prescribed at each visit. These data were used t estimate frequencies and dses f antipsychtic medicatins used. The number f patients in the r grup wh were prescribed the antipsychtic at any time during the study perid was divided by the number in the grup t calculate frequencies f use. Average dses were calculated using the highest dse prescribed during the study. Because patients had mre antipsychtic medicatin changes (see belw), their ttal frequencies f receiving different antipsychtics are higher than the grup's. Antipsychtic medicatin changes were part f the standard dcumentatin f treatment. antipsychtic medicatin changes were inferred frm the chart recrding f a prescriptin fr an antipsychtic nt previusly nted fr that patient during the quarter. Duratin f availability f medicatins prescribed at a visit was based upn the fllwing data (in decreasing rder f preference): actual number f pills if chart nte indicated number f pills, actual number f days if chart nte indicated number f days, r days until next clinic visit if a clinic appintment was scheduled; if there was n infrmatin, then 30 days was assumed. Because patients acquired their medicatins frm multiple surces (Medicaid, lcal center pharmacy cntracts, patient assistance prgrams, and samples), there was n pssibility f using pharmacy medicatin fill data t lk at actual medicatin pssessin. Thus, active rders were used as a marker f ptential medicatin pssessin. Statistical Analyses. Tests fr differences between grups were based n 2-tailed tests with equal variance nt assumed fr cntinuus measures (based n Levene's test), chi-squares fr discrete values, and chi-squares with cntinuity crrectins fr dichtmus measures. As detailed elsewhere (Rush et al. 2003), hierarchical linear mdels (HLMs) were adapted t assess the impact 631

6 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. f n patient utcmes based n declining effects analyses develped fr this study by Kashner et al. (2003). This apprach allwed investigatrs t cmpare separately thse changes that ccurred initially (within 3 mnths) and ver time (12 mnths). Estimates fr the initial change in utcmes between baseline and the first 3- mnth fllwup were cmputed separately fr and fr. Fllwing the initial change, we estimated changes in utcmes ver the subsequent 9 mnths (i.e., mnths 3-12). Differences between and were cmputed fr initial changes (initial effects) and grwth rates (grwth-rate effects). Differences between and in the value f the utcme measure assessed at baseline wuld factrlad nt any grup differences bserved ver time. Thus, patient utcme measures were determined as change scres frm baseline values. Because grups differed n a number f variables that culd ptentially affect utcmes, statistical cmparisns were dne using adjusted values. The basis and ratinale fr the methdlgy are discussed in detail in Kashner et al. (2003) and Rush et al. (2003). In brief, raw data were adjusted using cvariates knwn t affect health utcmes, selecting items that were significantly assciated with the primary utcme variable (BPRS lg ) in this study. Fr each dmain, cvariates included the mst significant cvariate that was linearly assciated with utcmes based n a univariate mdel. Additinal variables were included prvided they were statistically significant at a 0.05 alpha level. Thus, the cvariate dmains (items assessing them) were need (baseline symptm scre, age), predispsitin t seek care (years f educatin, patient perceptin f benefits), enabling factrs (family size, dispsable incme), and demgraphic items (ethnicity, race, sex). Final estimates were insensitive t mdel respecificatin, because including r excluding ther cvariates in the presence f the selected cvariates did nt change the results f / utcme cmparisns. Mrever, high mdel reliability (> 75%), final HLM estimates that were very similar t their least squares starting estimates, and ur use f rbust standard errrs, gave investigatrs cnfidence that reprted estimates were relatively free f misspecificatin errr in either the estimated effects r the respective standard errrs upn which significance tests were based. Grwth-rate effects were used t determine whether initial effects increased, remained cnstant, r declined during fllwup. Typical HLM analyses utilize a grwth effects mdel that is pwered t detect grwth in differences between patients wh receive a treatment and get better, and thse in a cntrl cnditin wh either get wrse, d nt get better, r d nt imprve as much as thse in the interventin grup. Initial examinatin f ur data, hwever, indicated an initial effect in favr f the grup and, at least with sme analyses, a tendency fr a declining effect ver time (i.e., the cntrl grup begins t "catch up" with the interventin grup ver time). This declining effect ver time after an initial effect may actually be expected in service interventin studies fr chrnic disease states where differences between interventin and cntrl grups ver time may be cmplex. Grwth effect mdels d nt cnsider initial effects separately frm further grwth, and they cllapse differences between treatment grups and cntrls ver time int a single parameter. Thus, they are nt pwered t detect a declining effect. The declining effects mdel develped fr analysis f these data adds an additinal parameter in that it examines the initial effect and then the cntinuing effect ver time after the initial effect. Thus, it has greater pwer t detect a declining effect after an initial effect r n change after an initial effect and is a superir analytic mdel t use fr these types f data (Kashner et al. 2003). Specifically, time since baseline was entered as a cntinuus variable in a time level I and patient level II HLM. Dependent variables were patient utcmes measured at 3-mnth intervals and cmputed as change scres by subtracting each fllwup assessment frm the respective value determined at baseline. Fr each treatment grup ( and ), the initial change and grwth rates were cmputed, respectively, by the regressin cnstant and time cefficient, while initial and grwth-rate effects (-) were cmputed by grup indicatr and time X grup-indicatr interactin. The grup-indicatr variable assumes the value f 1 fr patients and 0 fr patients. Fr Trails A and B data, values were transfrmed t natural lgarithms t nrmalize distributins. T grup the cgnitive test results int a summary measure fr each patient, each scre was cnverted int a z scre, and the z scres were summed fr each patient at each time pint. Summary scres f cgnitin, using z scres, have prven t be sensitive measures f drug effects in schizphrenia and prvide a measure f the verall magnitude f change (Purdn et al. 2000; Bilder et al. 2002; Green et al. 2002). Results A ttal f 512 patients met the criteria fr the study and signed infrmed cnsent; f these, 9 did nt cmplete baseline, 29 failed t reprt fr any fllwup visit, and 9 had a fllwup visit but did nt cmplete at least ne primary symptm measure (BPRS ]g ). The remaining 465 evaluable patients cmpleted the primary symptm measure at baseline and at least ne fllwup visit, including 165 patients frm fur clinics, 144 patients frm 632

7 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 fur clinics using n algrithms fr any f the three disrders, and 156 patients seen in clinics using an algrithm fr anther disrder. The grup and the grup seen in clinics nt using ther algrithms cnstituted the primary analytic sample (n 309). Fr the primary analytic sample, baseline BPRS 18 was lwer fr than fr patients (38.75 [SD ] vs [SD = 10.71], A = -6.63, t = 5.31, df = 307, p < 0.001). With lwer initial values in the grup, regressin t the mean bias wuld wrk against finding a favrable effect n utcme, and thus the analytic apprach is cnservative. The HLM analyses f the primary analytic sample used all subjects with at least ne pstbaseline BPRS lg rating. The percentages f subjects meeting this criterin at 3, 6, 9, and 12 mnths were 100 percent, 95 percent, 91 percent, and 86 percent, respectively. Thus, retentin f subjects in the study was excellent. Table 1 lists the demgraphic characteristics f the primary analytic sample ( and grups), as well as the grup f patients seen in a clinic in which clinicians were using algrithms fr biplar r majr depressive disrder (-AC). The grups did nt differ significantly frm ne anther n mst variables. Mst cvariates (see list in legend t table 2) were nt statistically significant predictrs f change scres, and thus ptential biases intrduced by these factrs are expected t be small. Initial BPRS 18 scres and Hispanic status were significant predictrs f BPRS ]8 change scres. BPRS lg change scres drpped by an average acrss subsequent time pints f ABPRS, g = (standard errr [SE] = 0.05, t = 12.28, df = 269, p < 0.001) fr each nt mat BPRS, 8 P ' baseline symptm scres were abve mean values, underscring cncerns fr regressin t the mean biases. Cmpared with Caucasians, BPRS 18 scres declined mre in Hispanic patients, by an average acrss pstbaseline time pints f ABPRS 18 = (SE= 1.08, t = 3.52, df= 269, p< 0.001). Table 2 presents unadjusted BPRS 18 scres fr all three grups. Statistical analyses were dne using adjusted values. Table 3 cntains adjusted data n the main symptm measures. The initial change is the change in scre ver the first 3 mnths. The grwth rate is the quarterly change in scres ver the next 9 mnths. Fr the BPRS 18, SANS, and Calgary Depressin Scale, decreases in scres represent imprved symptms. Fr the SF-12 mental and physical, increases in scres indicate imprvements in these patient self-reprts. On the primary symptm utcme measure, the BPRS 18 bth grups had significant decreases in scres ver the first 3 mnths (table 3). The decline was significantly greater in the grup cmpared with the grup. Over the subsequent 9 mnths, the grup had a further significant decline in symptms, catching up with the grup in terms f symptm imprvement. These results are illustrated in figure 2. Negative symptms, as measured by the SANS, declined significantly in bth grups ver the first 3 mnths, but the tw grups did nt differ significantly frm ne anther (table 3). The and grups did nt differ significantly in initial r subsequent changes in scres n the Calgary Depressin Scale (table 3). Depressive symptms did imprve significantly in bth grups during the first 3 mnths. There were n verall grup differences n the SF-12 mental r physical (table 3). Unadjusted cgnitive test perfrmance scres fr all grups are shwn in table 4, with results at baseline, 3 mnths, and 9 mnths. T put all scres n cmparable dimensins, we cnverted them t z scres and cmputed the z-scre differences. Table 5 shws these results fr the primary cmparisn between and grups. During the first quarter, the grup had significantly greater imprvements than the grup in scres n Trails A and Verbal Fluency (letters). By the end f the third quarter, Verbal Fluency (categries) was als significantly mre imprved in the grup than in the grup. Results n the cmbined tests, expressed as z scres, were significantly mre imprved in the grup at bth 3 and 9 mnths after study entry. The cmbined z scres are shwn in figure 3. The -AC grup allwed secndary cmparisns with that culd be cmpared with the results f cmparisns with. Secndary symptm cmparisns f the grup with the -AC grup are summarized in table 6. The greater initial decline in BPRS )8 scre in the grup was nt fund in this cmparisn, althugh significant initial effects favring imprvement in the grup were nted n the SF- 12 mental and physical. The greater imprvements in cgnitive functin in the grup, fund in the primary cmparisn, were replicated in the cmparisn with the -AC grup. The z scres and differences between grups are shwn in table 7. and grups differed with respect t physician behavirs that reflected the impact f implementatin. patients had mre medicatin changes and mre medicatin visits, especially in the first quarter (table 8). The frequency f using different antipsychtics varied between grups and acrss time (table 9). Average dses were similar in mst instances, with higher dses f lanzapine in the grup being the nly significant difference. 633

8 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. Table 1. Schizphrenia patients: Demgraphic characteristics assessed at baseline by treatment grup Characteristic (n=165) (n=144) -AC (n=156) Statistic P Age, mean l SD (yrs) F(2,460) = Age, % (yrs) <rl X 2 (12) = Female, % X 2 (2) = Ethnicity, % African-American Hispanic Caucasian Other High schl graduate (r GED), % X 2 (6) = 13.4 X*(2) = Yrs in schl, mean l SD F(2,459) = Marital status, % Divrced Married Single (never married) Separated Widwed x 2 (8) = Emplyment, % Full-time Part-time Unemplyed X 2 (4) = Receiving financial assistance, % X 2 (2) = Receiving Medicaid, % Family size, mean i SD X 2 (2) = 3.1 F(2,460) = Living alne, % x 2 (2) = Dispsable mnthly incme, mean ± SD F(2,429) = 10.0 Length f illness, mean 1 SD (yrs) F(2,461) = Schizaffective disrder (nt biplar), % X 2 (2)= Significant medicatin side effect burden, % X 2 (2) = Cncurrent alchl prblems, % x2(2) = 36.3 Cncurrent drug prblems, % X 2 (2) =

9 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 Table 1. Schizphrenia patients: Demgraphic characteristics assessed at baseline by treatment grup cntinued Characteristic (n = 165) (n=144) -AC (n=156) Statistic Cncurrent medical cnditins, % X 2 (6) = Nne Patient Perceptin f Benefits scre, mean ± SD ± ± ±7.9 F(2,457) = Nte. = algrithm-guided treatment; SD = standard deviatin; - treatment as usual; -AC = treatment as usual in an algrithm clinic. 1 2 x 2 using chi-square with cntinuity crrectin. 2 Includes fd stamps. 3 Ttal mnthly incme minus rent r mrtgage payment. 4 Scres f 5 indicate alchlism n the Michigan Alchlism Screening Test (Selzer 1971). 5 Scres >5 indicate drug prblems n the Drug Abuse Screening Test (Skinner 1982). 6 Patient Perceptin f Benefits is a 10-item questinnaire ranging in scre frm 10 t 50, where 10 indicates that patients strngly agree and 50 indicates that patients strngly disagree that they will btain imprved functining if they get the care they need. Table 2. BPRS 18 scres at baseline and 3, 6, 9, and 12 mnths 1 Time (ms) Baseline Grup -AC -AC -AC -AC -AC n Mean BPRS 18 Nte.» algrithm-guided treatment; BPRS 18 = 18-item Brief Psychiatric Rating Scale; SD - standard deviatin; = treatment as usual; -AC «treatment as usual in an algrithm clinic. 1 Values shwn are unadjusted BPRS )8 scres and SDs fr each subject grup at the times nted. Fr analytic purpses, scres were adjusted fr baseline patient characteristics as described in Methds SD

10 Table 3. Adjusted estimates f initial change and grwth rates amng and patients with schizphrenia, fr selected utcmes 1 i S EL BPRS 18 2 Initial change Grwth rate SANS 3 Initial change Grwth rate y ± ± ± ±0.10 Calgary Depressin Scale 4 Initial change ±0.35 Grwth rate ±0.10 SF-12 mental 5 Initial change Grwth rate SF-12 physical 6 Initial change Grwth rate 1.67 ± ± ± ± 0.25 Clinic Clinic Difference 3 df t P 7 df t P 7 df t P I- t " , ± ± , ± ±0.26 1,253 1, , , , , ±0.39 ± ± ± ± ± ± ± , , , , ± ± ± ± ± ± ± ±0.31 Nte.» algrithm-guided treatment; BPRS 18 = 18-item Brief Psychiatric Rating Scale; SANS = Scale fr the Assessment f Negative Symptms; SF-12 = Shrt Frm Health Survey; = treatment as usual; -AC = treatment as usual in an algrithm clinic. 1 Cefficients represented as mean value ± standard errr. Adjusted fr mean values with respect t baseline symptm/functining scres, age (years), family size, dispsable incme, years f educatin, patient perceptin f benefits frm treatment, gender, African-American status, and Hispanic status. 2 Fr all patients, baseline BPRS 18 means and standard deviatins were ± 11.15, n 165 (), and ± 10.71, n= 144 (), fr a mean difference f-6.63 ± 1.25 (f» 5.31, df" 307, p < 0.001, equal variances assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks against finding an effect f lwer BPRS 18 fllwup scres. 3 Fr all patients, baseline SANS means and standard deviatins were ± 4.86, n = 164 (), and ± 5.05, n = 142 (), fr a mean difference f ± 0.57 (t = 1.81, df** 294, p = 0.071, equal variances nt assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks /nfaiw f finding an effect f lwer SANS fllwup scres. 4 Fr all patients, baseline Calgary Depressin Scale means and standard deviatins were 6.66 ± 5.00, n = 165 (), and 7.88 ± 4.95, n (), fr a mean difference f ± 0.57 ((= 2.14, df" 304, p = 0.033, equal variances assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks against finding an effect f lwer Calgary Depressin Scale fllwup scres. 5 Fr all patients, baseline SF-12 mental means and standard deviatins were ± 12.09, n = 161 (), and ± 9.41, n = 138 (), fr a mean difference f ± 1.25 (f = 0.68, = 294, p = 0.50, equal variances nt assumed, 2-tailed test), suggesting a negligible regressin t the mean bias that wrks against finding an effect f higher SF- 12 mental fllwup scres. 6 Fr all patients, baseline SF-12 physical means and standard deviatins were ± 11.40, n = 161 (), and ± 10.82, n (), fr a mean difference f 1.48 ± > 1.29 (f = 1.14, df= 296, p = 0.25, equal variances assumed, 2-tailed test), suggesting a negligible regressin t the mean bias that wrks against finding an effect f higher!"" SF-12 physical fllwup scres. 2 1,256 1,256 1,264 1,264 1,206 1,206 1,206 1, p

11 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 Figure 2. Adjusted Mmean Ssymptms (BPRS 18 ): and Grups c 0Q 55-i (n=144) -*-(n=165) Baseline Quarter Nte. = algrithm-guided treatment; = treatment as usual. The likelihd f rinding dcumentatin in the chart f an active rder fr an antipsychtic was 94 percent in the grup and 51 percent in the grup. The lw number in the grup des nt necessarily mean that the patients were nt taking an antipsychtic but des mean that half the time there was insufficient infrmatin in the chart t cnclude r infer that patients had enugh antipsychtic medicatin t last until the next clinic visit. Discussin The results indicate sme advantages f cmpared with in the treatment f schizphrenia and schizaffective disrder, but the differences are nt unifrm acrss time r acrss utcme dmain. This discussin will fcus first n the primary cmparisns between the interventin and in clinics nt using any interventins. The pssible implicatins f the results in the secndary grup, thse seen in clinics using fr anther disrder, will then be discussed. The magnitude f the symptm changes fund in this study f a ppulatin f typical public mental health patients was nt large, in either the cnditin r the cnditin. There are surprisingly few studies f lng-term symptm utcmes in schizphrenia utpatients with which ur results can be cmpared. In recent years, since the advent f the atypical antipsychtics, mst lng-term studies using active cmparatrs have been extensins f inpatient acute interventin studies. The pl f patients recruited int these extensin studies is quite different frm the pl f utpatients in ur study, as the frmer is selected fr thse already knwn t have benefited frm the inpatient treatment. In a large multinatinal study cmparing lanzapine with halperidl treatment f utpatients with schizphrenia, Tllefsn et al. (1997) fund that bserved case decreases in BPRS 18 scres at 6 weeks were 15.0 and 12.7 pints, respectively, beginning with mean baseline values f 51 t 52. The differences were statistically significant in a repeated measures analysis. The drput rates were 30 t 50 percent. In ur study, the decreases at 3 mnths were 5.65 and 3.36 in the and grups, respectively, beginning with adjusted mean values f 42 (table 3). The drput rates were less than 10 percent. Thus, the verall imprvements were greater in the lanzapine study, but this difference may be partly attributable t different drput rates and mre symptmatic patients at baseline. The difference between the active treatment grups, 2.3 BPRS scale pints, was identical in the tw studies. The magnitude f symptm changes bserved in the BPRS 18 in the current study can als be viewed in cmparisn with anther lnger term utpatient study. A recently published study f maintenance utpatient treatment fr schizphrenia with risperidne r halperidl fund that the rate f relapse was lwer with risperidne (Csernansky et al. 2002). Using endpint values, scres n the Psitive and Negative Syndrme Scale (Kay et al. 1987) decreased, n average, 3.1 pints in the risperidne grup and rse, n average, 2.8 pints in the halperidl grup, starting with baseline values f 65 and 67, respec- 637

12 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. Table 4. Mean cgnitive functin test scres, all grups 1 Test Trails A Trails B Verbal Fluency (letters) Verbal Fluency (categries) Hpkins Verbal Learning Test Grup -AC -AC -AC -AC -AC Baseline 79.0 (58.9) (n=158) 75.3 (48.2) (n= 134) 67.4 (43.7) (n=138) 169.9(91.9) (/7= 158) 168.4(86.8) (n=134) 134.4(68.2) (AJ= 139) 24.9(12.5) (n=158) 26.8(11.0) (n=138) 25.6(13.0) (n=152) 17.3(7.2) (n=>159) 18.4(6.0) (n=137) 18.7(8.0) (n=153) 15.0(6.5) (n=158) 15.1 (6.1) (n=138) 14.2(6.2) (n=152) 3 ms 64.6 (44.7) (n=148) 75.9 (58.4) (n 132) 62.4(47.1) (n=141) 152.8(89.1) (n=148) 151.2(80.8) (n=132) 133.7(81.8) (n=141) 26.8(12.4) (n=154) 26.9(11.5) (n=135) 26.9(13.6) (n=151) 19.1 (7.5) (n=155) 19.0(7.2) (n=137) 19.3(7.9) (n=151) 16.6(6.7) (n=154) 16.2(6.4) (n=136) 15.6(6.7) (n=151) 9 ms 61.5(42.1) (n=127) 66.4 (50.0) (n=113) 60.4(50.1) (n=124) 143.4(82.8) (n=127) (86.9) (n=113) 134.0(80.6) (n=124) 28.3(13.2) (n=128) 26.1 (12.1) (n=117) 26.2(12.9) (n=137) 19.6(7.4) (n=131) 18.2(7.3) (n=117) 18.2(8.1) (n=137) 17.2(6.7) (n=130) 16.1 (6.6) (n=116) 16.4(7.2) (n=137) Nte. = algrithm-guided treatment; - treatment as usual; -AC = treatment as usual in an algrithm clinic. 1 Values shwn are mean (standard deviatin) fr each test and grup at the times nted. Fr analytic purpses, scres were adjusted fr baseline patient characteristics as described in Methds. tively. In ur study, the 12-mnth decreases in BPRS 18 scres were 5.3 and 4.9 pints in the and grups, respectively. Because f very different entry criteria and rates f drput, and because early endpint values are handled differently in ur HLM analyses than in last bservatin carried frward (endpint) analyses, the results f the tw studies are nt directly cmparable. Nnetheless, bth studies indicate that, ver the curse f a year, verall reductins in symptmatlgy are mdest, whether patients are fllwed in research centers (as in the Csernansky et al. [2002] study) r in public mental health clinics (as in this study). Much mre dramatic effects might have been fund by enrlling acutely exacerbated inpatients. This was nt dne because ur preliminary studies fund that influencing inpatient medicatin management and crdinating the transitin f medicatin use frm inpatient t utpatient status was extrardinarily difficult in ur system. Figure 2 shws that frm 3 t 12 mnths the patients had further significant imprvements in BPRS lg 638

13 Table 5. Adjusted change scres In cgnitive functining at first and third quarter pstbaseline fr and patients with schizphrenia 1 t P xas N P B. Q3 1" I 2 Difference y df t P y df t P y df First quarter TMT-A (In sees) TMT-A (sees) TMT-B (In sees) TMT-B (sees) VFT (categries) VFT (letters) HVLT Ttal z scre change ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ON \ Third quarter TMT-A (In sees) TMT-A (sees) TMT-B (In sees) TMT-B (sees) VFT (categries) VFT (letters) HVLT Ttal z scre change ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.22 Nte. - algrithm-guided treatment; HVLT = Hpkins Verbal Learning Test; - treatment as usual, TMT-A = Trail Making Test, Part A; TMT-B Trail Making Test, Part B; VFT = Verbal Fluency Test. 1 Cefficients represented as mean ± standard errr. The TMT-A and TMT-B values (in secnds) were cnverted t natural lgarithms (In) fr statistical analyses. The values shwn are the changes In the time t perfrm the task (In values) and the changes cnverted int secnds as exp (g) exp (baseline mean) - exp (baseline mean). Z scres were cm- # puted fr each f the three tests and summed. The values shwn are fr the changes in sum z scres. Mean values were adjusted with respect t baseline BPRS 18 scre, length f 2: illness (years), family size, dispsable incme, years f educatin, Patient Perceptin f Benefits ttal scre, and ethnicity (African-American and Hispanic). Sample sizes fr first.g quarter TMT-A and TMT-B (: n - 128; : n = 120); VFT (categries) (: n = 136; : n = 126); VFT (letters) (: n - 135; : n - 125); HVLT (: n = 135; a- : n- 126); and z scre (: n- 126; : n= 117). Sample sizes fr third quarter TMT-A and TMT-B (: n = 111; : n= 103); VFT (categries) (:n= 117; : n = 108); VFT (letters) (: 0=115; : n - 109); HVLT (: n ~ 115; : n = 108); and z scre (: n - 108; : n - 102). Fr all patients, baseline In (TMT-A) scres 5' were 4.2 ± 0.6 () and 4.2 ± 0.5 () fr a mean difference f ± 0.5 (f- 0.1, df- 290, p 0.95, equal variances assumed, 2-tailed test). Baseline In (TMT-B) scres g> were 5.0 ± 0.6 () and 5.0 ± 0.6 () fr a mean difference f ± 0.6 (f = -0.2, df = 290, p = 0.89, equal variances assumed, 2-talled test). Baseline VFT (categries) jf scres were 17.3 ± 7.2 () and 18.4 ± 6.0 () fr a mean difference f -1.1 ± 6.7 (f = -1.4, df<= 293, p , equal variances nt assumed, 2-tailed test). Baseline VFT (let-». ters) scres were 24.9 ± 12.5 () and 26.8 ±11.0 () fr a mean difference f -1.9 ± 11.8 (t = -1.4, df" 294, p = 0.16, equal variances assumed, 2-tailed test). Baseline ^ HVLT scres were 15.0 ±6.5 () and 15.1 ±6.1 () fra mean difference f -0.1 ± 6.3 (f = -0.2, df- 294, p-0.84, equal variances assumed, 2-tailed test). Baseline ttal z g scres were-0.2 ±2.5 () and 0.1 ±2.1 () fr a mean difference f-0.3 ± 2.3 (f = 1.0, df' 285, p = 0.30, equal variances nt assumed, 2-tailed test). These baseline drf- ^ ferences suggest regressin t the mean biases that either are negligible r wrk against finding an effect. P

14 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. Figure 3. Sum f cgnitive test scres (z scres): and Ggrups 2 i (n= 122) -*- (n=137) Baseline 3 Mnths 9 Mnths Nte. - algrithm-guided treatment; = treatment as usual. scres and caught up with the patients. The fact that patients did nt evidence further imprvement has multiple pssible explanatins, sme f which may be able t be evaluated with further analyses. Because the apprach encuraged the treatment team t seek a high level f symptm respnse, particularly in terms f reductin in psitive symptms, the lack f a better respnse in this cnditin ver the lnger term culd mean that maximum benefit had already been achieved (ceiling effect) in this seriusly and chrnically ill patient ppulatin, r it culd signify that the clinicians were sufficiently satisfied with the initial respnses that they chse nt t strive fr further symptm reductin with subsequent medicatin changes. Unidentified factrs in the service delivery system culd have made it difficult fr the physicians t deliver mre assertive treatment. Further analyses f physician adherence t the algrithm's criteria fr adequacy f respnse may help reslve these questins. Analyses f the impact f adherence t the interventin package are, unfrtunately, nt straightfrward. It is much easier t adhere t guidance with respect t dsing, visit frequency, switching medicatins, and s n with cperative and respnsive patients than with uncperative r nnrespnsive patients. Therefre, a strng relatinship f adherence t the interventin package with gd utcmes can be the result f gd patient utcmes making adherence t the recmmendatins easier, rather than gd adherence making patient utcmes better. The results presented in tables 8 and 9 d indicate that physicians saw their patients mre frequently fr medicatin visits, made mre antipsychtic medicatin changes, and had different prescribing prfiles, as cmpared with their cunterparts. Mrever, physicians were much mre likely t have active medicatin rders in their charts. Thus, implementatin did affect imprtant physician behavirs. The presence f CCs in the clinics t assist physicians in caring fr patients undubtedly affected physicians' willingness t cnsider medicatin changes fr patients with less severe symptms r side effects. Thus, enrllment f patients in clinics was rapid, whereas the rate f medicatin changes in clinics was s slw that it became clear that these physicians must be using different criteria fr medicatin changes than physicians in clinics. The change in clinic culture was desirable, in terms f the gals f the interventin, but resulted in baseline differences between patient grups that culd have cnfunded the cmparisns between and. If ne disregards the data and, instead, examines the data in tables 3 and 5 slely frm the viewpint f the impact f the interventin n patients, the picture that emerges is ne f initial imprvements in virtually all measures. These imprvements were sustained ver time in the symptm measures (table 3) and increased ver time in the cgnitive measures (table 5). That is, the initial psitive effects f the interventin did nt dissipate, as might have been expected if they had resulted frm shrt-term effects f a nvel treatment. There were n verall significant grup differences in changes in negative symptms (SANS), depressive symptms (Calgary Depressin Scale), r patient-rated mental and physical functining (SF-12). Bth and 640

15 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 Table 6. Adjusted estimates f differences In initial change and grwth rates between patients and -AC patients 1 BPRS 18 2 Initial change Grwth rate SANS 3 Initial change Grwth rate Calgary Depressin Scale 4 Initial change Grwth rate SF-12 mental 5 Initial change Grwth rate SF-12 physical 6 Initial change Grwth rate ± ± ± ± ± ± ± ± ± ± 0.27 /-AC Difference Nte. = algrithm-guided treatment; BPRS 18 = 18-item Brief Psychiatric Rating Scale; SANS Scale fr the Assessment f Negative Symptms; SF-12 = Shrt Frm Health Survey; -AC = treatment as usual in an algrithm clinic. 1 Cefficients represented as mean value ± standard errr. Adjusted fr mean values with respect t baseline symptm/functining scres, age (years), family size, dispsable incme, years f educatin, patient perceptin f benefits frm treatment, gender, African- American status, and Hispanic status. 2 Fr all patients, baseline BPRS 18 means and standard deviatins were ± 9.93, n = 156 (-AC), and ± 11.15, n (), fra mean difference f ± 1.18 (f = 1.48, df= 318, p = 0.14, equal variances nt assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks against finding an clinic effect f lwer BPRS 18 fllwup scres. 3 Fr all patients, baseline SANS means and standard deviatins were ±4.79, n= 156 (-AC), and ±4.84, n= 164 (), fr a mean difference f 2.51 ± 0.54 (f = 4.66, df= 318, p< 0.001, equal variances nt assumed, 2-talled test), suggesting a ptential regressin t the mean bias that wrks in favr f finding an clinic effect f lwer SANS fllwup scres. 4 Fr all patients, baseline Calgary Depressin Scale means and standard deviatins were 7.03 ± 5.05, n = 156 (-AC), and 6.66 ± 5.00, n= 165 (), fr a mean difference f-0.37 ±0.56 (f-0.67, df=318, p = 0.51, equal variances nt assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks against finding an clinic effect f lwer Calgary Depressin Scale fllwup scres. 5 Fr all patients, baseline SF-12 mental means and standard deviatins were ± 10.50, n (-AC), and ± 12.09, n = 161 (), fr a mean difference f 2.45 ± 1.29 (f = 1.91, df = 306, p , equal variances nt assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks against finding an clinic effect f higher SF-12 mental fllwup scres. 6 Fr all patients, baseline SF-12 physical means and standard deviatins were ± 10.68, n= 148 (-AC), and ± 11.40, n = 161 (), fra mean difference f 0.44 ± 1.26 (t = 0.35, df= 307, p = 0.73, equal variances nt assumed, 2-tailed test), suggesting a ptential regressin t the mean bias that wrks against finding an clinic effect f higher SF-12 physical fllwup scres. df 1,322 1,322 1,320 1,320 1,333 1,333 1,256 1,256 1,256 1,256 t P shwed significant initial imprvements in SANS and Calgary scres. The clinicians were encuraged t be alert t depressive symptms and t treat them vigrusly, but n specific criteria fr treatment r fr respnse were used. Given the high prevalence f depressive symptms in patients with chrnic schizphrenia (Sins 2000), it might have been useful t incrprate mre specific recmmendatins fr assessing and adequately treating depressin in the prcedures. Further analyses may help determine whether antidepressant medicatins were used similarly in the and grups r were used mre aggressively by the clinicians withut achieving better results. In the case f negative symptms, a brief fur-item scale was administered by the CCs at each visit, t guide algrithm interventin. The respnse criterin fr negative symptms was nt stringent, because f the uncertainty in the literature as t what is an achievable level f imprvement. Clinicians were urged t use the scale results in the cntext f their wn clinical judgments abut the degree f impairment attributable t negative symptms and the risks and benefits f med- 641

16 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. u 1 a n patllent O 2, c sell (0 ** O Q. a> C a3 ex Ird n m fir CO jnctlifilng a> iltiv c O) "5.a O) _c CO 0) a Table 7. Adjusted cr patients 1 8 i c < - Q. CO s d p c\i -H V CM d +1 r OJ CO CO CO CO < * O O> 00 CO i- <7) 00 cvj a> +) CO CO d +1 CO d CD i3 _ S D> a c *- CT ^^ CO t-t CO m -C CD -C m CD «i= N a. m 1 i- : (D'Q O <e a & (D C l O T= ^ CD 2S g!i«! J s> as l2? 35 t: <N CD c c f-;? 2. c c >- s> ^: Q) CD O Q. j. E " O ^ E ^ -H W CD I f a. "Z' g «= I &«l 00 P O 5 -H 'a 5 CT H C/5^ CO ^ = ^ DC - ^ DD CD I CD S5SO CO CD CD. S O N fi CJ T3 icatin changes targeted at imprving negative symptms. The fact that there were greater imprvements in verall cgnitive perfrmance in the grup was especially interesting because f the grwing evidence that cgnitive deficits cntribute substantially t the functinal impairment characteristic f many patients with schizphrenia (Green 1996; Velligan et al. 1997). A brader battery f tests administered at each quarter with the ther utcme measures wuld have been desirable but was nt feasible, because f resurce limitatins and the burden n patients f extended assessments. The Hpkins Verbal Learning Test was selected because f its ease f administratin and its availability in multiple equivalent frms. Hwever, its sensitivity t change in patients with schizphrenia has nt been well demnstrated. This lack f sensitivity culd have cntributed t the lack f grup differences n this measure in this study. The time curse f imprvement was nt the same with each cgnitive test, althugh the verall trend was fr greater imprvements in the grup acrss time (figure 3). Time t perfrm the Trails A test decreased mst in the cmpared with the grup during the initial 3 mnths. Grup differences in imprvements n the Verbal Fluency tests (categries, letters) were, n the ther hand, greater ver the 9-mnth perid than ver the initial 3 mnths. This finding suggests a mre enduring effect f n this cmplex measure f initiatin, recall, and retrieval than was fund in the clinical symptm measures. Because was a multifaceted interventin, targeted mainly tward medicatin management and symptm imprvement, it is difficult t ascribe the apparent effects n cgnitin t any particular aspect f the interventin. The fact that the effect ccurred in bth grup cmparisns is smewhat reassuring as t its validity, but we recgnize the need fr cnfirmatin f the finding in future studies, as well as the imprtance f experimental designs that will permit identificatin f elements f the interventin that influence cgnitive test perfrmance. Regarding the secndary cmparisns between the grup and the -AC grup, results were smewhat different than thse fund in the primary cmparisns, with regard t symptm measures. Significantly greater imprvement in BPRS scres in the grup during the first 3 mnths was nt fund, but the SF-12 mental and physical did imprve mre in the grup during this time perid (tables 3 and 6). These differences are nt easily explained. Given the relatively small magnitude f the grup differences n symptm measures, hwever, it may nt be t surprising that the symptm findings were smewhat unstable acrss cmparisn grups. 642

17 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 Table 8. Medicatin changes and visits 1 Medicatin changes 1 Medicatin visits 2 Grup (2.29) 2.76(1.11) (1.45) 2.05(1.08) Quarter (1.39) 1.81 (1.03) Nte. = algrithm-guided treatment; BPRS 18» 18-item Brief Psychiatric Rating Scale; = treatment as usual (1.24) 1.57 (0.78) 1 Unadjusted values shwn fr medicatin changes are percentages f patients in each quarter fr each grup with at least ne medicatin change during the quarter, excluding medicatin changes at study entry. The data were dichtmized as presence/absence f change rather than the number f changes being cunted because f the large number f zer changes. A binmial generalized hierarchical linear mdel suitable fr analyzing dichtmus data was used. The mdel cntained terms fr treatment grup, quarter in study, and time-by-quarter interactin. The cvariates were baseline BPRS 18, age, family size, dispsable incme, years f educatin, patient perceptin f benefits, gender, African-American status, and Hispanic status. The treatment grup-by-quarter effect was significant (f, 634 = 16.3, p< ). 2 Unadjusted values shwn fr medicatin visits are mean (standard deviatin) fr each grup ver the curse f each quarter after study enrllment. A Pissn generalized hierarchical linear mdel suitable fr analyzing cunt data was used. The mdel cntained terms fr treatment grup, quarter in study, and time-by-quarter interactin. The cvariates were baseline BPRS 18, age, family size, dispsable incme, years f educatin, patient perceptin f benefits, gender, African-American status, and Hispanic status. The treatment grup-by-quarter effect was significant (f 3 %& = 18.2, p < ). The cgnitive functin test results shwed a mre cnsistent pattern. All grups imprved ver time, with greater imprvements being sustained in the cmpared with bth f the grups (tables 5 and 7). These findings f greater imprvement in cgnitive test scres in the grup are f great interest but shuld nt be verinterpreted. Further analyses will test whether there were functinal cnsequences in terms f resurce utilizatin and need fr unscheduled interventins. One might argue that there was an "algrithm culture" effect that encuraged clinicians using interventins t be mre aggressive in treating residual symptms. This culd accunt fr the greater initial imprvement in the BPRS in -AC patients than in patients. This cnclusin is highly tentative, but it wuld be interesting t design future studies that specifically address the "hal effect" f changing the management f ne disrder n management f ther disrders treated by the same clinicians. This study enrlled utpatients in public mental health clinics. It was nt pssible t blind clinicians r raters t the grup assignments. Mrever, the clinicians were free t treat each patient as they saw fit, even thugh they were cached t fllw the algrithm manual. In additin, all patients in the grup were "medicatin failures" (with regard t efficacy r side effects) based n individual physician judgment and had a primary medicatin change at study entry, whereas patients in the grup culd be enrlled n the basis f either having a primary medicatin change r having a high level f symptmatlgy. Thus, ur findings reveal utcmes assessed by nnblinded but independent raters and reflect the actual (i.e., less than perfect) levels f algrithm implementatin achieved in participating clinics. It is pssible that better results might have been fund if it had been pssible t ensure that clinicians always fllwed the algrithm's recmmendatins. It is als cnceivable that rater bias in favr f culd have influenced the results, althugh the fact that the research raters were nt part f the clinical treatment teams makes this less f a cncern, as des the bservatin that grup differences in utcmes varied acrss utcme dmains. Because patients in the and grups were nt randmly assigned r matched and were chsen n the basis f smewhat different inclusin criteria, grup differences culd have affected the results. The statistical prcedures attempted t cntrl fr grup differences by cntrlling fr selected cvariates, including need fr services, predispsing factrs, enabling factrs, and ther demgraphic variables. While cautin is recmmended when statistical cntrls are used instead f randm assignment, the changes between unadjusted and adjusted estimates f initial and grwth effects were small, indicating that the declining effects mdel applied t these data is rbust. Last, we wish t reemphasize that the results presented here are fr and as actually implemented in these tw grups f patients. The results reflect what was achieved with relatively mdest additinal resurces in an underresurced system, using guidelines that clinicians likely implemented t varying degrees. 643

18 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. Table 9. Unadjusted percentage using medicatins at any time during study and average maximum dse (SD) 1 Medicatin Grup Percentage using Dse Olanzapine (9.7) 16.6(9.0) vs. x 2 =12.5, 1 df, p = ,132 = 9-4 p = Risperidne (2.6) 5.2 (4.0) vs. X 2 = 0.01,1 df, p = '1.95=1-7 p = Quetiapine vs. Clzapine vs. Halperidl vs. Thithixene vs X 2 =31.3, 1 df, p< X 2 = 4.7, 1 df, p = X 2 = 2.5, 1 df, p = X 2 = 2.3, 1 df, p = (292.5) (208.0) V= 1-7 p= (201.0) (408.0) '1.5 = 0.7 p = (11.0) 11.5(10.7) '1,25 =0-02 p = (10.6) 21.0(16.7) f i 3 = 0.8 p = Nte. - algrithm-guided treatment; BPRS 18 = 18-item Brief Psychiatric Rating Scale; SD» standard deviatin; = treatment as usual. 1 Frequencies (%) f prescriptins fr antipsychtics after the initial visit, fr all antipsychtics where the sum f + was 210% during the first quarter. The percentage receiving medicatin was analyzed using a lgistic regressin. Treatment grup was used as a predictr f use/nnuse f medicatin alng with baseline BPRS 18, age, family size, dispsable incme, years f educatin, Patient Perceptin f Benefits, gender, African-American status, and Hispanic status. The dses are the average highest dse f the antipsychtic during the study. Patients wh did nt receive at least ne pstbaseiine dse f the medicatin are nt included in the dse analysis fr that medicatin. An analysis f cvariance was used fr dse with the same cvariates listed abve. Subsequent analyses will examine the relative csts f the Alphs, L.D.; Summerfelt, A.; Lann, H.; and Muller, R.J. interventins and f resurce utilizatin in the and The Negative Symptm Assessment: A new instrument t grups. assess negative symptms f schizphrenia. Psychpharmaclgy Bulletin, 25(2): , References American Psychiatric Assciatin. Practice guidelines fr the treatment f patients with schizphrenia. American Addingtn, D.; Addingtn, J.; and Maticka-Tyndale, E. Jurnal f Psychiatry, 154(4)(Suppl):l-63, Assessing depressin in schizphrenia: The Calgary Andreasen, N.C. Negative symptms in schizphrenia: Depressin Scale. British Jurnal f Psychiatry, Definitin and reliability. Archives f General Psychiatry, 163(Suppl 22):39-44, : ,

19 The Texas Medicatin Algrithm Prject Schizphrenia Bulletin, Vl. 30, N. 3, 2004 Bauer, M.S. A review f quantitative studies f adherence t mental health clinical practice guidelines. Harvard Review f Psychiatry, 10: , Benedict, R.H.B.; Schretlen, D.; Grninger, L.; and Brandt, J. Hpkins Verbal Learning Test Revised: Nrmative data and analysis f inter-frm and test-retest reliability. Clinical Neurpsychlgist, 12(1 ):43 55, Bilder, R.M.; Gldman, R.S.; Vlavka, J.; Czbr, P.; Hptman, M.; Sheitman, B.; Lindenmayer, J.P.; Citrme, L.; McEvy, J.; Kunz, M.; Chaks, M.; Cper, T.B.; Hrwitz, T.L.; and Lieberman, J.A. Neurcgnitive effects f clzapine, lanzapine, risperidne, and halperidl in patients with chrnic schizphrenia r schizaffective disrder. American Jurnal f Psychiatry, 159: ,2002. Buchanan, R.W.; Kreyenbuhl, J.; Zit, J.M.; and Lehman, A. Relatinship f the use f adjunctive pharmaclgical agents t symptms and level f functin in schizphrenia. American Jurnal f Psychiatry, 159(6): , Cadle, CD.; Velligan, D.I.; DiCcc, M.A.; Bw- Thmas, C.C.; and Miller, A.L. The reliability and validity f a brief cgnitive assessment. [Abstract]. Schizphrenia Research, 53(Suppl):125, Cradck, J.; Yung, A.S.; and Sullivan, G. The accuracy f medical recrd dcumentatin in schizphrenia. Jurnal f Behaviral Health Services & Research, 28(4): , Csernansky, J.G.; Mahmud, R.; and Brenner, R. A cmparisn f risperidne and halperidl fr the preventin f relapse in patients with schizphrenia. New England Jurnal f Medicine, 346:16-22, Frances, A.; Dcherty, J.P.; and Kahn, D.A. Expert cnsensus guidelines series: Treatment f schizphrenia. Jurnal f Clinical Psychiatry, 57(Suppl 12B):5-58, Gilbert, D.A.; Altshuler, K.Z.; Rag, W.V.; Shn, S.P.; Crismn, M.L.; Tprac, M.G.; and Rush, A.J. Texas Medicatin Algrithm Prject: Definitins, ratinale, and methds t develp medicatin algrithms. Jurnal f Clinical Psychiatry, 59: , Green, M.F. What are the functinal cnsequences f neurcgnitive deficits in schizphrenia? American Jurnal f Psychiatry, 153(3): , Green, M.F.; Marder, S.R.; Glynn, S.M.; McGurk, S.R.; Wirshing, W.C.; Wirshing, D.A.; Liberman, R.P.; and Mintz, J. The neurcgnitive effects f lw-dse halperidl: A tw-year cmparisn with risperidne. Bilgical Psychiatry, 51(12): , Kashner, T.M.; Carmdy, T.J.; Suppes, T.; Rush, A.J.; Crismn, M.L.; Miller, A.L.; Tprac, M.G.; and Trivedi, M.H. Catching-up n health utcmes: The Texas Medicatin Algrithm Prject. Health Services Research, 38: ,2003. Kay, S.R.; Fiszbein, A.; and Opler, L.A. The Psitive and Negative Syndrme Scale (PANSS) fr schizphrenia. Schizphrenia Bulletin, 13(2): , Lehman, A.F., and Steinwachs, D.M. Translating research int practice: The Schizphrenia Patient Outcmes Research Team treatment recmmendatins. Schizphrenia Bulletin, 24(1): 1-10, Lezak, M.D. Neurpsychlgical Assessment. New Yrk, NY: Oxfrd University Press, Miller, A.L.; Chiles, J.A.; Chiles, J.K.; Crismn, M.L.; Rush, A.J.; and Shn, S.P. The Texas Medicatin Algrithm Prject (TMAP) schizphrenia algrithms. Jurnal f Clinical Psychiatry, 60(10): , Overall, J.E., and Grham, D.R. The Brief Psychiatric Rating Scale. Psychlgical Reprts, 10: , Purdn, S.E.; Jnes, B.D.; Stip, E.; Labelle, A.; Addingtdn, D.; David, S.R.; Breier, A.; Tllefsn, G.D.; and the Canadian Cllabrative Grup fr Research in Schizphrenia. Neurpsychlgical change in early phase schizphrenia during 12 mnths f treatment with lanzapine, risperidne, r halperidl. Archives f General Psychiatry, 57: , Reitan, R.M. The relatin f the trail making test t rganic brain damage. Jurnal f General Psychiatry, 53:97-107, Reitan, R.M. The validity f the trail making test as an indicatr f rganic brain damage. Perceptual and Mtr Skills, 8: , Rush, A.J.; Crismn, M.L.; Kashner, T.M.; Tprac, M.G. Carmdy, T.J.; Trivedi, M.H.; Suppes, T.; Miller, A.L. Biggs, M.M.; Shres-Wilsn, K.; Witte, B.; Shn, S.P. Rag, W.V.; and Altshuler, K.Z. Texas Medicatin Algrithm Prject, phase 3 (TMAP-3): Ratinale and study design. Jurnal f Clinical Psychiatry, 64: , Rush, A.J.; Rag, W.V.; Crismn, M.L.; Tprac, M.G.; Shn, S.P.; Suppes, T.; Miller, A.L.; Trivedi, M.H.; Swann, A.C.; Biggs, M.M.; Shres-Wilsn, K.; Kashner, T.M.; Pigtt, T.; Chiles, J.A.; Gilbert, D.A.; and Altshuler, K.Z. Medicatin treatment fr the severely and persistently mentally ill: The Texas Medicatin Algrithm Prject. Jurnal f Clinical Psychiatry, 60: , Selzer, M.J. The Michigan Alchlism Screening Test: The quest fr a new diagnstic instrument. American Jurnal f Psychiatry, 127:89-95,

20 Schizphrenia Bulletin, Vl. 30, N. 3, 2004 A.L. Miller et al. Siris, S.G. Depressin in schizphrenia: Perspective in the era f "atypical" antipsychtic agents. American Jurnal f Psychiatry, 157: ,2000. Skinner, H.A. The drug abuse screening test. Addictive Behavirs, 7: , Suppes, T.; Swann, A.C.; Dennehy, E.B.; Habermacher, E.D.; Masn, M.; Crismn, M.L.; Tprac, M.G.; Rush, A.J.; Shn, S.P.; and Altshuler, K.Z. Texas Medicatin Algrithm Prject: Develpment and feasibility testing f a treatment algrithm fr patients with biplar disrder. Jurnal f Clinical Psychiatry, 62:439^47, Tllefsn, G.D.; Beasley, CM.; Tran, P.V.; Street, J.S.; Krueger, CM.; Tamura, R.N.; Graffe, K.A.; and Thieme, M.E. Olanzapine versus halperidl in the treatment f schizphrenia and schizaffective and schizphrenifrm disrders: Results f an internatinal cllabrative trial. American Jurnal f Psychiatry, 154{4): , Tprac, M.G.; Rush, A.J.; Cnner, T.M.; Crismn, M.L.; Dees, M.; Hpkins, C; Rwe, V.; and Shn, S.P. The Texas Medicatin Algrithm Prject Patient and Family Educatin Prgram: A cnsumer-guided initiative. Jurnal f Clinical Psychiatry, 61:477^86, Velligan, D.I.; Mahurin, R.K.; Diamnd, PL.; Hazletn, B.C.; Eckert, S.L.; and Miller, A.L. The functinal significance f symptmatlgy and cgnitive functin in schizphrenia. Schizphrenia Research, 25:21-31, Ventura, J.; Lukff, D.; Nuechterlein, K.H.; Liberman, R.P.; Green, M.E; and Shaner, A. Manual fr the expanded Brief Psychiatric Rating Scale. Internatinal Jurnal f Methds in Psychiatric Research, 3: , Ware, J.E.; Ksinski, M.; and Keller, S.D. A 12-item shrt-frm health survey (SF-12): Cnstructin f scales and preliminary tests f reliability and validity. Medical Care, 34: , Yung, A.S.; Sullivan, G.; Burman, M.A.; and Brk, R. Measuring the quality f utpatient treatment fr schizphrenia. Archives f General Psychiatry, 55(7): , Acknwledgments Results f this study were presented in part at the annual meeting f the American Cllege f Neurpsychpharmaclgy, San Juan, Puert Ric, December 12, 2000, and at the annual meeting f the American Psychiatric Assciatin, New Orleans, LA, May 7, This research was supprted by Natinal Institute f Mental Health Grant MH-53799, the Rbert Wd Jhnsn Fundatin, the Meadws Fundatin, the Lightner-Sams Fundatin, the Nanny Hgan Byd Charitable Trust, the Texas Department f Mental Health and Mental Retardatin, the Center fr Mental Health Services, the Department f Veterans Affairs, a Health Services Research and Develpment Research Career Scientist Award (RCS92^H)3) (T.M.K.), the Betty J Hay Distinguished Chair in Mental Health and the Rsewd Crpratin Chair in Bimedical Science (A.J.R.), the United States Pharmacpeia] Cnventin, Mental Health Cnnectins (a partnership f Dallas Cunty and Texas State mental health authrities with the Department f Psychiatry f the University f Texas Suthwestern Medical Center, funded by the Texas State Legislature and the Dallas Cunty Hspital District), the University f Texas at Austin Cllege f Pharmacy, and the Suthwestern Drug Crpratin Centennial Fellwship in Pharmacy (M.L.C.). The fllwing pharmaceutical cmpanies prvided unrestricted educatinal grants: Abbtt Labratries, AstraZeneca, Bristl-Myers Squibb, Eli Lilly and Cmpany, Frest Labratries, GlaxSmithKline, Janssen Pharmaceutica, Nvartis, Organn, Pfizer, and WyethAyerst Labratries. We deeply appreciate the cnsultatins prvided by Barbara Bums, Ph.D., Rbert Drake, M.D., Susan Essck, Ph.D., William Hargreaves, Ph.D., Teh-wei Hu, Ph.D., Anthny Lehman, M.D., and Greg Teague, Ph.D., withut whse expertise this study culd nt have been accmplished. We als wish t thank the Natinal and Texas Alliance fr the Mentally HI and the Natinal and Texas Depressive and Manic Depressive Assciatin, fr prviding patient and family educatinal materials. We appreciate greatly the assistance f Gus Sicard, Ph.D., fr his translatin f the educatinal, clinical, and research evaluatin materials int Spanish. We thank Karla Starkweather, TMAP Cmmunicatins Directr, Texas Department f Mental Health and Mental Retardatin, Austin, fr invaluable assistance in the cnduct f this study. Mst imprtant, we wish t express ur gratitude t the persnnel at each Cmmunity Mental Health Center fr allwing us t cnduct this research: Andrews Center, Tyler, Center fr Health Care Services, San Antni; Life Management Center, El Pas; Lubbck Reginal MHMR Center, MHMRA f Harris Cunty, Hustn; Tri- Cunty MHMR Center, Cnre; and Trpical Texas MHMR Services, Edinburg, Harlingen, and Brwnsville. We appreciate the secretarial supprt f FastWrd (Dallas) and David Savage, and thank Andrew Sedill, M.D., fr establishing the TMAP Web site ( dshs.state.tx.us/rnhprgrarns/tmaptc.shtm). We wuld als like t thank the ther Assistant Mdule Directrs: Sherwd Brwn, M.D., Ph.D., and Teresa Pigtt, M.D.; and the Algrithm Management Team Crdinatrs: Judith Chiles, B.S.N., Ellen Dennehy, Ph.D., Ellen Habamacher, B.S., and Trade Key, B.S.N., R.N. 646