Neurocognitive Assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project Schizophrenia Trial: Development, Methodology, and Rationale

Neurocognitive Assessment in the ClinicalAntipsychotic Trials of Intervention

Effectiveness (CATIE) Project SchizophreniaTrial: Development, Methodology,

and Rationale

by Richard S.E. Keefe, Richard C. Mohs, Robert M. Bilder, Philip D. Harvey,Michael F. Qreen, Herbert Y. Melt^er, James M. Qold, and Mary Sano

Abstract

Patients with schizophrenia are severely impaired incrucial aspects of neurocognitive function. Thisimpairment is the strongest clinical correlate of poorlong-term outcome and adaptive dysfunction. Reportsof neurocognitive enhancement with second generationantipsychotic medications have thus offered promisefor improvement in the long-term outcome of patientswith schizophrenia. However, the majority of thesestudies have had serious weaknesses in methodology,such as open-label design, small samples, or inappro-priate dosing of medications. More recent studies haveaddressed these methodological issues but have been ofshort duration and have largely been sponsored bypharmaceutical companies. The Clinical AntipsychoticTrials of Intervention Effectiveness (CATIE) project isa unique opportunity to address the comparative neu-rocognitive effectiveness of available antipsychoticmedications. This article describes the neurocognitivemethods used hi the schizophrenia trial of the CATTEproject, including the selection and training of neu-rocognitive raters, patient inclusion criteria for assess-ment, rationale for the choice of neurocognitive instru-ments, and methodology for each neurocognitive test

Keywords: Neurocognitive function, cognition,antipsychotic medications, neuropsychology, schizo-phrenia, clinical trials.

Schizophrenia Bulletin, 29(l):45-55, 2003.

Neurocognitive functioning in schizophrenia is severelyimpaired. In several landmark studies, the severity of cog-nitive impairment has reached two standard deviationsbelow the mean in crucial aspects of cognitive functions(e.g., Saykin et al. 1991). Even meta-analytic techniques,

which tend to underestimate the size of a statistical effect,have suggested that patients with schizophrenia performmore than a full standard deviation below the normal meanin numerous areas of neurocognitive ability (Heinrichs andZakanis 1998). Neurocognitive impairment is present atthe first episode of psychosis, and many cognitive domainsmay be as severely impaired in first episode patients as inpatients with chronic schizophrenia (Hoff et al. 1992;Saykin et al. 1994; Bilder et al. 2000).

Neurocognitive impairment is associated with variousaspects of schizophrenia. Patients with more severe cogni-tive deficits tend to have more severe negative symptoms(Manschreck et al. 1985; Addington et al. 1991; Strauss1993) and symptoms of disorganization (Spitzer 1993),and worse adaptive dysfunction (Green 1996). While thecorrelations between severity of general cognitive deficitsand positive symptoms have usually been nonsignificant ornegative, some aspects of cognitive impairment, such asworking memory, may also be associated with the severityof positive symptoms (Bressi et al. 1996; Carter et al.1996). Most important, the severity of cognitive deficits inschizophrenia is associated with various aspects of pooroutcome, such as the inability to acquire skills, poor socialproblem-solving, and poor community functioning (Green1996; Green et al. 2000). In fact, cognitive impairmentmay be a better predictor of poor outcome than any othersymptom domain (Green 1996).

Nearly 50 years of research has indicated that firstgeneration antipsychotics at standard doses provide littlebenefit with regard to the cognitive disturbances ofpatients with schizophrenia (Medalia et al. 1988; Cassenset al. 1990; Blyler and Gold 2000). However, second gen-

Send reprint requests to Dr. R. Keefe, Box 3270, Duke UniversityMedical Center, Durham, NC 27710, e-mail: [email protected].

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eration antipsychotic medications may significantlyimprove cognitive performance in patients with schizo-phrenia. Clozapine (Buchanan et al. 1994; Lee et al.1994), risperidone (Green et al. 1997; Kern et al. 1998;Purdon et al. 2000), and olanzapine (Meltzer and McGurk1999; Purdon et al. 2000) treatments are associated withimproved cognitive performance in patients with schizo-phrenia. A meta-analysis of studies assessing the cognitiveeffects of second generation antipsychotics, primarilyclozapine or risperidone, suggested significant improve-ment in cognition with the second generation medicationseven when the results of each study were corrected formultiple comparisons (Keefe et al. 1999). Data publishedafter this meta-analysis was completed suggest thatolanzapine and quetiapine may have cognitive perform-ance-enhancing properties that are at least as substantialas those reported with risperidone and clozapine (Sax et al.1998; Meltzer and McGurk 1999; Velligan and Miller1999; Purdon et al. 2000; Purdon et al., in press; Keefe etal., submitted). It should be noted, however, that the effectsizes for neurocognitive improvement with second genera-tion antipsychotics compared to first generation antipsy-chotics are estimated to be small to medium (Harvey andKeefe 2001), and some have questioned whether these rel-ative improvements with the second generation drugs arenot secondary to other clinical changes, such as decreasedextrapyramidal symptoms (EPS), decreased anticholiner-gic use, and improved negative symptoms that are associ-ated with freedom from first generation drugs (Harvey andKeefe 2001; Carpenter and Gold 2002).

One of the goals of the Clinical Antipsychotic Trialsof Intervention Effectiveness (CATTE) project is to deter-mine the relative impact of the available antipsychoticmedications on relevant outcomes in schizophrenia, partic-ularly with regard to those outcomes that result inincreased effectiveness. Because cognitive impairment hasbeen found to be strongly associated with functional abil-ity, it is possible that cognitive improvement may be oneof the key elements of long-term effectiveness. Surpris-ingly, few studies have demonstrated a relationshipbetween treatment-related cognitive improvement andlong-term improvement in functional outcome or qualityof life (Buchanan et al. 1994; Meltzer and McGurk 1999),and no study with double-blind methodology or randomassignment of medication has demonstrated that any of theavailable antipsychotic medications improve cognitivefunction in patients in general, with those improvementssignificantly correlated with better long-term outcomes.The type of study that would be required to assess theseaspects of effectiveness longitudinally with a sample sizesubstantial enough to generate adequate power is veryrare. The CAilfc project presents an ideal opportunity todetermine the relative impact of antipsychotic medications

on cognition and to evaluate the impact of cognitiveimprovement (or worsening) on measures of treatmenteffectiveness.

In this article, we describe the rationale, development,and methodology for assessing neurocognitive function inthe CATIE project.

Neurocognitive Advisory Group

The choice of tests for a neurocognitive battery is oftencontroversial. Because this project promises to yield apotentially rich data base, it was important that the batter-ies of tests chosen for the project be approved by leaders inschizophrenia and dementia research. It was determinedthat approval of the batteries and the neurocognitiveapproach for the trials would be particularly importantgiven that numerous independent investigators may desireaccess to the neurocognitive data base for ancillary stud-ies. Thus, the first step in determining the methodology forneurocognitive assessment in the CATTE project was toappoint and convene a Neurocognitive Advisory Group(NAG), in concert with National Institute of Mental Health(NIMH) staff and the External Scientific Advisory Board.NAG comprises the following individuals: Richard Keefe(director), Richard Mohs (formerly codirector, currently aconsultant to NAG), Robert Bilder, Terry Goldberg,Michael Green, Philip Harvey, Herbert Meltzer, and MarySano. James Gold also joined the meeting as an ad hocmember to help align the neurocognitive battery of theCATTE project with the battery of tests used for the NIMHTreatment of Negative Symptoms and Cognitive Impair-ments project, which is investigating the cognitive effectsof glycine and d-cycloserine in patients with schizophre-nia. This group met on January 10, 2000, to discuss theresearch design and the batteries of tests to be used for theschizophrenia and dementia clinical trials. In addition,because various methodological challenges are intrinsic tothe neurocognitive component of clinical trial research, theconsultants used this opportunity to discuss several rele-vant assessment issues: tester training and certificationmethods, the development of specific exclusion criteria forthe neurocognitive component of the study, bilingual test-ing, optimal test batteries, and the overlap of test con-structs between separate trials of different disorders.

Assessment Training

Overview. The aim of the CATIE NeurocognitiveAssessment Unit training program is for testers and inves-tigators to achieve a thorough understanding of the ratio-nale and methods of the neurocognitive assessment proto-col. Considerable preparation preceded the production of

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manuals and training materials. The basic manuals anddata forms not only document planned procedures foreach study but also serve as source documents for trainingin-house and site staff. The proper training of site person-nel responsible for collecting, editing, and transmittingdata is essential for ensuring a high-quality study.Accordingly, prior to enrollment of subjects at any of thesites, the Neurocognitive Assessment Unit trained siteinvestigators and staff on all aspects of study design andimplementation of neurocognitive assessments. Our phi-losophy was that training in multisite studies is mosteffective when it occurs in close temporal proximity tothose critical points in the study timeline when site staffmust acquire specific knowledge and skills in order toimplement study tasks. Based on protocol design and siteparticipation in multiple protocols, approximately 100sites required neurocognitive tester certification: 65 in theschizophrenia trial, and 35 in the dementia trial. Toincrease cost efficiency and to ensure timely startup,testers were also certified based upon their prior involve-ment in studies using similar neurocognitive instruments.This reduced individual tester evaluations to 85 testers.

Specifics of Training Plan. All potential neurocognitivetesters completed a Tester Evaluation Form to ensure thatthey had sufficient experience to collect accurate cogni-tive data from the relevant patient populations. Potentialtesters were scheduled for group and individual trainingby the Neurocognitive Assessment Unit staff at theInvestigator Meeting. To help approved testers prepare forthe meeting and training, each site was sent copies of theneurocognitive assessment manual and instructionalvideotape prior to the meeting. The manual includesdescriptions of how to administer and score each test,score sheets if required, and detailed instructions forpreparing and sending the raw test materials for dataentry. The videotape demonstrating the test procedures foreach test in the battery serves as a training and referencetool. It has also been useful as a training aid for newtesters who did not attend the initial training meetings.Testers were informed that prior to the collection of neu-rocognitive data at their site, they would need to be certi-fied for their ability to complete each of the tests of thetest battery.

Training Meeting. The details of the final batteries werepresented during the Neurocognitive Assessment Trainingat the Investigator Meeting. Testers from each investiga-tive site attended this meeting to learn, practice, andbecome expert in the administration and scoring proce-dures for the diagnosis-specific neurocognitive batteries.The meeting included a presentation of all testing andscoring procedures to the group. Following this presenta-

tion, testers had opportunities to practice the tests in smallgroups supervised by psychologists fully familiar with theentire battery. Although many of the testers had extensiveexperience with the tests in the battery, or with psycholog-ical assessment in general, all were required to pass certi-fication procedures. The rationale of this certification wasexplained to testers: even highly qualified psychologistscan develop idiosyncratic data collection methods thatmay thus differ from site to site. Testers were instructedthat although their method may indeed be superior to themethod established for this trial, consistency across sitesis the overriding goal.

Certification of Testers. Testers were told that theywould be expected to master the testing procedures priorto the initiation of the trial at their site. To verify masteryof all testing procedures, all testers met individually witha Neurocognitive Assessment Unit evaluator to determinewhether they were satisfactorily proficient with the neu-rocognitive testing batteries. Each potential tester admin-istered the complete neurocognitive battery to the neu-rocognitive evaluator, who demonstrated some of thechallenges that could be expected when testing patientswith schizophrenia. A list of particularly important chal-lenges was made prior to the meeting as a reference forevaluators, so that each potential tester would be given theopportunity to be tested similarly. For example, testerswere challenged by "patients" who deviated from therules in various ways, or who had sudden decrements inperformance. Testers who failed the initial certificationprocedures were given an opportunity to practice testadministration and scoring procedures during the meeting,and then later attempt to be recertified. Certified testerswere sent a document indicating that they were permittedto conduct neurocognitive testing for the CATTE project

Following initial certification, each tester wasrequired to send the computer test files, source documents,and summary score sheets from the first five completedassessments. Data collection and scoring procedures wereaudited by following each measure from the raw testingmaterial or response sheet, through the relevant scoringprocedures, to the recording of the data on summary scoresheets, to the online data from the computer data base.These results were reviewed by the NeurocognitiveAssessment Unit personnel, and any errors were correctedwith a full explanation of the necessary changes. Testerswere required to complete five consecutive testing sessionswithout error.

Postmeeting Certification. A small number of testerswere not able to attend the initial Investigator Meeting.Arrangements were made for these testers to follow thesame procedures as those who attended the meeting, with

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the exception that Neurocognitive Assessment Unit per-sonnel visited these sites to conduct the same certificationprocedures as had been completed at the meeting. Theseprocedures and the necessary documents were made avail-able to new sites via the CATIE website.

Several sites requested the certification of an addi-tional tester to perform testing in the event of vacation,sickness, or other potential absence of the primary tester.All additional and replacement testers underwent the sameevaluation procedures. These procedures, made availableto all principal investigators and testers on the CATIEwebsite, are as follows: complete a form assessing testingexperience and send it to the Neurocognitive AssessmentUnit; obtain a copy of the most recent version of the man-ual and review the manual, testing procedures, instruc-tional video, and tests with the help of a Certified Tester;following intensive practice, test the Certified Tester, testan individual under the supervision of the Certified Tester;and finally, contact the Neurocognitive Assessment Unit toarrange a Phone-Questionnaire Interview.

Initial and Ongoing Site Interaction and AssessmentThe performance of neurocognitive testers has been moni-tored during the study, and any administration and scoringproblems have largely been addressed and resolved asthey occur. Neurocognitive Assessment Unit staff areavailable on a daily basis by telephone or e-mail to answerquestions or issues that may occur at the sites.

A few weaknesses in the clarity of the neurocogni-tive procedure instructions have been communicated tothe CATTE Neurocognitive Assessment Unit throughoutthe course of the study. These issues have precipitatedcommunications from the Unit to all testers and princi-pal investigators in the form of letters or mass e-mails.In addition, the certification procedures and relevantupdates are made available to testers on the CATTE web-site.

Raw data from each site are entered directly into thedata base using a web-based data entry system. As anadditional check on the quality of neurocognitive data,the Neurocognitive Assessment Unit has made randomrequests for testers to send the source documents andsummary scores for patients tested in the study. Thesescores are compared to those recorded in the electronicdata base for the study.

Neurocognitive Assessment Procedures

Testers. NAG recommended that two testers be used fromeach site and that the same tester should complete theassessments for a particular patient, especially at the base-line and 8-week assessments for the schizophrenia trial.

Timing of Assessments. The timing of neurocognitiveassessments presented a unique challenge, becausepatients could potentially change phases of the study, andthus the antipsychotic medication they received, at leastthree times during their participation in the study (Stroupet al., this issue). The group weighed the merits of follow-ing an "effectiveness model" by maintaining a fixedassessment schedule based upon the initial randomizationof a patient to a specific study arm, versus the merits of an"efficacy model" of renewing the time schedule each timea patient entered a new treatment phase of the study. Thefavorable component of the effectiveness approach wasthat the neurocognitive effects of the initial treatment ran-domization could be determined with parallel timing in allpatients. The unfavorable component was that thisapproach would preclude direct determination of the neu-rocognitive effects of changes in antipsychotic medicationthat occurred in later phases of the study. However, thegroup also acknowledged that restarting the testing sched-ule each time a patient entered a new phase of the studywas likely to produce a greatly variable baseline level ofperformance that could be explained by a patient's previ-ous treatment and was thus not random. We decided on amix of the two. Because little was (and is) known aboutthe relative short-term impact of the available antipsy-chotics on cognition, the group determined that the effec-tiveness model would be followed, with additional assess-ments after 2 months of treatment in the second phase ofthe study. This strategy would enable a larger data basefor investigating the relative impact of antipsychotics dur-ing a time period consistent with standard treatmentchoices.

While the baseline neurocognitive assessments will beaffected by numerous factors such as substance abuse, pre-vious polypharmacy, and variable clinical state, the groupfelt that baseline neurocognitive assessments should becollected on all patients when possible. Without baselinedata, we would not be able to determine if differencesacross treatment groups at this stage were due to differen-tial short-term effects on cognition, or due to baseline neu-rocognitive differences across groups. A relatively earlyfollowup assessment of 2 months would meet these twopurposes.

In sum, the group suggested the following timesequence of neurocognitive assessments for the schizo-phrenia trial, based upon time from randomization: base-line, 2 months, 6 months, and 18 months or end of study.For patients who enter a second phase of the study, testingis also conducted after 2 months in the second phase. Ifthere is temporal overlap of less than 1 month between anassessment that is based upon the initial schedule and thephase 2, month 2 assessment, only one of the assessmentsis performed.

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Inclusion Criteria

Spanish-Speaking Subjects. The group decided that,when possible, it would be important to test patients whouse Spanish as their primary language. A manual forSpanish-speaking subjects in the United States was devel-oped with assistance from a cross-cultural neuropsycholo-gist, Dr. Lidia Artiola. For those tests not available inSpanish, test instructions, materials, and procedures weretranslated into Spanish. Sites with testers who planned totest patients in Spanish were required to demonstrate test-ing competency in Spanish and English.

Assessment of Primary Language. In patients for whomEnglish is not die primary language, the group determinedthat English testing could proceed if a sixth grade readinglevel using the Wide Range Achievement Test, third edi-tion (WRAT-ffl), Reading test (Wilkinson 1993) wasdemonstrated.

Pervasive Developmental Disorder. The group deter-mined that patients who have received a diagnosis of per-vasive developmental disorder (mental retardation) shouldbe excluded.

Adjunctive Medications. Regarding adjunctive medica-tions during the trial, the group suggested that medica-tions used continually, such as anticholinergics, wereacceptable. Medications used infrequently, such as one-time use of benzodiazepines for anxiety, might interferewith test performance, and were not to be given on theday of testing.

Previous Testing Experience. Patients who have participatedin neurocognitive research studies with repeated assessmentsof the measures in this study might perform at higher thanexpected levels. An assessment of previous experience (withinthe past 6 months) with the tests in the neurocognitive batterywas included in the neurocognitive protocol.

Neurocognitive Assessment Battery

The proposed neurocognitive assessment battery for thistrial was developed as a result of the meetings of NAG andthe Neurocognitive Assessment Unit. A number of guide-lines were used to facilitate the selection of tests. Theseguidelines are based on the suggestions of Mohs (1995),Davidson and Keefe (1995), and Keefe et al. (1999)regarding the use of neurocognitive measures to assesstreatment response. The guidelines include (1) adequatepsychometric properties of the procedure, including mini-mal ceiling and floor effects in the diagnostic group being

studied; (2) reliability in the diagnostic group being stud-ied; (3) known deficits compared to normal controls in thediagnostic group being studied; (4) minimal test-retestpractice effects and/or availability of alternate forms; (5)ease of administration to reduce examiner error acrosssites; (6) brevity; (7) relevance to the clinical populationbeing studied; (8) relevance to specific hypotheses aboutthe effect of second generation antipsychotic treatment oncognition in the group being studied; (9) relation to impor-tant outcome variables, such as community functioning;(10) previous suggestions that second generation or firstgeneration antipsychotic treatments have a possible posi-tive or negative impact on the functions measured by thetest; and (11) if possible, available normative data.

Computerized Assessments. One discussion pointamong the group members was the risk/benefit of comput-erized versus pencil-and-paper testing. Several groupmembers expressed concerns about computerized testinggiven their previous experiences with computerized testsoften resulting in more missing data points than noncom-puterized tests. We ultimately chose a combination of thetwo methods. To minimize some of the difficulties causedby tests administered from variable computers and soft-ware platforms, we purchased 65 desktop computers,developed and installed the software for the computerizedtests at the Neurocognitive Assessment Unit, and shippedthe test-ready computers to each site. This methodallowed us to maintain consistent computerized test con-ditions across sites and ensured that novel software-hard-ware interaction difficulties would be minimized through-out the course of the study.

Neurocognitive Assessments

The following assessments are completed at the baselinevisit only: education level; previous experience with thetests in the neurocognitive battery; and the WRAT-IIIReading subtest. To complete the WRAT-III Reading sub-test, patients simply read aloud a series of letters andwords of increasing difficulty. If for some reason theseassessments cannot be completed at the baseline visit, theycan be completed at a subsequent visit.

The following neurocognitive tests are given at eachneurocognitive visit in the order listed. The battery is esti-mated to take an average of 90 minutes.

Controlled Oral Word Association Test (PhonologicalFluency)

Category Instances (Category Fluency)Wechsler Intelligence Scale for Children-third edition

(WISC-m) MazesLetter-Number Span Test

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Hopkins Verbal Learning TestFace Emotion Discrimination Task (FEDT)Wechsler Adult Intelligence Scale-Revised

(WAIS-R) Digit Symbol TestGrooved PegboardComputerized Continuous Performance Test (CPT)Computerized Test of Visuospatial Working MemoryComputerized Wisconsin Card Sorting Test (WCST)

The neurocognitive functions and the recommendedtests to measure them for the schizophrenia trial aredescribed below. (The tests are not described in order ofadministration.)

Verbal Fluency. Verbal fluency is severely impaired inpatients with psychotic disorders and dementia. One ofthe most robust effects of second generation antipsychoticmedication on cognition is the improvement of verbal flu-ency (Keefe et al. 1999; Harvey and Keefe 2001). Evenafter the analyses from all studies were corrected for mul-tiple comparisons, four of six studies demonstrated signif-icant improvement on verbal fluency measures with cloza-pine.

Controlled Oral Word Association Test (Bentonand Hamscher 1978). Subjects are asked to generate asmany words as possible that start with a given letter (F, A,or S) in each of three 60-second trials. Measures: numberof correct words generated in each category.

Category Instances (Benton and Hamscher 1978).In three separate trials, subjects are given 60 seconds togenerate as many words as possible within the categoriesof animals, fruits, and vegetables. Measures: number ofcorrect words generated in each category (Benton andHamscher 1978).

Working Memory. Working memory has been describedas a fundamental aspect of cognition (Goldman-Rakic1987). Recent developments in the understanding of pre-frontal functions in humans have followed extensive workon the neural circuitry underlying working memory func-tion and dysfunction. Although conventional antipsy-chotics block dopamine receptors in the prefrontal cortex,and this has been found to impair working memory func-tions in nonhuman primates under normal conditions(Sawaguchi and Goldman-Rakic 1994), conventionalantipsychotics do not impair or improve working memoryfunctions in patients with schizophrenia when given atusual doses (see reviews by Medalia et al. 1988; Cassenset al. 1990; Goldberg and Weinberger 1996). The evi-dence to support clozapine-related enhancement of work-ing memory functions is weak. While one study reportedimprovement in all cognitive tests, including auditoryconsonant trigrams, with clozapine treatment (Galletly et

al. 1997), other work suggests that treatment with cloza-pine does not improve verbal working memory asassessed by auditory consonant trigrams (Hagger et al.1993; Lee et al. 1994) or digits backward (Grace et al.1996). Risperidone may improve verbal, visuospatial, andcentral executive aspects of working memory functions.Risperidone treatment had a greater beneficial effect thanhaloperidol treatment on verbal working memory asassessed by a digit span distraction test (Green et al.1997) and digits backward (Rossi et al. 1997). Data fromMeltzer and McGurk (1999) suggest that in patients withschizophrenia, risperidone may also improve visuospatialworking memory functions. Thus, preliminary work indi-cates that various aspects of working memory may beimproved by treatment with risperidone. The neurocogni-tive battery includes two measures of working memory.

Letter-Number Span test of auditory workingmemory (Gold et al. 1997). Patients are presented aurallywith clusters of letters combined with numbers (e.g.,N6G2). They are asked to reorder the cluster and tell theexperimenter the numbers first, from lowest to highest,then the letters in alphabetical order. Measure: number ofcorrect sequences.

Computerized test of visuospatial working mem-ory (Hershey et al. 1999). Subjects must focus on a cen-tral fixation cross on a computer screen. While the cross isfixated, a cue appears for 150 ms in one of 32 possiblelocations at a 4.5-inch radius from the central fixation. Adelay period (5 or 15 seconds) is then imposed. Duringthe delay, a series of geometric shapes appears in place ofthe fixation cross. The subject must press the spacebarwhenever the diamond shape appears. After the delay, thefixation cue returns, and the subjects must point on thecomputer screen to where they remember seeing the cue.On the cue-present trials the cue is present during theresponse phase. This set of trials gives an indication ofsubjects' pointing accuracy. Mean error in millimeters(distance between recall and actual target) is calculatedfor each subject for each type of trial. There are eight tri-als at each delay and eight cue-present trials. Measures:mean error for each type of trial.

Verbal Learning and Memory. Verbal memory is severelyimpaired in schizophrenia (Saykin et al. 1991) and dementia(Mohs et al. 1997) and is significantly associated with out-come in patients with schizophrenia (Green 1996).Improvement in verbal memory with any of the second gen-eration antipsychotic medications would be of great value.One study showed improvement of declarative verbal learn-ing/memory with risperidone compared to clozapine andhaloperidol (Bilder et al. 2002), while an advantage forolanzapine over haloperidol and risperidone was suggestedin another study (Purdon et al. 2000). Verbal memory is

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most often assessed with measures of recall of stories or listsof words. An important feature of memory testing in longi-tudinal treatment studies is the use of alternate forms to min-imize confusion between practice effects and genuine treat-ment effects. Alternate forms are available for tests of verbalmemory and learning of lists of words.

Hopkins Verbal Learning Test (Brandt 1991). Thistest consists of 12 nouns read aloud for three consecutivetrials, each trial followed by a free-recall test. Six alter-nate forms are used and counterbalanced across sites andacross assessment periods. Measures: number of itemsrecalled on each trial.

Social Cognition. The cognitive processes involved inhow people perceive, interpret, and process informationabout themselves, others, and social situations are com-monly impaired in persons with schizophrenia (Perm et al.1997), which may contribute to impairments in a varietyof social outcomes (Corrigan and Toomey 1995; Penn etal. 1996; Mueser et al. 1997). Social cognition may be akey intervening variable between basic cognition andfunctional outcome (Green and Nuechterlein 1999) andmay be an important intervention target. Despite theimportance of this component of cognition, no data haveassessed its response to pharmacological treatment

FEDT (Kerr and Neale 1993). Facial emotion dis-crimination is assessed with the FEDT, which requires thesubject to determine whether two faces presented next toone another are expressing the same or different emotions.Thirty pairs of target faces are presented to the patient.Measures: the number of faces correctly discriminated.

Motor Function. Motor functions have been found toimprove with various second generation antipsychotics(Gallhoffer et al. 1996; Myer-Lindenberg et al. 1997;Purdon et al. 2000). In addition to the direct measures ofmotor function, the cognitive functions that are mostresponsive to second generation antipsychotics have atimed component. This pattern may be a result of theabsence of EPS from second generation antipsychoticmedications. That is, because timed tests all involve somedegree of dependence upon motor skills, which areimpaired by EPS, the advantage of second generationantipsychotics could partially be a result of the reducedEPS. Thus, it is important to include tests of motor func-tions in the battery. Furthermore, motor functions arerelated to outcome (Bilder et al. 1985), underscoring theimportance of this domain. A Grooved Pegboard test isused to measure motor function, and the Digit SymbolTest of the WAIS-R is used to measure a related con-struct, graphomotor speed.

Grooved Pegboard (Lafayette InstrumentCompany 1989). Patients are asked to insert in a speci-

fied order 25 pegs with keys into a pegboard with ran-domly positioned slots. Two 45-second trials are com-pleted with the dominant hand. Measure: average numberof pegs successfully inserted.

WAIS-R Digit Symbol Test (Wechsler 1974). Eachnumeral (1 through 9) is associated with a different simpleform. Patients are given a list of numerals and are asked tocopy as many forms associated with the numerals as possiblein 90 seconds. Measure: number of forms accurately copied.

Attention. Attention is a fundamental cognitive deficit inpatients with schizophrenia (Nuechterlein and Dawson1984) and is associated with outcome in these patients(Green 1996). It is one of the few measures that demon-strate some improvement with first generation antipsy-chotic medications (Medalia et al. 1988; Blyler and Gold2000). In previous studies, attention has been found toimprove with risperidone (Stip and Lussier 1996; Rossi etal. 1997; Kern et al. 1998; Bilder et al. 2002), clozapine(Zahn et al. 1994; Grace et al. 1996), and olanzapine(Meltzer and McGurk 1999; Purdon et al. 2000; Bilder etal. 2002; Keefe et al., submitted). Attention is traditionallymeasured with the CPT.

Computerized CPT. The Identical Pairs version ofthe CPT (Cornblatt et al. 1988) has high test-retest relia-bility, making it ideal for studies with repeated assess-ments. CATTE uses a version of the CPT that includesthree 150-trial conditions of increasing difficulty. Thisprocedure ensures that data can be collected on the morecognitively impaired patients, yet very few patients per-form perfectly under the most difficult conditions. Eachcondition involves the presentation of stimuli on a com-puter screen at the rate of one per second. In the firstcondition, two-digit numbers are presented and the sub-ject lifts his or her finger whenever the two-digit numberis a repeat of the previous two-digit number. The secondand third conditions are the same as the first condition,except that the numbers are three digits and four digits,respectively. This test is administered on a desktop com-puter with a high-resolution monitor and an externalmouse.

Executive Function. Various components of executivefunctions are impaired in patients with schizophrenia(Goldberg et al. 1987; Saykin et al. 1991), including setshifting, abstraction, problem-solving, and allocation ofcognitive resources (Bressi et al. 1996). Two of the mostfrequently cited components of executive function deficitin schizophrenia are card-sorting (Goldberg et al. 1987)and completion of mazes (Gallhoffer et al. 1996).

WCST, 64-card computerized version (WCST-64P)(Heaton et al. 1993). Performance on the WCST has beenfound to improve with clozapine, risperidone, and olanza-

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pine, although many negative findings have been reported(reviewed in Meltzer and McGurk 1999). This area of cog-nition is particularly challenging in clinical trials withrepeated assessments because a usual component of a mea-sure of executive function is to learn the rules of the testOnce these rules are learned, they are often remembered,even after a long (e.g., 6-month) delay period This issue ishighlighted through the use of the WCST. Subjects sort aseries of stimulus cards by matching them to four "keycards" that differ by form, color, and number. Successfulperformance on the WCST depends upon learning how tosort the cards and how to switch the sorting strategy whenappropriate, because the "correct" sorting strategy changesafter 10 consecutive correct responses. There is some con-troversy as to whether patients with schizophrenia benefitfrom previous exposure to the WCST. An early study withvery chronic subjects suggested that patients with schizo-phrenia did not learn from previous assessments with theWCST (Goldberg et al. 1987). However, data from patientswith heterogeneous cognitive performance (Green et al.1990; Bellack et al. 1996) suggest that the performance ofmany patients with schizophrenia does improve withrepeated exposure to the test. This issue may be particularlyimportant in this project, because the mechanism by whichsecond generation antipsychotic medications improve cog-nition to a greater extent than first generation antipsychoticsmay be related to the improvement of episodic memory,which may help patients recall how they performed the teston previous testing sessions. Subcortical dopaminergicblockade may inhibit this improvement (Robbins 1990;Robbins et al. 1990). This notion has been supported by datasuggesting that schizophrenia patients treated with risperi-done continue to benefit from repeated exposure to a test ofprocessing capacity, while patients treated with haloperidolare limited in the gains they receive from additional admin-istrations of the test (Harvey et al. 2000). Thus, the sole useof a test such as the WCST to measure executive function inthis study may lead to confusion between improvements inexecutive function and improvements in episodic memory.Furthermore, differences in performance resulting from thedifferent second generation medications may be difficult todetect if a sizable percentage of patients leam the test wellenough to perform at near-perfect levels. Thus, we chose a64-card version of the WCST for this study to minimizelearning effects and decided to administer it on a desktopcomputer to minimize scoring errors. A 64-card computer-ized version of the WCST had been used with success in apreviously completed industry trial. Measures: number ofperseverative errors; completed number of categories andadditional consecutive cards in the final category.

WlSC-m mazes (Wechsler 1991). This is anothertest of executive function that is administered for this trial.The performance of patients with schizophrenia on maze

tasks, usually impaired in schizophrenia, has been foundto be improved with risperidone (Gallhoffer et al. 1996).In this test, patients use a pencil to attempt to drawthrough a series of nine mazes without entering blindalleys. Performance is timed. Measure: raw score.

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Acknowledgments

This article was based on results from the ClinicalAntipsychotic Trials of Intervention Effectiveness(CATTE) project supported with Federal funds from theNational Institute of Mental Health (NIMH) under con-tract NO1 MH90001. The aim of this project is to examinethe comparative effectiveness of antipsychotic drugs inconditions for which their use is clinically indicated,including schizophrenia and Alzheimer's disease. Theproject was carried out by principal investigators from theUniversity of North Carolina, Duke University, the Uni-versity of Southern California, the University ofRochester, and Yale University in association with Quin-tiles, Inc., and the program staff of the Division of Inter-ventions and Services Research of the NIMH and investi-gators from 84 sites in the United States. AstraZenecaPharmaceuticals LP, Bristol-Myers Squibb, Forest Phar-maceuticals, Inc., Janssen Pharmaceutica Products, L.P.,Eli Lilly and Company, Otsuka Pharmaceutical Co., Ltd.,Pfizer Inc., and Zenith Goldline Pharmaceuticals, Inc.,provided medications for the studies.

The Authors

Richard S.E. Keefe, Ph.D., is Director, NeurocognitiveAssessment Unit, Clinical Antipsychotic Trials of Interven-tion Effectiveness project; and Associate Professor of Psy-chiatry and Behavioral Sciences, Duke University MedicalCenter, Durham, NC. Richard C. Mohs, Ph.D., is LillyResearch Fellow, Eli Lilly and Company, Indianapolis, IN.Robert M. Bilder, Ph.D., is Chief of Medical Psychology-Neuropsychology, Neuropsychiatric Institute and Hospital,Geffen School of Medicine, University of California, LosAngeles. Philip D. Harvey, Ph.D., is Professor of Psychiatry,ML Sinai School of Medicine. Michael F. Green, Ph.D., isProfessor in Residence, Department of Psychiatry andBiobehavioral Sciences, University of California, LosAngeles, CA. Herbert Y. Meltzer, M.D., is Bixler Professorof Psychiatry, Vanderbilt University School of Medicine,Nashville, TN. James M. Gold, Ph.D., is Associate Profes-sor of Psychiatry, Maryland Psychiatric Research Center,University of Maryland School of Medicine, Baltimore,MD. Mary Sano, Ph.D., is Professor, Department of Psychi-atry, Mount Sinai School of Medicine, Bronx Veterans Med-ical Research Center, Bronx, NY.

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Neurocognitive Assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Project Schizophrenia Trial: Development, Methodology, and Rationale

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