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5April 2009Kristian S. Hill - James L. Reilly - Margret S.H. HarrisTin Khine - John A. SweeneyOculomotor and neuropsychological effectsof antipsychotic treatment for schizophreniaAshish DesaiDigitizing the moving face: asymmetries of emotionand genderStefan Winblad - Pauls Hellström - Christopher LindbergStefan HansenFacial emotion recognition in myotonic dystrophy type 1correlates with CTG repeat expansionEdoardo Santucci - Michela BalconiThe multicomponential nature of movement-relatedcortical potentials: functional generatorsand psychological factorsNeuropsychological Trends – ends/57354359

Oculomotor and neuropsychologicaleffects of antipsychotic treatmentfor schizophreniaKristian S. Hill 1, 2 - James L. Reilly 2Margret S.H. Harris 2 - Tin Khine 2 - John A. Sweeney 2, 3Center for Cognitive Medicine, Department of Psychiatry, University of Illinoisat Chicago, Chicago, IL2Department of Psychiatry, University of Illinois at Chicago, Chicago, IL3Department of Psychiatry, University of Pittsburgh, Pittsburgh, [email protected] enhancement has become an important target for drug therapies in schizophrenia. Treatment development in this area requires assessment approaches that aresensitive to procognitive effects of antipsychotic and adjunctive treatments. Ideally,new treatments will have translational characteristics for parallel human and animalresearch. Previous studies of antipsychotic effects on cognition have relied primarily on paper-and-pencil neuropsychological testing. No study has directly comparedneurophysiological biomarkers and neuropsychological testing as strategies for assessing cognitive effects of antipsychotic treatment early in the course of schizophrenia.Anti psychotic-naive patients with schizophrenia were tested before treatment withrisperidone and again 6 weeks later. Matched healthy participants were tested overa similar time period. Test-retest reliability, effect sizes of within-subject change, andmultivariate/univariate analysis of variance were used to compare 3 neurophysiological tests (visually guided saccade, memory-guided saccade, and antisaccade) withneuropsychological tests covering 4 cognitive domains (executive function, attention,memory, and manual motor function). While both measurement approaches showedrobust neurocognitive impairments in patients prior to risperidone treatment, oculomotor biomarkers were more sensitive to treatment-related effects on neurocognitivefunction than traditional neuropsychological measures. Further, unlike the pattern ofmodest generalized cognitive improvement suggested by neuropsychological measures,the oculomotor findings revealed a mixed pattern of beneficial and adverse treatment-Neuropsychological Trends – ends/7

Kristian S. Hill et al.related effects. These findings warrant further investigation regarding the utility ofneurophysiological biomarkers for assessing cognitive outcomes of antipsychotic treatment in clinical trials and in early-phase drug development.Keywords: Schizophrenia; Neuropsychology; Antipsychotics; Oculomotor;Cognition1. IntroductionNeurocognitive deficits are core features of schizophrenia that cause considerable long-term disability (Bilder et al., 2000; Hill et al., 2004). Consequently,the amelioration of cognitive deficits has become a major focus of new drugdevelopment for schizophrenia (Green & Nuechterlein, 1999; Buchanan etal., 2005). Traditional neuropsychological approaches and cognitive neuroscience/neurophysiological methodologies represent 2 different approachesfor characterizing cognitive deficits in schizophrenia and the impact of anti psychotic treatment on cognitive processes. The relative benefits and disadvantages of each approach are not well characterized because very few studiesevaluating the cognitive efficacy of antipsychotic treatments have includedboth neurophysiological biomarkers and traditional neuropsychological testsas outcome measures. Comparative evaluation of neuro physiological andneuropsychological assessments is important because of the urgent need forinformative and efficient assessment of neurocognitive outcomes in clinicaltrials.Most studies of cognitive outcome in schizophrenia have utilized clinical neuropsychological tests for evaluating treatment-related effects (Hill etal., 2004; Purdon et al., 2000). The neuropsychological approach typicallyuses standardized clinical tests with normative data that permit direct testby-test comparison with population expectations. Neuropsychological testsare often multidimensional, relying on numerous cognitive processes, soas to efficiently identify patients with abnormalities in one or more brainregions. Neuropsychological studies have been instrumental in conceptualizing schizo phrenia as a brain disorder and has spurred interest in cognitive aspects of the disorder and associated morbidity. Indeed, much of theemphasis on cognitive enhancement in schizophrenia has resulted from studies demonstrating a significant relationship between neuropsychological andfunctional deficit (Green, 1996). Neurocognitive impairments are now wellrecognized to have implications for treatment planning and course of illness(Green & Nuechterlein, 1999).Neuropsychological Trends – ends/8

Oculomotor and neuropsychological effects of antipsychotic treatment of schizophreniaThere are clear advantages to the neuropsychological approach, especiallyin large multisite clinical trials, such as ease of use, portability, establishedreliability and normative data, availability of psychologists experienced withsuch testing, low cost, and few technology requirements. However, against abackground of clinical improvement, a somewhat surprising finding acrossneuropsychological studies of antipsychotic drugs has been the modest andgeneralized improvement in performance that is similar in overall magnitudeto practice effects seen in healthy individuals (Buchanan et al., 1994; Rollniket al., 2002). While this modest level of improvement may be greater withatypical antipsychotics, compared with conventional neuroleptics, the profileof change is similar (Bilder et al., 2002; Purdon et al., 2000). These findingssuggest that the procognitive effects of available antipsychotic treatments areeither quite modest or that the clinical neuropsychological “assay” may bea weak approach for detecting change in brain function and cognition overtime.By comparison, neurophysiological biomarker approaches test highlyspecific cognitive processes that have been linked to specific regional brainfunction and transmitter systems. One strength of the biomarker approachis greater ease for parametric manipulation of tasks to isolate componentcognitive processes. This approach espouses experimental investigation ofphysiological processes by utilizing theoretically based manipulation of anexperimental parameter to produce and evaluate pharmacological effectson those processes. In this manner, the biomarker approach has closer tiesto animal models, and, by virtue of closer links to brain physiology, thisapproach may be more sensitive to pharmacologic manipulations thanbehavioral approaches. By way of comparison, it is important to note thatwhile neuropsychological studies have shown a generalized picture of cognitive improvement after antipsychotic treatment, animal models typicallyshow a more circumscribed impact of dopaminergic drugs on cognitive andmotor abilities (Arnsten, 1998; Ragozzino, 2002). Specifically, behavioralpharmacology studies have shown specific negative neurocognitive effectsof dopaminergic drugs such as declines in executive abilities following prefrontal dopamine depletion (Brozoski et al., 1979) and after disruption ofthalamocortical circuitry via D2 blockade (Arnsten et al., 1995).Recent efforts by the NIMH-MATRICS program to develop a standard for industry-sponsored trials evaluating cognition-enhancing treatmentsin schizophrenia have focused primarily on tests with a long history in clinical neuropsychology (Buchanan et al., 2005). While the neuropsychologicalapproach has provided much of the impetus for bringing cognition into focusas a treatment target, the utility of neuropsychological methods for detectingtreatment-related responses may be constrained by psychometric propertiesNeuropsychological Trends – ends/9

Kristian S. Hill et al.that limit differential sensitivity to subtle dysfunction (ceiling effects) andsevere deficits (floor effects) as well as variability in measurement reliabilityand sensitivity to drug effect (Chapman & Chapman, 1973; Strauss & Summerfelt, 1994).The advancement of treatment for cognitive deficits in schizophreniahas come to a critical juncture. Because new drugs are developed for this purpose, efficient and valid tools to evaluate procognitive pharmacotherapies areneeded to accelerate the development of effective cognition-enhancing treatments for schizophrenia to reduce the personal and societal burden associatedwith cognitive deficits. In some settings, neurophysiological biomarkers havebeen reported to be more sensitive to drug effects than neuropsychologicaltests (Barrett et al., 2004; Burke & Reveley, 2002). Therefore, this studywas designed to directly compare the differential sensitivity of oculomotorparadigms and neuropsychological tests with risperidone treatment.A major strength of the cognitive neuroscience/neurophysiological approach is the foundation in animal models linking discrete cognitiveprocesses to specific brain region and receptor systems. Behavioral pharmacology research has clarified the effects of certain drugs on specific functional brain systems, and these findings can be used to guide predictionsand interpretation of drug effects in humans. Oculomotor studies have arich tradition in nonhuman primate research that has a close homology tocognitive processes and their neurobiological substrates in humans. Whereasour neuropsychological studies have shown little or no cognitive changeassociated with antipsychotic treatment (Hill et al., 2004; Schuepbach etal., 2004), oculomotor studies with overlapping samples treated with risperidone have revealed both beneficial and adverse treatment-related effects(Harris et al., 2006; Reilly et al., 2006). The present report directly compares the sensitivity and reliability of neuropsychological data and oculomotor biomarkers with regard to monitoring cognitive effects of risperidonein a sample of antipsychotic-naive, first-episode schizophrenia patients.2. Method2.1. ParticipantsFollowing evaluation for first-episode psychosis, 29 antipsychotic-naivepatients (18 male, 11 female) were recruited at the University of PittsburghMedical Center. All patients met criteria for schizophrenia based on theNeuropsychological Trends – ends/10

Oculomotor and neuropsychological effects of antipsychotic treatment of schizophreniaStructured Clinical Interview for Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition (SCID) (First et al., 1997). A sample of 26 healthyindividuals (17 male, 9 female) recruited from the community were freefrom any Axis I diagnosis based on SCID. As shown in Table 1, groups werematched on age, sex, parental socioeconomic status, and estimated intellectual abilities (Ammon Quick Test, Ammons & Ammons, 1962). All participants were free of substance abuse within the last 3 months, a lifetime historyof substance dependence, and history of neurological disease including headinjury with loss of consciousness or systemic disorders known to affect brainfunction. The study was approved by the University of Pittsburgh Institutional Review Board, and all participants provided written consent.Data from each test has been presented previously in detailed reports(Hill et al., 2004; Harris et al., 2006; Reilly et al., 2006). The current patientand healthy groups differed somewhat from those used in previous reportsin that the sample for this report was restricted to participants who hadcompleted all neuropsychological and eye movement tests of interest so thatcross-test comparisons could be made with the same subjects. The patientsample was further restricted to those treated with risperidone monotherapy.Thus, a core sample of about two thirds of the data previously reported (Hillet al., 2004; Harris et al., 2006; Reilly et al., 2006) were included in thisreport.Selection of outcome variables was challenging given the wide rangeof oculomotor and neuropsychological impairments linked to schizophrenia.Outcome variables in the present study were limited to a number of keyoutcome variables (scored in the same manner as noted in prior reports (Hillet al., 2004; Harris et al., 2006; Reilly et al., 2006) that characterize coreneuro psychological and oculomotor deficits.Clinicians blind to neurobehavioral findings assessed clinical symptomatology in the patient group using the Brief Psychiatric Rating Scale(BPRS), the Scales for the Assessment of Negative and Positive Symptoms,and the 24-item Hamilton Depression Rating Scale (see Table 1).Medication and dosage decisions were made by the treating psychiatristbased on clinical efficacy and tolerance of side effects. Following all baselineneuropsychological, oculomotor, and clinical assessments, patients begantreatment with risperidone (4.13 mg/day 1.39). Follow-up assessmentswere conducted approximately 6 weeks later. Just 4 patients were prescribedlow-dose benztropine (1 or 2 mg) at the 6-week follow-up, and ratings ofextrapyramidal symptoms (McEvoy et al., 1991) were minimal (3.77 4.52).Neuropsychological Trends – ends/11

Follow-up39.55 (8.90)4.83 (2.89)11.86 (2.77)15.43 (7.03)1.531.281.281.281.271.7850.39102.0815.659.53 .001 .001 .01 .01.25.18.74.13.781.0.22.71PNote: SES, Socioeconomic Status; BPRS, Brief Psychiatric Rating Scale; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for theAssessment of Negative Symptoms; HDRS, Hamilton Depression Rating Scale; AQT, Ammons’ Quick Test.98.83 (8.16)Baseline51.97 (8.09)10.38 (2.83)13.76 (2.79)22.57 (11.02)1.531.531.531.750.121.66101.19 (6.68)10.0889.7%10.3%14.03 (3.29)3.17 (1.04)2.76 (1.30)88.0%12.0%15.04 (2.01)3.08 (1.06)2.31 5.4%34.6%1.5311.656.6225.97 (7.98)23.77 (4.33)Age (y)SexMaleFemaleRaceCaucasianAfrican AmericanAsian/Latino/OtherDominant HandRightLeftEducationSESParental SESIntelligenceAQTClinical ScalesBPRSSAPSSANSHDRS (24 items)dfAnalysisFlc2Schizophrenia (SZ) n 29DemographicsHealthy comparison (HC) n 26Table 1. Group demographics and clinical data for patients

Oculomotor and neuropsychological effects of antipsychotic treatment of schizophrenia2.1. Neuropsychological evaluationThe neuropsychological battery included 8 tests characterizing 4 commonlyassessed cognitive domains (executive function, attention, memory, andmotor skills). Table 2 lists the individual scores within each neuropsychological domain for patients and healthy individuals. With the exception ofalternate forms of the California Verbal Learning Test, the same tests wereadministered at follow-up. There was no discernable relationship betweenneuropsychological and oculomotor measures for either patients or healthyindividuals.2.2. Eye movement studiesParticipants were tested alone in a darkened black room free from extraneous stimuli that could interfere with performance on eye movement tasks.Detailed methods for data acquisition and processing have been publishedpreviously (Harris et al., 2006; Reilly et al., 2006).2.3. Visually guided saccadesThis task is used to evaluate visual orienting and allocation of attention acrossthe visual field by measuring saccadic eye movements to the appearance ofunpredictable peripheral targets. Electrooculography recordings of saccadeswere acquired for 54 trials as targets stepped 10 , 20 , or 30 of visual anglefrom center fixation. Saccade latencies (milliseconds) and gain (amplitude ofsaccade divided by target displacement) were selected for analysis.2.4. Antisaccade taskThe aim of this task is to evaluate the ability of participants to suppress thenatural tendency to look toward unpredictable peripheral targets when theyappear and instead voluntarily shift attention and point of gaze to anotherlocation. Targets were presented at one of 6 locations (8 , 16 , or 24 to theleft or right of center fixation) while participants maintained center fixation.The instructions were to look to the mirror location of the target on theother side of the visual field. Thirty-six trials were administered. The proportion of successfully performed trials and the response latency for successfultrials were obtained.Neuropsychological Trends – ends/13

Oculomotor measuresVGS-Latency (ms)VGS (gain)Antisaccade latency (ms)Antisaccade percent errorsMGS-gainMGS-resting error (degree)Neuropsychological measuresStroop color-word scoreControlled Oral Word Association¹Trail-Making Test: part B time²CVLT: learning trials 1-5CVLT: long delay free recallWMS-R visual reproduction IWMS-R visual reproduction IITrail-Making test: part A time²WAIS-R digit spanWAIS-R digit SymbolGrooved pegs: dominant handGrooved pegs: nondominant handHealthy controls (n 26)217 (24.53)0.94 (0.04)394 (75.43)0.13 (0.09)0.97 (0.16)-0.48 (1.49)54.12 (9.55)44.76 (8.95)48.12 (21.27)54.77 (6.52)12.76 (2.26)37.12 (2.69)36.77 (2.37)20.54 (5.78)17.56 (3.80)70.36 (7.48)61.42 (12.32)69.75 (8.82)51.60 (8.50)43.64 (9.59)51.92 (15.67)54.62 (8.34)11.88 (2.89)37.69 (2.31)35.23 (4.69)23.88 (7.49)17.64 (3.76)67.60 (8.24)63.73 (10.31)66.88 (6.73)6 Wk221 (29.89)0.95 (0.05)407 (88.02)0.19 (0.13)0.95 (0.11)-0.69 2.89.79.74.85.82.75.76.56Spearman r 4.88 2.57 6.96 0.27 7.41-1.51 4.37 13.99-0.45 4.08 3.62-4.29 1.81 0.02 3.19 30.31 2.56 30.49Percent changeTable 2. Raw score means, reliability coefficients, and percent change over time for each neuropsychologicaland oculomotor measure by group

225 (44.06)0.91 (0.05)453 (95.83)0.35 (0.21)0.81 (0.17)-1.98 (1.73)42.09 (9.95)41.07 (12.26)63.90 (29.46)45.74 (11.55)9.39 (3.71)33.69 (4.41)32.17 (6.19)32.38 (14.66)14.90 (3.55)53.38 (12.30)76.93 (21.92)85.25 (16.35)207 (33.46)0.93 (0.04)487 (123.74)0.41 (0.20)0.87 (0.17)-1.19 (1.56)41.00 (8.49)36.28 (10.27)74.72 (28.65)46.43 (13.48)10.61 (3.50)32.86 (5.32)30.76 (6.54)32.52 (17.72)14.97 (3.98)50.83 (8.73)71.46 (16.30)80.75 .71.58.66.79.62-5.57 2.66 13.20 14.48-1.49-11.50 2.53 4.58-0.43-0.47 5.02-7.65 8.70-2.04 6.98 14.72-4.80-66.67Note: ICC, Intraclass Correlation; VGS, Visually Guided Saccades; MGS, Memory-Guided Saccades; CVLT, California Verbal Learning Test;WMS-R Wechsler Memory Scale-Revised; WAIS-R, Wechsler Adult Intelligence Scale-Revised.¹ Multilingual Aphasia Examination.² Halstead-Reitan Neuropsychological Battery.Oculomotor measureVGS-latency (ms)VGS-gainAntisaccade latency (ms)Antisaccade percent errorsMGS-gainMGS-resting error (degree)Neuropsychological measuresStroop color-word scoreControlled Oral Word Association¹Trail-Making Test: part B time²CVLT: learning trials 1-5CVLT: long delay free recallWMS-R visual reproduction IWMS-R visual reproduction IITrail-Making test: part A time²WAIS-R digit spanWAIS-R digit SymbolGrooved pegs: dominant handGrooved pegs: nondominant handSchizophrenia patients (n 29)

Kristian S. Hill et al.2.5. Memory-guided saccade taskThis working memory task is used to evaluate the ability to remember thespatial location of targets over brief periods of time. While participants maintained central fixation, peripheral targets appeared for 100 milliseconds at 9 ,18 , or 27 of visual angle to the right or left of center.Participants were instructed to maintain central fixation during delayperiods of 1, 2, 4, or 8 seconds, after which the central light was extinguished,signaling the participant to look to the remembered target location. Two primary measurements of performance accuracy were obtained over 24 trials:(1) gain (amplitude of saccade divided by target displacement) of the initialsaccade to the remembered target location and (2) error of the final restingeye position (in degrees of visual angle from target) after any additional saccades were made to shift gaze to the remembered location.2.6. Data analysisPerformance was pooled over all trials in each oculomotor paradigm to focusstatistical analyses on group differences and the differential change over timein the 2 groups. Arcsine transformations for proportional data and naturallogarithm transformations for reaction time data were used for computingintraclass correlations (ICCs) and effect sizes. To evaluate the sensitivity ofeach approach, omnibus 2-way (group by time) repeated measures multivariate analysis of variance (MANOVA) was conducted separately for neuropsychological and oculomotor measures. A significant group by time interactionwould indicate a treatment-related effect that differs from practice effects inhealthy individuals. To clarify any significant omnibus multivariate interactions, univariate analysis of variance was computed for each dependent variable. To further explore the differential sensitivity of neuropsychological andoculomotor measures, between-group effect sizes were computed to quantifydisease effects. It is unclear whether measures with large or small effect sizesfor disease-related deficits will be more sensitive to treatment-related effects.Thus, we calculated orthogonal within-group effect sizes to evaluate changeover time, independent of magnitude of patient impairment. Within-groupeffect sizes were averaged for neuropsychological and oculomotor measuresto contrast their relative sensitivity to treatment-related effects.Neuropsychological Trends – ends/16

Oculomotor and neuropsychological effects of antipsychotic treatment of schizophrenia3. Results3.1. Clinical featuresAfter treatment, patients showed clinical improvement reflected in reducedBPRS scores, positive symptom ratings, and negative symptom ratings (seeTable 1). There was no relationship between symptom change and oculomotor or neuropsychological change. Medication dose and change in positivesymptoms were not significantly correlated with changes in oculomotor orneuropsychological measures.3.2. Group by time effectsTable 2 lists the means and SDs of test performance for both the baseline and6-week follow-up assessments. Two-way repeated measures MANOVA wascompleted separately to evaluate the differential sensitivity of neuropsychological and oculomotor measures to treatment with risperidone. Specifically,we reasoned that the group by time interaction and the effect size for thisterm indicated the relative sensitivity of assessment approaches to treatmentrelated effects. For oculomotor measures, results indicated significant maineffects for group (F(6,46) 5.18, P .001) and time (F(6,46) 5.82, P .001) as well as a significant group by time interaction (F(6,46) 4.32, P .01). Results of the 2-way MANOVA for neuropsychological tests indicated significant main effects for group (F(12,32) 4.26, P .001) and time(F(12,32) 4.07, P .001) but a nonsignificant group by time interaction(F(12,32) 1.71, P .11). Thus, level of neuropsychological impairmentrelative to healthy individuals was consistent over time despite hospitalization and pharmacological intervention. Results of these omnibus repeatedmeasures MANOVA indicated a significant time by group interaction foroculomotor but not neuropsychological measures, suggesting that oculomotor measures were more sensitive to the neurocognitive effects of risperidonetreatment. To clarify the significant multivariate interaction term for oculomotor measures, a series of univariate repeated measures ANOVAs werecompleted for eye movement tests. Results are shown in Figure 1 and illustrate the significant group by time interactions in 4 of 6 oculomotor variables, after correcting for multiple comparisons (Hochberg, 1998). Observedeffect sizes for the univariate group by time interactions are an indicator ofthe relative sensitivity to treatment-related effects and clearly favor the oculomotor measures. Effect sizes for these 2-way ANOVA (Cohen, 1988) rangedNeuropsychological Trends – ends/17

Kristian S. Hill et al.from near zero for antisaccade variables to small for visually and memoryguided saccade variables. On the other hand, the nonsignificant omnibusMANOVA indicated that comparable effect sizes for the neuropsychologicalmeasures were near zero.Figure 1. Modification effects on oculomotor/neuropsychological measures3.3. Effect size of baseline differences and treatment-related effectsBetween-group comparisons at baseline. The relative sensitivity of each performance parameter to illness effects was assessed via between-group effectsize comparisons, while comparisons of within-group effect sizes assessedtreatment-related effects (Cohen’s d 38 was used for both within- and betweengroup comparisons: small effects – 0.20, medium 0.20 to 0.50, and large 0.80). Figure 2 illustrates the magnitude of patient deficits before and aftertreatment, relative to healthy participants. Neuropsychological deficits (0.91 0.40) were numerically but not significantly larger than oculomotor deficits(0.60 0.39) at baseline, F(1,16) 2.44, P 14. With a few minor exceptions, the between-group effect size estimates prior to treatment revealed agenerally flat profile of moderate to large neuropsychological impairmentsacross domains. In contrast, performance deficits for oculomotor measuresvaried considerably in magnitude at the baseline testing. On the visuallyguided saccade task, patients showed latency differences that were modest inmagnitude and no impairment in saccade accuracy. Antisaccade deficits wereNeuropsychological Trends – ends/18

Oculomotor and neuropsychological effects of antipsychotic treatment of schizophrenialarge and more consistent with the level of neuropsychological impairment.Patients displayed relatively small effect sizes for impairments in the accuracyof memory-guided saccades.Figure 2. Oculomotor performance as a function of pre- and post-treatmentNeuropsychological Trends – ends/19

Kristian S. Hill et al.Figure 3. Modification effects on oculomotor/neuropsychological measuresNeuropsychological Trends – ends/20

Oculomotor and neuropsychological effects of antipsychotic treatment of schizophreniaWithin-group comparison of change over time. A second set of effect size estimates were obtained to assess treatment-related effects by comparing baselineand follow-up performance separately for each group. That is, for patients,within-group effect size estimates reflect a combination of practice effects,drug effects, and general clinical stabilization. In the absence of an activetreatment, the same effect size most likely represents practice effects in thehealthy group.Thus, the discrepancy between practice effects in healthy individualsand the combination of practice effects with pharmacological effects andclinical stabilization in patients provides a general index of treatment-relatedeffects. As illustrated in Figure 3, oculomotor measures were more sensitiveto the effects of risperidone treatment than neuropsychological measures.The schizophrenia group showed significantly more change (F(1,16) 4.65,P .05) on oculomotor measures (0.41 0.18) compared with neuropsychological test scores (0.22 0.16) in terms of the average absolute value ofwithin-subject effect sizes. In contrast, healthy controls showed similar levelsof change across the 2 testing sessions (F(1,16) 0.01, P .92) for bothoculomotor (0.30 0.24) and neuropsychological variables (0.31 0.16). Itis noteworthy that the practice-related neuropsychological change in healthyparticipants was not greater (F(1,22) 0.68, P .42) than the change in neuropsychological performance exhibited by patients based on the combinedfactors of practice effects, clinical stabilization, and procognitive therapeuticefficacy of risperidone.Both groups showed similar levels of change over time on the antisaccade task suggesting that effects of acute risperidone treatment were nogreater than practice effects seen in healthy individuals on this task. Effectson visually guided saccades were complicated in that patients showed abnormally speeded latencies prior to treatment, whereas a slowing in reactiontime was observed, in which patients were slower than healthy participants,following treatment and clinical stabilization. The schizophrenia group alsoshowed a modest (2.04%) but consistent decline following treatment in thegain (or accuracy) of visually guided saccades. Whereas healthy participantsshowed reduced spatial error of responses on the memory-guided saccadetask over time, patients showed less accurate responses following treatment(which were not due to anticholinergic effects (Reilly et al., 2005).Effect size (d ) estimates for treatment-related neuropsychological changeover time revealed small effects for 10 of 12 variables. Patients showed moderate change (Cohen’s d .50) for just 2 variables including improvementsfor Verbal Fluency and Trails B. In both cases, mean change for the schizophrenia group (Trails B: 14.48% fa

[email protected] Abstract. Cognitive enhancement has become an important target for drug therapies in schizo-phrenia. Treatment development in this area requires assessment approaches that are sensitive to procognitive eff