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Original Article |

Adverse Effects of Risperidone on Spatial Working Memory in First-Episode Schizophrenia FREE

James L. Reilly, PhD; Margret S. H. Harris, MA; Matcheri S. Keshavan, MD; John A. Sweeney, PhD
[+] Author Affiliations

Author Affiliations: Center for Cognitive Medicine, Department of Psychiatry, University of Illinois at Chicago (Drs Reilly and Sweeney and Ms Harris); Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pa (Drs Keshavan and Sweeney); and Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Mich (Dr Keshavan).


Arch Gen Psychiatry. 2006;63(11):1189-1197. doi:10.1001/archpsyc.63.11.1189.
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Context  Working memory impairments are a central neurocognitive feature of schizophrenia. The nature of these impairments early in the course of illness and the impact of antipsychotic drug treatment on these deficits are not well understood. The oculomotor delayed response task is a translational spatial working memory paradigm used to characterize the neurophysiologic and neurochemical aspects of working memory in the primate brain.

Objective  To examine oculomotor delayed response task performance in patients with first-episode schizophrenia before and after antipsychotic drug treatment.

Design, Setting, and Participants  Twenty-five antipsychotic drug–naive, acutely ill patients with first-episode schizophrenia performed an oculomotor delayed response task at baseline before any drug treatment and again after 6 weeks of risperidone treatment. Twenty-five matched healthy controls were studied in parallel.

Main Outcome Measure  Accuracy for remembered spatial locations on an oculomotor delayed response task.

Results  Before treatment, patients demonstrated baseline impairment in the ability to maintain spatial location information in working memory at longer delay-period durations (8 seconds), when maintenance demands on working memory were greatest. After 6 weeks of risperidone treatment and significant clinical improvement, this pretreatment impairment worsened such that patients were uniformly impaired across all delay period durations (1-8 seconds). This occurred in the absence of any generalized adverse effect on oculomotor systems or significant extrapyramidal adverse effects.

Conclusions  Deficits in the maintenance of spatial information in working memory are present early in the course of illness. Risperidone treatment exacerbated these deficits, perhaps by impairing the encoding of information into working memory. Studies with nonhuman primates performing oculomotor delayed response tasks suggest that the apparent adverse effect of risperidone might result from treatment-related changes in modulatory functions of prefrontal D1 receptor systems.

Figures in this Article

Cognitive dysfunction represents a core feature of schizophrenia, and working memory deficits are a key component of this dysfunction.13 Working memory impairments are prognostic indicators of relapse and social functioning46 and may be endophenotypes for schizophrenia inasmuch as they are found among patients' unaffected first-degree relatives.79

Working memory is subserved primarily by the dorsolateral prefrontal cortex (DLPFC),10,11 a region established by neuropsychologic, neurophysiologic, and neuroimaging studies to be disturbed in schizophrenia.1216 The oculomotor delayed response (ODR) task is a spatial working memory paradigm that has been used in studies of nonhuman primates to provide much of our current understanding of the neurophysiologic and neurochemical features of working memory systems.17,18 This task requires individuals to remember a spatial location for a period of time, after which they make a saccadic eye movement to the remembered location guided only by information maintained in working memory. In nonhuman primates, spatially tuned neurons in the DLPFC (Brodmann areas 46/8a) code the location information via increased firing rates during delay periods, when location information is held in working memory.1921 Prefrontal dopaminergic D1 receptor activation modulates the ability of these pyramidal cells to sustain increased firing rates during delay periods and, in turn, support behavioral performance on this task.2224 Given the role of dopaminergic abnormalities in schizophrenia2527 and the impact of antipsychotic medications on dopamine systems, this translational task has the potential to be an especially useful tool for understanding working memory deficits in schizophrenia and how they are affected by pharmacologic treatment.

Impairments in ODR task performance among unaffected relatives of patients with schizophrenia7,8 suggest that spatial working memory deficits are probably present at illness onset. However, the nature and the magnitude of these deficits early in the course of illness are not well characterized. More important, how these impairments are affected by antipsychotic drug treatments has yet to be directly investigated. Studies2833 documenting impaired ODR task performance among patients with schizophrenia have typically used medicated, chronically ill patients, which makes disentangling disease and medication effects difficult. The few studies3436 of untreated or never-treated patients are limited by the use of cross-sectional rather than longitudinal designs and by treatment with heterogeneous antipsychotic medications and adjunctive agents. Also, the effects of delay period duration have not been investigated systematically in these studies, so it remains unclear whether performance deficits reflect a problem initially encoding information into working memory or a faster rate of information decay once information is encoded.

In the present study, treatment-naive patients with first-episode schizophrenia performed an ODR task at baseline and again after 6 weeks of risperidone treatment. Matched controls were studied during a similar time frame. The delay period during which information was remembered varied between 1 and 8 seconds to determine whether patient performance changed as a function of increased temporal maintenance demands and whether treatment differentially affected performance across delay period durations. Subsets of both groups were available for additional assessments at 26- and 52-week follow-up.

PARTICIPANTS

Twenty-five antipsychotic drug–naive patients (7 women and 18 men) met criteria for schizophrenia according to the Structured Clinical Interview for DSM-III-R37 and additional information reviewed at consensus diagnosis meetings. Patients had experienced psychotic symptoms on average for 1 year before entering the study (median duration of untreated illness, 11.8 months). Twenty-five healthy individuals (8 women and 17 men) without any Axis I disorders according to the Structured Clinical Interview for DSM-III-R were recruited from the community. Groups were matched for age, IQ, sex, parental socioeconomic status, and handedness (Table). All the participants met the following criteria: (1) age 18 to 49 years, (2) no systemic or neurologic disease, (3) no electroconvulsive therapy, (4) no history of head trauma, (5) no lifetime history of substance dependence or history of substance abuse within 3 months, (6) no anticonvulsant drug therapy for 1 month or benzodiazepine use for 5 half-lives before testing, and (7) no caffeine intake or cigarette smoking 1 hour before testing. The study was approved by the University of Pittsburgh, Pittsburgh, Pa, institutional review board, and all the participants provided informed consent.

Table Graphic Jump LocationTable Demographic and Clinical Characteristics of Patients With Schizophrenia and Controls

Patients' baseline ODR studies were conducted before treatment initiation, and follow-up testing occurred on average 6 weeks later. After the baseline evaluation, patients were treated with risperidone (mean ± SD dose = 4.0 ± 1.5 mg). Clinical psychologists and psychiatrists blind to ODR task performance completed clinical ratings in parallel with each testing using the Brief Psychiatric Rating Scale,42 the Scales for the Assessment of Positive43 and Negative44 Symptoms, and the 24-item Hamilton Depression Rating Scale45 (Table). Extrapyramidal adverse effects38 were modest at the 6-week retesting (Table), but 5 patients were taking low-dose benztropine mesylate (1 or 2 mg).

ODR TASK

Participants were tested in a darkened room, and a technician in an adjacent room provided instructions via an intercom. Participants sat facing a circular black arc with a 1-m radius and red light–emitting diodes subtending approximately 0.2° of visual angle in the horizontal plane at eye level. A chin and forehead rest minimized head movement.

Trials began with a brief tone concurrent with the appearance of a central fixation cue (Figure 1). After the participant maintained central fixation for 1.5 seconds, a target appeared for 0.1 seconds unpredictably at 9°, 18°, or 27° of visual angle to the right or left of center. The central cue was sustained during and after this target presentation, and the participant was instructed not to look at the peripheral target but to remember its location. After an unpredictable delay of 1, 2, 4, or 8 seconds, during which central fixation was maintained, the central light was extinguished, cueing the participant to look to the location where the target had appeared. After 1.5 seconds during which the participant could make 1 or more saccadic movements to the remembered location, the correct target location was illuminated for 2 seconds to provide feedback regarding performance accuracy. Twenty-four trials were administered. Eye movements were recorded using electro-oculography. Recordings for each trial were calibrated and measured as described elsewhere.46

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Figure 1

Oculomotor delayed response task paradigm. Participants fixate on the central location while a target briefly (0.1 seconds) appears 9°, 18°, or 27° to the right or left. Participants were instructed to remember the location of the peripheral target while maintaining central fixation for an unpredictable variable delay period (1, 2, 4, or 8 seconds) and then to shift their gaze to the remembered target location after the central light was extinguished. A correction light appeared after 1.5 seconds and remained illuminated for 2 seconds at the location where the peripheral target had been presented to provide participants with feedback about their performance on each trial.

Graphic Jump Location

Two primary measurements of performance accuracy were obtained: (1) gain (amplitude of saccade/target displacement) of the primary saccade, which reflects the accuracy of the initial movement to the remembered target location, and (2) error of final resting eye position (in degrees of visual angle from target) after any additional saccades were made to position the eyes at the desired location before appearance of the feedback light. The first of these measures can be affected by problems with initiating voluntary behavior without sensory guidance, and the second can be more sensitive to problems with maintaining spatial location information in working memory because participants have the opportunity to correct for error in initial motor commands.47 The percentage of trials during which participants incorrectly looked immediately toward to-be-remembered targets (prosaccade errors) was monitored. Latency, peak velocity, and duration of primary saccades were also measured. The latter 2 measures did not differ between patients and controls at any study point and therefore are not reported.

STATISTICAL ANALYSES

Data from identical trials were averaged before statistical analyses. Data for each participant were pooled across the 3 peripheral target positions because there were no significant group × target position interactions. Repeated-measures analysis of variance was used to compare patients with schizophrenia and controls (between-subject factor), with time (baseline and 6-week follow-up), direction (rightward and leftward trials), and delay period (1, 2, 4, and 8 seconds) as within-subject factors. Effect sizes48 are reported for within- and between-subject effects. Secondary analyses were conducted in the subset of participants available for retesting at 26- and 52-week follow-up to examine the longer-term stability of effects.

ACCURACY OF PRIMARY SACCADES AND FINAL RESTING EYE POSITION

Gain of patients' primary saccades to remembered target locations was reduced relative to that of controls (F1,48 = 9.75; P = .003). The magnitude of this group effect was greater at 6-week follow-up than at baseline (F1,48 = 9.73; P = .003), reflecting a significant worsening of patients' saccade gain after treatment initiation (t24 = 4.00; P = .001; Cohen d = −0.8) (Figure 2A). In contrast, there was no significant change in gain over time among controls (t24 = −0.92; P = .37; Cohen d = 0.2). Patients also demonstrated progressively poorer gain relative to controls as a function of increased delay period (F3,46 = 4.47; P = .008). At baseline, patients were impaired relative to controls at the 8-second delay period (t48 = 3.05; P = .004; Cohen d = −0.9) but not at the shorter delay periods. In contrast, at 6-week follow-up, patients were impaired relative to controls at all delay periods (P<.01 for all; Cohen d≤−0.8 for all) (Figure 3A). Finally, patients' primary saccades were less accurate when remembered target locations were to the right of center fixation before and after treatment (F1,48 = 5.39; P = .03) (Figure 4A).

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Figure 2

Mean gain of primary saccades (A) and error of resting eye position (B) for patients with schizophrenia and controls. Patients' primary saccades and resting eye position were significantly less accurate at 6-week follow-up relative to controls. The effect sizes (Cohen d) are for between-group comparisons at each study visit and within-group changes from baseline to 6-week follow-up. *P = .05 and †P<.001 for comparisons between patients and controls. Error bars represent SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3

Mean gain of primary saccades (A) and error of resting eye position (B) for patients with schizophrenia and controls at baseline and 6-week follow-up. Patients' accuracy of primary saccades and final resting eye position were decreased only at the longer delay period at the baseline evaluation but across all delay periods at 6-week follow-up compared with controls. *P = .07 and ‡P = .004 for comparisons between patients and controls at baseline. †P≤.02 for all comparisons between patients and controls at follow-up. Error bars represent SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4

Mean gain of primary saccades (A) and error of resting eye position (B) for patients and controls. Primary saccades and final resting eye positions for target locations in the right hemifield were less accurate for patients than were their responses to left hemifield targets. *P = .05 and †P<.001 for comparisons between patients and controls. Error bars represent SE.

Graphic Jump Location

Patients' performance remained inaccurate compared with that of controls after making additional saccades to correct for any initial motor programming error (F1,48 = 7.91; P = .007). The magnitude of this group difference was greater at 6-week follow-up than at baseline (F1,48 = 8.84; P = .005), reflecting a significant worsening of patients' error in final resting eye position after treatment initiation (t24 = 3.27; P = .003; Cohend = −0.7) (Figure 2B). This change over time was not seen among controls (t24 = −0.90; P = .38; Cohen d = 0.2). Patients' inaccuracy of final resting eye positions was also greater than that of controls as a function of increased delay-period duration (F3,46 = 3.07; P = .04). Patients' baseline inaccuracy tended to be greatest at only the 8-second delay period (t48 = 1.87; P = .07; Cohen d = −0.5), whereas at 6-week follow-up they differed significantly from controls at all delay periods (P<.02 for all; Cohen d≤−0.7 for all) (Figure 3B). Patients' final resting eye positions were significantly less accurate for locations in the right hemifield compared with controls at both times (F1,48 = 7.65; P = .008) (Figure 4B).

LATENCY AND PROSACCADE ERRORS

Patients were slower than controls in initiating primary saccades to remembered locations (F1,48 = 10.24; P = .002). This effect did not change after treatment and did not vary as a function of delay period or response direction.

At each time point, patients committed more prosaccade errors than controls (F1,48 = 8.32; P = .01). Both groups showed a comparable decline in errors from baseline (12% for patients vs 8% for controls) to 6-week follow-up (9% for patients vs 3% for controls).

DURATION OF UNTREATED ILLNESS, CLINICAL RATINGS, AND MEDICATION DOSE

The duration of untreated psychosis was unrelated to baseline ODR task performance or to changes in performance from baseline to 6-week follow-up. Improvement in clinical symptom ratings was unrelated to changes in ODR task performance from baseline to 6-week follow-up. Extrapyramidal adverse effect ratings and medication doses at 6-week testing were uncorrelated with changes in task performance from baseline to follow-up, although doses were in a relatively narrow range. Exclusion of the 5 patients taking benztropine at 6-week follow-up did not change any findings.

PERFORMANCE AT THE 26- AND 52-WEEK FOLLOW-UP EVALUATIONS

The stability of the present findings was examined in secondary analyses of a demographically matched subset of patients (n = 13) and controls (n = 18) who completed additional follow-up testing at both 26 and 52 weeks. These subgroups did not differ from participants in their respective larger groups in demographic characteristics or task performance at baseline or 6-week follow-up. The patient subgroup did not differ from the complete patient group in clinical ratings at baseline, risperidone dose at 6 weeks, or degree of clinical improvement at 6 weeks. Mean ± SD risperidone doses at 26-week (3.6 ± 1.4 mg) and 52-week (3.5 ± 1.6 mg) follow-up were consistent with that at 6 weeks. One patient was taking benztropine (1 mg) at both later time points.

Throughout the 1-year follow-up period, patients remained significantly less accurate than controls in primary saccade gain (F1,29 = 10.90; P = .003; Cohen d = −0.9) and final resting eye position (F1,29 = 11.80; P = .002; Cohen d = −1.0). Neither accuracy measure at later time points differed from that at 6 weeks for patients or controls.

Antipsychotic drug–naive patients with first-episode schizophrenia performed an ODR task before and 6 weeks after initiation of risperidone treatment. Before treatment, patients demonstrated impairment in spatial working memory reflected by reduced accuracy of both primary saccade gain and final resting eye position. This impairment was evident only when patients were required to maintain information over the longer delay periods (8 seconds). In contrast, after 6 weeks of risperidone treatment, patients' baseline impairment was exacerbated such that they were uniformly inaccurate at all delay periods, including very brief delays (1 second). This decline in performance occurred in the absence of significant extrapyramidal adverse effects. Furthermore, these impairments persisted to the 1-year follow-up testing, indicating that patients did not habituate to apparent adverse effects of risperidone. Patients also had longer response latencies and committed more prosaccade inhibitory errors compared with controls. These performance variables did not change differentially in patients after treatment.

SPATIAL WORKING MEMORY IMPAIRMENT IN TREATMENT-NAIVE SCHIZOPHRENIA

The present study provides new evidence of impairment in spatial working memory during the early phase of untreated schizophrenia. To our knowledge, this is the first study to report a delay-dependent effect among treatment-naive patients with schizophrenia. This finding suggests that in the acute stages of recent-onset schizophrenia, spatial information is effectively encoded in working memory but that there is a faster rate of decay of spatial information from working memory systems under increased maintenance conditions.

At first glance, that patients in the current study did not demonstrate baseline ODR performance deficits at shorter delay periods may seem contrary to the notion that this is a core disease impairment also present among unaffected first-degree relatives of patients with schizophrenia.7,8 Similar to previous investigations with patients, delay period duration was not parametrically varied in these family studies, so relatives' performance across a range of delay period durations is not known. The seminal study by Park et al,9 which first demonstrated impaired ODR task performance in treated patients with schizophrenia and their relatives, used 10-second delay periods. This period approximates the delay interval at which baseline impairments were detected in the present study. It remains to be determined whether onset of the disorder increases preexisting deficits that are present before treatment initiation. However, the pretreatment findings suggest the possibility that the core spatial working memory deficit in schizophrenia involves a diminished ability to maintain information in working memory over time but not a reduced ability to encode information into working memory stores.

We also found greater impairment in patients when targets were presented in the right hemifield. This effect, which did not change after treatment, is consistent with previously reported findings49 in which chronically ill, medicated patients with schizophrenia committed more errors when manually identifying the location of remembered targets presented in the right visual field. This laterality bias in the present untreated first-episode sample indicates that the observed hemifield-specific impairment is present at illness onset and thus is not accounted for by effects of treatment or progression of illness. This directional impairment does not reflect a failure to attend and accurately encode information presented in the right hemifield given that a previous study46 showed comparable accuracy of visually guided saccades made to the left and right visual fields in this sample. In controls performing an ODR task, the contralateral prefrontal cortex has been shown to maintain spatial information of targets presented in the corresponding hemifield across delay periods.50 Therefore, the present findings suggest greater disturbance in left prefrontal cortex systems, supporting the maintenance of information in spatial working memory in schizophrenia.

On the basis of neurophysiologic studies of nonhuman primates performing the ODR task, pharmacologic investigations of working memory in nonhuman primates and healthy human subjects, and receptor binding studies of medication-free patients with schizophrenia, one possible explanation for the present findings is that patients' baseline impairment in spatial working memory results from altered D1 receptor activity or distribution in the DLPFC.23 Studies of monkeys performing ODR tasks have established that the maintenance of spatial location information in working memory is modulated by D1 receptor activity. Without sufficient D1 stimulation, pyramidal neurons fail to sustain the firing rate needed to retain information in working memory systems over time, and performance deteriorates as a result. Microinjections of D1, but not D2, receptor antagonists into the nonhuman primate DLPFC reduce the accuracy of saccades to remembered targets but have no impact on saccades to visual targets.51 Neurophysiologic studies have established that there is an optimal, but narrow, range of D1 receptor activity of prefrontal neurons during the delay period when information has to be remembered on the ODR task, with either too much or too little receptor stimulation associated with working memory impairment.24 This “inverted U”–shaped relationship between D1 modulation and working memory is supported by behavioral studies demonstrating that D1 agonists enhance working memory performance in dopamine-deficient monkeys,52,53 whereas D1 antagonists lead to a reversal of impairment in monkeys with experimentally induced dopamine elevation in the DLPFC.54 Evidence of a similar D1 receptor modulation of working memory performance in humans is provided by demonstrations of enhanced working memory after the administration of pergolide mesylate, a combined D1 and D2 agonist, but not the selective D2 agonist bromocriptine mesylate.55

Alterations in prefrontal D1 receptor activation in antipsychotic drug–free patients have been reported in some studies,56,57 although the nature of this alteration is unclear, as both down-regulation and up-regulation have been observed. Using a selective D1 ligand, Abi-Dargham et al58 found increased D1 receptor binding in antipsychotic drug–free patients with schizophrenia. Increased D1 binding in patients predicted impairment on a verbal working memory task, particularly as task demands increased. This increased D1 receptor availability may reflect a compensation, albeit functionally inadequate, for deficient mesocortical dopaminergic input.58 Therefore, it is possible that suboptimal D1 receptor function in the DLPFC could contribute to the poorer pretreatment performance of the patients on the ODR task, particularly when demands on D1 activity to support working memory were greatest (ie, at the longest delay period).

ADVERSE EFFECTS OF RISPERIDONE ON SPATIAL WORKING MEMORY

To our knowledge, this is the first study to document a significant worsening of spatial working memory in patients with schizophrenia after initiating risperidone treatment. After 6 weeks of treatment, patients' performance declined beyond their initial baseline deficit, and impairment was seen across all delay period durations rather than just in high-maintenance demand conditions. The posttreatment deficits at even 1-second delay periods raise the possibility that encoding processes for working memory were adversely affected by treatment. This effect is striking in that the magnitude of change in patients' performance from baseline to follow-up is greater than that of the group difference between controls and patients before treatment (Figure 2). Patients' performance at baseline and 6-week follow-up was highly positively correlated, suggesting that an individual patient's relative performance within the group is maintained as the group average declines after treatment. This finding points to a consistent treatment effect. Impairments were maintained through 1-year follow-up, indicating that patients did not habituate to apparent treatment effects. The magnitude of the patients' deficits after treatment is highly consistent with those of a recently published meta-analysis3 of 124 studies examining working memory in schizophrenia, most of which included medicated patients.

Our observation of worsened impairment on an ODR task after treatment initiation in patients with schizophrenia may be best understood in the context of knowledge about risperidone's pharmacologic properties and recent neurochemical studies with nonhuman primates. In the dopamine system, risperidone strongly antagonizes dopamine D2 and has relatively low affinity for D1 receptors.59 Antagonism of D2 receptors in the PFC does not affect mnemonic performance on this task,60 and thus, risperidone's effect on D2 receptors is not likely to account for the treatment-related impairment report herein. However, exposure to either typical or atypical antipsychotic medications, including risperidone, induces a robust reduction of D1 receptor expression in the PFC (an approximately two-thirds reduction for risperidone) but not in the striatum.61

Haloperidol administration to monkeys has been shown to result in impaired spatial working memory on an ODR task that was reversed with the administration of a selective full D1 agonist.53 Examination of risperidone's effects on working memory in monkeys has not been reported, but similar effects are expected given risperidone's somewhat greater prefrontal D1 down-regulation compared with haloperidol.61 It is thus possible that risperidone's apparent adverse effect on ODR performance observed in the present study could result, at least in part, from a treatment-related down-regulation of DLPFC D1 receptors. In this case, a reduction in D1 activity associated with risperidone treatment might further compromise a system that at baseline is already dysfunctional in its support of working memory processes.

Pharmacologic effects on neurotransmitter systems other than dopamine, such as antagonism of the serotonin 2A receptor, might also contribute to risperidone's effects on ODR performance. The role of this receptor in working memory has been examined, albeit to a lesser extent than dopamine receptors. Iontophoresis of a serotonin 2A antagonist on monkey prefrontal neurons, which were neurophysiologically determined to show memory field activity, diminished the activity of these neurons during delay periods of the ODR task.62 This suggests that there may be deleterious effects on working memory associated with serotonin 2A antagonism. It is thus possible that the decline in patient performance after treatment may also result in part from antagonism of serotonin 2A receptors in the prefrontal cortex uniquely or in combination with D1 receptor down-regulation.

Patients' worsening of performance on the ODR task is not likely to result from generalized adverse treatment effects on oculomotor systems. First, the accuracy of both the primary saccade and final resting eye position declined after treatment, the latter of which relies less on the programming or execution of an initial precise motor response. Second, other saccade parameters, including peak velocity, latency, and duration, were not affected by treatment, and these are typically more sensitive indices of drug-induced changes in oculomotor systems.63 Third, risperidone doses were not high enough to induce significant extrapyramidal adverse effects that could affect motor programming of saccades. Finally, in a previous study46 of first-episode patients performing a visually guided saccade task, of which patients in the present study are a smaller subset, we reported a very mild decline in saccade accuracy after starting risperidone treatment. The average decline in memory-guided saccades was 4.5 times greater than that of saccades made in the presence of a visual target. Furthermore, the change in memory-guided saccade accuracy from baseline to 6-week follow-up was not related to changes in visually guided saccades.

The present findings of impaired ODR task performance after risperidone treatment stand in contrast to some recent neuropsychologic studies6467 that reported a modest improvement in working memory after treatment with atypical antipsychotic agents, including risperidone. Several factors may account for this apparent discrepancy. First, studies reporting neuropsychologic improvement with risperidone treatment have not followed treatment-naive patients over time and often report an advantage relative to a conventional antipsychotic drug rather than improvement per se. Second, the absence of a parallel healthy comparison group in larger clinical trials focused on cognitive outcomes, coupled with significant practice effects with many neuropsychologic tests, might exaggerate apparent procognitive treatment effects suggested by improved scores at retesting.68 Third, and perhaps most important, working memory is a complex and variably defined construct that includes decidedly different cognitive components. Performance on traditional neuropsychologic measures, such as those used in most larger clinical trials,64,65 is multifactorial and often requires maintenance, manipulation, and sequencing of information across trials. The ODR task taps a specific aspect of working memory: the maintenance of spatial information in short-term memory stores to guide future behavior. Because of its translational origins, the neurophysiologic basis and neurochemical regulation of this cognitive process is far more established than that of more complex processes required for most neuropsychologic measures of working memory. It is possible that subcomponents of working memory, and the brain systems that support them, may well be differentially affected by antipsychotic drug treatment. For example, complex problem solving and decision making might be enhanced, whereas the ability to maintain information online might be reduced. Differentiating how treatment affects the various aspects of working memory will require the development and use of paradigms that uniquely tap such subprocesses.

Certain limitations of this study require consideration. Without an untreated patient group followed in parallel with treated patients, the possible role of disease progression as a cause of worsening ODR task performance cannot be logically excluded. However, for several reasons, we believe that this is an unlikely explanation for the current findings. First, it is unlikely that patients who have been ill on average for a year before entering the study would have a sudden, stepwise, and consistent disease-related deterioration precisely at the time when medication treatment is initiated. Second, if the decline in task performance was somehow related to disease progression, then it is likely that the degree of impairment at baseline or the magnitude of decline after treatment would be associated with a greater length of untreated psychosis. This was not the case. Third, in the subset of patients who were available at the 26- and 52-week follow-up evaluations, there was no further deterioration in ODR task performance from the 6-week to the later follow-up visits. Whether the observed effects are specific to risperidone or to classes of antipsychotic drugs cannot be determined based on these findings. This question needs to be addressed in a future study using a randomized clinical trial design with a comparison drug.

We believe that the results of this study underscore the need for greater use and further development of translational tasks and biomarkers as an approach for advancing understanding of treatment effects on neurocognitive systems in schizophrenia. In another study69 using an antisaccade task with these same patients, we reported improvement after risperidone treatment in the ability to suppress context-inappropriate responses and to more quickly plan and implement behavioral responses. These findings are in contrast to the adverse treatment effects on working memory reported herein. Such a dissociation of risperidone's effects on “executive” prefrontal abilities highlights the value of translational approaches that focus on discrete cognitive operations for parsing beneficial and adverse treatment-related changes in neural systems. Such differentiation of treatment effects on cognitive operations is rarely possible with standard neuropsychologic tests.70 With increased clinical and scientific interest given to developing pharmacologic interventions targeting cognitive symptoms in schizophrenia, neurophysiologic testing that provides a translational bridge between pharmacologic studies with animal models and clinical studies may better clarify the nature of medication effects on cognition and thereby enhance the drug development process.

Correspondence: John A. Sweeney, PhD, Center for Cognitive Medicine, University of Illinois at Chicago, 912 S Wood St, Mail Code 913, Chicago, IL 60612 (jsweeney@psych.uic.edu).

Submitted for Publication: January 20, 2006; accepted March 13, 2006.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants MH62134, MH45156, MH01433 from the National Institute of Mental Health and grant M01 RR00056 from the National Center for Research Resources/General Clinical Research Center, National Institutes of Health; and the National Alliance for Research on Schizophrenia and Depression.

Acknowledgment: We thank Cameron Carter, MD, Gretchen Haas, PhD, and Debra Montrose, PhD, and the clinical staff of the Pittsburgh Center for the Neuroscience of Mental Disorders for their assistance with diagnostic and psychopathologic assessments.

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Baddeley  A Working Memory: Theory and Practice.  New York, NY Oxford University Press1986;
Goldman-Rakic  PS Circuitry of primate prefrontal cortex and regulation of behavior by representational memory In:Mountcastle  VBed.Handbook of Physiology, Section 1: The Nervous System Vol V: Higher Functions of the Brain, Part 1. Bethesda, Md American Physiology Society1987;373- 417
Barch  DMCarter  CSBraver  TSSabb  FWMacDonald  A  IIINoll  DCCohen  JD Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry 2001;58280- 288
PubMed Link to Article
Callicott  JHBertolino  AMattay  VSLangheim  FJPDuyn  JCoppola  RGoldberg  TEWeinberger  DR Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 2000;101078- 1092
PubMed Link to Article
Goldberg  TEHyde  MKleinman  JEWeinberger  DR Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr Bull 1993;19797- 804
PubMed Link to Article
Manoach  DSGollub  RLBenson  ESSearl  MMGoff  DCHalpern  ESaper  CBRauch  SL Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2000;4899- 109
PubMed Link to Article
Weinberger  DRBerman  KFZec  RF Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry 1986;43114- 124
PubMed Link to Article
Hikosaka  OWurtz  RH Visual and oculomotor functions of monkey substantia nigra pars reticulata, III: memory-contingent visual and saccade responses. J Neurophysiol 1983;491268- 1284
PubMed
Goldman-Rakic  PS The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry 1999;46650- 661
PubMed Link to Article
Funahashi  SBruce  CJGoldman-Rakic  PS Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 1989;61331- 349
PubMed
Rao  SGWilliams  GVGoldman-Rakic  PS Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. J Neurophysiol 1999;811903- 1916
PubMed
Goldman-Rakic  PS Cellular basis of working memory. Neuron 1995;14477- 485
PubMed Link to Article
Sawaguchi  TGoldman-Rakic  PS D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 1991;251947- 950
PubMed Link to Article
Goldman-Rakic  PSCastner  SASvensson  THSiever  LJWilliams  GV Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 2004;1743- 16
PubMed Link to Article
Williams  GVGoldman-Rakic  PS Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995;376572- 575
PubMed Link to Article
Abi-Dargham  AMoore  H Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist 2003;9404- 416
PubMed Link to Article
Davis  KLKahn  RSKo  GDavidson  M Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;1481474- 1486
PubMed
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44660- 669
PubMed Link to Article
Broerse  ACrawford  TJDen Boer  JA Differential effects of olanzapine and risperidone on cognition in schizophrenia? a saccadic eye movement study. J Neuropsychiatry Clin Neurosci 2002;14454- 460
PubMed Link to Article
Karoumi  BVentre-Dominey  JVighetto  ADalery  Jd'Amato  T Saccadic eye movements in schizophrenic patients. Psychiatry Res 1998;779- 19
PubMed Link to Article
McDowell  JEClementz  BA Ocular-motor delayed-response task performance among schizophrenia patients. Neuropsychobiology 1996;3467- 71
PubMed Link to Article
Park  SHolzman  PS Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 1992;49975- 982
PubMed Link to Article
Park  SHolzman  PS Association of working memory deficit and eye tracking dysfunction in schizophrenia. Schizophr Res 1993;1155- 61
PubMed Link to Article
Ross  RGHarris  JGOlincy  ARadant  A Eye movement task measures inhibition and spatial working memory in adults with schizophrenia, ADHD, and a normal comparison group. Psychiatry Res 2000;9535- 42
PubMed Link to Article
Crawford  TJHaeger  BKennard  CReveley  MAHenderson  L Saccadic abnormalities in psychotic patients, I: neuroleptic-free psychotic patients. Psychol Med 1995;25461- 471
PubMed Link to Article
Crawford  TJHaeger  BKennard  CReveley  MAHenderson  L Saccadic abnormalities in psychotic patients, II: the role of neuroleptic treatment. Psychol Med 1995;25473- 483
PubMed Link to Article
Muller  NRiedel  MEggert  TStraube  A Internally and externally guided voluntary saccades in unmedicated and medicated schizophrenic patients, part II: saccadic latency, gain, and fixation suppression errors. Eur Arch Psychiatry Clin Neurosci 1999;2497- 14
PubMed Link to Article
Spitzer  RLWilliams  JBWGibbons  MFirst  M Structured Clinical Interview for DSM-III-R (SCID).  New York New York State Psychiatric Institute1987;
McEvoy  JPHogarty  GESteingard  S Optimal dose of neuroleptic in acute schizophrenia: a controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991;48739- 745
PubMed Link to Article
Ammons  CHAmmons  RB The Quick Test (QT): provisional manual. Psychol Rep 1962;11111- 161
Hollingshead  AB Four Factor Index of Social Status.  New Haven, Conn Department of Sociology, Yale University1975;
Oldfield  RC The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;997- 113
PubMed Link to Article
Overall  JEGorham  DR The Brief Psychiatric Rating Scale. Psychol Rep 1962;10799- 812
Link to Article
Andreasen  NC Scale for the Assessment of Positive Symptoms.  Iowa City University of Iowa Press1984;
Andreasen  NC Scale for the Assessment of Negative Symptoms.  Iowa City University of Iowa Press1984;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Reilly  JLHarris  MSKeshavan  MSSweeney  JA Abnormalities in visually guided saccades suggest corticofugal dysregulation in never-treated schizophrenia. Biol Psychiatry 2005;57145- 154
PubMed Link to Article
Krappmann  PEverling  S Spatial accuracy of primary and secondary memory-guided saccades in schizophrenic patients. Schizophr Res 1998;30183- 185
PubMed Link to Article
Rosenthal  R Meta-analytic Procedures for Social Research.  Newbury Park, Calif Sage1991;
Park  S Hemispheric asymmetry of spatial working memory deficit in schizophrenia. Int J Psychophysiol 1999;34313- 322
PubMed Link to Article
Muri  RMGaymard  BRivaud  SVermersch  AIHess  CWPierrot-Deseilligny  C Hemispheric asymmetry in cortical control of memory-guided saccades: a transcranial magnetic stimulation study. Neuropsychologia 2000;381105- 1111
PubMed Link to Article
Sawaguchi  TGoldman-Rakic  PS The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 1994;71515- 528
PubMed
Arnsten  AFCai  JXMurphy  BLGoldman-Rakic  PS Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 1994;116143- 151
PubMed Link to Article
Castner  SAWilliams  GVGoldman-Rakic  PS Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 2000;2872020- 2022
PubMed Link to Article
Arnsten  AFGoldman-Rakic  PS Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 1998;55362- 368
PubMed Link to Article
Muller  UVon Cramon  DYPollmann  S D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 1998;182720- 2728
PubMed
Okubo  YSuhara  TKazutoshi  SKobayashi  KInoue  OTerasaki  OSomeya  YSassa  TSudo  YMatsushima  EIyo  MTateno  YToru  M Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997;385634- 636
PubMed Link to Article
Karlsson  PFarde  LHalldin  CSedvall  G PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 2002;159761- 767
PubMed Link to Article
Abi-Dargham  AMawlawi  OLombardo  IGil  RMartinez  DHuang  YHwang  DRKeilp  JKochan  LVan Heertum  RGorman  JMLaruelle  M Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;223708- 3719
PubMed
Miyamoto  SDuncan  GEMarx  CELieberman  JA Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005;1079- 104
PubMed Link to Article
Wang  MVijayraghavan  SGoldman-Rakic  PS Selective D2 receptor actions on the functional circuitry of working memory. Science 2004;303853- 856
PubMed Link to Article
Lidow  MSElsworth  JDGoldman-Rakic  PS Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. J Pharmacol Exp Ther 1997;281597- 603
PubMed
Williams  GVRao  SGGoldman-Rakic  PS The physiological role of 5-HT2A receptors in working memory. J Neurosci 2002;222843- 2854
PubMed
Kroboth  PDFolan  MMBauer  KSTullock  WWright  ESweeney  JA Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same time course? J Clin Pharmacol 1998;38337- 346
PubMed Link to Article
Green  MFMarshall  BD  JrWirshing  WCAmes  DMarder  SRMcGurk  SKern  RSMintz  J Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997;154799- 804
PubMed
Harvey  PDGreen  MFMcGurk  SRMeltzer  HY Changes in cognitive functioning with risperidone and olanzapine treatment: a large-scale, double-blind, randomized study. Psychopharmacology (Berl) 2003;169404- 411
PubMed Link to Article
McGurk  SRCarter  CGoldman  RGreen  MFMarder  SRXie  HSchooler  NRKane  JM The effects of clozapine and risperidone on spatial working memory in schizophrenia. Am J Psychiatry 2005;1621013- 1016
PubMed Link to Article
Meltzer  HYMcGurk  SR The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25233- 255
PubMed Link to Article
Hill  SKSchuepbach  DHerbener  ESKeshavan  MSSweeney  JA Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naive patients with schizophrenia. Schizophr Res 2004;6849- 63
PubMed Link to Article
Harris  MSReilly  JLKeshavan  MSSweeney  JA Longitudinal studies of antisaccades in antipsychotic-naive first-episode schizophrenia. Psychol Med 2006;36485- 494
PubMed Link to Article
Reilly  JL Treatment effects of atypical antipsychotic medication on neurocognition in first-episode schizophrenia: differential sensitivity of neuropsychological and neurophysiological measures [abstract]. J Int Neuropsychol Soc 2005;11196

Figures

Place holder to copy figure label and caption
Figure 1

Oculomotor delayed response task paradigm. Participants fixate on the central location while a target briefly (0.1 seconds) appears 9°, 18°, or 27° to the right or left. Participants were instructed to remember the location of the peripheral target while maintaining central fixation for an unpredictable variable delay period (1, 2, 4, or 8 seconds) and then to shift their gaze to the remembered target location after the central light was extinguished. A correction light appeared after 1.5 seconds and remained illuminated for 2 seconds at the location where the peripheral target had been presented to provide participants with feedback about their performance on each trial.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2

Mean gain of primary saccades (A) and error of resting eye position (B) for patients with schizophrenia and controls. Patients' primary saccades and resting eye position were significantly less accurate at 6-week follow-up relative to controls. The effect sizes (Cohen d) are for between-group comparisons at each study visit and within-group changes from baseline to 6-week follow-up. *P = .05 and †P<.001 for comparisons between patients and controls. Error bars represent SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3

Mean gain of primary saccades (A) and error of resting eye position (B) for patients with schizophrenia and controls at baseline and 6-week follow-up. Patients' accuracy of primary saccades and final resting eye position were decreased only at the longer delay period at the baseline evaluation but across all delay periods at 6-week follow-up compared with controls. *P = .07 and ‡P = .004 for comparisons between patients and controls at baseline. †P≤.02 for all comparisons between patients and controls at follow-up. Error bars represent SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4

Mean gain of primary saccades (A) and error of resting eye position (B) for patients and controls. Primary saccades and final resting eye positions for target locations in the right hemifield were less accurate for patients than were their responses to left hemifield targets. *P = .05 and †P<.001 for comparisons between patients and controls. Error bars represent SE.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable Demographic and Clinical Characteristics of Patients With Schizophrenia and Controls

References

Elvevag  BGoldberg  TE Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 2000;141- 21
PubMed Link to Article
Goldman-Rakic  PS Working memory dysfunction in schizophrenia. J Neuropsychiatry Clin Neurosci 1994;6348- 357
PubMed
Lee  JPark  S Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol 2005;114599- 611
PubMed Link to Article
Liddle  PF Cognitive impairment in schizophrenia: its impact on social functioning. Acta Psychiatr Scand Suppl 2000;40011- 16
PubMed Link to Article
Meltzer  HYThompson  PALee  MARanjan  R Neuropsychologic deficits in schizophrenia: relation to social function and effect of antipsychotic drug treatment. Neuropsychopharmacology 1996;1427S- 33S
PubMed Link to Article
McGurk  SRMeltzer  HY The role of cognition in vocational functioning in schizophrenia. Schizophr Res 2000;45175- 184
PubMed Link to Article
Glahn  DCTherman  SManninen  MHuttunen  MKaprio  JLonnqvist  JCannon  TD Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry 2003;53624- 626
PubMed Link to Article
McDowell  JEBrenner  CAMyles-Worsley  MCoon  HByerley  WClementz  BA Ocular motor delayed-response task performance among patients with schizophrenia and their biological relatives. Psychophysiology 2001;38153- 156
PubMed Link to Article
Park  SHolzman  PSGoldman-Rakic  PS Spatial working memory deficits in the relatives of schizophrenic patients. Arch Gen Psychiatry 1995;52821- 828
PubMed Link to Article
Baddeley  A Working Memory: Theory and Practice.  New York, NY Oxford University Press1986;
Goldman-Rakic  PS Circuitry of primate prefrontal cortex and regulation of behavior by representational memory In:Mountcastle  VBed.Handbook of Physiology, Section 1: The Nervous System Vol V: Higher Functions of the Brain, Part 1. Bethesda, Md American Physiology Society1987;373- 417
Barch  DMCarter  CSBraver  TSSabb  FWMacDonald  A  IIINoll  DCCohen  JD Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry 2001;58280- 288
PubMed Link to Article
Callicott  JHBertolino  AMattay  VSLangheim  FJPDuyn  JCoppola  RGoldberg  TEWeinberger  DR Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 2000;101078- 1092
PubMed Link to Article
Goldberg  TEHyde  MKleinman  JEWeinberger  DR Course of schizophrenia: neuropsychological evidence for a static encephalopathy. Schizophr Bull 1993;19797- 804
PubMed Link to Article
Manoach  DSGollub  RLBenson  ESSearl  MMGoff  DCHalpern  ESaper  CBRauch  SL Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2000;4899- 109
PubMed Link to Article
Weinberger  DRBerman  KFZec  RF Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral blood flow evidence. Arch Gen Psychiatry 1986;43114- 124
PubMed Link to Article
Hikosaka  OWurtz  RH Visual and oculomotor functions of monkey substantia nigra pars reticulata, III: memory-contingent visual and saccade responses. J Neurophysiol 1983;491268- 1284
PubMed
Goldman-Rakic  PS The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia. Biol Psychiatry 1999;46650- 661
PubMed Link to Article
Funahashi  SBruce  CJGoldman-Rakic  PS Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 1989;61331- 349
PubMed
Rao  SGWilliams  GVGoldman-Rakic  PS Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. J Neurophysiol 1999;811903- 1916
PubMed
Goldman-Rakic  PS Cellular basis of working memory. Neuron 1995;14477- 485
PubMed Link to Article
Sawaguchi  TGoldman-Rakic  PS D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 1991;251947- 950
PubMed Link to Article
Goldman-Rakic  PSCastner  SASvensson  THSiever  LJWilliams  GV Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl) 2004;1743- 16
PubMed Link to Article
Williams  GVGoldman-Rakic  PS Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995;376572- 575
PubMed Link to Article
Abi-Dargham  AMoore  H Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist 2003;9404- 416
PubMed Link to Article
Davis  KLKahn  RSKo  GDavidson  M Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991;1481474- 1486
PubMed
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987;44660- 669
PubMed Link to Article
Broerse  ACrawford  TJDen Boer  JA Differential effects of olanzapine and risperidone on cognition in schizophrenia? a saccadic eye movement study. J Neuropsychiatry Clin Neurosci 2002;14454- 460
PubMed Link to Article
Karoumi  BVentre-Dominey  JVighetto  ADalery  Jd'Amato  T Saccadic eye movements in schizophrenic patients. Psychiatry Res 1998;779- 19
PubMed Link to Article
McDowell  JEClementz  BA Ocular-motor delayed-response task performance among schizophrenia patients. Neuropsychobiology 1996;3467- 71
PubMed Link to Article
Park  SHolzman  PS Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 1992;49975- 982
PubMed Link to Article
Park  SHolzman  PS Association of working memory deficit and eye tracking dysfunction in schizophrenia. Schizophr Res 1993;1155- 61
PubMed Link to Article
Ross  RGHarris  JGOlincy  ARadant  A Eye movement task measures inhibition and spatial working memory in adults with schizophrenia, ADHD, and a normal comparison group. Psychiatry Res 2000;9535- 42
PubMed Link to Article
Crawford  TJHaeger  BKennard  CReveley  MAHenderson  L Saccadic abnormalities in psychotic patients, I: neuroleptic-free psychotic patients. Psychol Med 1995;25461- 471
PubMed Link to Article
Crawford  TJHaeger  BKennard  CReveley  MAHenderson  L Saccadic abnormalities in psychotic patients, II: the role of neuroleptic treatment. Psychol Med 1995;25473- 483
PubMed Link to Article
Muller  NRiedel  MEggert  TStraube  A Internally and externally guided voluntary saccades in unmedicated and medicated schizophrenic patients, part II: saccadic latency, gain, and fixation suppression errors. Eur Arch Psychiatry Clin Neurosci 1999;2497- 14
PubMed Link to Article
Spitzer  RLWilliams  JBWGibbons  MFirst  M Structured Clinical Interview for DSM-III-R (SCID).  New York New York State Psychiatric Institute1987;
McEvoy  JPHogarty  GESteingard  S Optimal dose of neuroleptic in acute schizophrenia: a controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 1991;48739- 745
PubMed Link to Article
Ammons  CHAmmons  RB The Quick Test (QT): provisional manual. Psychol Rep 1962;11111- 161
Hollingshead  AB Four Factor Index of Social Status.  New Haven, Conn Department of Sociology, Yale University1975;
Oldfield  RC The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;997- 113
PubMed Link to Article
Overall  JEGorham  DR The Brief Psychiatric Rating Scale. Psychol Rep 1962;10799- 812
Link to Article
Andreasen  NC Scale for the Assessment of Positive Symptoms.  Iowa City University of Iowa Press1984;
Andreasen  NC Scale for the Assessment of Negative Symptoms.  Iowa City University of Iowa Press1984;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Reilly  JLHarris  MSKeshavan  MSSweeney  JA Abnormalities in visually guided saccades suggest corticofugal dysregulation in never-treated schizophrenia. Biol Psychiatry 2005;57145- 154
PubMed Link to Article
Krappmann  PEverling  S Spatial accuracy of primary and secondary memory-guided saccades in schizophrenic patients. Schizophr Res 1998;30183- 185
PubMed Link to Article
Rosenthal  R Meta-analytic Procedures for Social Research.  Newbury Park, Calif Sage1991;
Park  S Hemispheric asymmetry of spatial working memory deficit in schizophrenia. Int J Psychophysiol 1999;34313- 322
PubMed Link to Article
Muri  RMGaymard  BRivaud  SVermersch  AIHess  CWPierrot-Deseilligny  C Hemispheric asymmetry in cortical control of memory-guided saccades: a transcranial magnetic stimulation study. Neuropsychologia 2000;381105- 1111
PubMed Link to Article
Sawaguchi  TGoldman-Rakic  PS The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 1994;71515- 528
PubMed
Arnsten  AFCai  JXMurphy  BLGoldman-Rakic  PS Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 1994;116143- 151
PubMed Link to Article
Castner  SAWilliams  GVGoldman-Rakic  PS Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 2000;2872020- 2022
PubMed Link to Article
Arnsten  AFGoldman-Rakic  PS Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism. Arch Gen Psychiatry 1998;55362- 368
PubMed Link to Article
Muller  UVon Cramon  DYPollmann  S D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 1998;182720- 2728
PubMed
Okubo  YSuhara  TKazutoshi  SKobayashi  KInoue  OTerasaki  OSomeya  YSassa  TSudo  YMatsushima  EIyo  MTateno  YToru  M Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature 1997;385634- 636
PubMed Link to Article
Karlsson  PFarde  LHalldin  CSedvall  G PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 2002;159761- 767
PubMed Link to Article
Abi-Dargham  AMawlawi  OLombardo  IGil  RMartinez  DHuang  YHwang  DRKeilp  JKochan  LVan Heertum  RGorman  JMLaruelle  M Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;223708- 3719
PubMed
Miyamoto  SDuncan  GEMarx  CELieberman  JA Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005;1079- 104
PubMed Link to Article
Wang  MVijayraghavan  SGoldman-Rakic  PS Selective D2 receptor actions on the functional circuitry of working memory. Science 2004;303853- 856
PubMed Link to Article
Lidow  MSElsworth  JDGoldman-Rakic  PS Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. J Pharmacol Exp Ther 1997;281597- 603
PubMed
Williams  GVRao  SGGoldman-Rakic  PS The physiological role of 5-HT2A receptors in working memory. J Neurosci 2002;222843- 2854
PubMed
Kroboth  PDFolan  MMBauer  KSTullock  WWright  ESweeney  JA Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same time course? J Clin Pharmacol 1998;38337- 346
PubMed Link to Article
Green  MFMarshall  BD  JrWirshing  WCAmes  DMarder  SRMcGurk  SKern  RSMintz  J Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997;154799- 804
PubMed
Harvey  PDGreen  MFMcGurk  SRMeltzer  HY Changes in cognitive functioning with risperidone and olanzapine treatment: a large-scale, double-blind, randomized study. Psychopharmacology (Berl) 2003;169404- 411
PubMed Link to Article
McGurk  SRCarter  CGoldman  RGreen  MFMarder  SRXie  HSchooler  NRKane  JM The effects of clozapine and risperidone on spatial working memory in schizophrenia. Am J Psychiatry 2005;1621013- 1016
PubMed Link to Article
Meltzer  HYMcGurk  SR The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25233- 255
PubMed Link to Article
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