Longitudinal studies of antisaccades in
antipsychotic-naive first-episode schizophrenia
MARGRET S. H. HARRIS1, JAMES L. REILLY1, MATCHERI S. KESHAVAN2
AND JOHN A. SWEENEY1*
1Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, IL, USA;
2Wayne State University, Detroit, MI, USA
Background. Prefrontal cortical dysfunctions, including disturbances in adaptive context-specific
behavior, have been reported in neuropsychological and brain imaging studies of schizophrenia.
Some data suggest that treatment with antipsychotic medications may ameliorate these deficits.
Method. We investigated antisaccade performance in 39 antipsychotic-naive, first-episode schizo-
phrenia patients who were re-evaluated 6 weeks after treatment initiation. A group of matched
healthy subjects were examined at similar time-points. Patients and healthy individuals available
for longer-term testing were re-assessed 26 and 52 weeks after initial testing.
Results. Before treatment, patients showed elevated rates of response suppression errors and pro-
longed latencies of correct antisaccades. Increased rates of antisaccade errors were associated with
faster response latencies during a separate, visually guided saccade task, but only prior to treatment.
Throughout the 1-year follow-up, patients progressively improved in their ability to voluntarily
suppress context-inappropriate behavior. Although treatment assignment was by clinician choice,
results of exploratory analyses revealed that patients treated with risperidone progressively planned
and initiated correct antisaccades more quickly than patients receiving haloperidol.
Conclusions. Deficits in the voluntary control of spatial attention are exaggerated during acute
episodes of illness, but remain an enduring aspect of prefrontal dysfunction in schizophrenia even
after treatment. During acute illness, speeded sensorimotor transformations may compound these
deficits and contribute to the heightened distractibility associated with acute psychosis. Continued
improvement in task performance throughout the 1-year follow-up suggests that partial normal-
ization of prefrontal cognitive functions resulting from antipsychotic treatment may have a longer
and more gradual time course than the reduction of acute psychotic symptoms.
Many cognitive abnormalities in schizophrenia
are believed to result from disturbances in pre-
frontal cortical systems. Following up on find-
ings from traditional neuropsychological studies
(Goldberg et al. 1993; Bilder et al. 2000; Hill
et al. 2004), several groups have used laboratory
(Sweeney et al. 2002; Brownstein et al. 2003)
and functional brain imaging studies (Gur et al.
2000; Hazlett et al. 2000; Barch et al. 2001;
Ho et al. 2003) with oculomotor paradigms
to evaluate disturbances in prefrontal systems.
knowledge established through investigations
with non-human primates (Bruce & Goldberg,
Munoz, 2000), studies of patients with focal
brain lesions (Guitton et al. 1985; Pierrot-
Deseilligny, 1994) and functional brain imaging
studies of healthy individuals (O’Driscoll et al.
1995; Sweeney et al. 1996; Heide et al. 2001).
* Address for correspondence: Professor John A. Sweeney,
Center for Cognitive Medicine, 912 S. Wood St, MC 913, University
of Illinois at Chicago, Chicago, IL 60612, USA.
Psychological Medicine, 2006, 36, 485–494.
f 2006 Cambridge University Press
First published online 3 January 2006. Printed in the United Kingdom
Neuropsychological impairments implicating
prefrontal cortical dysfunction in schizophrenia
include a difficulty successfully suppressing be-
havior that is typically appropriate but is in-
appropriate in specific behavioral contexts
(Everling & Fischer, 1998; Barch et al. 1999). A
widely used oculomotor task that evaluates the
ability to inhibit context-inappropriate behav-
ior is the antisaccade paradigm (Hallett, 1978;
Munoz & Everling, 2004). During the anti-
saccade task, subjects fixate on a central target,
which, at an unpredictable time, steps to a
location in the periphery. Subjects are instructed
to inhibit the natural tendency to look toward
the peripheral target (antisaccade error), but
rather to immediately look in the opposite
direction to the mirror location (correct anti-
of response suppression, the latencies of correct
antisaccades away from peripheral targets re-
flect the speed of processing for planning and
generating voluntary action without sensory
guidance. Prefrontal cortex is known to be
crucial for supporting successful performance
on this task (Sweeney et al. 1996; Walker et al.
1998; Pierrot-Deseilligny et al. 2003).
To date, most published antisaccade studies
of schizophrenia have been cross-sectional
investigations of clinically stable, medicated
patients. Increased antisaccade error rates in
schizophrenia patients have been a relatively
consistent observation (Fukushima et al. 1990;
Clementz et al. 1994; Curtis et al. 2001).
However, findings are less consistent with re-
gard to how quickly patients can initiate correct
antisaccade responses. While some studies
found prolonged latencies in schizophrenia
patients (Fukushima et al. 1990; Sereno &
Holzman, 1995; Curtis et al. 2001), others found
no impairment (Clementz et al. 1994; Hutton
et al. 2002).
There are few published studies of treatment
and state-of-illness effects on antisaccades. A
study comparing treated and untreated first-
episode schizophrenia patients revealed in-
creased error rates for both patient groups, but
longer antisaccade latencies only for treatment-
naive patients (Hutton et al. 1998). This suggests
that treatment may enhance the speed of com-
putational processes required for initiating anti-
saccades. However, Crawford and colleagues
(1995) found no differences in error rates or
antisaccade latencies between unmedicated and
medicated chronic schizophrenia patients, and
in either parameter in a sample of 17 initially
neuroleptic-naive patients after treatment. In
another follow-up study, Gooding and col-
schizophrenia outpatients after 3 years, and re-
ported a reduction in antisaccade error rates but
no change in antisaccade latencies at retesting.
The present study investigated antisaccade
performance in 39 antipsychotic-naive patients
with first-episode schizophrenia before treat-
ment initiation during the acute phase of illness,
and again after 6 weeks of treatment. Subjects
available for additional retesting were evalu-
ated again at 26 and 52 weeks after baseline
assessments. Matched healthy individuals were
tested at similar time-points. Our specific aims
were to characterize deficits prior to treatment,
and to determine whether clinically effective
treatment with antipsychotic medications im-
pacted antisaccade task performance. Such
investigations of performance levels on oculo-
phases of illness in the same group of patient
participants may be useful for studying the
specific effects of treatments on prefrontal cor-
tical functioning and for evaluating the efficacy
of treatment approaches for cognitive rehabili-
tation of schizophrenia patients.
Written informed consent was obtained from
39 antipsychotic-naive patients (16 females, 23
males) meeting DSM-IV criteria for schizo-
phrenia (n=36) or schizoaffective disorder –
Structured Clinical Interview for DSM-III-R
(SCID; Spitzer et al. 1987) and collateral clinical
data reviewed at consensus diagnosis meetings.
Patients had an average age of 24.7 (S.D.=6.9)
years, an average IQ (Ammon’s Quick Test)
of 97.9 (S.D.=10.7), and their parents had an
average socio-economic status (Hollingshead,
1975) of 2.4 (S.D.=1.1).
Forty-one healthy individuals (13 females,
28 males) recruited from the surrounding
community matched the patient group on age,
gender, IQ and parental socio-economic status.
486 M. S. H. Harris et al.
Healthy individuals had an average age of 24.0
(S.D.=5.5), an average IQ of 102.7 (S.D.=11.1),
and an average parental socio-economic status
of 2.2 (S.D.=1.0). Healthy participants did not
meet criteria for any present or past Axis I dis-
order according to SCID interviews. The study
protocol was approved by the Institutional
Review Board of the University of Pittsburgh.
All subjects met the following criteria: (1) age
between 15 and 45 years; (2) no known systemic
or neurologic disease; (3) no prior treatment
with electroconvulsive therapy; (4) no history of
head trauma with loss of consciousness for more
than 10 minutes; (5) no lifetime history of sub-
stance dependence and no substance abuse for
at least 3 months prior to study participation;
(6) no anticonvulsants (for at least 1 month) or
benzodiazepines (five half-lives) prior to testing;
and (7) no coffee, tea or cigarettes 1 hour prior
to testing. Follow-up studies were conducted
6 weeks after baseline testing. All subjects
who could be located and were available for
additional testing were also retested at 26 and
Clinicians with no knowledge of findings
from the eye movement studies (see next section)
completed clinical ratings with patients in par-
allel witheach testing. Ratingsincluded theBrief
Psychiatric Rating Scale (Overall & Gorham,
1962), the Schedule for the Assessment of Nega-
tive Symptoms (SANS; Andreasen, 1984a), the
Schedule for the Assessment of Positive Symp-
toms (SAPS; Andreasen, 1984b) and the
McEvoy et al. 1991) (see Table 1). Following
baseline assessments, 23 patients were treated
with risperidone (4.0¡1.7 mg), 11 patients were
treated with haloperidol (3.8¡2.5 mg), and one
patient was treated with olanzapine (20 mg).
The remaining four patients were treated with
one of these medications in a double-blind
clinical trial. Medication doses were stable in the
week prior to testing. Treatment assignment was
not randomized and for the most part reflected
the primary treatment choice of the clinical team
of a typical antipsychotic (haloperidol) during
earlier recruitment and an atypical antipsy-
chotic medication (risperidone) during the later
phase of recruitment. The medication adminis-
tered was consistent for each patient through-
out study participation. Although this was not
a randomized clinical trial, a comparison of
patients treated with risperidone or haloperidol
was conducted to provide preliminary data
about differential effects of these medications on
neurocognitive parameters of interest.
Eye movement studies
Subjects were tested alone in a darkened black
room free from extraneous stimuli that could
interfere with performance on eye movement
tasks. Subjects were positioned in a chin and
forehead rest to minimize head movement. They
sat facing a circular black arc with a 1-m radius
and red-light-emitting diodes embedded in the
horizontal plane at eye level used to present
visual stimuli. Electrodes were placed at the
lateral and nasal canthi of each eye to obtain
electro-oculography (EOG) recordings (Grass
Neurodata 12 Acquisition System, Astro-Med
Inc., West Warwick, RI, USA). Blinks were
monitored using electrodes placed above and
below the left eye. A technician in an adjacent
room provided task instructions via intercom.
Table 1. Clinical ratings, daily antipsychotic medication dose (mg/day), and extrapyramidal
side-effect ratings for all patients at baseline and follow-up time-points [mean (S.D.)]
Baseline (n=39)6 weeks (n=39) 26 weeks (n=29)52 weeks (n=28)
BPRS, Brief Psychiatric Rating Scale; SANS, Schedule for the Assessment of Negative Symptoms; SAPS, Schedule for the Assessment of
Positive Symptoms; EPSEs, Extra-Pyramidal Side-Effects Scale.
* p<0.05, ** pf0.01, *** pf0.001 (p values represent significance levels from paired samples t tests for significant changes from baseline
Antisaccades in first-episode schizophrenia487
To minimize potential impact of baseline
drift in EOG signals over the course of testing,
eye position recordings were independently
calibrated for each trial using data obtained
when subjects fixated central and peripheral
targets. Recordings were analyzed using custom
software developed in our laboratory. An al-
gorithm identified saccade initiation when eye
velocity rose above 30 deg/s, and saccade ter-
mination when eye velocity returned below
that level. Anticipatory saccades with latencies
less than 70 ms were not included in analyses.
Trials were rejected if a blink occurred in the
interval between 100 ms prior to presentation
of peripheral targets and the end of primary
Subjects were required to fixate a central target
for 3–5 s, after which it was extinguished and
a peripheral target appeared immediately but
unpredictably at one of six locations, 8, 16, or
24 degrees to the left or right of center fixation.
Subjects were instructed not to look at the
peripheral target, but rather to immediately
look to the exact mirror location (in the op-
posite direction). The peripheral target was ex-
in the exact mirror location provided feedback
regarding the location of the correct antisaccade
Subjects were trained using slow presentations
of the task during which a technician provided
verbal instructions about task demands and
made errors on two consecutive trials, they were
reminded of task instructions to ensure that
performance deficits did not result from con-
fusion about task requirements. Trials with re-
sponse suppression errors in which subjects
looked toward the target before making anti-
saccades away from it were not included in
analyses of antisaccade response latencies.
Visually guided saccade task
In a separate visually guided saccade task, sub-
jects were instructed to look to visual targets
when they appeared. Trials began with a center
fixation target before peripheral targets were
presented at unpredictable locations in the
left or right visual field. A detailed description
of these methods and data were presented
previously (Reilly et al. 2005). The saccade
latency data from that study are included here
to show their relationship to antisaccade task
Reliability of saccadic eye movement
parameters over time
To examine the temporal stability of eye move-
ment parameters, intra-class correlations (ICCs)
for antisaccade latency and error rate were
calculated separately for patients and healthy
subjects from baseline to the 52-week follow-up.
Patients demonstrated significant ICCs for both
parameters (antisaccade latency: ICC=0.63,
p=0.014; error rate: ICC=0.60, p=0.021).
Healthy subjects showed similar test–retest
reliability over the 1-year study period (anti-
saccade latency: ICC=0.63, p=0.007; error
rate: ICC=0.77, p<0.001). Recalculation of
ICC’s from the 6-week to the 52-week follow-
up, excluding baseline data collected when
patients were treatment-naive and acutely ill,
yielded similar findings.
Data were averaged across identical trials (e.g.
all trials with targets 8 deg to the left of center)
for each subject prior to statistical analyses.
An arcsine transformation was performed on
the antisaccade error rate data to render them
more amenable to parametric statistical analy-
sis. Because the emphasis of the present study
was on comparisons of patients and healthy
individuals over time, data from leftward and
rightward saccades were pooled as there were
no significant subject grouprdirection inter-
actions. Similarly, because grouprtarget lo-
cation interactions were not significant, target
location effects are not presented in detail
While data were available for all subjects
at the baseline and 6-week testing, data were
available at the 26-week follow-up for only 29
patients and 29 healthy subjects and at the
52-week follow-up for only 28 patients and 27
healthy subjects. To estimate group and treat-
ment differences throughout the 1-year follow-
up period, we used longitudinal pattern-mixture
1997). In these models, time was a random effect
and subject group or medication type was a
fixed effect. To determine whether there was
488 M. S. H. Harris et al.
a problem including data from participants
who missed an assessment, models were fit
adding another fixed parameter corresponding
to whether a subject had complete or missing
data at the 26- or 52-week follow-up. This
parameter did not improve model fit in any
analyses, indicating that subject attrition did
not influence the pattern of results. Additional
analyses revealed no significant differences in
demographic background, clinical ratings, or
medication dosage between those with and with-
out complete follow-up data.
Comparisons of patients and healthy individuals
Response suppression failure
The random effects models of the antisaccade
error rate data indicated significant effects for
time [F(1,78)=41.32, p<0.001], subject group
[F(1,102)=56.95, p<0.001], and a timer
group interaction [F(1,102)=17.72, p<0.001].
Patients showed impaired performance during
the acute phase of illness compared to healthy
individuals, but gradual improvement through-
out the 1-year follow-up. However, their error
rate remained significantly elevated compared
to healthy individuals at all time-points (see
Fig. 1). Comparing baseline to the 1-year
follow-up, patients showed a 41.7% reduction
in antisaccade errors (p<0.001) while healthy
individuals showed a 9.5% decrease (p=0.48).
Latency of correct antisaccade responses
The random effects model for latencies of cor-
rect antisaccades across all time-points yielded
significant effects for time [F(1,78)=14.33,
p<0.001] and subject group [F(1,102)=7.28,
p<0.01], but the interaction was not significant.
The time effect reflected a progressive reduction
in antisaccade latencies in both patients and
healthy subjects throughout the study. Patients’
antisaccade latencies decreased from baseline
to 52 weeks by 14.7% (p=0.007) and healthy
individuals by 8.8% (p=0.01). Although both
groups showed progressively faster response
latencies over the course of the study, responses
of schizophrenia patients remained slower
throughout the study.
Speed–accuracy trade-off curves are presented
in Fig. 2. As illustrated, the progressive re-
duction in antisaccade error rates in schizo-
phrenia patients was not accounted for by a
slowing of response latencies in this group, de-
signed to prevent prosaccade errors. Addition-
ally, the faster response latencies at follow-up
in both patients and healthy individuals did
Antisaccade error rate (%)
B 6 wk 26 wk 52 wk
subjects (–$–), patients treated with haloperidol (–!–), and patients
treated with risperidone (–&–) at baseline (B), 6-week, 26-week,
and 52-week follow-up assessments. Between-group comparisons
of schizophrenia patients and healthy individuals were significant
at all time-points (all p’s<0.001). Baseline: healthy (n=41), halo-
peridol (n=11), risperidone (n=23); 6-week follow-up: healthy
(n=41), haloperidol (n=11), risperidone (n=23); 26-week follow-
up: healthy (n=29), haloperidol (n=8), risperidone (n=13); 52-
week follow-up: healthy (n=27), haloperidol (n=8), risperidone
Mean (S.E.) rate of antisaccade errors for healthy
Antisaccade latency (ms)
Antisaccade error rate (%)
ance for patients (–$–) and healthy subjects (–#–) at baseline (B),
6-week, 26-week, and 52-week follow-up assessments. Baseline:
healthy (n=41), schizophrenia (n=39); 6-week follow-up: healthy
(n=41), schizophrenia (n=39); 26-week follow-up: healthy (n=29),
schizophrenia (n=29); 52-week follow-up: healthy (n=27), schizo-
Speed–accuracy trade-off during antisaccade task perform-
Antisaccades in first-episode schizophrenia489
not come at the cost of reduced response accu-
racy within either participant group. Rather,
faster response initiation in both groups likely
represents positive practice effects from prior
Response latencies on the visually guided
saccade task and antisaccade error rates
Patients showed faster latencies of visually
guided saccades than healthy subjects prior to
treatment, as we have reported elsewhere (Reilly
et al. 2005). The effect is of interest for the
present study because faster saccadic responses
to visual input might lead to more frequent
errors on the antisaccade task because stop
signal commands could be less able to prevent
saccades toward unpredictably appearing tar-
gets. To examine the relationship between vis-
ually guided saccade latencies and antisaccade
performance, we correlated visually guided
saccade latencies with antisaccade error rates
using the targets most proximate to central
fixation, because antisaccade error rates and
speeding of visually guided saccade latencies
were greater when targets were presented closer
to central fixation. Results at baseline testing
showed a significant association between vis-
ually guided saccade latencies and error rates
on the antisaccade task for patients, but not
healthy individuals (see Fig. 3). This correlation
in the patient group was no longer significant
6 weeks after treatment (r=x0.13, p=0.44) or
at later follow-up testings.
Comparisons of patients receiving haloperidol
and patients receiving risperidone
Patients treated with haloperidol and risperi-
done did not differ on demographic or clinical
ratings at baseline, nor did they show different
clinical responses to treatment.
Response suppression failure
The random effects model of antisaccade error
rate data showed a significant effect for time
showed similar decreases of antisaccade error
rates regardless of medication type. Patients
treated with risperidone showed a 39.8% re-
duction in antisaccade error rate (p=0.019)
treated with haloperidol showed a 48.0% re-
Latency of correct antisaccades
The random effects model for latencies of
risperidone versus haloperidol revealed signifi-
cant effects for time [F(1,32)=16.06, p<0.001],
for drug type [F(1,41)=7.24, p=0.01] and for
an interaction between time and drug type
[F(1,41)=6.61, p=0.01]. Patients treated with
risperidone showed progressively faster anti-
saccade response initiation over the course
of the 1-year follow-up. In contrast, patients
treated with haloperidol showed no consistent
decrease in response latencies over the 1-year
follow-up period. As shown in Fig. 4, patients
latencies from baseline to 52 weeks by 22.7%
(p=0.004), while patients treated with halo-
peridol showed a reduction in response latency
of only 1.1% over the 1-year study period
Relationships with clinical ratings and
ratings from baseline to follow-up (see Table 1).
Changes from baseline in antisaccade task per-
formance were not associated with changes in
clinical ratings or medication dosage at any
time-point. Extrapyramidal side-effect ratings
did not differ across haloperidol and risperidone
treatment (t=0.83, p=0.43, at 6-week follow-
up when complete data were available for the
significantly on clinical
Antisaccade error rate (%)
Visually guided saccade latency (ms)
(n=41), schizophrenia (n=39). $, Schizophrenia (r=x0.44,
p=0.006); #, healthy subjects (r=x0.27, p=N.S.).
Correlations of percentage of antisaccade errors and vis-
490 M. S. H. Harris et al.
sample), nor were they related to task perform-
ance. Seven patients in the haloperidol group
and four patients in the risperidone group re-
ceived anticholinergic treatment (benztropine),
but analyses revealed no differences in task
performance for these individuals.
Deficits in prefrontal cortical functioning have
been widely reported in schizophrenia using
neuropsychological testing (Bilder et al. 2000;
Hill et al. 2004), oculomotor studies using the
antisaccade and other tasks (Sweeney et al.
2002; Brownstein et al. 2003), and functional
brain imaging (Gur et al. 2000; Hazlett et al.
2000; Barch et al. 2001; Ho et al. 2003). The
present study provides new information re-
garding the effects of treatment on deficits in one
cognitive ability supported by prefrontal cortex,
the ability to voluntarily suppress context-
inappropriate behavioral responses. Findings
from the present study indicate that the volun-
tary control of spatial attention and eye move-
ments was impaired during the acute phase
of schizophrenia prior to treatment, at which
time the deficit appeared to be exacerbated
by a state-related speeding of visual orienting
responses. Treatment with antipsychotic medi-
cation improved the ability to suppress context-
inappropriate responses. In post-hoc analyses,
risperidone was more effective than haloperidol
in reducing the time required to plan and initiate
Deficits in voluntary response initiation and
inhibition in acute schizophrenia
Three separate processes are necessary for the
successful execution of the antisaccade task.
First, individuals need to covertly shift exogen-
ous attention and localize new visual targets
(Corbetta et al. 1993; Perry & Zeki, 2000). The
second component is the ability to successfully
inhibit the natural context-inappropriate reflex-
ive tendency to shift gaze to suddenly appearing
visual stimuli. Third, individuals need to gener-
ate an internal plan to execute a voluntary
antisaccade in the opposite direction to the
target displacement. The latter two endogenous
processes of response suppression and the vol-
untary generation of behavior are believed to
be mediated primarily by prefrontal systems in-
volving specific frontostriatal circuitry (Guitton
et al. 1985; Funahashi et al. 1993; Raemaekers
et al. 2002; Pierrot-Deseilligny et al. 2003).
Abnormalities in the endogenous control of
attention by prefrontal executive systems have
long been considered core cognitive deficits
in schizophrenia. Disturbances in antisaccade
task performance are one manifestation of this
impairment (McDowell et al. 2002). Similar to
the majority of previous findings with chronic
medicated patients (Fukushima et al. 1990;
Clementz et al. 1994; Sereno & Holzman, 1995;
Curtis et al. 2001), antipsychotic-naive first-
episode schizophrenia patients in the current
study showed deficits in endogenous attentional
control during the acute phases of illness as
reflected in increased levels of response sup-
pression failure (antisaccade errors) as well as
As we have reported previously, first-episode
schizophrenia patients respond more quickly
than healthy subjects to visual inputs when they
are acutely ill, suggesting dysfunction of neo-
cortical systems regulating automatic shifts of
attention to visual stimuli (Reilly et al. 2005).
Other evidence for dysfunction of exogenous
attentional systems supporting visual orienting
can be found in studies examining performance
digms (Posner et al. 1988) and investigations
Antisaccade latency changes
from baseline (ms)
B 6 wk26 wk 52 wk
latencies (ms) for healthy subjects (–$–), patients treated with halo-
peridol (.....!.....), and patients treated with risperidone (- - -&- - -)
from baseline (B) to 6-week, 26-week, and 52-week follow-up
assessments. Negative values reflect faster latencies compared to
baseline. Baseline: healthy (n=41), haloperidol (n=11), risperidone
(n=23); 6-week follow-up: healthy (n=41), haloperidol (n=11),
risperidone (n=23); 26-week follow-up: healthy (n=29), haloperidol
(n=8), risperidone (n=13); 52-week follow-up: healthy (n=27),
haloperidol (n=8), risperidone (n=12).
Antisaccade latencies. Mean change of correct antisaccade
Antisaccades in first-episode schizophrenia 491
of the gap effect on latencies of visually guided
saccades (Clementz, 1996). The relationship
we now demonstrate between speeded visual
orienting and increased antisaccade error rates
suggests that a hyper-responsiveness of exo-
genous visual attention systems during the acute
phase of illness may exacerbate the impact of
more persistent deficits in endogenous executive
systems and lead to especially severe impair-
ments in the cognitive control of attention.
The combination of these deficits in exogenous
and endogenous attentional systems may in
part explain the heightened distractibility ob-
served clinically in patients experiencing acute
Effects of treatment with antipsychotic
Treatment with antipsychotic medication led
to a significant improvement in performance
of the antisaccade task. This effect appears to
result from a more rapid and complete normal-
ization of exogenous attentional systems as
assessed by visually guided saccade latencies
(Reilly et al. 2005) and a more gradual and only
partial normalization in the ability to volun-
tarily inhibit context-inappropriate behavior.
Patients treated with risperidone or haloperidol
both showed robust and similar improve-
ments in the ability to suppress inappropriate
responses, suggesting improvement in aspects
of prefrontal cortical function required for this
task. Our findings also demonstrate that never-
improved in their ability to voluntarily plan
and initiate context-appropriate behavioral re-
sponses more efficiently after treatment. How-
ever, the improvement in antisaccade latencies
after treatment was primarily seen among
patients receiving risperidone. These findings
are partially consistent with those of Burke &
Reveley (2002), who observed significantly
lower error rates and faster antisaccade latencies
when chronic patients were treated with risperi-
done rather than typical antipsychotics in a
crossover study. In the present study, patients
treated with haloperidol did not differ on demo-
graphic or clinical ratings at baseline from
patients treated with risperidone, nor did the
two patient groups show different clinical re-
sponses to treatment. Thus, the observed differ-
ence in the effects of haloperidol and risperidone
on antisaccade latency did not result from
group differences in symptom severity prior
to treatment or in their responsiveness to treat-
ment. Rather, pharmacological differences be-
tween risperidone and haloperidol appear to
account for this difference, such as the effect of
risperidone in blocking 5-HT2Areceptors that
are widely distributed throughout prefrontal
cortex (Tamminga, 2003). While the specific
mechanisms remain to be determined, there
appear to be advantageous effects of risperi-
done, relative to haloperidol, on frontostriatal
systems that facilitate the ability to quickly
plan and enact adaptive cognitively controlled
Continued gradual improvement after treat-
ment initiation in the ability to quickly initiate
antisaccade responses suggests that the time
course of benefits of antipsychotic medication
on some prefrontal functions may be more
gradual and prolonged than the more immedi-
ate reduction in psychotic symptoms, as sug-
gested by Keefe and colleagues (1999). Of note,
these indications of progressive improvement in
prefrontal function using the antisaccade task
stand in contrast to findings from our parallel
neuropsychological studies in this population,
which failed to detect improvements on tests of
attention or executive abilities (Hill et al. 2004).
This suggests that the finer temporal resolution
and other advantages provided by oculomotor
paradigms, such as the more direct linkage to
animal models, may confer important benefits
for their use in detecting change in cognitive
abilities over time, including beneficial effects of
pharmacological treatments on neurocognitive
This study was supported by funds received
from NIH grants MH62134, MH45156 and
MH01433 and the NIH/NCRR/GCRC grant
no. M01 RR00056. We thank Drs Cameron
Carter, Gretchen Haas and Debra Montrose,
and the clinical core staff of the Center for the
Neuroscience of Mental Disorders (MH45156)
for their assistance in diagnostic and psycho-
pathological assessments. We also wish to thank
Dr Robert Gibbons and Subhash Aryal for
their statistical consultation.
492 M. S. H. Harris et al.
DECLARATION OF INTEREST
Andreasen, N. C. (1984a). Scale for the Assessment of Negative
Symptoms. University of Iowa Press: Iowa City, IA.
Andreasen, N. C. (1984b). Scale for the Assessment of Positive
Symptoms. University of Iowa Press: Iowa City, IA.
Barch, D. M., Carter, C. S., Braver, T. S., Sabb, F. W., MacDonald,
A., Noll, D. C. & Cohen, J. D. (2001). Selective deficits in pre-
frontal cortex function in medication-naive patients with schizo-
phrenia. Archive of General Psychiatry 58, 280–288.
Barch, D. M., Carter, C. S., Hachten, P. C., Usher, M. & Cohen,
J. D. (1999). The ‘benefits’ of distractibility: mechanisms under-
lying increased Stroop effects in schizophrenia. Schizophrenia
Bulletin 25, 749–762.
Bilder, R. M., Goldman, R. S., Robinson, D., Reiter, G., Bell, L.,
Bates, J. A., Pappadopulos, E., Willson, D. F., Alvir, J. M.,
Woerner, M. G., Geisler, S., Kane, J. M. & Lieberman, J. A.
(2000). Neuropsychology of first-episode schizophrenia: initial
characterization and clinical correlates. American Journal of
Psychiatry 157, 549–559.
Brownstein, J., Krastoshevsky, O., McCollum, C., Kundamal, S.,
Matthysse, S., Holzman, P. S., Mendell, N. R. & Levy, D. L.
(2003). Antisaccade performance is abnormal in schizophrenia
patients but not in their biological relatives. Schizophrenia
Research 63, 13–25.
Bruce, C. J. & Goldberg, M. E. (1985). Primate frontal eye fields.
I. Single neurons discharging before saccades. Journal of
Neurophysiology 53, 603–635.
Burke, J. G. & Reveley, M. A. (2002). Improved antisaccade per-
formance with risperidone in schizophrenia. Journal of Neurology,
Neurosurgery & Psychiatry 72, 449–454.
Clementz, B. A. (1996). The ability to produce express saccades as
a function of gap interval among schizophrenia patients.
Experimental Brain Research 111, 121–130.
Clementz, B. A., McDowell, J. E. & Zisook, S. (1994). Saccadic
system functioning among schizophrenia patients and their first-
degree biological relatives. Journal of Abnormal Psychology 103,
Corbetta, M., Miezin, F. M., Shulman, G. L. & Petersen, S. E. (1993).
A PET study of visuospatial attention. Journal of Neuroscience
Crawford, T. J., Haeger, B., Kennard, C., Reveley, M. A. &
Henderson, L. (1995). Saccadic abnormalities in psychotic patients.
II. The role of neuroleptic treatment. Psychological Medicine 25,
Curtis, C. E., Calkins, M. E., Grove, W. M., Feil, K. J. & Iacono,
W. G. (2001). Saccadic disinhibition in patients with acute and
remitted schizophrenia and their first-degree biological relatives.
American Journal of Psychiatry 158, 100–106.
Everling, S. & Fischer, B. (1998). The antisaccade: a review of basic
research and clinical studies. Neuropsychologia 36, 885–899.
Everling, S. & Munoz, D. P. (2000). Neuronal correlates for
preparatory set associated with pro-saccades and anti-saccades
in the primate frontal eye field. Journal of Neuroscience 20,
Fukushima, J., Morita, N., Fukushima, A. K., Chiba, T., Tanaka, S. &
Yamashita, I. (1990). Voluntary control of saccadic eye movements
in patients with schizophrenic and affective disorders. Journal of
Psychiatry Research 24, 9–24.
Funahashi, S., Chafee, M. V. & Goldman-Rakic, P. S. (1993).
Prefrontal neuronal activity in rhesus monkeys performing a
delayed anti-saccade task. Nature 365, 753–758.
Goldberg, T. E., Hyde, M., Kleinman, J. E. & Weinberger, D. R.
(1993). Course of schizophrenia: neuropsychological evidence
for a static encephalopathy. Schizophrenia Bulletin 19, 797–804.
Goldman-Rakic, P. S. (1988). Topography of cognition: parallel
distributed networks in primate association cortex. Annual Review
of Neuroscience 11, 137–156.
Gooding, D. C., Mohapatra, L. & Shea, H. B. (2004). Temporal
stability of saccadic task performance in schizophrenia and bipolar
patients. Psychological Medicine 34, 921–932.
Guitton, D., Buchtel, H. A. & Douglas, R. M. (1985). Frontal lobe
lesions in man cause difficulties in suppressing reflexive glances and
in generating goal-directed saccades. Experimental Brain Research
Gur,R. E., Cowell, P. E.,Latshaw,
Grossman, R. I., Arnold, S. E., Bilker, W. B. & Gur, R. C.
(2000). Reduced dorsal and orbital prefrontal gray matter
volumes in schizophrenia. Archives of General Psychiatry 57,
Hallett, P. E. (1978). Primary and secondary saccades to goals
defined by instructions. Vision Research 18, 1279–1296.
Hazlett, E. A.,Buchsbaum,M. S.,
Fleischman, M. B., Shihabuddin, L., Haznedar, M. M. & Harvey,
P. D. (2000). Hypofrontality in unmedicated schizophrenia
patients studied with PET during performance of a serial verbal
learning task. Schizophrenia Research 43, 33–46.
Hedeker, D. & Gibbons, R. D. (1997). Application of random-effects
pattern-mixture models for missing data in longitudinal studies.
Psychological Methods 2, 64–78.
Heide, W., Binkofski, F., Seitz, R. J., Posse, S., Nitschke, M. F.,
Freund, H. J. & Koempf, D. (2001). Activation of frontoparietal
cortices during memorized triple-step sequences of saccadic eye
movements: an fMRI study. European Journal of Neuroscience 13,
Hill, S. K., Schuepbach, D., Herbener, E. S., Keshavan, M. S. &
Sweeney, J. A. (2004). Pretreatment and longitudinal studies of
neuropsychological deficits in antipsychotic-naive patients with
schizophrenia. Schizophrenia Research 68, 49–63.
Ho, B. C., Andreasen, N. C., Nopoulos, P., Arndt, S., Magnotta, V. &
Flaum, M. (2003). Progressive structural brain abnormalities
and their relationship to clinical outcome: a longitudinal magnetic
resonance imaging study early in schizophrenia. Archives of
General Psychiatry 60, 585–594.
Hollingshead, A. B. (1975). Four Factor Index of Social Status.
Yale University, Department of Sociology: New Haven, CT.
Hutton,S. B., Crawford,T. J.,
Chapman, M., Kennard, C., Barnes, T. R. E. & Joyce, E. M.
(1998). Smooth pursuit and saccadic abnormalities in first-episode
schizophrenia. Psychological Medicine 28, 685–692.
Hutton, S. B., Joyce, E. M., Barnes, T. R. E. & Kennard, C. (2002).
Saccadic distractibility in first-episode schizophrenia. Neuro-
psychologia 40, 1729–1736.
Keefe, R. S. E., Silva, S. G., Perkins, D. O. & Lieberman, J. A.
(1999). The effects of atypical antipsychotic drugs on neurocogni-
tive impairment in schizophrenia: a review and meta-analysis.
Schizophrenia Bulletin 25, 201–222.
McDowell, J. E., Brown, G. G., Paulus, M., Martinez, A., Stewart,
S. E., Dubowitz, D. J. & Braff, D. L. (2002). Neural correlates of
refixation saccades and antisaccades in normal and schizophrenia
subjects. Biological Psychiatry 51, 216–223.
McEvoy, J. P., Hogarty, G. E. & Steingard, S. (1991). Optimal dose
of neuroleptic in acute schizophrenia: a controlled study of the
neuroleptic threshold and higher haloperidol dose. Archives of
General Psychiatry 48, 739–745.
Muller, N., Riedel, M., Eggert, T. & Straube, A. (1999). Internally
and externally guided voluntary saccades in unmedicated and
medicated schizophrenic patients: Part II. Saccadic latency, gain,
and fixation suppression errors. European Archives of Psychiatry
and Clinical Neuroscience 249, 7–14.
Munoz, D. P. & Everling, S. (2004). Look away: the anti-saccade task
and the voluntary control of eye movement. Nature Reviews
Neuroscience 5, 218–228.
O’Driscoll, G. A., Alpert, N. M., Matthysse, S. W., Levy, D. L.,
Rauch, S. L. & Holzman, P. S. (1995). Functional neuroanatomy
of antisaccade eye movements investigated with positron emission
A.,Turetsky, B. I.,
Jeu, L. A.,Nenadic,I.,
Puri,B. K., Duncan,L. J.,
Antisaccades in first-episode schizophrenia493
tomography. Proceedings of the National Academy of Sciences
USA 92, 925–929.
Overall, J. E. & Gorham, D. R. (1962). The Brief Psychiatric Rating
Scale. Psychological Report 10, 799–812.
Perry, R. J. & Zeki, S. (2000). The neurology of saccades and covert
shifts in spatial attention: an event-related fMRI study. Brain 123,
Pierrot-Deseilligny, C. (1994). Saccade and smooth-pursuit impair-
ment after cerebral hemispheric lesions. European Neurology 34,
Pierrot-Deseilligny, C., Muri, R. M., Ploner, C. J., Gaymard, B.,
Demeret, S. & Rivaud-Pechoux, S. (2003). Decisional role of
the dorsolateral prefrontal cortex in ocular motor behaviour.
Brain 126, 1460–1473.
Posner, M. I., Early, T. S., Reiman, E., Pardo, P. J. & Dhawan, M.
(1988). Asymmetries in hemispheric control of attention in
schizophrenia. Archives of General Psychiatry 45, 814–821.
Raemaekers, M., Jansma, J. M., Cahn, W., van der Geest, J. N.,
van der Linden, J. A., Kahn, R. S. & Ramsey, N. F. (2002).
Neuronal substrate of the saccadic inhibition deficit in schizo-
phrenia investigated with 3-dimensional event-related functional
magnetic resonance imaging. Archives of General Psychiatry 59,
Reilly, J. L., Harris, M. S., Keshavan, M. S. & Sweeney, J. A.
(2005). Abnormalities in visually guided saccades suggest cortico-
fugal dysregulation in never-treated schizophrenia. Biological
Psychiatry 57, 145–154.
Sereno, A. B. & Holzman, P. S. (1995). Antisaccades and smooth
pursuit eye movements in schizophrenia. Biological Psychiatry 37,
Spitzer, R. L., Williams, J. B. W., Gibbons, M. & First, M. (1987).
Structured Clinical Interview for DSM-III-R (SCID). New York
State Psychiatric Institute: New York.
Sweeney, J. A., Levy, D. & Harris, M. S. (2002). Commentary: eye
movement research with clinical populations. In Brain’s Eye:
Neurobiological and Clinical Aspects of Oculomotor Research (ed.
J. Hyo ¨ na ¨ , D. P. Munoz, W. Heide and R. Radach), pp. 507–522.
Elsevier Science B.V. Amsterdam, The Netherlands.
Sweeney, J. A.,Mintun, M. A.,
Brown, D. L., Rosenberg, D. R. & Carl, J. R. (1996). Positron
emission tomography study of voluntary saccadic eye movements
and spatial working memory. Journal of Neurophysiology 75,
Tamminga, C. A. (2003). Similarities and differences
antipsychotics. Journal of Clinical Psychiatry 64 (Suppl. 17),
Walker, R., Husain, M., Hodgson, T. L., Harrison, J. & Kennard, C.
(1998). Saccadic eye movement and working memory deficits fol-
lowing damage to human prefrontal cortex. Neuropsychologia 36,
Kwee, S., Wiseman,M. B.,
494 M. S. H. Harris et al.