Psychopharmacology (2001) 157:284–291
DOI 10.1007/s002130100803
O R I G I N A L I N V E S T I G AT I O N
S. B. Hutton · T. J. Crawford · H. Gibbins
I. Cuthbert · T. R. E. Barnes · C. Kennard
E. M. Joyce
Short and long term effects of antipsychotic medication
on smooth pursuit eye tracking in schizophrenia
Received: 27 November 2000 / Accepted: 9 April 2001 / Published online: 20 July 2001
© Springer-Verlag 2001
Abstract Rationale: Smooth pursuit abnormalities have
been observed in antipsychotic naive first-episode pa-
tients, suggesting that they are intrinsic to the illness.
However, it is not clear whether these abnormalities are
as severe as those observed in more chronic patients. In
addition, although research suggests that there are no
short-term effects of conventional antipsychotic medica-
tion, the effects of long-term antipsychotic medication
on smooth pursuit eye movements are relatively un-
known. Objectives: To determine the short and long term
effects of antipsychotic medication on the smooth pur-
suit performance of first-episode and chronic patients
with schizophrenia. Methods: We compared the smooth
pursuit performance of antipsychotic-treated and untreat-
ed first-episode and chronic schizophrenic patients with
healthy controls using a comprehensive range of perfor-
mance measures. This included velocity gain, the num-
ber, type and size of intrusive and corrective saccades,
and the average time between the change in direction of
the target and the change in direction of the eye move-
ment, a measure of subjects’ ability to predict target
movement. Results: Chronic schizophrenic patients had
significantly reduced velocity gain, took longer to re-
spond to the change in target direction and made more
S.B. Hutton · H. Gibbins · I. Cuthbert · T.R.E. Barnes
E.M. Joyce (✉)
Department of Psychiatry,
Division of Neuroscience and Psychological Medicine,
Imperial College School of Medicine, St Dunstan’s Road,
London W6 8RP, UK
e-mail: e.joyce@ic.ac.uk
Tel.: +44-20-88467336, Fax: +44-20-88467372
C. Kennard
Department of Sensorimotor Control,
Division of Neuroscience and Psychological Medicine,
Imperial College School of Medicine, St Dunstan’s Road,
London W6 8RP, UK
T.J. Crawford
Mental Health and Neural Systems Research Unit,
Department of Psychology, Lancaster University,
Lancaster LA1 4YF, UK
catch-up saccades than both first-episode schizophrenic
patients and controls. First-episode patients were im-
paired relative to controls only on the measure of veloci-
ty gain. There were no differences between antipsychotic-
naive and treated first-episode patients. Antipsychotic-
free chronic patients were significantly less impaired on
velocity gain than matched continuously treated chronic
patients. These results were not influenced by group dif-
ferences in age and symptom severity. Conclusions: These
results show that: 1) the main index of smooth pursuit, ve-
locity gain, is impaired early in the course of schizophre-
nia; 2) whereas velocity gain is unaffected by short-term
(weeks) medication, it is worsened by chronic (years)
treatment; 3) other indices of smooth pursuit, catch-up
saccades and ability to predict target movement, are ad-
versely influenced by illness chronicity rather than medi-
cation.
Keywords Smooth pursuit · Eye tracking · Schizophrenia ·
Antipsychotic medication · Eye movement
Introduction
The study of oculomotor abnormalities in schizophrenic
patients provides a potentially powerful tool, both for
understanding the neuropathology underlying schizo-
phrenia, and for identifying genetically relevant pheno-
typic markers (Clementz 1998). Eye movements can be
broadly categorised as either fast saccadic movements,
which serve to foveate an object of interest, or slower
smooth pursuit movements, which allow a moving object
to remain foveated. Abnormal smooth pursuit eye track-
ing has been extensively documented in chronic schizo-
phrenic patients and their first-degree relatives, and is
currently considered to be an important indicator of ge-
netic vulnerability for the illness (see Levy 1994; Hutton
and Kennard 1998 for reviews). The observation of ab-
normal smooth pursuit in antipsychotic naive first-epi-
sode patients has strengthened arguments that this abnor-
mality represents a core and enduring trait deficit in

schizophrenia, which is present at an early stage in the
illness (Campion et al. 1992; Sweeney et al. 1994;
Hutton et al. 1998a). However, it is not clear whether the
nature and severity of the smooth pursuit dysfunction is
the same in first-episode patients as it is in chronic pa-
tients. This is an important issue, as neurodevelopmental
models of schizophrenia would predict that deficits ob-
served at first-episode ought to be qualitatively and
quantitatively similar to those observed in chronic pa-
tients. If, however, schizophrenia involves progressive
neurodegenerative pathology, then the severity and/or
nature of smooth pursuit dysfunction would be expected
to change over the course of the disorder.
In order for the effects of illness chronicity on smooth
pursuit performance to be accurately assessed, the poten-
tially confounding effects of antipsychotic medication
must also be addressed. There are several reasons why
antipsychotic medication might be expected to influence
smooth pursuit performance. Firstly, the common action
of antipsychotic drugs is dopamine receptor blockade
(Creese et al. 1976) and dopamine innervation of the
striatum is though to regulate fronto-striatal output path-
ways which include oculomotor circuitry (Alexander et
al. 1986). Although this oculomotor circuitry is tradition-
ally considered to be involved in saccadic control, neuro-
imaging evidence suggests smooth pursuit and saccades
are controlled by similar neural areas (Berman et al.
1999; O’Driscoll et al. 2000). Secondly, in patients with
schizophrenia, the dopamine receptor blockade caused
by antipsychotic medication often leads to parkinsonian
side effects, and smooth pursuit deficits have been ob-
served in patients with Parkinson’s disease (White et al.
1983; Waterston et al. 1996). These deficits can be re-
versed with L-dopa treatment (Gibson et al. 1987). Final-
ly, single doses of conventional antipsychotic medication
also lead to smooth pursuit dysfunction in healthy con-
trols (King 1994; Malaspina et al. 1994).
The majority of studies addressing medication effects
conclude that antipsychotic treatment does not have a
major impact on smooth pursuit performance in schizo-
phrenic patients (Holzman et al. 1974; Levy et al. 1983;
Siever et al. 1986; Spohn et al. 1988; Litman et al. 1989;
Hutton et al. 1998a). However, these studies have only
addressed the effects of relatively short-term treatment or
treatment withdrawal and few studies have addressed the
long-term effects of antipsychotic medication. Campion
and colleagues (1992) compared antipsychotic-naive pa-
tients with patients who had been treated for more than
5 years and found equivalent levels of smooth pursuit
dysfunction in both groups suggesting that long-term
medication is not associated with smooth pursuit dys-
function. However, Kufferle and colleagues (1990)
found that a group of previously treated patients who had
not received medication in the 2 years prior to testing
were significantly less impaired than a group of patients
who had been taking medication during that time. Fur-
ther, Sweeney and colleagues (1992), using precise oc-
ulographic techniques, found that smooth pursuit perfor-
mance was significantly more impaired in a group of
285
treated, chronic patients than in a group of treated first-
episode patients. None of these studies was able to dis-
entangle the effect of long-term medication from that of
illness duration.
The aim of this study was to assess systematically the
effects of illness chronicity and antipsychotic medication
on smooth pursuit function in schizophrenia. In order to
examine the effects of illness chronicity, we compared
the eye tracking performance of both first-episode and
chronic schizophrenic patients with a group of healthy
controls. We used a comprehensive range of perfor-
mance measures, including smooth pursuit velocity gain
(the ratio of eye velocity to target velocity) and a mea-
sure of the predictive component of smooth pursuit. In
addition, we identified and quantified all intrusive and
corrective saccades made during pursuit as these can
provide important information concerning the nature of
the pursuit dysfunction (Friedman et al. 1992a). All pa-
tients were tested with the same stimulus conditions, and
the measures were computed using identical procedures.
In order to examine the contribution of short- and
long-term antipsychotic treatment to smooth pursuit dys-
function, and any possible interaction this may have with
illness chronicity, the first-episode patients were divided
into those who were antipsychotic-naive at the time of
testing, and those who had been receiving antipsychotic
medication. The chronic patients were divided into those
who had been antipsychotic free for at least 6 months,
and those who had been treated continuously. In order to
establish any differences in the effects of treatment with
conventional and atypical antipsychotic drugs, we com-
pared first episode patients receiving traditional antipsy-
chotics with those receiving atypical antipsychotics.
Materials and methods
Subjects
The study participants were recruited from Tower Hamlets, River-
side, Kingston and Richmond, Merton Sutton and Wandsworth
Health Authorities, London, UK. The Local Research Ethics Com-
mittees for these Health Authorities reviewed and approved the
study. All patients provided written informed consent.
Patients with first-episode schizophrenia (n=67) were part of a
larger ongoing prospective study of first-episode schizophrenia in
West London where patients are recruited from a geographically
defined catchment area. Consenting patients were assessed by re-
search clinicians using the Scale for the Assessment of Positive
Symptoms (SAPS; Andreasen 1984b), the Scale for the Assess-
ment of Negative Symptoms (SANS; Andreasen 1984a) and the
Comprehensive Psychopathological Rating Scale. All patients
were re-assessed at 6 months and a DSM-IV diagnosis of schizo-
phrenia was confirmed for each patient in a diagnostic review with
two psychiatrists, applying the SCID criteria. The velocity gains
of 31 of these patients have been presented previously (Hutton et
al. 1998a). Patients with chronic schizophrenia (n=36) were iden-
tified from outpatient case-notes by a research clinician. Consent-
ing patients were assessed with the SAPS and SANS and DSM-
III-R criteria were applied. The velocity gains of 27 of these pa-
tients have been presented previously (Crawford et al. 1995). The
data on the chronic group were reanalysed by SBH for the present
study in order to derive velocity gain and additional performance
measures described below. Fifty-four healthy volunteers served as
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Table 1 Group details: mean (SD). SAPS Scale for the Assessment of Positive Symptoms, SANS Scale for the Assessment of Negative
Symptoms, CPZ Chlorpromazine equivalents, mg/day
Group n Age SAPS
(years) total
Controls 54 26.9 (5.3) – –
Anitpsychotic naive 20 27.6 (7.8) 36.3 (16.6)
first-episode patients
Antipsychotic-treated 47 24.3 (6.9) 37.5 (19.8)
first-episode patients
Antipsychotic-free 16 37.5a (11.7) 23.1 (20.8)
chronic patients
Antipsychotic-treated 20 37.8a (12.0) 28.3 (15.0)
chronic patients
a Significantly different from controls, antipsychotic-treated and antipsychotic-naive first-episode patients
b Significantly different from antipsychotic-treated and antipsychotic-free chronic patients
c Significantly different from antipsychotic-treated chronic patients
controls with no history of psychiatric or neurological disorder in
themselves and in their first-degree relatives, and no history of al-
cohol or drug abuse.
Patients were considered first-episode if this was their first
presentation with a psychotic illness and if they had been receiv-
ing antipsychotic medication for no longer than 12 weeks (Lieber-
man et al. 1992). As they were consecutively recruited they were
not selected for medication status; some patients had already be-
gun treatment by the time they were identified by our team where-
as others were still antipsychotic-naive. Twenty first-episode pa-
tients were antipsychotic-naive at the time of testing. Within the
47 treated first-episode patients, 19 were receiving the atypical an-
tipsychotic drugs olanzapine (n=12) or risperidone (n=7) at the
time of testing, and the remainder were receiving conventional an-
tipsychotics. Of the treated first-episode patients, 36% were re-
ceiving concurrent anticholinergic medication. Two patients were
receiving benzodiazepines as hypnotics.
Medication status was a key criterion in the recruitment strate-
gy for the chronic patient group. In order to avoid selection bias,
care was taken to identify treated and untreated patients from the
same population. Thus the majority of patients were attenders at
an outpatient depot clinic. Antipsychotic free patients were de-
fined as those who had not attended at least for the past 6 months
but had attended previously. Sixteen patients had been free of anti-
psychotic medication for at least 6 months, and 20 patients had
been receiving conventional antipsychotics continuously. Of these,
approximately 46% were also receiving anticholinergic medica-
tion and none were receiving benzodiazepines. We also assessed
premorbid IQ (NART; Nelson 1982) current level of social func-
tioning and parental social class, in order to establish the extent to
which the drug-treated and drug-free chronic patients were
matched for education and socio-economic status.
Duration of psychosis was calculated for each patient, and du-
ration of treatment was calculated for each treated patient (see Ta-
ble 1).
Apparatus
The smooth pursuit stimulus was a bright red laser spot back pro-
jected onto a semi-opaque screen. The target oscillated horizontal-
ly with a triangular waveform of amplitude 22.5 degrees. Four ve-
locities, 10, 20, 30 and 36 deg/s were used, and six full cycles re-
corded at each velocity. Subjects were comfortably seated 1.5 m
from the screen and head movements were restrained using an ad-
justable headrest. All paradigms were conducted in the dark. Eye
movements were recorded using a Skalar IRIS infrared limbus re-
flection device. A hardware anti-aliasing filter (cut-off frequency
200 Hz) was used to filter eye position and the sampling rate was
500 Hz. Stimulus display and data sampling were controlled by a
SANS Duration of Duration of CPZ
total illness (weeks) treatment
(weeks)
– – –
28.2b (23.8) 82.2b (102.9) – –
23.5b (16.2) 61.5b (93.4) 7.32c (5.5) 422.4c (289.2)
15.9 (16.0) 756.9 (726.2) – –
12.7 (17.0) 621.1 (548.7) 656 (582.4) 1216.0 (229.9)
PDP 11/73 computer or an IBM compatible PC. The smooth pur-
suit paradigm was preceded by a calibration trial in which nine
equally spaced LED lights with known horizontal positions were
illuminated sequentially, the subject being asked to fixate each tar-
get in turn.
Data analysis
When tracking a smoothly moving object, the smooth pursuit and
saccadic systems work together interactively. A measure of the
smooth pursuit system’s ability to match eye velocity to target ve-
locity is provided by a measure of velocity gain, the ratio of the
eye velocity to target velocity. A velocity gain value of 1 indicates
perfect smooth pursuit performance, values lower than 1 indicate
that the eye is moving more slowly than the target. The number
and type of saccades made during smooth pursuit can also provide
important information concerning the nature of the underlying eye
tracking deficit (Friedman et al. 1992a). The saccades made dur-
ing smooth pursuits are typically either corrective [catch-up sac-
cades (CUS) and back-up saccades (BUS)] or intrusive [anticipa-
tory saccades (AS) and square wave jerks (SWJ)]. Accurately
tracking a smoothly moving object involves predictive processes
(van den Berg 1988). One measure of the predictive component of
smooth pursuit is the time difference (lag) between the target and
the eye changing direction at the end of each ramp. Large lag val-
ues indicate poor prediction of target movement.
Smooth pursuit analysis was performed using the Eyemap
analysis package (Amtech GmbH, Heidelberg, Germany). Saccad-
ic eye movements were identified by the software using accelera-
tion (an increase in eye velocity of 30 degrees per second) and
amplitude (>0.5 of a degree) criteria. Based mainly on the criteria
of Abel et al. (1991) and Friedman et al. (1992a), the saccades
were then classified by the operator (SBH) as CUS, BUS, AS or
SWJ. Briefly, CUS were defined as saccades that occurred in the
direction of target motion during smooth pursuit, and which took
the eye from a position behind the target to a position on or near
the target. BUS were defined as saccades which occurred in a di-
rection opposite to the target motion and serve to bring the eyes
from a position ahead of the target to a position on or near the tar-
get. SWJ were defined as intrusions into smooth pursuit consisting
of an initial small saccade in either direction, followed by a short
period of continued pursuit and terminated by another small sac-
cade, similar in size to the first, in the opposite direction. Finally,
following Ross et al. (1999b), who have argued that small sac-
cades (<4 degrees) which move the eye ahead of the target should
be termed “leading saccades”, true AS were defined as large (>4
degrees) intrusive saccades which took the eye to a position ahead
of the target, and were followed by a short period of low, or zero
velocity gain, and/or a BUS.

Smooth pursuit velocity gain (GAIN) was measured by first
identifying and excluding saccadic movements and blinks from
the data. In each ramp a 50-ms portion of smooth pursuit eye
movement was selected and expressed as peak velocity gain (eye
velocity/target velocity). This portion was always collected from
the middle third of each half cycle, to avoid acceleration and de-
celeration transients at the beginning and end of each ramp. The
ramp was selected by the operator determining the portion of the
ramp in which pursuit was optimal (i.e. the velocity gain was near-
est to 1).
A temporal measure of smooth pursuit lag (LAG) was calculat-
ed by measuring the time at which the eye movement changed di-
rection at the end of each ramp, and subtracting from this the time
at which the target changed direction.
Statistical analyses
Performance on the measures of GAIN and LAG was compared
between the two groups of schizophrenic patients and the controls
using ANCOVA with target speed (Speed) as a within subjects-
factor and Group (first-episode, chronic, control) as a between-
subjects factor. As the chronic patients were older than the first-
episode patients and controls, and increased age has been shown
to be associated with decreased smooth pursuit function (Ross et
al. 1999a), age was entered as a covariate. The number of sac-
cades were compared using ANCOVA, with group as the between
subjects factor and age as the covariate. Significant main effects
and interactions were further explored using post-hoc t-tests.
The interactions between acute and chronic medication and
disease chronicity were explored by ANCOVA with Treatment
(antipsychotic-free/antipsychotic-naive versus antipsychotic-treat-
ed) and Chronicity (first-episode versus chronic) as between sub-
ject factors. The GAIN and LAG measures were collapsed across
target speed. In order to control for group differences in age and
symptom severity age, SAPS and SANS scores were entered as
covariates. The SAPS and SANS scores for three antipsychotic-
treated chronic patients, two antipsychotic-free chronic patients
and one treated first-episode patient were unavailable. For the pur-
poses of the ANCOVA, these patients were assigned SAPS and
SANS scores equal to their respective group means. The results
were unchanged when the analysis was repeated excluding these
patients.
Finally, in the first-episode patients, the effects of conventional
versus atypical antipsychotic treatment were explored using inde-
pendent t-tests.
Results
Subject characteristics
287
(t=1.72, P=0.09) but there were no differences between
these groups for symptom severity (SAPS, t=–0.23,
P=0.8; SANS, t=0.94, P=0.35) or duration of illness
(t=0.79, P=0.43). Antipsychotic-free chronic patients did
not differ from their treated counterparts in age (t=0.07,
P=0.94), symptom severity (SAPS, t=0.8, P=0.43;
SANS, t=–0.54, P=0.59) or duration of illness (t=–0.54,
P=0.59). Nor did the antipsychotic-free and antipsychot-
ic-treated patients differ in terms of their premorbid IQ
(t=0.62, P=0.54), current level of social functioning
(t=–0.44, P=0.66) or parental social class (t=–1.03,
P=0.31).
The first-episode patients receiving atypical antipsy-
chotics did not differ in age (t=0.38, P=0.71), symptom
severity (SAPS, t=–0.39, P=0.70; SANS, t=0.67,
P=0.50) or duration of treatment (t=0.7, P=0.95), from
those receiving conventional antipsychotics. There was a
trend for first-episode patients receiving atypical anti-
psychotics to have been ill for longer than patients re-
ceiving conventional antipsychotics (t=–1.89, P=0.07).
The mean daily dose of antipsychotic medication was
converted to chlorpromazine equivalents, mg/day. Reli-
able data were obtained for 46 out of the 47 treated first
episode patients and 15 out of the 20 treated chronic pa-
tients. Mean daily dose was greater in the treated chronic
schizophrenic patients than in the treated first-episode
patients (t=2.32, P=0.02). The duration of treatment was
also significantly longer in the treated chronic patients
compared to the treated first-episode patients (t=–7.46,
P<0.001), as was duration of illness (t=–6.82, P<0.001).
Comparisons between first-episode patients,
chronic patients and controls
The smooth pursuit velocity gain for the three groups is
displayed in Fig. 1. Velocity gain decreased with increas-
ing target speed for all groups [F(3,459)=10.01,
P<0.001]. There was also a significant main effect of
Group [F(2,153)=21.8, P<0.001] and a Group×Speed in-

The groups were matched for sex ratio (male/female –

control: 36/18; first episode: 55/12; chronic schizophre-
nia: 25/11, chi square=4.16, P=0.12) Table 1 shows that
the first-episode patients showed a greater severity of
positive and negative symptoms compared with the
chronic patients (first-episode SAPS total score=37.2,
chronic SAPS total score=25.9; t=2.77, P<0.01; first-epi-
sode SANS total score=24.4, chronic SANS total
score=14.2; t=2.63, P<0.05]. The groups also differed in
age [F(2,154)=30.3, P<0.001]. Chronic patients were
significantly older than the first-episode patients
(t=–6.62, P<0.001) and control subjects (t=–5.9,
P<0.001), who did not differ (t=1.4, P=0.17). Fig. 1 Smooth pursuit velocity gain across four target speeds for
There was a trend for the antipsychotic-naive first-ep- controls (circles), first-episode schizophrenic patients (squares)
isode patients to be older than their treated counterparts and chronic schizophrenic patients (triangles)
288
Fig. 2 LAG across the four target speeds for controls (circles),
first-episode patients (squares) and chronic patients (triangles)
Table 2 Mean (SD) corrective and intrusive saccades. CUS catch-
up saccades, BUS back-up saccades, AS anticipatory saccades,
SWJ square wave jerks
Group CUS BUS AS SWJ
Controls 83.7 (22.1) 11.4 (7.3) 2.7 (3.7) 5.9 (6.9)
First-episode 79.8 (27.0) 6.8 (5.7)b 3.2 (4.0) 3.1 (5.3)c
Chronic 116.4 (32.1)a 6.0 (4.5)b 3.1 (3.9) 6.2 (7.4)
a Chronic patients significantly different to first-episode patients
and controls
b Chronic and first episode patients significantly different to con-
trols
c First-episode patients significantly different to controls and
chronic patients
teraction [F(6,459)=10.5, P<0.001]. The main effect of
the covariate, Age, was also significant [F(1,153)=12.4,
P=0.01]. Analysis of the main effect of Group demon-
strated that both the first-episode (t=4.51, P<0.001) and
chronic (t=7.19, P<0.001) patients were impaired rela-
tive to controls, and chronic patients were additionally
impaired relative to the first-episode patients (t=4.32,
P<0.01). The interaction reflects the greater effect of tar-
get speed on the chronic patients compared to the first-
episode patients and controls.
LAG times are displayed in Fig. 2. LAG times de-
creased with increasing target speed for all groups
[F(3,441)=12.75, P<0.001]. The ANCOVA also revealed
a significant main effect of Group [F(2,147)=5.53,
P=0.005]. The Group×Speed interaction was not signifi-
cant [F(6,441)=1.22, P=0.29]. Analysis of the main ef-
fect indicated that chronic patients had significantly lon-
ger LAG times than first-episode patients (t=–5.71,
P=0.001) and controls (t=–5.48, P=0.001), who did not
differ (t=0.15, P=0.89).
The mean numbers of intrusive and corrective sac-
cades are displayed in Table 2. The groups differed in the
number of CUS made [F(2,142)=8.75, P<0.001]: chronic
patients made more CUS than first-episode patients
[t(90)=–5.96, P<0.001] and controls [t(79)=–5.38,
Fig. 3 Interaction between chronicity (first-episode schizophrenia,
squares versus chronic schizophrenia, triangles) and antipsychotic
drug treatment (antipsychotic-naive/antipsychotic-free AN/AF,
versus antipsychotic-treated AT) for smooth pursuit velocity gain
P<0.001], who did not differ [t(117)=1.17, P=0.24].
There were also differences in the number of BUS made
[F(2,142)=11.55, P<0.001]. Both chronic [t(79)=3.51,
P=0.001] and first-episode patients [t(117)=3.75,
P<0.01] made fewer BUS than controls but there was no
difference between the two patient groups [t(90)=0.68,
P=0.5]. There were no differences between the three
groups in the number of AS made [F(2,142)=0.23,
P=0.79]. Finally, there were differences in the number of
SWJ made [F(2,142)=5.33, P<0.01]. First-episode pa-
tients made fewer SWJ than either controls (t=2.9,
P<0.005) or chronic patients (t=2.66, P<0.01) who did
not differ (t=–0.19, P=0.85).
In summary, chronic schizophrenic patients had sig-
nificantly reduced velocity gain, took longer to respond
to the change in target direction and made more catch up
saccades than both first-episode schizophrenic patients
and controls. First-episode patients were impaired rela-
tive to controls only on the measure of velocity gain.
Interactions between illness chronicity
and treatment status
The effects of illness chronicity and antipsychotic treat-
ment on GAIN are displayed in Fig. 3. Chronic patients
had generally more impaired velocity gain than first-epi-
sode patients [F(1,96)=7.61, P<0.01], and treated patients
had generally more impaired velocity gain than antipsy-
chotic na / antipsychotic free patients [F(1,96)=
14.29, P=0.001]. However, these main effects were modi-
fied by a significant Chronicity×Treatment interaction
[F(1,99)=5.22, P<0.05]. The main effect of the covariate
Age was significant [F(1,96)=10.79, P=0.001]. The main
effects of the covariates SAPS and SANS were not sig-
nificant [SAPS: F(1,96)=1.15, P=0.29; SANS: F(1,96)=
0.156, P=0.69]. The difference between antipsychotic-na-
ive and antipsychotic-treated first-episode schizophrenic
patients was not significant (t=0.91, P=0.37), whereas an-
tipsychotic-treated chronic patients were significantly
more impaired than antipsychotic-free chronic patients
(t=–3.20, P<0.005). The difference between the antipsy-

Table 3 Oculomotor perfor-
mance in first-episode patients Group GAIN
treated with conventional and
atypical antipsychotics: mean Conventional 0.85 (0.14)
(SD) Atypical 0.90 (0.05)
Fig. 4 Interaction between chronicity (first-episode schizophren-
ics, squares versus chronic schizophrenics, triangles) and antipsy-
chotic drug treatment (antipsychotic-naive/antipsychotic-free
AN/AF, versus antipsychotic-treated AT) for LAG
chotic-naive first-episode and antipsychotic-free chronic
patients approached significance (t=1.87, P=0.07).
The effects of Chronicity and Treatment on LAG are
displayed in Fig. 4. Chronic patients were generally
slower than first-episode patients to change the direction
of their eye movements in response to the change in tar-
get direction [F(1,96)=6.47, P<0.02]. However the main
effect of Treatment [F(1,96)=0.94, P=0.33] and Chronic-
ity×Treatment interaction [F(1,96)=0.17, P=0.68] were
not significant. The effects of the covariates age and
SANS were significant [age: F(1,96)=10.96, P<0.001;
SANS F(1,96)=5.36, P<0.05]. Older subjects and sub-
jects with fewer negative symptoms had larger LAG val-
ues. The effect of the covariate SAPS was not significant
[F(1.96)=0.01, P=0.91].
Chronic schizophrenic patients made more catch-up
saccades than first episode patients [F(1,85)=8.86,
P>0.005], but the main effect of Treatment [F(1,85)=
1.47, P=0.23] and Chronicity×Treatment interaction
[F(1,85)=0.15, P=0.70] were not significant. The effect
of the covariate Age was significant [F(1,85)=6.99,
P=0.01]. The effects of the covarites SAPS [F(1,85)=
0.06, P=0.80] and SANS [F(1,85)=0.24, P=0.63] were
not significant.
In summary, although chronic schizophrenic patients
have reduced velocity gain relative to first-episode pa-
tients, this effect is mainly due to the particularly poor
performance of the treated chronic patients. The velocity
gains of antipsychotic-free chronic patients showed were
similar in degree to those of both treated and antipsy-
chotic-naive first-episode patients. These results were
significant when we controlled statistically for differ-
ences due to age and symptom severity. Although dura-
tion of treatment influenced velocity gain, this was not
the case for LAG, a measure of the speed at which sub-
289
LAG CUS BUS AS SWJ
91.9 (27.5) 80.6 (27.8) 7.7 (6.3) 3.7 (4.2) 3.8 (5.4)
97.5 (25.9) 72.1 (25.8) 5.9 (4.6) 1.9 (3.0) 2.3 (5.7)
jects can switch direction in keeping with the target,
which was also slower in the chronic patients.
Comparison of conventional and atypical antipsychotics
in treated first-episode patients
The effects of conventional versus atypical antipsychotic
medication on smooth pursuit function in treated first-
episode patients are displayed in Table 3. There was a
trend (t=–1.9, P=0.07) for patients taking atypical anti-
psychotic medication at the time of the first episode to
be less impaired on the measure of GAIN than the pa-
tients taking conventional antipsychotic medications. No
other comparisons were significant (P>0.15 in all cases).
Discussion
The main findings of this study are that smooth pursuit
eye tracking is significantly more impaired in chronic
schizophrenic patients than in first-episode schizophren-
ic patients and that this difference is mainly mediated by
the effects of long-term treatment with antipsychotic
medication. Thus, smooth pursuit velocity gain was sig-
nificantly better in chronic schizophrenic patients who
had been free of antipsychotic medication for at least
6 months, compared to those who had been treated con-
tinuously, and was similar in degree to that of first epi-
sode patients.
Our results are consistent with those of Bartfai and
colleagues (1983), who found less smooth pursuit im-
pairment in a group of never medicated patients com-
pared to a group of previously medicated patients, and
those of Kufferle and colleagues (1992), who found that
smooth pursuit velocity gain was significantly less im-
paired in a group of chronic patients who had been medi-
cation free for at least 2 years compared to a group who
had remained treated. Together with our findings, these
suggest that long-term treatment with antipsychotic med-
ication is associated with a decrease in velocity gain,
which reverses significantly after a prolonged antipsy-
chotic-free period.
One criticism of studies comparing two separate
groups of patients, one treated and one drug-free, is that
there may be factors explaining the differences in smooth
pursuit performance other than medication status. Indeed
the fact that some patients remain untreated for lengthy
periods may suggest that they have a milder illness. In
our study, care was taken to recruit patients from the
same population. Thus most patients were recruited from
a depot clinic, untreated patients being those who had
failed to attend for at least 6 months. They were also
290
matched for symptom severity, duration of illness and in-
dices of premorbid educational attainment, socio-eco-
nomic status and social function, all of which may reflect
the severity of illness. To preclude more subtle group dif-
ferences explaining the results, however, a longitudinal
within-subjects design would be necessary.
Several studies have addressed the effects of antipsy-
chotic treatment on smooth pursuit function by compar-
ing chronically treated patients before and after a medi-
cation-free period (Holzman et al. 1974; Shagass et al.
1974; Spohn et al. 1988) or have tested medication-free
patients and then again after medication has been re-
introduced (Levy et al. 1983; Siever et al. 1986). None
found changes in smooth pursuit consistent with drug ef-
fects. However in all of these studies the antipsychotic-
free/antipsychotic-treated intervals were short. Most
were in the order of 2–4 weeks and the longest was of 10
weeks. Our results with first-episode patients are consis-
tent with these findings. We found no differences in
smooth pursuit velocity gain in antipsychotic-naive and
antipsychotic-treated first-episode patients matched for
age, symptom severity at presentation and duration of ill-
ness. As our antipsychotic-treated first-episode patients
had been receiving medication for an average of 7.3
weeks, this supports the proposal that patients with
schizophrenia have an intrinsic impairment in smooth
pursuit performance, which is not further exacerbated by
short-term treatment with conventional antipsychotics.
This is also supported by Sweeney and colleagues
(1992), who found greater smooth pursuit impairments
in long-term treated chronic patients compared to short-
term treated first-episode patients.
Although our results suggest that a considerable com-
ponent of the reduced velocity gain commonly observed
in chronic schizophrenic patients may be due to the effects
of long-term antipsychotic medication, the difference in
velocity gain between the antipsychotic-free chronic and
antipsychotic-naive first-episode patients approached sig-
nificance. Further, other indices of smooth pursuit perfor-
mance, unaffected by medication status, also indicate that
illness chronicity may also influence smooth pursuit. We
have replicated the findings of Sweeney and colleagues
(1994), who compared chronic patients who had been an-
tipsychotic-free for at least 28 days with antipsychotic-na-
ive first-episode patients and found a non-significant dec-
rement in velocity gain in the chronic patients and in-
creased rate of catch-up saccades compared to antipsy-
chotic-naive first-episode patients. In addition, we found
that chronic, but not first-episode, schizophrenic patients
demonstrated a significant impairment on the measure of
predictive pursuit unrelated to treatment factors.
The precise role of predictive processes in smooth
pursuit dysfunction is not clear. However, other studies
confirm that chronic patients with schizophrenia have
difficulties with this aspect of pursuit (Trillenberg et al.
1998) and have further demonstrated that predictive pur-
suit correlates to some extent with measures sensitive to
frontal lobe dysfunction (Radant et al. 1997). One hy-
pothesis is that some deterioration in certain frontal cir-
cuits occurs over the course of schizophrenia. Evidence
for such a deterioration comes from neuropsychological
studies which have demonstrated that chronic schizo-
phrenic patients are significantly more impaired than
first-episode schizophrenic patients on a test of attention-
al set shifting sensitive to frontal function (Elliot et al.
1995; Hutton et al. 1998b; Pantelis et al. 1999).
An alternative explanation is that the small residual
smooth pursuit impairment in antipsychotic-free chronic
compared to antipsychotic-naive first-episode patients
may reflect irreversible changes in brain morphology
following long-term administration of antipsychotic
drugs. Certainly the most consistent effects of long-term
antipsychotic drug treatment are seen in striatum and in-
clude changes in neuronal size and synaptic morphology
(see Harrison 1999 for a review). These would therefore
be expected to affect the function oculomotor circuitry
but whether they are irreversible or not is still under de-
bate (Jeste 1998).
The conclusion that long-term treatment with antipsy-
chotic medication worsens smooth pursuit performance
can only be made with respect to the conventional anti-
psychotic drugs as no chronic patient was receiving one
of the newer “atypical” drugs. Indeed we have prelimi-
nary evidence to suggest that atypical drugs may be less
detrimental, as within the treated first-episode patient
group, we found a trend for the patients taking the atypi-
cal antipsychotics olanzapine and risperidone to have
less impaired velocity gain than patients taking conven-
tional antipsychotic medication. While previous research
has suggested that atypical antipsychotics actually im-
pair smooth pursuit performance rather than improve it
(Friedman et al. 1992b; Litman et al. 1994), these studies
only addressed the effects of clozapine. Atypical antipsy-
chotics are defined by their relative lack of extrapyrami-
dal side effects rather than by any specific pharmacologi-
cal property. Compared to risperidone and olanzapine,
clozapine has relatively high affinity for histamine re-
ceptors. This results in significant sedative qualities, par-
ticularly early in the course of treatment. As other seda-
tive medications are known to impair smooth pursuit
performance (Masson et al. 2000), the detrimental ef-
fects of clozapine may reflect its histaminergic proper-
ties. Further research is required in order to replicate the
finding of comparatively unimpaired smooth pursuit per-
formance in patients receiving olanzapine and risperi-
done, and explore possible mechanisms for this effect.
In conclusion, we have demonstrated that smooth pur-
suit dysfunction is more severely impaired in chronic pa-
tients with schizophrenia compared to first-episode pa-
tients. The severity of the dysfunction in chronic pa-
tients, at least in terms of the reduction in velocity gain,
appears to be due mainly to the consequences of long-
term antipsychotic medication. Further longitudinal re-
search is needed to fully elucidate the influence of medi-
cation on smooth pursuit performance in schizophrenia.
Acknowledgements This research was supported by The Well-
come Trust. We are grateful to B. Puri, M. Chapman, S. Mutsatsa,
B Haeger and M. Reveley for patient assessments.

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