Psvchiatry Research, 41:25-36 Elsevier

25

Effect of Typical Antipsychotic Medications and Clozapine on Smooth Pursuit Performance in Patients With Schizophrenia Lee Friedman,

John A. Jesberger,

Received

25,199l;

February

and Herbert Y. Meltzer

revised version received September

23.1991;

accepted October 27, 1991.

Abstract. The effect of typical neuroleptic drugs or clozapine on smooth pursuit eye movements was tested in 13 patients with schizophrenia or schizoaffective disorder with a repeated measures design. Nineteen normal control subjects were also studied. Compared with controls, patients in the unmedicated state had low smooth pursuit gain, had a higher rate of corrective catch-up saccades, and tended to spend less time engaged in the tracking task. The patients did not significantly differ from controls on catch-up saccade amplitude, square wave jerk rate, or anticipatory saccade rate. Medication with clozapine, but not typical neuroleptics, was associated with an increase in median catch-up saccade amplitude. Number of days on clozapine and clozapine dose both correlated significantly with a worsening of oculomotor performance. No effect of medication with typical neuroleptics was found, although there was some evidence suggesting that such an affect may occur after more prolonged treatment. Key Words. Eye movements,

neuroleptics,

saccadic intrusions.

It is well established that patients with schizophrenia have abnormal smooth pursuit eye movements. The possible effect of neuroleptic drugs on eye tracking has been reviewed in a number of recent publications (Levy et al., 1983; Lipton et al., 1983; Abel and Hertle, 1988; Spohn et al., 1988). No consistent evidence of an effect of neuroleptics has been reported. Many of these studies, however, were performed before recent advances in the assessment of smooth pursuit performance (for review, see Clementz and Sweeney, 1990). Recent studies of eye tracking in schizophrenia adopt a neuro-ophthalmologic approach to eye movement assessment (Abel and Ziegler, 1988; Clement2 and Sweeney, 1990). The primary measure of the smooth pursuit system is gain, defined as the ratio of eye velocity to target velocity (Leigh and Zee, 1983). A number of studies have reported low gain in patients with schizophrenia compared with normal controls (for

Lee Friedman, Ph.D., is Assistant Professor of Psychiatry, Laboratory of Biological Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH. John A. Jesberger, B.A., is a research assistant at Case Western Reserve University. Herbert Y. Meltzer, M.D., is Professor of Pharmacology and Douglas Bond Professor of Psychiatry, Case Western Reserve University. Dr. Meltzer is also Director of Research, Psychiatry Service, Veterans Administration Medical Center, and Vice Chairman of Research, Department of Psychiatry, University Hospitals of Cleveland. (Reprint requests to Dr. L. Friedman, Dept. of Psychiatry, University Hospitals of Cleveland, Hanna Pavilion, 2040 Abington Rd., Cleveland, OH 44106, USA.) 0165-1781/92/$03.50

@ 1992 Elsevier Scientific

Publishers

Ireland

Ltd

26 review, see: Friedman et al., 1991), although a few studies did not confirm this finding (Oepen et al., 1990; for outpatients only, Schmid-Burgk et al., 1982). When gain is low, and thus position error (the difference between eye position and target position) accumulates, the saccade system brings the eye back to target with 1988). Some recent investigations have catch-up saccades (Abel and Ziegler, reported an increased rate of catch-up saccades in patients with schizophrenia (Levin et al., 1982; Moser et al., 1990; Abel et al., 1991; Friedman et al., 1991). Other saccades occurring during pursuit are classified as intrusive (Abel and Ziegler, 1988). Intrusive saccades have no apparent function-they do not correct for position error, and they are disruptive of optimal tracking performance. Although a variety of intrusive saccades can occur in various neurologic disorders (Daroff, 1977; Weinreb, 1983), usually only two types appear in psychiatric populations: squarewave jerks (Levin et al., 1982) and anticipatory saccades (Whicker et al., 1985; Kaufman and Abel, 1986). Square-wave jerks are pairs of small saccades in opposite directions separated by a normal intersaccadic interval. Anticipatory saccades are large saccades that take the eye well ahead of target, where the eye remains for a brief period, either until the target catches up with the eye or until another saccade moves the eye back to target (Abel and Ziegler, 1988). Recently, two studies have reported on the effect of neuroleptics on eye tracking using neuro-ophthalmologic techniques. Litman et al. (1989) reported that neuroleptics had no effect on gain. This report also found no evidence for a difference in saccade rates during tracking, although corrective saccades and intrusive saccades were not distinguished. In another recent study, Rea et al. (1989) evaluated eye tracking in patients with schizophrenia on admission and for 4 consecutive weeks, during the course of clinical recovery. On average, dose (in chlorpromazine equivalents) increased and psychopathology decreased throughout the study. The number of large saccades (> 5” of visual angle) during smooth pursuit was decreased, whereas the number of small saccades (3’-5’) was increased (Rea et al., 1989) over the 4-week study period. Furthermore, the decrease in the number of large saccades showed a significant negative correlation with the neuroleptic dose increase (r = -0.77). The purpose of the present report was to assess the potential effect of typical neuroleptics or clozapine on gain, catch-up saccade rate, catch-up saccade saccades in patients with amplitude, square-wave jerk rate, and anticipatory schizophrenia. The effect of clozapine on eye tracking is of interest since clozapine has a different pharmacologic profile from that of conventional antipsychotic agents (Meltzer, 1989) and is more effective in treating positive and negative symptoms (Kane et al., 1988). Methods Subjects. The patients in this report were divided into two nonoverlapping groups: Group 1 consisted of six patients with schizophrenia, tested both in the unmedicated state and after treatment with typical neuroleptics (2 with thioridazine, 1 each with the following: haloperidol, thiothixene, loxapine, and trifluoperazine). Group 2 consisted of six patients with schizophrenia and one patient with schizoaffective disorder tested both in the unmedicated state and after treatment with clozapine. Nineteen normal control subjects were included for

27

comparison with all 13 patients in the unmedicated state. Research Diagnostic Criteria (Spitzer et al., 1978) were used. Diagnoses were based on a review of all data available from previous admissions and on interviews using the Schedule for Affective Disorders and Schizophrenia (SADS; Endicott and Spitzer, 1978; Spitzer and Endicott, 1978) supplemented with additional questions from the Present State Examination (Wing et al., 1974). All diagnoses were made by consensus of a research psychiatrist and other research and clinical personnel who collected the primary clinical data. The median (range) duration of illness of patients in group 1 was 10.5 (l-20) years and for group 2 was 14 (4-25) years. The median number of previous hospitalizations in group 1 was 7 (l-10) and for group 2 was 3 (I-30). The median age at illness onset was 22.5 (18-31) for group 1 and 20 (17-35) years for group 2. When tested in the drug-free state, patients in group 1 had been free of neuroleptic treatment for a median of 14.5 days (12-19), and patients in group 2 had been free of neuroleptic treatment for a median of 16 (8-20) days. When tested in the medicated state, patients in group 1 had been receiving typical antipsychotic agents for a median of 28.5 (14-90) days. The patients in group 2 had been receiving clozapine for a median of 44 (15-28 1) days. The median dosage of typical neuroleptics for the patients in group 1 was 540 mg (155-1500) chlorpromazine equivalents (Davis, 1976; for loxapine: Arana and Hyman, 1991). The median dosage of clozapine for the patients in group 2 was 200 mg (150-500). All patients were tested off all benzodiazepines for a minimum of 4 days, and off chloral hydrate for a minimum of 2.5 days. In most cases, a much longer time had elapsed since either of these medications had been taken. Our requirement that patients be unmedicated for at least 1 week, and off benzodiazapines and chloral hydrate, as mentioned above, would probably result in a bias against inclusion of the most impaired patients . Normal control subjects were recruited by advertisement primarily from hospital staff. For details of subject selection criteria, see Friedman et al. (1991). The median age of the patients in group 1 was 34.5 (21-42) years, that in group 2 was 32 (22-60) years, and that in the normal control group was 34 (21-61) years. Eye Movement Recording. Horizontal eye movements were recorded monocularly from the dominant eye with infrared oculography. A detailed description of the recording methodology has been reported elsewhere (Friedman et al., 1991). The stimuli were displayed on a 38.5 cm (horizontal) X 30.5 cm monitor positioned 100.4 cm in front of the subject. The target was a bright spot subtending 0.2’ horizontal and 0.1’ vertical visual angle. For each of 10 smooth pursuit tasks, the target started at O’, moved to the right (or left, 5 tasks each direction) at a velocity of 5’/second to 10” right, remained stationary for 1 second, moved at the same velocity to loo left, remained stationary for 1 second, moved at the same velocity to 10’ right, and stopped. Each task had a duration of approximately 15-20 seconds. All data analysis was performed off-line with a package of custom computer programs. Only periods of smooth pursuit uninterrupted by blinks were analyzed. Assessment of Smooth Pursuit. Smooth pursuit recordings typically consist of straightline segments interrupted by saccades. The start and end of each segment were marked interactively. The eye movement data consisted of a series of sampled data points (400/set) whose amplitudes indicated eye position. To compute segment gain, a regression line (least squares) for the eye position data was computed, and the slope of this line was divided by the slope of the target position trace. Gain averaged over time was calculated for each subject by taking the sum of the product of gain and duration for each segment and dividing by the summed durations of all pursuit segments. The gain was calculated after pursuit segments with outlying or extreme gain values had been removed (Friedman et al., 1991). A catch-up saccade was defined as a small saccade (< 5” ) in the direction of target motion, which brought the eye closer to the target. The detection and measurement of catch-up saccades was a multi-step process (for details, see Friedman et al., 1991). Since the median amplitude was always smaller than the mean, subjects were compared on the former only. Also, the overall rate of catch-up saccades per second of smooth pursuit was calculated. A square-wave jerk was defined as an

28

intrusion into smooth pursuit consisting of a small initial saccade in either direction immediately followed by a short period of continued pursuit and terminated by another small saccade in the opposite direction of the first. The interval between saccade pairs had to be from 150 to 450 ms. Neither saccade could exceed an amplitude of 5’. To be counted as an intrusion into pursuit, a square-wave jerk must have been preceded and followed by clear

periods of pursuit. Thus, square-wave jerks at the transition between pursuit and fixation were not counted. The overall rate of square-wave jerks was then calculated. Anticipatory saccades were defined as large saccadic intrusions that took the eye ahead of target, typically followed by a period of ocular fixation for at least 250 ms, during which time smooth pursuit gain diminished by at least 50%. The saccade had to be in the direction of target motion and at least 5” in amplitude. The anticipatory saccade was defined as ending when the eye returned to the target, either by waiting for the target to catch up, or by making a return saccade to the target. A single anticipatory saccade could be made up of more than one successive saccade, as long as at least one saccade exceeded 5” in amplitude. Neither control subjects nor patients tracked the target 100% of the time. Some time was occupied by blinks and by other periods during which the eyes were not in the vicinity of the target or were not moving in the same direction as the target. These lapses of performance were not included in this analysis. The percent of time tracking the moving target was calculated and included as a variable in the analysis. The interrater reliability of all smooth pursuit measures was above 0.9 (intraclass correlation coefficient). of Psychopathology. Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962; Rhoades and Overall, 1988) data were available during the unmedicated state for 11 of the 13 patients (6/6 in group 1, 5/7 in group 2), and during the medicated state for all Assessment

patients. The total score, the Positive (Kane et al., 1988) were examined.

Symptom

subscale,

and the Negative Symptom

subscale

Experimental Design and Statistical Analyses. The first step was a determination of the appropriateness of parametric statistics. The distributional characteristics of most of the variables in the present study violated either the assumption of normality of distribution or the assumption of homogeneity of variance between groups. Therefore, all tests were performed with nonparametric statistics. An advantage of this approach is that nonparametric tests are generally more conservative than parametric tests and are thus more appropriate for a relatively small sample as included herein. Spearman rank order correlation coefficients (rs) were used. All p values presented are two-tailed.

Results Comparisons Between Control Subjects and Unmedicated Schizophrenic Patients. Table 1 presents the results of this comparison for all variables, with the

exception of the anticipatory saccade rate. There was a trend for control subjects to be engaged in the tracking task for a larger percentage of time. Patients had significantly lower gain-the strongest effect in the study. Patients also had significantly elevated catch-up saccade rates. No differences were found in median catch-up saccade amplitude or square-wave jerk rate. The anticipatory saccade rate had an unusual frequency distribution. The majority of normal control subjects and the majority of patients had none of these events (74% for normals, 64% for patients). A few normals (5 or 26%) and a few patients (3 or 23%, 1 from group 1 and 2 from group 2) had one to three of these events. One patient, from group 1, had 25 anticipatory saccades. Patients did not differ significantly from control subjects on the anticipatory saccade rate.

29

Table 1. Comparisons between controls and unmedicated schizophrenic patients Schizophrenic Controls (n = 19)

patients (n = 13)

Median

Range

Median

Range

% of time tracking

90.4

64.9-98.0

80.6

32.6-96.0

p value’ 0.058

Gain

0.82

0.70-0.97

0.69

0.39-0.90

0.004

0.84

0.23-l .87

1.49

0.45239

0.025

0.71

0.50-l 57

0.86

0.50-l .36

0.166

0.27

0.09-0.68

0.23

0.04-0.93

0.863

Catch-up saccades, rate/set of tracking Median catch-up saccade amplitude Square-wave

jerks, rate/xc

of tracking

1.Mann-Whitney

U statistic.

Comparisons Between Groups 1 and 2 in the Unmedicated State. There were no significant differences between the two patient groups in the unmedicated state on any eye-tracking variable. Also, the patient groups did not differ significantly in illness duration, age of onset, number of previous admissions, age, or number of days off or on medication. Effect of Medication on Psychopathology. For groups 1 and 2 combined, there was a trend toward a reduction in the BPRS total score (Wilcoxon test,p = 0.0926) and in the BPRS positive symptom score @ = 0.0926) but not in the BPRS negative symptom score (p = 0.4838). The effect of medication on psychopathology was not significant when evaluated for each patient group separately, although the direction was toward improvement except for negative symptoms on clozapine (3 patients increased slightly, 1 patient improved, and 1 patient did not change). Thus, these patients generally were not experiencing marked symptom improvement with medication at the time of the eye-tracking study. Effect of Medication on Smooth Pursuit. The median amplitude of catch-up saccades increased significantly with medication in groups 1 and 2 combined, but when each patient group was tested for the effect individually, only group 2 (which received clozapine) showed a significant effect (Table 2). This effect is illustrated in Fig. 1, which shows that six of seven patients had an increase in the median amplitude of catch-up saccades after clozapine, with one patient showing no change. On the other hand, after typical neuroleptics, three subjects increased, one decreased, and two did not change. There were no other statistically significant medication effects and no trends. Of the nine patients in both groups who had no anticipatory saccades before medication, none had anticipatory saccades after medication. The group 1 patient with one anticipatory saccade before medication had no anticipatory saccades after medication. The group 1 patient with 25 anticipatory saccades before medication had only 12 anticipatory saccades after medication. Thus, there is a hint that typical neuroleptics may reduce the number of anticipatory saccades in

30 individual patients. Of the two group 2 patients who had one to three anticipatory saccades, one had no anticipatory saccades after medication and one had six anticipatory saccades. Table 2. Test of the medication

effect Group 1

Group 2

Typical antipsychotic agents (n = 6)

Clozapine (n = 7)

Unmedicated

Medicated

Unmedicated

Medicated

Median (Range)

Median (Range)

Median (Range)

Median (Range)

% of time tracking

64.9 (32.6-93.8)

83.2 (61.7-94.0)

82.3 (60.1-96.0)

84.2 (77.4-97.8)

Gain

0.58 (0.40-0.78)

0.57 (0.24-0.98)

0.74 (0.39-0.90)

0.70 (0.52-0.86)

1.65 (0.74-2.18)

1.58 (0.63-2.38)

1.45 (0.45-2.39)

1.49 (0.86-3.01)

0.97 (0.64-1.36)

1 .OO(0.64-l .86)

0.71 (0.50-l .21)

0.86 (0.57-l .25)’

0.27 (0.04-0.56)

0.15 (0.05-0.72)

0.23 (0.17-0.93)

0.22 (0.09-0.56)

Catch-up saccades, rate/ set of tracking Median catchup saccade amplitude Square-wave

jerks, rate/

set of tracking

1. Wilcoxon test for both groups combined indicated a significant increase in median amplitude of catch-up saccades @ = 0.0125). For group 1 alone, the effect was not significant (p = 0.2012), whereas for group 2 alone, the increase was statistically significant @ = 0.0277).

Fig. 1. Plot showing the effect of either typical neuroleptics median amplitude of catch-up saccades TYPICAL

or clozapine

on

CLOZAPINE

NEUROLEPTICS 2.000 -

1.250-

0.500 J. PRE

0.500POST

,

/ PRE

POST

Ordinate is o of visual angle, a measure of saccade size. PRE indicates data in the unmedicated indicates data in the medicated state.

state, and POST

31 Relationship

Between

Eye-Tracking

Measures

and

Psychopathology.

Baseline BPRS ratings were tested for correlation with baseline eye-tracking measures, and BPRS ratings from the medication period were tested for a correlation with eye-tracking measures from the same period. There was only one significant correlation, which could have occurred by chance, but is nonetheless of interest: Medicated patients with more severe psychopathology (BPRS total score) tended to track a lower percentage of the time (I-~= -0.5746, p = 0.040). When the patient groups were compared individually, percentage of time tracking was significantly correlated with BPRS total score in the clozapine group (rs = -0.991, p < 0.001) but not in the typical neuroleptic group (r, = -0.2571, p = 0.623). There were no correlations between change in eye-tracking pattern and change in psychopathology for groups 1 and 2 combined or for each patient group evaluated separately. Relationship Medication.

Between Eye-Tracking Measures and Duration No statistically significant correlations were found

Relationship

Between

Off or On

between the number of days off medication and eye-tracking measures during the unmedicated state, or between number of days on medication and eye-tracking measures in the medicated state. Significant correlations were found between number of days on medication and improvement in eye-tracking measures. First, there was a negative correlation between number of days on medication and improvement in the median amplitude of catch-up saccades in groups 1 and 2 combined (r, = -0.7427, p = 0.004). When groups 1 and 2 were examined separately, this relationship held for the clozapine group (rs = -0.8727,~ = 0.010) and showed a strong trend for the typical neuroleptic graup (rs = -0.7537, p = 0.084). Thus, the more days a patient had been on antipsychotic medication, the greater the degree of enlargement (worsening) of the median amplitude of catch-up saccades found. Second, there was a negative correlation between the number of days on medication and lowering (worsening) of gain for groups 1 and 2 combined (r, = -0.6022, p = 0.029). When groups I and 2 were examined separately, this relationship held for the typical neuroleptic group (r, = -0.8286, p = 0.042) but not for the clozapine group (r, = -0.3604, p = 0.427). Thus, the more days a patient had been treated with a typical neuroleptic, but not clozapine, the lower (worse) the gain. Eye-Tracking

Measures

and Age or Illness Duration.

There were no correlations between age and any eye-tracking measure for the normal control subjects. Among the patients, illness duration and age were highly correlated (rs t 0.8262, p < O.OOl), as might be expected. Thus, the independent influence of these factors is difficult to examine. For this reason, the data for illness duration and age are reported together. Age of onset was less highly correlated with age (r, = 0.5380, p = 0.058), and the data for this variable are reported separately. For groups 1 and 2 combined, age and illness duration were uncorrelated with any eye-tracking variable in either the unmedicated or the medicated state. However, age and illness duration were positively correlated with improvement in eye-tracking measures as a result of medication (age with improvement in catch-up saccade rate:

32

illness duration with improvement in gain: rs = 0.6878, duration with improvement in catch-up saccade rate: rs = 0.7978, p = 0.001). In other words, the older subjects were more likely to improve in eye tracking as a result of medication. Examination of the correlations with only patients who received typical neuroleptics revealed that neither age nor illness duration was correlated with improvement. However, the correlations within the clozapine group were high (illness duration and improvement in gain: rs = 0.8571,p = 0.014; illness duration and improvement in catch-up saccade rate: rs = 0.8929,p = 0.007;illness duration and improvement in Yc of time tracking: rs = 0.7857, p = 0.036). Within the clozapine group, one patient was markedly older (60 years) than the others (22-36 years) and had been ill longer (25 years) than the others (5-16 years). Even with this subject removed, however, illness duration was still highly correlated with improvement in catch-up saccade rate (rs = 0.8286, p = 0.042). rs = 0.7934, p = 0.001;

p = 0.009; illness

Relationship Between Eye-Tracking Measures and Number of Previous Hospitalizations. For groups 1 and 2 combined, number of previous hospitalizations was correlated significantly with improvement in median catch-up saccade amplitude (rs = 0.5816, p = 0.037). This correlation was also significant for the clozapine group (rs = 0.7615, p = 0.047), but not for the group treated with typical neuroleptics (rs = 0.5441, p = 0.264). Thus, clozapine-treated patients who had a relatively large number of hospital admissions were more likely to show an improvement on catch-up saccade amplitude. Relationship Between Eye-Tracking Measures and Age of Onset. For both groups 1 and 2 combined, there were no correlations between age of onset and any eye-tracking variable. Age of onset was significantly negatively correlated with improvement in square-wave jerk rate (r, = -0.9429, p = 0.005) in group 1 (typical neuroleptics). In other words, older-onset patients were less likely to improve (have fewer square-wave jerks) as a result of typical antipsychotic medication. Relationship Between Medication Dosage and Improvement in Eye-Tracking Measures. For patients who received clozapine, medication dose was significantly negatively correlated with improvement in total tracking time (rs = -0.8524, p = 0.015), median catch-up saccade amplitude (rs = -0.8228, p = 0.023), and square-wave jerk rate (rs = -0.9636, p < 0.001). In other words, the patients who received larger doses of clozapine improved less on eye-tracking measures than those who received smaller doses. No significant correlations between dose of typical neuroleptic and improvement in eye-tracking were found. Discussion In the present study, eye-tracking dysfunction was present in patients withdrawn from medication, which is consistent with previous findings indicating that the eyetracking deficit is not an effect of medication. This is supported by evidence of eye-tracking dysfunction in never-medicated patients (Diefendorf and Dodge, 1908;

33 Couch and Fox, 1934; White, 1938; Karson, 1979) and in patients withdrawn from medication (Shagass et al., 1974; Stevens, 1978; Levy et al., 1983; Holzman et al., 1974; Bartfai et al., 1983; Saletu et al., 1986; Siever et al., 1986; Spohn et al., 1988; Keefe et al., 1989; Friedman et al., 1991). In the present study, patients were withdrawn from typical neuroleptic medication for a minimum of 8 days, with a median of 15 days. This length of withdrawal may not be optimal for eliminating a potential influence of neuroleptic medication, since plasma neuroleptic concentrations have been noted beyond this point (Sramek et al., 1987). However, no relationship between length of medication withdrawal and smooth pursuit measures was noted. In the present study, typical neuroleptics did not worsen or improve eye-tracking performance. These findings are consistent with those of most studies that have looked for such an effect with a wide variety of smooth pursuit measures (Holzman et al., 1974; Rea et al., 1989; for review, see Levy et al., 1983; Lipton et al., 1983; Abel and Hertle, 1988; Spohn et al., 1988). However, several issues must be considered before the failure to find a medication effect is accepted. The patients in the present study did not experience marked symptom improvement, and it is possible that patients who responded more fully might have shown improved eye-tracking performance. Mitigating against this interpretation is the fact that there was no correlation between change in eye tracking and change in psychopathology. A failure to find a medication effect could reflect the relative chronicity of the patients, as indicated by long illness durations and a large number of previous hospitalizations. However, there was no evidence that patients who were ill longer or were hospitalized more often improved less than the others. It is possible that an effect of typical neuroleptics on eye tracking occurs after longer treatment intervals than were tested herein. In the present study, there is some evidence consistent with this hypothesis: the patients who were on typical neuroleptics longer tended to improve less on gain and median catch-up saccade amplitude. There was a hint that typical neuroleptics might reduce the occurrence of anticipatory saccades, but since these events are relatively rare, a large patient sample would be necessary to demonstrate such an effect. In contrast to the results with typical neuroleptics, there was evidence that clozapine worsened smooth pursuit performance. First, there was a significant increase in median catch-up saccade amplitude after clozapine treatment. One possibility is that this effect is a chance finding, and certainly if the probability of this finding had been corrected for multiple comparisons, it would not have reached statistical significance. Another possibility is that patients who received clozapineand who were generally treatment-resistant-differed in some way from patients who received typical neuroleptics. However, no eye-tracking differences between these patient groups in the unmedicated state were detected. Although there was only one significant mean effect of clozapine, correlational analyses also provided support for a clozapine effect. There was a significant negative correlation between number of days on clozapine and improvement in median catch-up saccade amplitude, which suggests that the effect of clozapine in enlarging catch-up saccade size is cumulative over time. Furthermore, clozapine dose showed a significant negative correlation with improvement in median catch-up saccade amplitude, percentage of time tracking, and square-wave jerk rate.

34 Since catch-up saccades correct for the position error that accumulates during low gain tracking, an increased catch-up saccade amplitude could result from a slow or inaccurate detection of position error. It is not clear why clozapine, but not typical neuroleptics, would cause this, but it may be related to clozapine’s distinct pharmacological profile (Meltzer et al., 1989). Clozapine, relative to typical neuroleptics, has a lower affinity for the dopamine D, receptor and a higher affinity for the serotonin 5HT, receptor. Although dopamine and y-aminobutyric acid have been widely implicated in ocular motor control (Albin et al., 1989), there is little evidence linking serotonin to eye movement. Stott et al. (1989) reported a reduction in gain after administration of GR 38032F, a 5HT, antagonist. A case report has linked L-tryptophan with square-wave jerks and saccadic hypometria in a patient with depression (Baloh et al., 1981). If the present results can be replicated, more research will be required to determine why clozapine, but not typical neuroleptics, has this effect. Regardless of the neurochemical underpinnings of this effect, the likely anatomical sites for control of catch-up saccade amplitude are the frontal eye field (MacAvoy and Bruce, 1989) and the middle temporal and medial superior temporal areas (Diirsteler et al., 1987). Acknowledgment. This research was supported by grants from the USPHS (MH-41684 and MH-41594 to Dr. Meltzer, and MH-47574 to Dr. Friedman), the Cleveland and John Pascal Sawyer Memorial Foundations, and the National Alliance for Research in Schizophrenia and Depression. H.Y.M. is a recipient of a USPHS Research Career Scientist Award (MH-47808). The authors thank Drs. John Kenny, Bryan Roth, and George Jaskiw for helpful comments during the preparation of this article.

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Effect of typical antipsychotic medications and clozapine on smooth pursuit performance in patients with schizophrenia.

The effect of typical neuroleptic drugs or clozapine on smooth pursuit eye movements was tested in 13 patients with schizophrenia or schizoaffective d...
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