932
BIOL PSYCHIATRY 1992;32:932-938
Lithium Effect on Smooth Pursuit Eye Movements of Healthy Volunteers K.-M. Flechtner, A. Mackert, K. Thies, K. Frick, and B. M011er-Oerlinghausen
Smooth pursuit eye movement (SPEM) dysfunctions in major affective disorder patients have been reported to be associated with lithium treatment. We report that SPEM of 13 healthy volunteers, either taking lithium ( n = 7) or placebo ( n = 6), were not significantly impaired by lithium. This could point to a pathophysiologic difference between affective disorder patients and a normal population.
Introduction Since the early publications of Holzman et al (1973, 1974) many studies have replicated the finding of disturbed smooth pursuit eye movements (SPEM) in schizophrenic patients (Shagass et al 1974, 1976; Salzman et al 1978; May 1979; lacono et al 1981; Bartfai et al 1983; Cegalis et al 1983). Abnormal SPEM are considered to be one of the most promising candidates for a biological marker of schizophrenia. About two-thirds of schizophrenic patients and about half of their first-degree relatives are reported to show SPEM dysfunctions compared to only 8%-12% in a normal population (Holzman et al 1974). Twin studies have demonstrated that SPEM dysfunctions may be genetically transmitted (Holzman et al 1974, 1978; lacono and Lykken 1979). Although most investigators have found that impaired SPEM are more common in schizophrenic patients than among affective disorder patients (Diefendorf and Dodge 1908; Karson 1979; Cegalis and Sweeney 1981) other studies indicate that patients with major affective disorders have also abnormal SPEM in a substantial percentage (Shagass et al 1974; Klein et al 1976; Salzman et al 1978; Lipton et al 1980; Levin et al 1981; Holzman et al 1984). These conflicting results call into question the specificity of abnormal SPEM to schizophrenia. Impaired smooth pursuit is also known to occur unspecificaily in various neurologic disorders and as an effect of sedative drugs such as diazepam (Rothenberg et al 1981; Bittencourt et al 1983), barbiturates (Holzman et al 1975) or alcohol (Levy et al 1981). Neuroleptics and antidepressants are generally considered not to induce SPEM dysfunctions (Levy et al 1983; Lipton et al 1983). In 1982 lacono et al reported evidence that lithium contributed t~ poor smooth pursuit performance in bipolar affective disorder patients, although the
Psychiatrische Klinik und Poliklinik der Freien Universit~it Berlin, Germany. Address reprint reques!s to Dr, K,-M. Flechtner, Psychiatrische Klinik und Poliklinik der Freien Universitat Berlin, Eschenallee 3, D-IO00 Berlin 19, Germany, Received October 16, 1991; revised June 25, 1992. This paper was presented in part at the 5th World Congress of Biological Psychiatry in Florence, June 1991. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
Li Effect on Smooth Pursuit Eye Movements
BIOL PSYCHIATRY 1992;32:932-938
933
patients did not differ from normal subjects. Levy et al (1985) were able to show that SPEM dysfunctions in patients with major affective disorders were closely associated with lithium carbonate medication. The authors conclude that abnormal SPEM are not characteristic of patients with affective disorders independently of a drug effect. Recently these results could be confirmed by another study (Holzman et al 1991). The finding explains the disparity in prevalence of impaired SPEM between affective disorder patients and their first-degree relatives and supports the hypothesis that SPEM dysfunctions are specific for schizophrenia in psychiatric populations. Systematic studies about the effect of iithium on SPEM in various populations are lacking, though. Therefore, little can be said about the significance of these lithium-induced changes of oculomotor control. It is known that certain drug effects occur only in psychiatric patients but not in healthy subjects (Small et ai 1972). We, therefore, wanted to know if lithium disrupts SPEM in a nonpatient popuiation.
Methods Sixteen male subjects who had responded to a newspaper announcement participated in the study. Three subjects dropped out because the second testing was ~ot possible for various reasons. Subjects with a history of psychiatric illness for themselves or their first-degree relatives were excluded from the study. Also a history of severe medical or neurological illness, and alcohol or drug abuse led to exclusion. Subjects were not permitted to take any drugs besides lithium during the study. Every second day urine specimens wen screened for illicit drugs. Subjects received either placebo or lithium carbonate randomly in a double blind manner. Seven subjects were in the lithium group, six in the placebo group. The mean age of the two groups--placebo versus lithium--was not significantly different: 25.8 _+ 7.8 and 28.8 _ 2.5 years. Every second day blood concentrations of lithium were measured and after 2 weeks all subjects had a lithium blood level above 0.6 mEq/L. Eye movements were examined with dc electrooculography before intake of lithium or placebo and after 2 weeks. Silversilver chloride electrodes were placed at the outer canthi of both eyes and under and above the left eye to control for vertical eye movements and blink artifacts. Subjects were seated comfortably in a darker,ed room and had their head fixated on a headrest to inhibit head movements. Stimulus programs were displayed on a horizontal board of 511 light-emitting diodes that was operated by a personal computer (PC) in a second room. To induce smooth pursuit eye movements a red light spot moved continuously across the board with a frequency of 0.4 Hz in a pendular manner. After amplification eye movements and stimulus signals were simultaneously charted on a Siemens EEG Mingograph and recorded on a magnetic tape. Signals were then digitized at a sampling rate of 500 Hz and transferred off-line from the tape to a Vax 11/750 computer. Eye movement signals were displayed on a monitor and trials with blinks and artifacts were removed. Smooth pursuit eye movements were analysed using a Fast Fourier Transformation (FI~T). Then a signal-to-noise analysis was done. The power at 0.4 Hz, which is the signal power, was divided by the power representing noise (0.8-12 Hz). The logarithmic ratio signal/noise was taken as a measure for quality of pursuit eye movements. In addition the paper charts of the eye movements were rated independently by three raters using a five-point rating scale introduced by Shagass et al 1974. Interrater correlation was between r = 0.82 and r = 0.93.
K.-M. Flechtner et al
BIOL PSYCHIATRY 1992;32:932-938
934
Table 1. Scores on O~,al~':~~; ~ P~oi~:~ a~d 7~equency Analysis for Subjects Receiving Placebo (n - 6) or Lithium (n -- 7) First testing
Second testing
p
Placebo group Qualitative rating Frequency analysis
1.2 _.+ 0.45 4.22 .4- 1.2
1.2 -- 0.45 4.57 - 0.8
NS NS
Lithium group Qualitative rating Frequency analysis
1.4 - 0.53 4.19 - 0.6
i.8 - 1.2 3.50 -- 1.5
NS NS
Comparison between first and second testing for each group. Values are means ± SD.
Results At the first testing the two groups did not differ in quality of smooth pursuit eye movements, that is their base-line values were not significantly different (two-tailed t-test). After 2 weeks there was no significant difference between the first and second testing in both groups (paired samples t-test), see Table 1 and Figures 1 and 2. There was a negative but nonsignificant correlation between lithium blood concentration and qualitative ratings (r ": -0.62; p > 0.10) or frequency analysis (r - - 0 . 6 3 ; p > 0.10). These negative correlations would indicate that higher lithium plasma concentrations were associated with better pursuit.
Discussion We were not able to find a significant mean effect of lithium carbonate on smooth pursuit eye movements. However, at the second testing the scores of the qualitative ratings for the pursuit movements had a nonsignificant tendency to be higher, indicating a poorer quality of tracking. This coincides with the impression that there were more artifacts, that is, high-frequency noise etc., in the lithium group. The qualitative rating is an overall rating with no clearly defined criteria that distinguish between each score. It is possible that despite our effort to exclude these artifacts they had an effect on the overall scores. In the computerized data all frequencies above 12 Hz were entirely cut off and excluded. On principle these data can be freed better from artifacts than the original charts and they do not show this tendency. At the time of the second testing three subjects of the total group had improved scores (differing by one point) in the qualitative ratings and three subjects scored worse (differing by 1, 2, and 3 points). In the lithium group two subjects had worse scores by 2 and 3 points and one subject scored better by 1 point. In the placebo group, one subject got better and two subjects got worse by one point. If a score of 3 points and above is considered to indicate impairment of smooth pursuit eye movements then only two subjects had SPEM dysfunctions, all other subjects had scores of 1 and 2 points. These two subjects had received lithium and had scores of 3 and 4 points. Our strategy for the ratings was to assess an average of all eye movement cycles. If only the best cycles had been rated, no subject would have a score equal to or above 3 points, which means no subject would be considered to have impaired smooth pursuit eye movements. In the frequency analysis the two subjects scoring worst in the qualitative ratings had average values. Holzman et al 1991 report impairment of SPEM in 64% of lithiumtreated bipolar manic patients based on qualitative ratings. In 9 of 11 patients, a general
Li Effect on Smooth Pursuit Eye Movements
Subject 1:
before lithium
Subject 1: blood level: .66 mEcl/L
SubJect 2: before lithium
Subject 2: blood level: .84 mEq/L
SubJect s:
Subject 8: blood level: .88 mEcl/L
before lithium
Subject 4: before lithium
Subject 4: blood level: .73 mEaJL
Subject S: before lithium
Sublect S: blood level: .83 mEcl/L
Subject 6: before lithium
Subject 6: blood level: .89 mEcl/L
SubJect 7: beforo lithium
Sublect 7: blood level: .82 mEcl/L
BIOLPSYCHIATRY 1992;32:932-938
935
Figure I. Sample tracings of subjects receiving lithium carbonate. Left side: before lithium, right side: after lithium. Tracings of each panel depict left and right eye position.
qualitative degradation of eye-tracking integrity, a lowering of gain, and an increase in the number of saccadic events was found. The magnitude of changes were neither stable within subjects nor predictable in their course and there was no clear correlation to lithium blood levels. Rather patients seemed to manifest the effects of lithium idiosyncratically. Levy et al 1985 found in 88% of affective disorder patients SPEM dysfunctions after lithium treatment. Over half of lithium-treated patients in remission also showed impairment of smooth pursuit eye movements. The time between the beginning of lithium treatment and the onset of SPEM dysfunctions ranged from 1 day to 6 weeks. Among inpatients there were significant correlations between quality of SPEM and red blood lithium concentrations (RBC) and lithium RBC/plasma ratios, but not with plasma lithium concentrations. Among patients in remission there was even an inverse relationship be-
936
K.-M. Flechtner et al
BIOL I~SYCHIATRY 1992;32:932-938
Subject 8: Time I
Subject 8: Time 2
Subject 9: Time 1
Subject 9: Time 2
Subject 10: Time 1
Subject 10: Time 2
~
'~
Subject 11: Time 1
Subject 11: Time 2
Subject 12: Time 1
Subject 12: Time 2
Subject 13: Time 1
Sub|e~t lS: Time
Figure 2. Sample tracings of subjects receiving placebo. Tracings of each panel depict left and right eye position.
tween quality of SPEM and plasma lithium concentration. In both studies SPEM impairment did not appear alongside with clinical side effects or even lithium toxicity. The minimum plasma lithium concentrations at which Levy et al 1985 found abnormal pursuit was 0.40 mE/L. The time of onset of the change from normal to abnormal pursuit ranged from 1 day to 6 weeks in patients who had not taken lithium previously. In the study of Holzman et al 1991 the average plasma lithium concentration was 1.02 mE/L with a minimum of 0.8 mE/L. Our subjects received lithium carbonate for a period of 2 weeks, which can be considered long enough for pharmacologic effects to take place. We did not observe any clinical side effects. Plasma lithium concentrat+ons were within the usual prophylactic range (0.64 - 0.89 mEq/L) with a mean of 0.78 mEq/L. These values are comparable to the ones reported by Levy et al 1985. Our results can therefore not be attributed to lower plasma lithium concentrations. They rather argue against the gener-
Li Effect on Smooth Pursuit Eye Movements
BIOL PSYCHIATRY 1992;32:932-938
937
alizability of lithium-induced SPEM dysfunctions in affective disorder patients. Most of the patients in the studies indicating a relation between impairment of SPEM and lithium treatment were chronically ill with many episodes of disorder (Iacono et al 1982; Levy et al 1985; Holzman et al 1991). One recent study was not able to find a lithium effect on SPEM in younger first-episode affective disorder patients (Gooding et al in press). Together with our results it now seems unclear to what extent or even if lithium induces SPEM impairment. It could well be that factors like age, history of medications, and prior episodes of disorder interact with lithium status in a way that can explain the individual differences of patients' eye-tracking performances observed in the abovementioned studies. Because the groups of our study were rather small it limits the power to detect small differences. Future studies should include larger samples of various psychiatric and nonpsychiatric populations.
References Bartfal A, Levander SE, Sedvall G 0983): Smooth pursuit eye movements, clinical symptoms, CSF metabolites, and skin conductance habituation in schizophrenic patients. Biol Psychiatry 18:791-798. Bittencourt P, Wade P, Smith A, Richens A 0983): Benzodiazepines impair smooth pursuit eye movements. Br J Clin Pharmacol 15:159-262. Cegalis JA, Hafez H, Wong PS (1983): What is deviant about deviant smooth pursuit eye movements in schizophrenia? Psychiatry Res 10:47-58. Cegalis JA, Sweeney JA 0979): Eye movements in schizophrenia: A quantitative analysis. Biol Psychiatry 14:13-26. Cegalis JA, Sweeney JA (1981): The effect of attention on smooth pursuit eye movements of schizophrenics. J Psychiatry Res 16:145-161. Diefendorf AR, Dodge R 0908): An experimental study of the ocular reactions of the insane from photographic records. Brain 31:451-489. Gooding DC, lacono WG, Katsanis J, Beiser M, Grove WM: The association between lithium carbonate and smooth pursuit eye tracking among first-episode patients with psychotic affective disorders. Psychophysiology (in press). Holzman PS, Proctor LR, Hughes DW (1973): Eye tracking patterns in schizoplu'enia. Science 181:179-181. Holzman PS, Proctor LR, Levy DL, Yasillo NJ, Meltzer HY, Hurt SW (1974): Eye tracking dysfunctions in schizophrenic patients and their relatives. Arch Gen Psychiatry 31:143-151. Holzman PS, Levy DL, Uhlenhuth El/, Proctor LR, Freedman DX 0975): Smooth pursuit eye movements and diazopam, CPZ, and secobarbital. Psychopharmacologia 44:11 l-115. Holzman PS, Kringlen E, Levy DL, Proctor LR, Haberman S (1978): Smooth pursuit eye movements in twins discordant for schizophrenia. J Psychiatry Res 14:111-122. Holzman PS, Kringlen E, Levy DL, Haberman S (1980): Deviant eye tracking in twins discordant for psychosis: A replication. Arch Gen Psychiatry 32:627--631. Holzman PS, Solomon CM, Levin S, Waternaux C (1984): Pursuit eye movement dysfunctions in schizophrenia. Family evidence for specificity. Arch Gen Psychiatry 41:136-139. Holzman IS, O'Brian C, Waternaux C (1991): Effects of lithium treatment on eye movements. Biol Psychiatry 29:1001-1015. lacono WG, Lykken DT (1979): Eye tracking and psychopathology. Arch Gen Psychiatry 36:13611369. Iacono WG, Tuason VB, Johnson RA (1981): Dissociation of smooth pursuit and saccadic eye tracking in remitted schizophrenics. Arch Gen Psychiatry 38:991-996.
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K.-M. Hechtner et al
lacono WG, Peloquin l.J, Lumry AE, Valentine RH, Tuason VB (1982): Eye tracking in patients with unipolar and bipolar affective disorder in remission. J Abnorm Psychol 91:35-44. Karson CN (1979): Oculomotor signs in a psychiatric population: A preliminary report. Am J Psychiatry 136:1057-1060. Klein RH, Salzman LF, Jones F, Ritzler B (1976): Eye tracking in psychiatric patients and their offspring (Abstract). Psychophysiology 13:186. Levin S, Holzman PS, Rothenberg SJ, Lipton RB (1981): Saccadic eye movements in psychotic patients. Psychiatry Res 5:47-58. Levy DL, Lipton RB, Holzman PS (I 981): Smooth pursuit eye movements: Effects of alcohol and chloral hydrate. J Psychiatry Res 16:1-11. Levy DL, Lipton RB, Holzman PS, Davis ,IM (1983): Eye tracking dysfunction unrelated to clinical state and treatment with haloperidol. Biol Psychiatry 18:813--819. Levy DL, Doms E, Shaughnessy R, Yasillo NJ et al (1985): Pharmacologic evidence for specificity of pursuit dysfunction to schizophrenia: Lithium carbonate associated with abnormal pursuit. Arch Gen Psychiatry 42:335-341. Lipton RB, Levin S, Holzman PS (1980): Horizontal and vertical pursuit eye movements, the oculocephalic reflex, and the functional psychoses. Psychiatry Res 3:193-203. Lipton RB, Levy DL, Holzman PS, Levin S (1983): Eye movement dysfunction in psychiatric patients: A review. Schiz Bull 9:13-32. May H,I (1979): Oculomotor pursuit in schizophrenia. Arch Gen Psychiatry 36:827. Mialet ,IP, Pichot P (1981): Eye tracking patterns in schizophrenia: An analysis based on the incidence of saccades. Arch Gen Psychiatry 38:183-186. Pivik RT (1979): Smooth pursuit eye movements and attention in psychiatric patients. Biol Psy. chiatry 14:859-879. Rothernberg S,I, Selkoe D (198 I): Specific oculomotor deficit after diazepam: Smooth pursuit eye movements Psychopharmacologia 74:237-240. Salzman LF, Klein RH, Strauss .IS (1978): Pendulum tracking in remitted psychiatric patients. J Psychiatry Res 14:12!- 126, Shagass C, Amadeo M, Overton DA (1974): Eye tracking performance in psychiatric patients. Bioi Psychiatry 14:245-261, Shagass C, Roemer RA, Amadeo M (1976): Eye tracking performance and the engagement of attention. Arch Gen Psychiatry 33:121-125, Small ,IG, Milstein V, Perez HC, Small IF, Moore DF (1972): EEG and neurophysiological studies of lithium in normal volunteers. Biol Psychiatry 5:65-77.
BIOL PSYCHIATRY 1992;32:932-938
Lithium Effect on Smooth Pursuit Eye Movements of Healthy Volunteers K.-M. Flechtner, A. Mackert, K. Thies, K. Frick, and B. M011er-Oerlinghausen
Smooth pursuit eye movement (SPEM) dysfunctions in major affective disorder patients have been reported to be associated with lithium treatment. We report that SPEM of 13 healthy volunteers, either taking lithium ( n = 7) or placebo ( n = 6), were not significantly impaired by lithium. This could point to a pathophysiologic difference between affective disorder patients and a normal population.
Introduction Since the early publications of Holzman et al (1973, 1974) many studies have replicated the finding of disturbed smooth pursuit eye movements (SPEM) in schizophrenic patients (Shagass et al 1974, 1976; Salzman et al 1978; May 1979; lacono et al 1981; Bartfai et al 1983; Cegalis et al 1983). Abnormal SPEM are considered to be one of the most promising candidates for a biological marker of schizophrenia. About two-thirds of schizophrenic patients and about half of their first-degree relatives are reported to show SPEM dysfunctions compared to only 8%-12% in a normal population (Holzman et al 1974). Twin studies have demonstrated that SPEM dysfunctions may be genetically transmitted (Holzman et al 1974, 1978; lacono and Lykken 1979). Although most investigators have found that impaired SPEM are more common in schizophrenic patients than among affective disorder patients (Diefendorf and Dodge 1908; Karson 1979; Cegalis and Sweeney 1981) other studies indicate that patients with major affective disorders have also abnormal SPEM in a substantial percentage (Shagass et al 1974; Klein et al 1976; Salzman et al 1978; Lipton et al 1980; Levin et al 1981; Holzman et al 1984). These conflicting results call into question the specificity of abnormal SPEM to schizophrenia. Impaired smooth pursuit is also known to occur unspecificaily in various neurologic disorders and as an effect of sedative drugs such as diazepam (Rothenberg et al 1981; Bittencourt et al 1983), barbiturates (Holzman et al 1975) or alcohol (Levy et al 1981). Neuroleptics and antidepressants are generally considered not to induce SPEM dysfunctions (Levy et al 1983; Lipton et al 1983). In 1982 lacono et al reported evidence that lithium contributed t~ poor smooth pursuit performance in bipolar affective disorder patients, although the
Psychiatrische Klinik und Poliklinik der Freien Universit~it Berlin, Germany. Address reprint reques!s to Dr, K,-M. Flechtner, Psychiatrische Klinik und Poliklinik der Freien Universitat Berlin, Eschenallee 3, D-IO00 Berlin 19, Germany, Received October 16, 1991; revised June 25, 1992. This paper was presented in part at the 5th World Congress of Biological Psychiatry in Florence, June 1991. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
Li Effect on Smooth Pursuit Eye Movements
BIOL PSYCHIATRY 1992;32:932-938
933
patients did not differ from normal subjects. Levy et al (1985) were able to show that SPEM dysfunctions in patients with major affective disorders were closely associated with lithium carbonate medication. The authors conclude that abnormal SPEM are not characteristic of patients with affective disorders independently of a drug effect. Recently these results could be confirmed by another study (Holzman et al 1991). The finding explains the disparity in prevalence of impaired SPEM between affective disorder patients and their first-degree relatives and supports the hypothesis that SPEM dysfunctions are specific for schizophrenia in psychiatric populations. Systematic studies about the effect of iithium on SPEM in various populations are lacking, though. Therefore, little can be said about the significance of these lithium-induced changes of oculomotor control. It is known that certain drug effects occur only in psychiatric patients but not in healthy subjects (Small et ai 1972). We, therefore, wanted to know if lithium disrupts SPEM in a nonpatient popuiation.
Methods Sixteen male subjects who had responded to a newspaper announcement participated in the study. Three subjects dropped out because the second testing was ~ot possible for various reasons. Subjects with a history of psychiatric illness for themselves or their first-degree relatives were excluded from the study. Also a history of severe medical or neurological illness, and alcohol or drug abuse led to exclusion. Subjects were not permitted to take any drugs besides lithium during the study. Every second day urine specimens wen screened for illicit drugs. Subjects received either placebo or lithium carbonate randomly in a double blind manner. Seven subjects were in the lithium group, six in the placebo group. The mean age of the two groups--placebo versus lithium--was not significantly different: 25.8 _+ 7.8 and 28.8 _ 2.5 years. Every second day blood concentrations of lithium were measured and after 2 weeks all subjects had a lithium blood level above 0.6 mEq/L. Eye movements were examined with dc electrooculography before intake of lithium or placebo and after 2 weeks. Silversilver chloride electrodes were placed at the outer canthi of both eyes and under and above the left eye to control for vertical eye movements and blink artifacts. Subjects were seated comfortably in a darker,ed room and had their head fixated on a headrest to inhibit head movements. Stimulus programs were displayed on a horizontal board of 511 light-emitting diodes that was operated by a personal computer (PC) in a second room. To induce smooth pursuit eye movements a red light spot moved continuously across the board with a frequency of 0.4 Hz in a pendular manner. After amplification eye movements and stimulus signals were simultaneously charted on a Siemens EEG Mingograph and recorded on a magnetic tape. Signals were then digitized at a sampling rate of 500 Hz and transferred off-line from the tape to a Vax 11/750 computer. Eye movement signals were displayed on a monitor and trials with blinks and artifacts were removed. Smooth pursuit eye movements were analysed using a Fast Fourier Transformation (FI~T). Then a signal-to-noise analysis was done. The power at 0.4 Hz, which is the signal power, was divided by the power representing noise (0.8-12 Hz). The logarithmic ratio signal/noise was taken as a measure for quality of pursuit eye movements. In addition the paper charts of the eye movements were rated independently by three raters using a five-point rating scale introduced by Shagass et al 1974. Interrater correlation was between r = 0.82 and r = 0.93.
K.-M. Flechtner et al
BIOL PSYCHIATRY 1992;32:932-938
934
Table 1. Scores on O~,al~':~~; ~ P~oi~:~ a~d 7~equency Analysis for Subjects Receiving Placebo (n - 6) or Lithium (n -- 7) First testing
Second testing
p
Placebo group Qualitative rating Frequency analysis
1.2 _.+ 0.45 4.22 .4- 1.2
1.2 -- 0.45 4.57 - 0.8
NS NS
Lithium group Qualitative rating Frequency analysis
1.4 - 0.53 4.19 - 0.6
i.8 - 1.2 3.50 -- 1.5
NS NS
Comparison between first and second testing for each group. Values are means ± SD.
Results At the first testing the two groups did not differ in quality of smooth pursuit eye movements, that is their base-line values were not significantly different (two-tailed t-test). After 2 weeks there was no significant difference between the first and second testing in both groups (paired samples t-test), see Table 1 and Figures 1 and 2. There was a negative but nonsignificant correlation between lithium blood concentration and qualitative ratings (r ": -0.62; p > 0.10) or frequency analysis (r - - 0 . 6 3 ; p > 0.10). These negative correlations would indicate that higher lithium plasma concentrations were associated with better pursuit.
Discussion We were not able to find a significant mean effect of lithium carbonate on smooth pursuit eye movements. However, at the second testing the scores of the qualitative ratings for the pursuit movements had a nonsignificant tendency to be higher, indicating a poorer quality of tracking. This coincides with the impression that there were more artifacts, that is, high-frequency noise etc., in the lithium group. The qualitative rating is an overall rating with no clearly defined criteria that distinguish between each score. It is possible that despite our effort to exclude these artifacts they had an effect on the overall scores. In the computerized data all frequencies above 12 Hz were entirely cut off and excluded. On principle these data can be freed better from artifacts than the original charts and they do not show this tendency. At the time of the second testing three subjects of the total group had improved scores (differing by one point) in the qualitative ratings and three subjects scored worse (differing by 1, 2, and 3 points). In the lithium group two subjects had worse scores by 2 and 3 points and one subject scored better by 1 point. In the placebo group, one subject got better and two subjects got worse by one point. If a score of 3 points and above is considered to indicate impairment of smooth pursuit eye movements then only two subjects had SPEM dysfunctions, all other subjects had scores of 1 and 2 points. These two subjects had received lithium and had scores of 3 and 4 points. Our strategy for the ratings was to assess an average of all eye movement cycles. If only the best cycles had been rated, no subject would have a score equal to or above 3 points, which means no subject would be considered to have impaired smooth pursuit eye movements. In the frequency analysis the two subjects scoring worst in the qualitative ratings had average values. Holzman et al 1991 report impairment of SPEM in 64% of lithiumtreated bipolar manic patients based on qualitative ratings. In 9 of 11 patients, a general
Li Effect on Smooth Pursuit Eye Movements
Subject 1:
before lithium
Subject 1: blood level: .66 mEcl/L
SubJect 2: before lithium
Subject 2: blood level: .84 mEq/L
SubJect s:
Subject 8: blood level: .88 mEcl/L
before lithium
Subject 4: before lithium
Subject 4: blood level: .73 mEaJL
Subject S: before lithium
Sublect S: blood level: .83 mEcl/L
Subject 6: before lithium
Subject 6: blood level: .89 mEcl/L
SubJect 7: beforo lithium
Sublect 7: blood level: .82 mEcl/L
BIOLPSYCHIATRY 1992;32:932-938
935
Figure I. Sample tracings of subjects receiving lithium carbonate. Left side: before lithium, right side: after lithium. Tracings of each panel depict left and right eye position.
qualitative degradation of eye-tracking integrity, a lowering of gain, and an increase in the number of saccadic events was found. The magnitude of changes were neither stable within subjects nor predictable in their course and there was no clear correlation to lithium blood levels. Rather patients seemed to manifest the effects of lithium idiosyncratically. Levy et al 1985 found in 88% of affective disorder patients SPEM dysfunctions after lithium treatment. Over half of lithium-treated patients in remission also showed impairment of smooth pursuit eye movements. The time between the beginning of lithium treatment and the onset of SPEM dysfunctions ranged from 1 day to 6 weeks. Among inpatients there were significant correlations between quality of SPEM and red blood lithium concentrations (RBC) and lithium RBC/plasma ratios, but not with plasma lithium concentrations. Among patients in remission there was even an inverse relationship be-
936
K.-M. Flechtner et al
BIOL I~SYCHIATRY 1992;32:932-938
Subject 8: Time I
Subject 8: Time 2
Subject 9: Time 1
Subject 9: Time 2
Subject 10: Time 1
Subject 10: Time 2
~
'~
Subject 11: Time 1
Subject 11: Time 2
Subject 12: Time 1
Subject 12: Time 2
Subject 13: Time 1
Sub|e~t lS: Time
Figure 2. Sample tracings of subjects receiving placebo. Tracings of each panel depict left and right eye position.
tween quality of SPEM and plasma lithium concentration. In both studies SPEM impairment did not appear alongside with clinical side effects or even lithium toxicity. The minimum plasma lithium concentrations at which Levy et al 1985 found abnormal pursuit was 0.40 mE/L. The time of onset of the change from normal to abnormal pursuit ranged from 1 day to 6 weeks in patients who had not taken lithium previously. In the study of Holzman et al 1991 the average plasma lithium concentration was 1.02 mE/L with a minimum of 0.8 mE/L. Our subjects received lithium carbonate for a period of 2 weeks, which can be considered long enough for pharmacologic effects to take place. We did not observe any clinical side effects. Plasma lithium concentrat+ons were within the usual prophylactic range (0.64 - 0.89 mEq/L) with a mean of 0.78 mEq/L. These values are comparable to the ones reported by Levy et al 1985. Our results can therefore not be attributed to lower plasma lithium concentrations. They rather argue against the gener-
Li Effect on Smooth Pursuit Eye Movements
BIOL PSYCHIATRY 1992;32:932-938
937
alizability of lithium-induced SPEM dysfunctions in affective disorder patients. Most of the patients in the studies indicating a relation between impairment of SPEM and lithium treatment were chronically ill with many episodes of disorder (Iacono et al 1982; Levy et al 1985; Holzman et al 1991). One recent study was not able to find a lithium effect on SPEM in younger first-episode affective disorder patients (Gooding et al in press). Together with our results it now seems unclear to what extent or even if lithium induces SPEM impairment. It could well be that factors like age, history of medications, and prior episodes of disorder interact with lithium status in a way that can explain the individual differences of patients' eye-tracking performances observed in the abovementioned studies. Because the groups of our study were rather small it limits the power to detect small differences. Future studies should include larger samples of various psychiatric and nonpsychiatric populations.
References Bartfal A, Levander SE, Sedvall G 0983): Smooth pursuit eye movements, clinical symptoms, CSF metabolites, and skin conductance habituation in schizophrenic patients. Biol Psychiatry 18:791-798. Bittencourt P, Wade P, Smith A, Richens A 0983): Benzodiazepines impair smooth pursuit eye movements. Br J Clin Pharmacol 15:159-262. Cegalis JA, Hafez H, Wong PS (1983): What is deviant about deviant smooth pursuit eye movements in schizophrenia? Psychiatry Res 10:47-58. Cegalis JA, Sweeney JA 0979): Eye movements in schizophrenia: A quantitative analysis. Biol Psychiatry 14:13-26. Cegalis JA, Sweeney JA (1981): The effect of attention on smooth pursuit eye movements of schizophrenics. J Psychiatry Res 16:145-161. Diefendorf AR, Dodge R 0908): An experimental study of the ocular reactions of the insane from photographic records. Brain 31:451-489. Gooding DC, lacono WG, Katsanis J, Beiser M, Grove WM: The association between lithium carbonate and smooth pursuit eye tracking among first-episode patients with psychotic affective disorders. Psychophysiology (in press). Holzman PS, Proctor LR, Hughes DW (1973): Eye tracking patterns in schizoplu'enia. Science 181:179-181. Holzman PS, Proctor LR, Levy DL, Yasillo NJ, Meltzer HY, Hurt SW (1974): Eye tracking dysfunctions in schizophrenic patients and their relatives. Arch Gen Psychiatry 31:143-151. Holzman PS, Levy DL, Uhlenhuth El/, Proctor LR, Freedman DX 0975): Smooth pursuit eye movements and diazopam, CPZ, and secobarbital. Psychopharmacologia 44:11 l-115. Holzman PS, Kringlen E, Levy DL, Proctor LR, Haberman S (1978): Smooth pursuit eye movements in twins discordant for schizophrenia. J Psychiatry Res 14:111-122. Holzman PS, Kringlen E, Levy DL, Haberman S (1980): Deviant eye tracking in twins discordant for psychosis: A replication. Arch Gen Psychiatry 32:627--631. Holzman PS, Solomon CM, Levin S, Waternaux C (1984): Pursuit eye movement dysfunctions in schizophrenia. Family evidence for specificity. Arch Gen Psychiatry 41:136-139. Holzman IS, O'Brian C, Waternaux C (1991): Effects of lithium treatment on eye movements. Biol Psychiatry 29:1001-1015. lacono WG, Lykken DT (1979): Eye tracking and psychopathology. Arch Gen Psychiatry 36:13611369. Iacono WG, Tuason VB, Johnson RA (1981): Dissociation of smooth pursuit and saccadic eye tracking in remitted schizophrenics. Arch Gen Psychiatry 38:991-996.
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BIOL PSYCHIATRY 1992;32:932-938
K.-M. Hechtner et al
lacono WG, Peloquin l.J, Lumry AE, Valentine RH, Tuason VB (1982): Eye tracking in patients with unipolar and bipolar affective disorder in remission. J Abnorm Psychol 91:35-44. Karson CN (1979): Oculomotor signs in a psychiatric population: A preliminary report. Am J Psychiatry 136:1057-1060. Klein RH, Salzman LF, Jones F, Ritzler B (1976): Eye tracking in psychiatric patients and their offspring (Abstract). Psychophysiology 13:186. Levin S, Holzman PS, Rothenberg SJ, Lipton RB (1981): Saccadic eye movements in psychotic patients. Psychiatry Res 5:47-58. Levy DL, Lipton RB, Holzman PS (I 981): Smooth pursuit eye movements: Effects of alcohol and chloral hydrate. J Psychiatry Res 16:1-11. Levy DL, Lipton RB, Holzman PS, Davis ,IM (1983): Eye tracking dysfunction unrelated to clinical state and treatment with haloperidol. Biol Psychiatry 18:813--819. Levy DL, Doms E, Shaughnessy R, Yasillo NJ et al (1985): Pharmacologic evidence for specificity of pursuit dysfunction to schizophrenia: Lithium carbonate associated with abnormal pursuit. Arch Gen Psychiatry 42:335-341. Lipton RB, Levin S, Holzman PS (1980): Horizontal and vertical pursuit eye movements, the oculocephalic reflex, and the functional psychoses. Psychiatry Res 3:193-203. Lipton RB, Levy DL, Holzman PS, Levin S (1983): Eye movement dysfunction in psychiatric patients: A review. Schiz Bull 9:13-32. May H,I (1979): Oculomotor pursuit in schizophrenia. Arch Gen Psychiatry 36:827. Mialet ,IP, Pichot P (1981): Eye tracking patterns in schizophrenia: An analysis based on the incidence of saccades. Arch Gen Psychiatry 38:183-186. Pivik RT (1979): Smooth pursuit eye movements and attention in psychiatric patients. Biol Psy. chiatry 14:859-879. Rothernberg S,I, Selkoe D (198 I): Specific oculomotor deficit after diazepam: Smooth pursuit eye movements Psychopharmacologia 74:237-240. Salzman LF, Klein RH, Strauss .IS (1978): Pendulum tracking in remitted psychiatric patients. J Psychiatry Res 14:12!- 126, Shagass C, Amadeo M, Overton DA (1974): Eye tracking performance in psychiatric patients. Bioi Psychiatry 14:245-261, Shagass C, Roemer RA, Amadeo M (1976): Eye tracking performance and the engagement of attention. Arch Gen Psychiatry 33:121-125, Small ,IG, Milstein V, Perez HC, Small IF, Moore DF (1972): EEG and neurophysiological studies of lithium in normal volunteers. Biol Psychiatry 5:65-77.
