Handedness and the risk of tardive dyskinesia

Handedness and the Risk of Tardive Dyskinesia Hal Morgenstern, William M. Glazer, and John T. Doucette

Previous results from five cross-sectional studies are conflicting about the relationship between hand preference and tardive dyskinesia (TD): two report a greater TD prevalence in left handers, and three report a greater prevalence in right handers. To help resolve these inconsistencies, the handedness-TD association was assessed in the Yale TD Study, a large prospective cohort investigation of outpatients maintained with neuroleptics. A consistent monotonic association was observed between the handedness score and TD incidence (p = 0.009). The estimated rate ratio, comparing left and mixed handers with pure right handers, adjusted for confounders, was 0.25 (95% confidence interval = 0.09, 0.70). The handedness effect (higher TD rate in right handers) was stronger for subjects with fewer negative symptoms, and it was stronger for men than for women. Although the specific biological mechanisms are unclear, these findings may reflect cerebral lateraIity in the pathophysiology of psychiatric disorders, possibly in combination with asymmetrical action of neuroleptic exposure.

Key Words: Tardive dyskinesia, handedness, epidemiology, psychiatry, neuroleptics, outpatients BIOL PSYCHIATRY 1996;40:35--42

Introduction Tardive dyskinesia (TD) is an abnormal movement disorder that occurs frequently among psychiatric patients treated with neuroleptic (antipsychotic) medications (American Psychiatric Association 1992; Morgenstern et al 1987). There is a growing body of evidence, however, that the occurrence of TD is also influenced by biological and clinical characteristics of the patients, possibly including the underlying pathology that the neuroleptics are used

From the Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA (HM); Department of Psychiatry, Yale University School of Medicine, New Haven, CT (WMG); and Department of Community Medicine, Mount Sinai School of Medicine, New York, NY (JTD). Address reprint requests to Hal Morgenstern, Ph.D., Department of Epidemiology, UCLA School of Public Health, 10833 Le Conte Avenue, Los Angeles, CA 90095-1772. Received December 5, 1994; revised June 26, 1995.

© 1996 Society of Biological Psychiatry

to treat. Specifically, TD has been observed to be associated with type of psychiatric diagnosis, negative symptoms, cognitive dysfunction, organic brain disease, and structural brain pathology (American Psychiatric Association 1992; Hoffman and Casey 1991; Krishnan et al 1988; Waddington 1989). Although these findings are sometimes inconsistent, there is little doubt that TD risk is affected by factors other than drug treatment. One relatively stable patient characteristic that has been linked with TD is handedness. Nevertheless, findings from the five published studies reporting this association are conflicting: two report a greater prevalence of TD in left handers (Joseph 1990; McCreadie et al 1982); and three report a greater prevalence of TD in fight handers (Barr et al 1989; Brown et al 1992; Kern et al 1991) (see Table 1). These inconsistencies could be due to the small sample sizes in all five studies, various selection biases resulting 0006-3223/96/$15.00 SSDI 0006-3223(95)00357-M

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H. Morgenstern

Table 1. Estimated Odds Ratio (OR) and 95% Confidence Interval (CI) for the Effect of Handedness (Not Right vs. Right) on TD Prevalence: Results of Five Cross-sectional Studies, 1982-1992 u Reference M c C r e a d i e et al 1982

No. o f Subjects b 116 Patients (37 Inpatients)

Ban- et al 1989

43 Inpatients

J o s e p h 1990

48 Outpatients

OR

9 5 % CI (OR)

2.36"

(0.98, 5.59)

0.20 d

(0.03, 1.02) (4.51, 107) (O.O2, 0.7O) (0.00, O.59)

21.00

K e r n et al 1991

32 Inpatients

0.14

B r o w n et al 1992

48 Inpatients

0.00

p Value 0.056 0.053 <0.001 0.015 0.012

a All results in this table are based on reanalyses of published findings by the authors of this paper. The odds ratio is interpreted as an estimate of the rate ratio for file effect of handedness on TD occurrence (see also Methods section); all effect estimates are unadjusted for any covariates. Confidence limits and p values are based on mid-p exact methods (Miettinen 1985; Vollset et al 1991); each p value is based on a two-sided test. a In the McCreadie et al study, all 116 subjects had clinical diagnoses of schizophrenia; 85 (73%) of these met Feighner criteria for probable or definite schizophrenia. In the other four studies, all subjects carried DSM-III or DSM-III-R diagnoses of schizophrenia, except in the study by Joseph, in which 33 (69%) of the patients were schizophrenics. " For Feighner-positive schizophrenics (see footnote b), OR - 5.36; 95% C1 = (1.76, 17.0); p = 0.003. For Feighner-negative schizophrenics, OR = 0.48; 95% CI = (0.02, 5.29), p = 0.616. d This result is based on categorizing subjects as right handed if their "laterality quotient" was 60 or greater (see Fig. 1 in Ban" et al 1989).

from the cross-sectional designs, uncontrolled confounding, and "publication bias," the phenomenon by which positive results are more likely to be published than negative results (Begg and Berlin 1988). In this paper, we report new findings on the association between handedhess and TD incidence in a large cohort study.

Methods The Yale TD Study is a prospective cohort investigation of 362 psychiatric outpatients maintained with neuroleptics at the Connecticut Mental Health Center in New Haven (Morgenstern and Glazer 1993). At the start of this study, the Connecticut Mental Health Center served a population of about 450,000 people in the greater New Haven area and carried an average daily census of 1278 patients distributed among five treatment units. Subjects were examined every 6 months for TD symptoms and other information, starting in 1985. This paper is based on about 5 years of follow-up on subjects who were examined at least twice. To be eligible for participation in the study, a patient had to meet each of the following three criteria: actively enrolled as an outpatient at the Connecticut Mental Health Center any time between July 1, 1985, and June 30, 1987; currently maintained with neuroleptic medication as evidenced by the presence of at least a 3-month prescription in the pharmacy; and free of persistent TD at intake with

e t al

no history of persistent TD movements. Patients were excluded if they had been previously diagnosed with persistent TD at the Yale TD Clinic (Glazer and Moore 1981) or if they were found to have persistent TD at baseline, as defined below. The outcome variable was the new occurrence (incidence) of persistent TD. The detection of TD cases was based on two applications of the Abnormal Involuntary Movement Scale (AIMS) (Guy 1976) at the beginning and end of each visit. Two criteria were used to diagnose new persistent cases of TD at follow-up visits: a total AIMS score (sum of seven anatomical scores) of 3 or more on both applications at two successive visits; and at least one anatomical AIMS score of 2 or more (i.e., mild movements) on both applications at the same two visits. Patients meeting AIMS criteria at each visit were reexamined by an experienced psychiatrist (WMG) to confirm the diagnosis. Interrater agreement on total AIMS scores was excellent during the course of this study (Morgenstern and Glazer 1993). Neuroleptic exposure history was determined retrospectively at baseline by patient self-report and chart review, which included records sent from other facilities. Neuroleptic dosages were determined from medical records alone, since most outpatients at the Connecticut Mental Health Center are unable to recall dosages reliably. To combine dosage levels for different drugs, we used the conversion values of Baldessarini (1985) for chlorpromazine equivalents (CPZE). The interview Schedule for Affective Disorders and Schizophrenia--Lifetime Version (Spitzer and Endicott 1978) was given to all subjects at baseline. Using Research Diagnostic Criteria (RDC), we classified subjects into five mutually exclusive, primary diagnostic groups: schizophrenia, schizoaffective disorder, affective disorders, mixed diagnoses (combinations of the first three groups), and other diagnoses. To measure hand preference, we applied the 17-item laterality questionnaire developed and recommended by Raczkowski and Kalat (1974). Subjects were asked to indicate whether they perform each of 17 tasks with their right hand (scored 100), left hand (scored 0), or both hands (scored 50). A summary score was obtained for each subject by computing the mean score for all tasks. We then did an item analysis, including factor analyses, to assess the internal consistency (reliability) of the scale. On the basis of these results, four items were dropped from the summary score because they were not strongly related to the other items; two of these deleted items reflect foot preference. The final handedness score is the mean score for the remaining 13 items: draw, write, deal cards, use a bottle opener, throw a ball, use a hammer, use a toothbrush, use a screwdriver, use an eraser, use a tennis racket,

Handedness and Risk of TD

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1996;40:35-42

use scissors, hold a match, and stir a liquid. Information on these items was available for 346 subjects. The value of coefficient alpha for the 13-item score is 0.98, suggesting very high internal consistency in this population. For purposes of analysis, the handedness score was categorized into four groups: 100 (completely right handed~treated as the reference group); 86-99 (predominantly right handed); 1-85 (mixed handed); and 0 (completely left handed). The severity of negative psychiatric symptoms at baseline was measured with the Scale for the Assessment of Negative Symptoms (SANS), a 25-item instrument reflecting five dimensions: affective flattening or blunting, alogia, avolition/apathy, anhedonia/associality, and attentional impairment (Andreasen 1982, 1984). Each item, including a global item for each dimension, is rated by the examiner on a six-point scale (0-5). On the basis of our previous assessment of the SANS in this population (Schuldberg et al 1990), the variable used in this paper is the sum of four global scores for all dimensions except attentional impairment. This global summary score was found to have excellent interrater agreement, internal consistency, and temporal stability. It was dichotomized into high (->7) and low (<7) categories for purposes of analysis. All statistical analyses in this report involve a persontime or "survival" approach. The incidence rate of persistent TD in a given group is the number of new cases detected at follow-up visits divided by the number of person-years experienced by persons at risk in that group. To estimate the effect of handedness on TD incidence, the rate for each handedness group (score < 100) was compared with the rate for the reference group of pure right banders (score = 100); this comparison was expressed as a rate ratio. Multivariable analysis, treating covariates as potential confounders and effect modifiers, was done with proportional-hazards modeling (Kalbfleisch and Prentice 1980). In previous analyses of these data, we identified four "risk factors" for persistent TD: age at baseline, race, years of previous neuroleptic use at baseline, and average neuroleptic dose (in CPZE) during follow-up (Morgenstern and Glazer 1993). Therefore, to estimate the handedness effect, we controlled for these four factors as potential confounders. Interaction effects between handedness and other predictors (potential modifiers of the handedness effect) were assessed by including product terms of these variables in the model (i.e., handedness X potential modifier). Thus, the null hypothesis for testing each statistical interaction is that the effects of the two predictors are multiplicative. To assess a possible biological interaction (synergy) between predictors, we also determined whether the effects were more than additive (Rothman 1986).

Table 2. Distribution of the Total Sample (362 Subjects), by Category of Selected Variables at Baseline Variable

Category

No. of Subjects

Percentage of Total

Gender

Male Female <30 30 -39 40-49 50-59 ->60 White Nonwhite

l 71 191 76 95 97 50 44 272 90

47.2 52.8 21.0 26.2 26.8 13.8 12.2 75.1 24.9

Schizophrenic Schizoaffective Affective Mixed Other

151 61 56 35 59

41.7 16.9 15.5 9.7 16.3

65 93 87 66 51

18.0 25.7 24.0 18.2 14.1

53 79 125 63 42

14.6 21.8 34.5 17.4 11.6

Age (years)

Race Primary RDC diagnosis

Years of neuroleptic use

Neuroleptic dosage (mg/day CPZE)

<2 2-4 5-9 10-14 -->15 <100 100-199 200-499 500-999 ~1000

Results Frequency distributions of the total sample by selected baseline variables are shown in Table 2. The median age of subjects at baseline was 41 years (range, 19-73 years); 53% were female and 25% were nonwhite (23% AfricanAmerican). The median duration of previous neuroleptic exposure was 6.1 years (range, 0.25-33 years), and the median age at first exposure was 26 years. The median neuroleptic dose at baseline was 250 rag/day CPZE (range, 0-3200 rag/day CPZE). Nearly 60% of the sample carried primary RDC diagnoses of schizophrenia or schizoaffective disorder; 16% had affective diagnoses; the remainder had mixed or other diagnoses. The crude (unadjusted) association between handedness and TD is shown in Table 3. There is a pronounced, consistent gradient in TD rate by handedness score (p for linear trend = 0.002): the rate is highest (0.0687/year) in pure fight handers (score = 100) and lowest (0/year) in pure left handers (score = 0). A similar association with TD was observed for each item in the handedness scale. Since there were no cases among completely left-handed subjects, this group was combined with the mixed-handed group (score = 1-85) in the proportional-hazards analyses.

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Table 3. Estimated TD Incidence Rate (per 100/Year) and Crude Rate Ratio (RR) with 95% Confidence Interval (CI), by Handedness Score Handedness Score

No. of Subjects

No. of Cases

T D Rate (per 100/Year)

RR

95% CI (RR)

0 (Left)

20

0

0.00 ~

0.00

1-85

50

4

2.25

0.33

(0.12, 0.91)

53

9

4.97

0.72

(0.36, 1.47)

223 346

49 62

6.87 5.42

1.00 --

---

86-99 100 (Right)' Total

b

(~The two-sided p value for a test of linear trend between handedness category and TD rate is 0.002. b The asymptomatic confidence limits are undefined because there are no cases in this hmldedness category. c The reference category (completely right-handed subjects).

Table 4 presents the estimated handedness effect, adjusted for baseline age, race, years of previous neuroleptic use at baseline, and average dose during follow-up. Again, there is consistent monotonic association between handedness score and TD incidence (p for linear trend --0.009). The adjusted rate ratio, comparing left and mixed handers (score = 0 - 8 5 ) with pure right handers (score = 100) is 0.25 (95% confidence interval [CI] = 0.09, 0.70). The estimated TD rate for predominantly right banders (score = 86-99) falls between the rates for the other two handedness groups. To consider other potential confounders of the handedness effect, including gender, psychiatric diagnosis, use of other psychiatric medications, and type of neuroleptic, we added covariates for these factors to the model. In none of these analyses, however, did the estimated handedness effect change appreciably from the results presented in Table 4. Potential interaction effects between handedness and certain other predictors (potential modifiers) were assessed by adding product terms to the model used above. To enhance precision and facilitate interpretation of resuits, the potential modifier was recoded as a dichotomy along with handedness, i.e., nonright handers (score < 100) vs. pure right handers (score = 100). Treating handedness as a dichotomy yielded an adjusted rate ratio

The results for each potential modifier are shown in Table 5. Appreciable differences in the adjusted RR for the handedness effect were observed for contrasting categories of negative symptoms (SANS score) at baseline (t7 = 0.048), gender (p = 0.112), and years of previous neuroleptic use at baseline (p = 0.118). The estimated handedness effect (adjusted RR) was stronger for subjects with low SANS scores (RR = 0.20) than for subjects with high SANS scores (RR = 0.73), and it was stronger for men (RR = 0.27) than for women (RR = 0.74); similar differences were observed on the additive scale. Although the adjusted RR was also stronger for subjects with more than 5 years of previous neuroleptic exposure (RR = 0.21) than for subjects with less exposure (RR = 0.66), the estimated effects of handedness and years of exposure were additive (i.e., the adjusted rate difference for the handedness effect did not differ by amount of previous neuroleptic exposure). This finding is consistent with no synergy between these two predictors (i.e., biological independence of effects) (Rothman 1986). Little or no interaction was observed on the multiplicative or additive scales with age, race, primary RDC diagnosis, or average neuroleptic dose.

Table 4. Adjusted Rate Ratio (RR)" and 95% Confidence Interval (CI) for the Effect of Handedness on TD Incidence, by Handedness Score

Discussion

Handedness Score 0-85 86-99 100 (Right handed) b

Adjusted RR

95% CI (RR)

p Value

0.25 0.75 1.00

(0.09, 0.70) (0.36, 1.55) --

0.008 0.436 0.009 ~

Rate ratios are adjusted, using proportional hazards analysis, for age at baseline, race, years of previous neuroleptic use at baseline, and average neuroleptic dose (in CPZE) during follow-up. t, The reference category. "The two-sided p value for a test of linear trend between handedness category and TD rate, controlling for the covariates listed in footnote a. The p values in the first two rows correspond to tests that each adjusted rate ratio is 1.

(RR), ignoring interactions, of 0.46 (95% CI =- 0.25,

0.86).

The findings of this study strongly suggest that the risk of tardive dyskinesia is greater in right-handed than left- or mixed-handed outpatients maintained with neuroleptics for several years. Most (82%) of our subjects, however, had 2 or more years of previous neuroleptic use at baseline. Therefore, even though the effects of handedness and amount of neuroleptic exposure appeared to be biologically independent, we cannot readily generalize our result to patients recently exposed to neuroleptics. In another large prospective cohort study, for example, Kane

Handedness and Risk of TD

et al (1982; 1984) found that certain factors were differentially related to the occurrence of early-onset vs. lateonset TD. We are reasonably confident that the observed handedness effect was not due to sampling error (chance) or bias resulting from selection methods or loss to follow-up, misclassification of key variables, or confounding by other known or suspected risk factors for TD (see also Morgenstern and Glazer 1993). There was a consistent exposureresponse gradient between the handedness score and the rate of TD, and this relationship was observed for various coding treatments of the handedness score (including treating it as a continuous variable; results not shown). Furthermore, we observed a similar effect of handedness, using other diagnostic criteria for TD, including "probable TD" detected at one visit (see Morgenstern and Glazer 1993). Although we can conclude that handedness affected the risk of TD in our sample, we cannot be as confident about the interaction effects observed with other predictors. Given the relatively low power for testing interactions, these findings will need to be replicated in other studies. Nevertheless, we believe they are useful for understanding the handedness effect in chronic psychiatric patients. In planning the Yale TD Study, we originally hypothesized that left handers would have a higher TD rate than would right handers. This hypothesis was based on the finding of McCreadie et al (1982) cited in the Introduction (see Table 1) and on evidence linking left handedness with other possible positive risk factors for TD, including cerebral atrophy (Andreasen et al 1982), left-hemisphere damage (Harris and Carlson 1988; Satz 1972), and cognitive impairment (Faustman et al 1991; Taylor et al 1982). We now believe that our original hypothesis was wrong because it was too simplistic and was probably based on an inaccurate finding. At this time, however, we can only speculate about the biological mechanisms involved in the relationship between handedness and TD. There is considerable evidence for asymmetries of cerebral structure and function in schizophrenia from studies of neuroimaging, electroencephalographic (EEG) mapping, neuropsychological function, and rotational behavior (Bracha 1989; Early et al 1989a,b; Flor-Henry 1976; Guenther et al 1986; Gur 1978; Reynolds et al 1990; Shenton et al 1992; Wexler 1980). It appears, moreover, that this cerebral asymmetry is not due entirely to the effect of neuroleptic exposure (Buchsbaum et al 1992a; Saykin et al 1994). Although most of this evidence suggests that schizophrenia involves left-hemisphere dysfunction, some evidence suggests right-hemisphere dysfunction (e.g., Andreasen 1994; Bracha 1989). Both dopaminergic and GABAergic activity may be involved (Bracha 1989; Reynolds et al 1990), and these neurotrans-

BIOLPSYCHIATRY 1996;40:35-42

39

mitter systems are thought to be involved in the pathophysiology o f T D (Haag et al 1992; Jeste et al 1986; Smith 1988). There is also evidence that handedness is associated with anatomical and neuropsychological indicators of cerebral asymmetry (Andreasen 1982; Manoach 1994; Satz and Green in press). In addition, indicators of cerebral asymmetry are associated with the clinical symptoms of schizophrenia, both positive symptoms (Bracha et al 1993; Shenton et al 1992) and negative symptoms (Andreasen et al 1992; Mayer et al 1985; Wolkin et al 1992). Although the evidence cited above supports the biological plausibility of a handedness effect on TD risk, we cannot infer specifically whether right or left handers should be at higher risk. Previous evidence for explaining the direction of our observed association comes from the study of Ueyama et al (1993), who found that TD was associated with cognitive and neuroradiological abnormalities of the left hemisphere in 27 right-handed schizophrenics who had been treated with neuroleptics for many years. If TD results from left-hemisphere pathology, as these authors suggest, right-handed schizophrenics may be at higher risk because they are more likely to overactivate their left hemisphere than are left-handed schizophrenics. Possible mechanisms for this overactivation might be increased blood flow in the left basal ganglia (Waziri 1980) or neurochemical dysregulation. In addition, since right-handed schizophrenics might be more lateralized than nonright-handed schizophrenics (Andreasen 1982; Manoach 1994; Satz and Green in press), nonright-handed patients may better be able to compensate for asymmetrical neuronal damage by drawing the necessary function from the undamaged side. Thus, left and mixed handers would be at lower risk of TD. The hemispheric asymmetry of schizophrenia has often been differentiated from the hemispheric asymmetry of other psychiatric disorders. For example, although schizophrenia may involve dysfunction of the left hemisphere, depression may involve dysfunction of the right hemisphere (Flor-H.enry 1976; Wexler 1980). Thus, one might expect the effect of right handedness on TD to be greater in schizophrenics than in other diagnostic groups; but such a difference was not observed in this study (see Table 5). An explanation for this apparent inconsistency may be that the hemispheric differentiation between schizophrenia and depression (noted above) is an oversimplification, in part due to the clinical and etiologic heterogeneity of schizophrenia and other psychiatric disorders (Bruder 1995). In fact, there is neuropsychological and other evidence of left-hemisphere dysfunction in psychiatric disorders other than schizophrenia (Bruder 1995; Robinson and Downhill 1995; Silverstein and Meltzer 1983; Taylor and Abrams 1983). Furthermore, the relationships between handedness and hemispheric asymmetry cited above have been ob-

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Table 5. Adjusted TD Rate Ratio (RR)" for Non Right-handed Subjects (Handedness Score < 100) Compared with Righthanded Subjects (Handedness Score = 100), by Category of Selected Covariates Covariate

Category

Adjusted R R

p Value b

Gender

Male Female <40 -->40 White Nonwhite

0.27 0.74 0.42 0.49 0.47 0.44

0.112

Schizophrenic Other

0.57 0.37

0.495

<5 ->5

0.66 0.21

0.118

0.35 0.51 0.20 0.73 0.46 (95% CI = 0.25, 0.86)

0.606

Age Race

0.806 0.920

Primary RDC diagnosis Years of neuroleptic use Average neuroleptic dosage (mg/day CPZE) S A N S ~ score

Total

<300 -->300 Low High --

0.048

a Rate ratios are adjusted, using proportional hazards analysis, for age at baseline, race, years of previous neuroleptic use at baseline, and average neuroleptic dosage (in CPZE) during follow-up. The ratio of adjusted rate ratios for the two categories of each covariate reflects the estimated magnitude of interaction on the multiplicative scale between that covariate and handedness (see also Methods section). b Corresponds to a two-sided test of the null hypothesis that the two categoryspecific adjusted rate ratios are equal (i.e., there is no interaction between handedness and the covariate on the multiplieative scale; see footnote a). Each p value was derived from a separate proportional hazards model that included a product term for handedness and the specific covariate. c Scale for the Assessment of Negative Symptoms (Andreasen 1984). A high score is a global summary score (excluding the attention scale) of 7 or greater at baseline (see also Methods section).

served in nonpsychotic populations (Glick et al 1982; Kim et al 1993; Peters 1995). It is also important to recognize that all subjects in this study had been treated, at least somewhat successfully, with neuroleptics for several years, possibly suggesting some degree of left-hemisphere dysfunction, regardless of diagnosis. As an alternative, the handedness effect observed in our population may be due to an asymmetrical mechanism of action for neuroleptics (Buchsbaum et al 1992b). Our finding that the handedness effect is greater in men than in women (see Table 5) is consistent with welldocumented differences in cerebral asymmetry in normal adults. There is extensive neuropsychological evidence, for example, that the male brain is more asymmetrically organized than is the female brain for both verbal and nonverbal functions (Bradshaw and Nettleton 1983; Mc-

Glone 1980). In addition, Gur et al (1991) found magnetic resonance imaging (MRI) evidence for gender differences in age-related brain atrophy: older men showed greater atrophy in the left hemisphere, and older women showed a symmetrical pattern of atrophy. There is also evidence of gender differences in the hemispheric imbalance of dopaminergic activity. For example, Bracha et al (1987), using an electronic device to measure rotational movement, found that right-handed men rotated to the fight more than did subjects in other handedness-gender groups. Their interpretation of this result is that there is more dopaminergic activity in the left hemisphere of right-handed men. Our finding of an interaction effect between handedness and gender is consistent with their finding: The highest TD rate was also observed for right-handed men. Although TD prevalence has often been found to be higher in women than in men (American Psychiatric Association 1992), findings from our study (Morgenstern and Glazer 1993) and another incidence study by Kane et al (1982) suggest that TD risk is not greater in women than in men. Another interaction effect observed in this study was between handedness and the SANS score; the handedness effect on TD was stronger in subjects with low SANS scores (fewer negative symptoms) than in subjects with high SANS scores. This finding is consistent with the results of Mayer et al (1985), who found a positive association between neuropsychological evidence of righthemisphere impairment and flat affect (a prominent negative symptom) in 48 chronic schizophrenics. Schizophrenics with high SANS scores, therefore, might be expected to have dysfunction in both hemispheres, indicating less hemispheric asymmetry. Thus, we would might expect a weaker handedness effect in patients with high SANS scores, as observed in this study: The TD rate was lowest in left handers with low SANS scores. We conclude that handedness is a risk factor for tardive dyskinesia among psychiatric outpatients treated with neuroleptics for several years. Although the specific biological mechanisms are unclear, this handedness effect may reflect cerebral laterality in the pathophysiology of psychiatric disorders, possibly in combination with asymmetrical action of neuroleptic exposure. On the basis of our results, however, we cannot predict whether the handedness effect would be observed in nonpsychotic populations or in psychiatric patients not treated with neuroleptics.

This study w a s funded b y grant # M H 3 9 6 6 5 f r o m the National Institute o f Mental Health.

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