Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings

B~

~YCHIATRY

587

Tardive Dyskinesia: Neuropsychological, Computerized Tomographic, and Psychiatric Symptom Findings James M. Gold, Michael F. Egan, Darrell G. Kirch, Terry E. Goldberg, David G. Daniel, Llewellyn B. Bigelow, and Richard Jed Wyatt

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, a ~ negative ~,mptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neurop~,chological testing, psychiatric sy,nptom ratings, and most h A cerebral computed tomog,aphy (CT) scans. Patients with TD significamly differed from controls on only I of 23 cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of "organicity.'" A b n o ~ l movements may result from specific dy.~unction within the more purely motor circuits of the basal ganglia without compromising other neural ~'s:ems involved in cognitive processing.

Introduction Tardive dyskinesia (TD) is a disorder of involuntary movements that affects about 15%20% o f schizophrenic patients exposed to long-term neuroleptic treatment (Kane and Smith 1982). Many researchers have attempted to identify clinical and neurobiologieal variables that are either associated with the disorder or that are risk factors for its development. Several lines of evidence suggest that patients with TD have a high prevalence of other signs of central nervous system dysfunction, including minor neurological signs exclusive of dyskinesia and ventficular enlargement as assessed by computed tomography (CT) (Owens et al 1985; Wegner et al 1985a). Cognitive dysfunction among TD patients has been reported on a variety of tasks, including measures of memory, verbal abstracting, reaction time, and visual tracking (Sorokin et al 1988; S ~ h n et al 1985; Struve and

From the Clinical and Research Services Branch (JFMG), the Neuropsychiatrt Branch (MFE, DGK, RSW), and the Clinical Brain Disorde~ Branch (IEG, DGD, LBB), National Institute of Mental Health. Address reprint requests to Dr. James M. Gold, NIMI-I Neuroscience Center at St. ~iz~beths, 2700 Martin Luther King Ave SE, Washington DC 20032. Received January 14, 1991; April 19, 1991. Published 1991 by Elsevier Science Publishing Company, lnc

LSSN/91/$0.00

588

BIOL PSYCHIATRY I ~ I ;30:587- 599

J.M. Gold et al

Wilner 1983; Wegner et al 1985a, 1985b). Several studies have also found that patients with TD have more negative symptoms, such as social withdrawal and anergia (Jeste et al 1984; Waddington and Youssef 1986). In essence, it has been argued that patients with TD represent a subgroup schizophrenia patients with more severe "organic" impairments. Several neuropsychological and neuroradiological investigations are at odds with such a direct association of TD and cognitive or structural central nervous system (CNS) abnormality among patients with schizophrenia (Hoffman et al 1987; Kolakowska et al 1986; Swayze et al 1988). One important issue that may partially underlie the contradictory findings is the age of the patient sample. Waddington (1987) noted that the cognitive and neuroradiological evidence for this "organic subtype'" has most often been found in relatively older populations, while the results among younger patients have been much less consistent. In this study we explored the hypothesis that patients who have TD represent an especially impaired subgroup of patients with schizophrenia by examining three different types of measures in a cohort of relatively young patients: neuropsychcdogical performance, clinical ratings of psychiatric symptoms, and lateral and third ventricular size determined by CT brain scan. The use of a comprehensive neuropsychological battery, including the major measures of the Halstead Reitan Battery (Reitan and Woifson 1985) as well as the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Wechsler 1981), is an important methodological advantage because most of the studies in this area have used limited testing instruments.

Method

Subject Selection A total of 250 charts of patients with a DSM-III diagnosis of schizophrenia who had voluntarily consented to participate in the program, of the NIMH Neuropsychiatric Research Hospital at Saint Elizabeths in Washington, DC, were initially reviewed by two investigators. The charts usually included records from prior hospitalizations and these were also examined. Of the 250 patients, 47 were residing in the program while the study was being conducted and they were examined directly. In order to establish a diagnosis of TD a clear description of persistent abnormal movements of the face, mouth, extremities or trunk had to be present in the chart. These descriptions needed to be sufficiently detailed, multiple, and spread over a sufficiently long period that the diagnosis could be considered as consistent with the criteria for persistent TD proposed by Schooler and Kane (1982) and Jeste and Wyatt (1982). Cases of abnormal movements limited to drug-free intervals (i.e., apparent withdrawal dyskinesias) were excluded from further consideration. An initial consensus diagnosis of TD was made in 32 patients--22 on the basis of chart information alone and 10 diagnosed on the basis of the chart and current AIMS (NIMH 1974) ratings. This initial consensus list was then submitted to a third rater who had personally observed nearly all members of the 250 patient sample. This rater (DK), who had previously studied other neurobiological factors associated with TD in this same population and was familiar with the assignment of prior diagnosis of TD in this cohort, also consulted the hospital charts and personal research notes available from the time of the patient's hospitalization. From the initial group of 32 TD patients, 3 were eliminated from the sample. In all cases

TD: Neuropsychological and CT Findings

B~L PS'eCHtA'tmY

589

the disagreement centered on the presence of stereotyped movements that resembled TD and had been previously iden6.fied as TD by some observers. In many cases abnormal movements were present lor years before entry into the N|MH; in fact, m ~ y of the TD patients sought admission to the program to participate in studies of experimental treatments for their motor abnormalities, Nearly alt of the TD patients (25 of 27) had abnormal movements of the; face and mouth. Abnormal movements were present at the time of the assessment in nearly all the TD cases; in a smMl number of cases the movements were noted several months later in the course of the hospita|ization. The control group was composed of schizophrenic patients from the same research program with availab!" neuropsychological data who had no evidence of abnormal movements as determ,,~ed from the prior r¢ view. Thus, patients rated as having ~ s sible TD on the basis of the chart review were eliminated from the ~ l of ~tential control subjects. Controls were selected blindly with respect to cognitive test scores, and were matched to the TD patients on gender, age, race, and educational background. Two TD patients who were significantly older than any available control were dropped from the study. Thus the final study sample was made up of 27 patients with TD and 27 without evidence of movement disorder. The possibility that some of the control patients had masked TD at the time of study could not be definitively riled out in all cases. Nevertheless, the historical information available for most patients was extensive and 16 of the control patients had an extended drug-free period during the course of their research hospitalization at NIMH, which in all likelihood wou|d have revealed any masked movements. This approach to the diagnosis of TD and control selection was deliberately conservative because it was based on historical data in the majol4ty of final study sample cases. Patients were included only when the determination of the presence or absence of TD was notably clear. Indeed, in nearly every case, a formal hospital diagnosis of TD had been made. and abnormal movements were recorded on the initial admitting note or physical e×amination. No attempt was made to rate the relative severity of the TD because of concern that it could not be done reliably from chart information.

Cognitive Measures Each patient in the study had been administered a battery of neuropsychoiogical tests as part of his or her initial clinical research evaluation. In all cases, the WAIS-R was administered. Most patients received a Halstead Reitan Battery, with the exception of the sensory perceptual and aphasia screening tests, following standard ad~nistration and scoring procedures. Some patients were missing data on one or more of these tests. The number of patients in each group on each measure c ~ be seen, along with overall group means, in Tables 2 and 3. Test sessions typically were extended over several different days to avoid patient fatigue.

Cerebral Computed Tomography Fifty-one patients (25 with TD and 26 controls) were scanned on a fourth-generation GE 9800 scanner at the National Institutes of Health in Bethesda, Maryland. All the scans were nonenhanced and consisted of 12 parallel planes I0 mm thick with a pixel size of 0.5 x 0.5 mm and matrix size of 512 x 512. No patient had unusual diag-

59O

BIOL PSYCHIATRY I~1 ;30:587-599

J.M. Gold et al

nostic abnormalities on the CT beyond those typically encountered in patients with schizophrenia. All scans were screened for evidence of asymmetric head placement in the CT scanner. The lateral ventricles and brain circumference were measured with a fixed arm planimeter at the level at which the bodies of the ventricles were most prominent and the ventricular-brain ratio (VBR) was calculated using ~ method of Synek and Reuben (1976). Reliability was established on a random set of 10 scans with a Pearson correlation of 0.92 between the VBR measurements of two raters. The third v e h i c l e maximum width measurements were made at the level of Monro's foramen or lower using a 7 x magnifier in 0. l-mm increments.

Behavioral Ratings Patients were evalaated with the Psychiatric Symptom Assessment Scale (PSAS) (Bigelow and Berthot 1989). This 23-item scale is a modification of the Brief Psychiatric Rating Scale (Overall and Gorham 1962). The items cover a broad range of symptoms, with explicit criteria for rating each item on a 0--6 scale of increasing severity. The ratings were performed daily by trained nursing staff. The ratings used in the study were made in the 7 days surrounding the start of neuropsychologicai testing.

Data Analysis The basic analysis of the neuropsychological, PSAS, and VBR data was done using ttests. The WAIS-R subtests were analyzed using a multivariate analysis of variance (MANOVA). The analysis of the Halstead Reitan was limited to t-tests because missing data resulted in a significant loss of sample size when a MANOVA was employed. Nonparametric Wilcoxon tests w e n also employed for each analysis and were consistent with the t-test results reported below.

Results

Patient Characteristics The final sample was composed of 27 TD patients and 27 controls, with 10 women and 17 men in each group. Each group was composed of 25 Caucasian and 2 black subjects. The subject selection procedure resulted in the two groups having very similar age and educational backgrounds (Table 1). The duration of illness (from first hospitalization) was slightly longer in the TD group, but this difference did not reach statistical significance (t = 0.28, p = 0.78). At the time of testing, two of the TD group and four of the control group were unmedicated. The average neuroleptic dose (converted to CPZ equivalents using Davis 1976) was not significantly different between the two groups: TD group = 940.21 mg, control group = 1!54.13 mg (t = - 1.01, p = 0.32). The effects of neuroleptic treatment on IQ, Halstead Reitan tasks, and other similar neuropsychological measures appear to be minimal in patients with chronic schizophrenia (Gold and Hurt 1990; Heaton and Crowley 1981; Medalia et al 1988; Spohn and Strauss (1989).

TD: Neumpsychological and CT Findings

BIOL ~YCHIATRY

~9|:

Table I. Demographic Information in Schizophrenic Patients with and without T~dive Dyskinesia With "I'D i 0 Female 17 Male

Age Education (yr) Duration o f illness (yr)

Wit,h,.mt T D [0 Femate ~7 Male

Me~

SD

Range

Mean

3D

~

30.44 12.63

5.68 1.84

(21-41 ~ (I0--l?)

30.19 12.63

5.41 !.57

(21~)~ ([~ [6)

9.41

4.38

(5-21)

9.00

6. [0

(I~-20~

Neuropsychologicai Results The composite IQ and scaled scores were similar between the two groups (Table 2). As a group, the TD patients scored slightly lower on most measures than controls. However, there was no significant difference between the groups on an o v e ~ l M ~ O V A on the I I WAIS-R subscales ( F [ l l , 41] = 0.53, p = 0.87). None of the individual subtest comparisons approached significance. Interestingly, there were more suggestive differences between the group means on the Verbal Scale than on the Performance ScMe. The Performance Scale subtests require motor speed and visual-motor coordination, abilities that might plausibly be affected by involuntary movements. The group means and probability values from t-tests on each m e ~ u ~ of the Halstead Reitan are listed in Table 3. In general the groups performed at remarkably similar levels. Of note, the groups performed at nearly identical levels on the Category Test, w ~ c h is considered a very sensitive indicator of the presence of any type of cogrfitive d y s ~ c t i o n

Table 2. IQ Results in Schizophrenic Patients with and without Tardive Dyskinesia (n = 27) With T D

Full-scale IQ Ve~-,d ' ~ Performance IQ Information Digit span Vocabulary Arithmetic Comprehensiona Similarities Picture completion Picture arrangement ~ Object assembly Block design Digit symbol ~TD n = 26.

W i ~ o u t "I'D

Me&l

SD

Mean

86.70 or, -,,~

! 1.31

90.22

l.~. l i

~,,~.u i

10.71

-

85.85 9.07 8.26 8.78

10.37 2.87 2.63 2.79 2.48 3.22 3.00 2.49 2.46 2.59 2.69 2.40

87.44 9.89 8.96 9.63 7.89 8.74 9.93 8.33 7.22 8.19 9.19 6.93

10.02 2.59 2.67 2.17 2.34 2.61 2.63 2.51 2.26 2.22 2.56 1.82

-

6.93 7.73 8.93 8.22

7.04 8.44 8.30 6.33

SD

t

p

9.82

- 1.22

0.23 O. 19 0.57 0.28 0.33 0.22 0.15 0.21 0.20 0.87 0.78 0.69 0.22 0.31

1.34

0.57 1.10 0.98 1.25 1.47 1.26 1.30 0.16 0.28 0.39 - 1.25 - 1.02

592

J.M. Gold et al

BIOL PSYCHIATRY 1991.30:587-599

Table 3. Neuropsychological Test Results in Schizophrenic Patients with and without Tardive Dyskinesia With TD

Category Test (errors) TPT" PH b time TPT" NPH' time TPT" Total time TPT" Memory TPT" Location Speech Sounds (errors) Rhythm (errors) Trails A time Trails B time Finger Tap PH b Finger Tap NPH'

Wilt

TD

n

Mean

SD

n

Mean

24 20 20 20 20 20 22 23 16 21 24 22

75.29 8.28 6.95 18.98 6.00 1.80 7.18 4.96 34.56 i!8.38 45.53 42.04

31.75 ! .93 2.40 7.16 1.33 1.54 5.34 3.97 14.09 58.48 6.59 5.48

24 23 23 23 23 23 26 26 25 27 27 27

74..29 7.73 6.86 18.48 6.35 2.9~ 7.65 • 5.~ 40.40 i 10.89 45.84 42.78

SD

t

p

34.86 1.91 2.44 4.67 1.87 2.01 3.76 4.04 15.14 44.94 7.73 6.53

0. I0 0.93 0.12 0.27 -0.69 - 2.09 -0.35 -0.47 - 1.24 0.50 --0.15 - 0.43

0.92 0.36 0.91 0.79 0.50 0.04 0.73 0.64 0.22 0.62 0.88 0.67

"Tactual PerformanceTest. ~Preferred hand. ' Nonpreferred hand.

(Reitan and Wolfson 1985). Both patient groups performed at nearly identical levels on Finger Tapping using both the preferred and nonpreferred hands. Thus there is no evidence that TD is associated with motor slowing in this sample. There was a significant difference between the groups on the Tactual Performance Test memory location score (t = - 2.091, p < 0.04). No between-group difference was found using impairment ratings summed across all Halstead Reitan measures.

CT Data The patients with TD had significantly smaller lateral ventricles than controls (t = - 2.32, p < 0.03). The VBR distributions can be seen in Figure 1. The TD group had a mean VBR of 5.31 (SD = 2.30) while the control group had a mean VBR of 6.97 (SD = 2.78). Measurements of the third ventricle did not differ (p = 0.46).

Clinical Symptom Ratings PSAS ratings were available on 25 TD and 24 control patients. The groups differed only on the: item for general abnormal movements, with the TD group being significantly higher, as expected (p < 0.003). No other differences approached significance, including ratings of "negative" symptoms such as affective blunting and social withdrawal.

Comment In this study of relatively young patients with tardive dyskinesia and closely matched controls, there were striking similarities between the groups on measures of cognitive functioning and clinical ratings of symptoms. This TD sample had significantly smaller ventricles than controls. The only compelling clinical-symptomatic difference between the groups occurred on the PSAS rating item for abnormal movements. This positive

TD: Neumpsychological and CT Findings

B~ ~vct~,e

593

12,

10

,aD o u, e-

m @

o o

o

ra

u

(N)

Q

@

o

o @

•

e,, Q

Figure I° Venmcul:arbrmn ratio in schizop~emc patients ~Ath and without t~dive dyskines}a.

@

With TO (N=25)

Without TO (N=27)

finding supports the validity of the retrospective diagnosis of abnormal movements that were present at the time of neuropsychological assessment. Our failure to identify betweengroup differences on a variety of measures calls into question a simple, strong association of tardive dyskinesia with global neuropsychologicai impairment, structural brain abnormalities, and negative symptoms.

Relationship to Prior Studies of Cognitive Impairment Several studies that have reported an association of TD and cognitive impairment have studied older populations and have used brief mental status examinations (Famuyima et al 1979; ltil et al 1981; Waddington et al 1987). Many of the patients in these studies appear to have been severely demented or mute. Thus it is clear that severe cognitive impairment may occur in some elderly TD patients. However, several reports of older patient samples have failed to document an association of TD and cognitive i m p a ~ e n t (Collerton et al 1985; Hoffman et al 1_987; Wolf et al 1983). The possibility, exists that some of the severely impaired TD patients included in these other studies may have had an illness other than, or in addition to, schizophrenia that was responsible for the severity of their dementia. This possibility is supported by one study of elderly patients that

5~

BIOL PSYCHIATRY I ~ ! ;3():587-.599

J.M. Gold et al

screened out severely demented patients and found only a minor cognitive difference between patients with and without TD (Myslobodsky et al 1985). In studies of cognitive performance in TD patients of age 30-55 years the results are mixed. Several studies using correlational or multiple regression analysis have reported a relationship between TD severity and cognitive impairment (DeWolfe et al 1988; Wade et al 1987, 1989). However, the results of investigations using between-group designs have been conflicting. Cognitive differences have been observed in several studies, and patients with TD never perform significantly better than their respective controls (Struve and Willner 1983; Wegner et al 1985a, 1985b). However, the findings are inconsistent across studies that have employed different measures of similar neuropsychological functions such as memory and abstracting ability (Kolakowska et al 1986; Manschreck et al 1990; Sorokin et al 1988). There is no evidence of a distinctive performance profile that can be linked to dysfunction of the basal ganglia. The current results are open to a variety of interpretations. In our view, the overall similarities between the groups on a variety of cognitive measures are the most striking feature of the data. However, the TD group tended to perform at slightly lower levels than controls on several measures (Tables 2 and 3). While these differences may merit further investigation, it is clear that young patients with TD do not demonstrate obvious deficits that are not also found in other chronically ill patients with schizophrenia without TD.

Relationship to Prior CT Studies Cerebral radiographic findings among patients with TD have been mixed to date. The bulk of evidence, across a wide age range, suggests that there are no consistent differences in cerebral ventricular size bctween patients with and without TD, althoush some positive findings have been reported (Branin et ai 1983; Famuyima et ai 1979; Hoffman et al 1987; Jeste et al 1980; Kolakowska et al 1986; Owens et al 1985; Sorokin et al 1988; Swayze et a! 1988). Most studies of younger schizophrenic patients with ~_ndwithout TD have not reported between-group differences in VBR. In light of this literature, we regard the present finding of significantly smaller lateral ventricles with a great degree of caution. !L-wever, it is clear that these data cast serious doubt on the hypothesis that TD is related to ventricular enlargement. Two prior studies measured the size of the third ventricle in CT scans and yielded inconsistent results (Aibus et ai i985; Barteis and Themeiis 1983); structural abnormality was associated with TD in the study using the older patient population.

Prior Clinical Symptom Studies An association of TD with "negative" symptoms of schizophrenia has been reported by several investigators, primarily, but not exclusively, in samples of elderly patients (Csernansky et al 1983; Jeste et al 1984; Manschreck et al 1990; Owens and Johnstone 1980; Waddington and Youssef 1986). In several reports these symptoms were very severe. Several recent studies have failed to find a relationship between TD and symptom severity or type in either elderly or young patients (Albus et al 1985; Hoffman et al 1987; lager et al 1986; Kolakowska et al 1986). The present study is generally consistent with the reports on younger populations in that no differences on measures of psychiatric signs and symptoms were found.

B ~ PsYCmA~Y

TD: Neumpsychological and CT Findings

595

TD and Cognitive Dysfunction in Other Basal Ganglia Disorders In order to gain further perspective on the cognitive imp~rment in TD, it is inswactive to compare TD with other movement disorders. P ~ i n ~ n ' s and Huntington's d ~ s e s , which also involve dysfunction of the b a ~ | ganglia~ have been examined with hhe Ha[~e~:q.t Reitan battery {Boll et al 1974; Norton |975; Reitan and Bo|~ | 9 7 | t . There appear to be large qualitative differences in the pattern of cognitive findings between TD and ~ s e other disorders. Parkinson's and Huntington's d i s e ~ patients de~nswat,e a deg~e of overall motor impairment that is far more ~vere t h ~ we found in TD patients. This degree of motor impairment was found in patients with a higher Verba} IQ t h ~ t~u:nd in our TD patients, suggesting a true differential impai~ent of motor funcuon. For example, the Parkinson's patients studied by Reitan and Boll (1971) had a Ve~aI IQ of 107 (20 poims higher than the TD ~oup), a Categou Test score of 77 (ne~ly identical to our current TD group), and yet had a Finger Tapping score of 3 0 . ~ with their prefe~ed hand. The current TD patients had a tapping ~core of 45.53 (50% better). In sb.ert. TD patients do not demonstrate the type of motor impai~ent seen in these other basal ganglia disorders. Further, both TD and nonTD patients w.th schizophrenia perform at similarly imgaired levels as patients with Parkinson's or Huntington's on nonmotor cognitive measures such as the Category Test. T h e ~ differences in cognitive profile imply that TD does not involve the same type of disruption of the basal ganglia ~ d its cortical connectivity that is found in these other disorders.. Recent neuroanatomic investigations provide for an increasir.gly differentiated model of the function of the basal ganglia. Alexander et M ( | 986, 1990) suggest ,hat there are at least five parallel, segregated anatomic circuits or loops involving the basal ganglia, thalamus, and frontal cortex, each of which has output connections to different frontal regions. They propose a relatively pure motor circuit that maintains somatotopic organizaton throughout the loop, terminating in the supplementary motor area. They suggest that this loop may be conceptualized as a series of subcircuits ded~,:ated to the movement of particular body parts. However, they also describe oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and anterior cingu|ate loops. This anatomic perspective would admit the possibility of relatively pure cases of motor abnormalities, potentially limited to particular body parts and lacking any higher cognitive component. Alternately, the disruption of the dorsolateral or orbitofrontal loops might be expected to have significant cognitive consequences, l h u s it is difficult to speak of the general ro~e ..... o~ me oa~m gmt~na in cognition without specifying which circuits are involved. It is likely that several of these loops are compromised by schizophrenia. Tentatively, we would suggest that the "'extra" pathology of TD found in young patients may be limited to specific aspects of the motor loop, specifically ~,ose circuits mediating hand and face movements (in most cases) since these are the most frequently observed symptoms. Alternately, the severe cognitive impairment observed in some younger patients and in older populations may be due to compromise ~f the more complex cognitive loops or other cortical abnorma'.:ties of independent origin. Unusually severe abnormalities of the more complex loops do not appear to be an obligatory feature of TD, and impairment of these loops is not limited to l:,ave~:ts with TD Thus, we suggest that the extra "organicity" in TD is quite specific and limited to aspects of the motor loop. This specific abnormality may occur in the context of a broader disruption to this system, imp!y~:g some heterogeneity among TD patients. It is clearly possible that this conclusion may only apply to schizophrenia, an illness that appears to involve abnormalities of the basal =

=

.

.

.

.

_~"

~L

t.

I

. . . .

1

-'~

5~

BIOL PSYCHIATRY ITS91;30:587-599

J.M. Gold et al

ganglia-cortical connectivity (at least in terms of dopamine dysregulation), and that in other diagnostic groups (such as mood disorder and mental retardation) there may exist different associations that do not involve this connectivity in the same fashion.

TD and Aging Cognitive, CT, and symptomatic differences between patients with and without TD, when present, are most likely to be observed in older patient samples. The contrast between the findings involving younger and older populations might be explained by methodological and sampling differences between studies. However, this contradictory literature raises the possibility that the neurobehavioral correlates of TD change with aging. There is simply vet3' little evidence that TD itself is a progressive disorder (Kane, personal communication), a possibility that could account for the age discrepancies. The most likely explanation of this pattern of findings is that there is an interaction between the neurological changes found in normal aging, or that result from other medical and neurological illness common in the elderly, and the underlying neuropathology of TD. If such an interaction is involved, there is no reason that significant, clinically detectable neurobehavioral differences are mandatory early in adulthood.

Limitations The present study has several important methodological limitations. The assessment of TD was done retrospectively and was limited to presence of the disorder, rather than quantification of severity. As several studies have found correlations between severity measures and other clinical, cognitive, or CT measures, such an assessment may be imdortant for a full understanding of the relationship of TD and other clinical variables. The validity of our conclusions clearly ~sts on our ability to accurately diagnose TD. We believe the fact that the original PSAS ratings of abnormal movements were significantly higher in our TD group support the validity of our retrospective diagnosis. More problematic is whether our controls were free of abnormal movements. Only 16 patients had drug-free periods, so that it is clearly possible that some cases of masked or mild TD were missed in the control sample. A related difficulty is present in any study of young patient populations, given that a certain portion of any young patient group will in fact later develop TD. That is, only in a very elderly sample (studied off medication) is it possible to assume that the underlying neurobiological substrate of TD is absent.

Conclusions It is clear that TD involves an alteration of brain function. However, this motor abnormality did not have a clear association with measures of brain structure, cognitive performance, or symptomatic presentation in this sample of relatively young patients with schizophrenia. Thus the "extra" abnormality of TD appears to be limited to the motor system in this sample, a limitation that is consistent with recent neuroanatomic investigations of the basal ganglia. These findings are generally consistent with the literature examining neurobehavioral measures in young TD patient groups, but are at odds with findings in older patients. This raises the possibility that TD may interact with the neurobehavioral changes found in normal aging.

TD: Neuropsychological an0 ~

Findings

The authors thank Rona|d Zec. Ph.D, for assistance w~Rhco]|¢ctmg ~ y c h ~ k ~ g ~ Wemberger. M D . for h~s comments on an earlier dr'M~of ~h~sm ~ L ~

~.

and D~aie[

References Albus M, Naber D, Muller-Spahn F, Douillet P, Reinenshofer T, Acken=hcil M ~|985~: T~dive dyskinesia: Relation to computer-tomographic, endocr/ne, and p s y c h ~ t h o l o g : ~ variab~s. Biol P~chiato" 20:1082-1089. Alexander GE, Cmtcher MD (1990): Functiona| architec~e of bas~ ganglia circuits: Neural substrates of parallel processing. Trends Neurosci 13:266-27 I, Alexander GE, DeLong MR, Stxick PL (1986~: ParaI[e| o~anization of fu~tion~[y ~ g a t e d circuits linking bas~! ganglia and cortex. Annu Re~' Ne,,osci 9:357-381. Banels M. "I~,emelis J (1983): Computerized Iomography in ~ i v e dy,skinesi:~. Arch Ps~ch~atr Nen~enkr 233:371-379. Bigelow LB. Berthol BD (1999~: The Psychia~c Symptom Assessment Scale ~PSASt. Psychopharmacol Bull 25: ! 69- ! 79. Boll TJ, Heavon R, Reitan RM ~i 974~: Neuropsychological and e~tiona[ correlates of Huntington's chorea. J Nerv Merit Dis 158:61-69. Branin M, Reisner T, Zeitlhofer J ( 1983): Tardive dyskinesia: Ctinica! correlation wi~: computed tomography in patients less than 60 years. J Neurol Neurosurg Psychiat~' 4 6 : 1 0 3 7 - 1 ~ , Collerton D, Fairbaim A, Britton P (1985~ Cognitive performance of ~dicated schizophrenics with tardive dyskinesia. Psvehoi Med 15:.~i !-315. Csemansky JG, Kaplan J, Holman CA. Hollister LE (1983): Serum ne~l:epfic activity, pl"olactin, and tardive dyskinesia in schizophrenic outpatients. P~'chopharm,acology 81:115- l 18. Davis I (1976): Comparative doses and costs of antipsychotic medication. Arch Gen P~'chiatG' 33:858-861. DeWolfe AS, Ryan II, Wolf MS (1988): Cognitive sequelae of ~ i v e dys~nesia. ,/Nerv Merit Dis 176:270-274. Famuyiwa OO. Eccleston D, Donaldson AA. Garside RF ( i979): Tardive dyskinesia and dementia. Br J Psychiatry ! 35:500-504. Gold JM, Hurt SW ( 1990): The effects of haloperidol on thought disorder and IQ in schizophrenia. J Pers Assess 54:390-400. Heato~ Y-,K, Crowley T.I (1981): Effects of psychiatric diso~ers and ~ e ~ somatic treatment on neuropsychological test results. In Ffiskov SB. Boll T.I (eds). Handbook of Clinical Neurop.~V~tr~OaOg~.. .

a'~v..wv

a v a n . . . v

sa~,~,

[~.p[,.~ - - w u ~

--,..~..,,

.

Hoffman WF, Labs SM, Casey DE (!987): Neuroteptic-induced Parki~sonism in older schizophrenics. Bioi Ps3'chiat~' 22:427-439. lager AC, Kirch DG, .|este DV, Wyatt R.I (1986): Defect ~vmptoms and abno~al inv',!unta,,',j move~nts in schizophrenia. Biol Psychtatry 21:75~-755. ltil TM, Reisberg B, Huque M. Mehta D (1981): Clinical profite~ of tardive dyskinesia. Compr Ps3.'chiatr~" 22:282-2~0. Jeste DV, Wyatt RJ ( 1982): Unc~.erstandin~ ~nd Treating Tardive Dyskinesta. New York: Guilford. Jeste DV, Wagner RL, Weinberger DR, Pdeth KG, Wyatt ILI (1980): Evaluation of CT scans in tardive dyskinesia. Am J Pc'chiatry ! 37:2~7-248. Jeste DV, Karson CN, lager :,-C, Bigelow LB, Wyatt RJ (1984): Association of abnormal involuntary movements and negative ~ymptoms. Psychopharmacol Bull 20:380-381. Kane JM, Smith JM (1982): Tardive dyskinesia. Arch Gen Psychiatry 39:473-481. Kolakowska T, Williams AO, Ardern M, Reveley MA (1986): Tardive d y s ~ e s i a in sch/zophremcs under 60 years of age. Bioi Psychiatry: 21:161-169.

598

BIOLPSYCHIATRY t~l ;30:587~5~

J.M. Gold et al

Manschreck TC, Keuthen NJ, Schneyer ML, Celada MT, Laughery J, C°~llins P {1990): Abnormal involuntary movements and chronic schizophrenic disorders. B:ol Psychiatr)., 27:150-158. Medulla A, Gold J, Merriam A (1988): The effects of neurolep~ics on neuropsychological test results of schizophrenics. Arch Clin Neuropsychoiogy 3:249-2~1, Myslobodsky MS, Tomer RA, Holden T, Kempler S, Sigal M (1985): Cognitive impairment in patients with tardive dyskinesia. J Nerv Ment Dis 173:!56-160, National Institute of Mental Health (1974): Abnormal lnvoluntal? Movements Scale CALMS){US Public Health Service Publication No MH-9-17). Washington:: US Government Printing Office. Norton JC ( 1975): Patterns of neuropsychological test performance in Huntington's Disease, J Nerv Ment Dis 161:276-279. Overall JE, Gorham DR ( 1962): The Brief Psychiatric Rating Scale. P~'chol Rep !0:799-812. Owens DGC, Johnstone EC (1980): The disabilities of chronic schizoph, enia--Oteir nature and the factors contributing to their development. Br J Psb.,chiatry 136:383-395, Owens DGC, Johnstone EC, Crow TJ, Frith CD, Jagoe JR, Kr,.et L (1985): Lateral ventricular size in schizophrenia: Relationship to the disease process and clinical mam[estatiot~s. P~,chol Med 15:27-41. Rcitan RM, Boll TJ (1971): Intellectual and cognitive functions in Parkinson's Disease. J Consult Clin Psvchol 37:364-369. Reitan RM, Wolfson D (1985): The Halstead-Reitan Neuropsychological Test Batter,,'. Tucson, AZ: Neuropsychology Press. Schooler NR, Kane JM (1982): Research diagnosis for tardive dyskinesia. Arch Gen Psychiatry 39:486-487. Sorokin JE, Giordani B, Mohs RC, et al (1988): Memory impairment in schizophrenic patients with tardive dyskinesia. Biol Psychiatr), 23:129-135. Spohn HE, Strauss ME ( 1989): Relation of neuroleptic and anticholinergic medication to cognitive function in schizophrenia. J Abnorm Psvchol 98:367-380. Spohn HE, Coyne L, Lacoursiere R, Mazur D, Hayes K (1985): Relation of neuroleptic dose and tardive dyskinesia to attention, information-processing, and psychophysiology in medicated schizophrenics. Arch Gen PsychiatD, 42:849-859. Struve FA, Willner AE (1983): Cognitive dysfunction and tardive dyskinesia. Br J Psychiatr), 143:597--600. Swayze VW, Yates WR, Andreasen NC, Alliger RJ( 1988): CT abnormalities in tardive dyskinesia. •

,s~.

zliTfiBV~

/~{",~

,~U,,J I--,~O,

Synek V, Reuben JR (1976): The ventricular-brain ratio using planimetric measurement of EM! scans. Br J Radiol 49:233-237. Waddington JL (1987): Tardive dyskinesia in schizophrenia and other disorders: Associations with aging, cognitive dysfunction and structural brain pathology in relation to neuroleptic exposure. Hum Psychopharmacol 2:i !-22. Waddington JL, Youssef HA (1986): An unusual cluster of tardiv, dyskinesia in schizophrenia: Association with cognitive dysfuncuon and negative symptoms. Am J P~ychiatr3., 143:1162! 165. Waddington JL, Youssef HA, Dolphin C, Kinsella A (1987): Cognitive dysfunction, negative symptoms, emd tardive dyskinesia in schizophrenia. Arch Gen Psychiatry 44:907-912. Wade JB, Taylor MA, Kasprisin A, Rosenberg S, Fiducia D (1987): Tardive dyskinesia and cognitive impairment. Biol Psychiatr)' 22:393-395. Wade JB, Lehmann L, Hart R, Linden D, Novak T, Harrier R ( 1989): Cognitive changes associated with tardive dyskinesia. Neurops3,chiatr), Neurops3,chol Behav Neurol 1:217-227. Wechsler D (1981): WAIS-R Manual. New York: Psychological Corporation.

TD: Neuropsychological and CT Findings

B~

PSYCfflATR¥

99 ~='~:~'.5~599

599

Wegner JT, Catalano F, Gibralter J, Kane JM (1985a): Schizophrenics with ~ v e dyskinesia. Arch Gen Ps)'chioto" 42:860-865. Wegner JT,, Kane JM, Weinhold P, Woerner M, Kinon B, Lieberman $ ~1985b~: Cognitive impairment in tardive dyskinesia. P~'chiatr3 ~Res |6:331-337. Wolf ME, Ryan JoL Mosnaim AD ( 1983~: Cognitive functions in talxtive dyskinesm. Psychot Med ! 3:671-674.