Tardive dyskinesia in schizophrenic patients: Correlation with negative symptoms

145

fsvchiarry Resrarc~h.28, I45- I5 I Elsevier

Tardive Dyskinesia in Schizophrenic With Negative Symptoms

Patients: Correlation

George Bartzokis, Mary Ann Hill, Lori Altshuler, Jeffrey L. Cummings, William Wirshing, and Philip R.A. May Received June 28, 1988; revised version received December 1989.

16. 1988; accepted February 23,

Abstract. The relationship between severity of tardive dyskinesia (TD) and the prominence of negative symptoms was assessed in 25 right-handed, medicated schizophrenic patients. TD was quantified using ultrasound detectors and frequency measurement techniques as well as with observer rating scales. Electromechanical studies revealed a systematic relationship between TD severity and negative symptoms; TD was more severe in patients with fewer negative symptoms. The correlation was small in magnitude. Key Words. Tardive dyskinesia, negative symptoms, electromechanical schizophrenia.

measures,

Schizophrenic syndromes can be characterized by a predominance of positive symptoms such as hallucinations and delusions or they may be dominated by negative clinical phenomena including blunted affect, apathy, anhedonia, social withdrawal, inattentiveness, and impoverished thought. Negative symptoms have been found by some investigators to correlate with larger cerebra1 ventricles, deficits on neuropsychological testing, a family history of schizophrenic spectrum disorders, poor response to treatment, and poor prognosis for recovery and rehabilitation (Andreasen et al., 1982; Dworkin and Lezenweger, 1984; Green and Walker, 1984; Lindenmayer et al., 1984; Andreasen, 1985; Keefe et al., 1987). Several studies have found that patients with tardive dyskinesia (TD) are more likely to exhibit negative symptoms than those without TD (McCreadie et al., 1982; Barnes and Braude, 1985; Guy et al., 1985; Waddington et al., 1985, 1987; Wegner et al., 1985a, 19856; Waddington and Youssef, 19863). Not all investigators have found consistent relationships between negative symptoms and TD (Myslobodsky et al., 1985) or with other aspects of the schizophrenic syndrome (Allen, 1984) and one investigative group originally identified a relationship between TD and negative symptoms but failed to confirm their findings in a later study (Jeste et al., 1984; Iager et al., 1986). At the time this work was done, George Bartzokis, M.D., Mary Ann Hill, Ph.D., Lori Altshuler, M.D., Jeffrey L. Cummings, M.D., William Wirshing, M.D., and Philip R.A. May, M.D. (deceased), were in the Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, and Psychiatry Service, West Los Angeles VA Medical Center (Brentwood Division). Dr. Cummings is also in the Department of Neurology, UCLA School of Medicine. (Reprint requests to Dr. J.L. Cummings, Neurobehavior Unit (691/BI 1 I), West Los Angeles VAMC (Brentwood Division), 11301 Wilshire Blvd., Los Angeles, CA 90073, USA.) 0165-1781/89/$03.50

Q 1989 Elsevier Scientific Publishers Ireland Ltd.

146 The current investigation further explores the relationship between TD and negative symptoms by determining correlations between TD severity and prominence of negative symptoms within a population of patients with clinically evident TD. Clinical ratings

and electromechanical

measures

were

used

to quantify

the TD.

Methods Twenty-five patients meeting D&U-III criteria (American Psychiatric Association, 1980) for schizophrenic disorder were included in the study. All subjects were male veterans with the clinical and treatment characteristics shown in Table 1. All were inpatients studied after stabilization of their treatment or outpatients on stable doses of medication. Negative symptoms were scored by psychiatrists using the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1981). Scores for each of the five subscales (affective flattening, alogia, avolition, anhedonia, and attentional impairment) plus a global SANS score were obtained.

Table 1. Population

demographic

data

Mean

SD

Median

Age

46.6

11.4

45.5

Age of onset

24.9

6.5

23

5-44

21.5

11.3

20

6-46

2000

3096

633

Length Daily

of

illness

neuroleptic

doset

Daily anticholinergic dose2

6.33

4.25

6

Range 29-66

22.7-12006 1-16

Note. Except for one patient who was receiving parafon forte, patients were receiving neuroleptics and anticholinergic medications only. 1. In chlorpromazine Nine patients were prolixin decanoate. treatment-resistant 2. In trihexyphenidyl tions

(CPZ) equivalents. Only 1 patient was off neuroleptics (4 months). receiving 1WCl CPZ equivalents/day, including all 6 patients on One patient was receiving 5000 CPZ equivalents/day as part of a therapeutic protocol. equivalents. Six patients were receiving no anticholinergic medica-

All patients met Schooler and Kane’s (1982) criteria for persistent TD, and the severity of TD was assessed clinically with the Abnormal Involuntary Movement Scale (AIMS) (Department of Health, Education, and Welfare, 1974). Each patient was videotaped while an AIMS examination was performed. The videotapes were reviewed by three physicians familiar with the evaluation of TD and each scored the patient’s movements as specified by the AIMS. If the raters did not agree in their scoring, the videotape was reexamined and the movements reviewed until a consensus was reached. TD was further quantitated using ultrasound techniques and frequency measures previously described (May et al., 1983). Right-sided and left-sided orofacial movements were counted with ultrasound detectors under standardized conditions for predetermined lengths of time (150 set). Resting movements of the right and left hand were recorded using a platform with a load cell under standard conditions and the millivolts of activity in each of eight octaves of frequency (0.25, 0.5, 1, 2, 4, 8, 16, and 32 Hz) were determined. BMDP Statistical Software (Dixon et al., 1985) was used to analyze the data. The distributions of the frequency measures were highly skewed, so values were log transformed to meet assumptions of the statistical analyses. Program 6D was used to plot and compute correlations between items of the SANS and the following TD measures: orofacial ultrasound, limb movements in the 2 and 4 Hz frequency bands, and components of the AIMS. Bonferroni corrections were applied to the significance levels to adjust for multiple testing.

147 Results AIMS Scores. The patients had moderate to severe TD. In decreasing order, the mean (* SD) AIMS scores for each body region were as follows: tongue (3.04 f 1.43), upper extremities (3.08 f 1. IO), lips (2.58 f 1.44), jaw (2.38 f 1.47), lower extremities (2.17 f 1.24), face (1.96 f 1.04), and trunk (1.83 f 1.17). SANS Scores. The patients had mild to moderate negative symptomatology. In decreasing order, the mean (* SD) SANS subtest scores were as follows: anhedonia (1.96 f 1.33), attention (1.67 f 1.37), avolition (1.67 f 1.40), affect (1.62 f 1.13), and alogia (1.50 f 1.17). The global SANS score was 8.42 (SD = 4.64). No significant correlations were found between the clinical ratings of TD severity and the SANS elements or the total SANS score. Frequency Measures of Hand Movement. Correlations between the SANS scores and the log of millivolts of activity in the upper limbs were consistently negative (i.e., patients with higher negative symptom scores exhibited less severe TD). As shown in Table 2, after Bonferroni adjustment for multiple testing, the negative relationships between activity in the ~-HZ frequency with affective blunting and with total SANS scores were significant. Similar negative trends were found between the specific frequencies of activity of interest (2 Hz, 4 Hz) and all the remaining SANS components, except anhedonia. These correlations, however, were not significant after Bonferroni adjustment. The negative trends are evident for measures of both the right and left sides of the body. To explore the possibility that these correlations were the product of confounding covariables such as the total neuroleptic dosage at time of testing or patient age, we performed a multiple regression analysis. After corrections were made for age and dose, the partial correlation between affective blunting and the right arm ~-HZ band is -0.4371, indicating that age and medication did not adequately account for the observed correlations. Ultrasound Measures of the Face. Facial movements counted by orofacial ultrasound devices also exhibited a negative correlation with negative symptoms (Table 3). Movements on the left and right sides of the face were negatively correlated with affective blunting (r = 4.496, p = 0.013 and r = -0.546, p = 0.005, respectively). The right-sided correlation remained significant after Bonferroni correction, After corrections were made for age and dose, the partial correlation between affective blunting and the ultrasound counts is -0.619, suggesting that the observed correlations could not be attributed to age and medication dosage. Discussion An important theme in TD research is the identification of populations of patients who are particularly vulnerable to the development of this movement disorder. Accepted risk factors for the development of TD include prolonged exposure to agents with dopamine-blocking properties and increasing age (Jeste and Wyatt, 1982; Kane and Smith, 1982). The presence of affective disorder as the underlying psychiatric

Table 2. Correlation between SANS scores and the log of millivolts of activity in 2- and ~-HZ frequencies SANS component

Limb

Frequency (Hz)

Total SANS score

R R L L

2 4 2 4

-0.392 -0.563 -0.334 -0.418

0.057 0.0041 0.112 0.041

Affective blunting

R R L L

2 4 2 4

-0.429 -0.548 -0.295 -0.287

0.036 0.0051 0.176 0.176

Alogia

-0.280 -0.444 -0.404 -0.402

0.187 0.029 0.049 0.051

Avolition

-0.227 -0.341 -0.305 -0.429

0.289 0.104 0.149 0.036

1

P

Anhedonia

R R L L

-0.223 -0.315 -0.114 -0.215

0.299 0.135 0.599 0.316

Attentional impairment

R R L L

-0.291 -0.427 -0.126 -0.194

0.170 0.037 0.563 0.368

Note. SANS = Scale for the Assessment of Negative Symptoms. R = right. L = left 1. Significant ip c 0.051

after Bonferroni adjustment for multiple testing.

Table 3. Correlation between SANS scores and the log of ultrasound measures of facial movement Ultrasound measures of the face Right r

Left D

r

D

Total SANS score

-0.361

0.083

-0.426

0.037

Affective blunting

-0.546

0.0051

-0.496

0.013

Alogia

-0.320

0.129

-0.329

0.117

Avolition

-0.187

0.386

-0.310

0.142

Anhedonia

-0.274

0.197

-0.358

0.087

Attentional imoairment

-0.047

0.829

-0.092

0.671

Note. SANS = Scale for the Assessment of Negative Symptoms. 1. Significant (p < 0.051 after Bonferroni adjustment for multiple testing

149 illness may further increase the vulnerability to TD (Mukherjee et al., 1982; Rush et al., 1982; Yassa et al., 1984). In addition to demographic factors, clinical markers of subpopulations of schizophrenic patients at increased risk for the development of TD are being sought. The presence of cognitive impairment and neurological soft signs may increase the likelihood of developing TD (Waddington et al., 1985, 1987; Wegner et al., 1985a, 19856; Thomas and McGuire, 1986; Waddington and Youssef, 1986a, 1986b; Wade et al., 1987), and several investigators have suggested that patients with prominent negative symptoms are more likely to manifest TD (McCreadie et al., 1982; Barnes and Braude, 1985; Guy et al., 1985; Wegner et al., 1985a, 1985b; Waddington et al., 1987). Unanimity concerning the last point, however, has not been reached (Bartels et al., 1985; Iager et al., 1986). In the current study, we determined the correlations between TD severity and prominence of negative symptoms within a group of schizophrenic patients with established TD. We hypothesized that if negative symptoms identify a subgroup of schizophrenic patients at increased risk for TD, then patients with more marked negative symptomatology might also have more severe dyskinetic movements. This hypothesis was not confirmed. In this sample, a small but significant negative correlation prevailed between negative symptoms and electromechanical measures of TD; patients exhibiting more marked TD had the lowest SANS scores. The direction of the correlation was consistent across several frequencies, for all elements of the SANS, and for both sides of the body. Furthermore, the correlations were identified by both facial ultrasound and limb frequency measurement techniques. The relationship could not be attributed to the confounding effects of age or medication. Several potential explanations exist for inconsistencies among studies. Differences might arise from studying heterogeneous schizophrenic subgroups. Recent genetic studies indicate that negative symptoms may be more characteristic of inherited schizophrenic disorders, and several investigators have found TD to be more prevalent among patients with nongenetic schizophrenia (Dworkin and Lczenweger, 1984; Bartels et al., 1985). Inadvertent inclusion of a greater number of patients with inherited schizophrenia would bias the results of TD prevalence determinations. Some studies have included schizophrenic patients in long-term institutions and with very severe negative symptoms, such as dementia and mutism (Waddington et al., 1987), and inclusion of such TD populations has been shown to inflate SANS ratings (Myslobosky et al., 1985; Spohn et al., 1985). The current study differs from previous investigations in several important ways, including differences in patient selection. Schizophrenic patients in Veteran Administration hospitals have a later onset of illness (after military enlistment), are generally higher functioning (the study included both inpatients and outpatients), and exhibit more moderate negative symptoms. None of the patients, for example, were mute. Relationships between TDand negative symptoms may exist only for the most severely intellectually impoverished patients. The relationship between negative symptoms and TD may be explained in several ways. Negative symptoms may identify a population vulnerable to TD, but they may not determine a spectrum of TD severity (i.e., negative symptoms may be a categorical marker and not a continuous variable). A similar circumstance exists in demographic studies of the production of TD by neuroleptics where exposure to these agents is

150

necessary for the occurrence of TD, but the total duration or amount of exposure is poorly correlated with TD severity. It may also be that the neurobiological mechanisms of TD and negative symptoms are relatively independent. If clinical ratings alone had been used in the present study, no relationship between negative symptoms and TD would have been identified. The negative correlations between SANS scores and TD were identified only by electromechanical measures, and although they reached statistical significance, they accounted for only a modest portion of the variance of the severity. This suggests that, at least in the moderate range of SANS scores, the interaction of TD and negative symptoms may not be clinically apparent and is of limited importance as a risk factor for TD. In the current study, the highest correlations between negative symptoms and movement abnormalities occurred in the ~-HZ frequency of motion. This finding has at least two potential explanations. First, although most TD occurs in the frequency below 2 Hz (Lees, 1985; Rondot and Bathien, 1986), the analogue method used in our laboratory will record at ~-HZ frequency all motion between 3 Hz and 6 Hz. Thus, the correlations may be with the higher frequency TD movements. Second, parkinsonian rest tremors have a frequency in the ~-HZ range, and the negative symptoms may correlate best with the parkinsonian component of patients who manifest both TD and drug-induced parkinsonism. Acknowledgments. This project was supported by the Veterans Administration. Preparation of this article was supported by NIMH grant MH-14584 and a National Alliance for Research on Schizophrenia and Depression (NARSAD) award.

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