Lateralized cerebral dysfunction in schizophrenia and depression: Gender and medication effects

Archrves ofClmca/ Neuropsycholog~, Vol 4, pp 33-44, 1989 Prank-d I” the USA All nghts reserved

Lateralized

CopyrIght :; 1989 Natvxal

Cerebral

Schizophrenia

0887-6177189 $3 Oil + 00 Academy of Neuropsychologlstr

Dysfunction

in

and Depression:

Gender and Medication

Effects

Mark F. Frazier Illmo~sState Marshall

Psychmtrrc

Institute

1. Silverstein

IllinoisState Psychratr~c Instjtute

and Northwestern

Unlvers/ty

Louis Fogg Rush-Presbyterian-St.

Luke’s Medml

Center

The neuropsychologicalfunctioning of 52 schrzophrenic and 39 major depressive patients was examined using the four Luria-Nebraska Neuropsychological Battery lateralizatron scales, with the effects of gender und medicatron status examrned alone and in interaction wrth diagnosis and laterality variables. Comparisons between the diagnostic groups revealed that gender rnfluences some aspects of neuropsychologleal performance, particularly those rnvolving bilateral complex cognrtive-perceptual rather than sensorlmotor skills. This effect was more dtstinct for depressives than schizophrenics when cerebral lateralrzation drfferences were present. There was no significant left hemisphere disadvantage for schrzophrenics which was gender-related. Medrcation status revealed no appreciable effects for depressrves, although both male and female schizophrenics receivrng neuroleptrcs showed a greater degree of complex perceptual-cognitrve d_vsfunction compared to unmedicated schizophrenics. Level of cerebral Impairment was equivalent for the right and left hemrspheres for both groups. Consequently, these data are not consistent wrth other findings demonstratrng differential hemispherrc disadvantages between schizophrenia and depression.

This research was supported by grant numbers 38288 and 30938 from the National Institute of Mental Health. Requests for reprints should be sent to Marshall L. Silverstein, Illinois State Psychiatric Institute, 1601 West Taylor Street, Chicago, IL 60612.

33

34

M. E Frazier, M. L. Silverstein, and L. Fogg

It has been noted regularly that more males than females are diagnosed as schizophrenic, and there is also a higher incidence of major depression among females (Flor-Henry, 1974). Flor-Henry (1976) has commented on a strong gender interaction with neuropsychological patterns of cerebral laterality in psychiatric populations. He has reported that left hemisphere dysfunction associated with schizophrenia was more prominent for males, whereas right hemisphere dysfunction associated with endogenous depression was more frequently presented by females. Dominant hemisphere disturbances in auditory processing have also been reported by Cur (1979) for schizophrenics, and Bruder and Yozawitz (1979) observed nondominant hemisphere disturbance among affective disorders. Further, increased sinistrality among schizophrenics has been interpreted as additional support for the dominant hemisphere hypothesis (Boklage, 1977; Gur, 1977). However, Lishman, Toone, Colbourn, McNeekan, and Mance (1978) and Wexler and Heninger (1979) reported evidence inconsistent with these findings, in which these authors noted no hemispheric asymmetry differences on auditory processing tasks between schizophrenics and depressives. The effect was attributable to an absence of a right hemisphere deficit in affective disorders. Geschwind and Behan (1982) proposed a gender-related biological association between cerebral dominance and asymmetries of cerebral function. They hypothesized an anatomical cerebral maldevelopment represented by differential cortical maturation in males influenced by testosterone. According to their view, development in the left hemisphere is delayed in utero by the presence of testosterone and occurs more frequently in males because the fetal testes secrete testosterone. This hormone has a suppressing effect on neuronal migration from core to cortex, thus interfering with left hemisphere development. The present report examines gender differences in lateralized cerebral dysfunction on the Luria-Nebraska Neuropsychological Battery in schizophrenia and depression. It is hypothesized that gender significantly influences the lateralization of cerebral disturbances associated with schizophrenic and major depressive disorders. Thus, it is anticipated that male schizophrenics will display greater neuropsychological disturbance than females on left hemisphere measures, while female major depression patients would be expected to display greater neuropsychological disturbance than males on right hemisphere lateralization measures. These cerebral laterality patterns are examined further as a function of medication status, in an effort to study the interactive effects of gender and medication status in psychopathology. The effects of medication on neuropsychological test performance have received little systematic research attention. Gruzelier and Hammond (1979) reported that administration of chlorpromazine normalized psychophysiological performance in schizo-

Lateraked

Dysfunction

3s

phrenics, however Cur (1979) and Bruder and Yozawitz (1979) reported no medication effect on auditory tasks for either schizoaffective or affective disorder patients. After reviewing twelve studies, Heaton and Crowley (1981) concluded that medication resulted in only minimal performance improvements. Thus, the present report also investigates the effects of neuroleptic medications in schizophrenics and tricyclic antidepressants in depressive disorders on the cerebral lateralization scores of the Luria-Nebraska, as well as the gender-related interactions between laterality and medication status. METHODS Subjects

The sample consisted of 52 schizophrenic and 39 major depressive hospitalized inpatients who were free of serious medical illness, neurological illness, alcohol and drug abuse. All patients were between the ages of 18 and 65, and patients who had been administered ECT during the past 24 months were not included in the study. There was no difference in chronicity (number of previous hospitalizations) between schizophrenics (M=2.78, SD=2.82) and depressives (M=2.71, SD= 1.96). Diagnoses were made according to the Research Diagnostic Criteria (RDC) of Spitzer, Endicott, and Robins (1978), using data derived from structured interviews designed to assess characteristics of previous episodes of psychopathology, together with the Present State Examination (PSE) of Wing, Cooper, and Sartorius (1974) administered at admission. Further, the Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-C) (Spitzer & Endicott, 1978) was administered weekly to obtain additional data on characteristics of the current episode of illness. Diagnoses were determined at discharge, by the research and clinical staff, based on a complete review of all of the above data. Demographic comparisons between the schizophrenia and major depression groups are presented in Table 1. The schizophrenics were younger than the depressives (t(89)=4.55, p< .OOl), however, there were no group differences for level of education, duration of hospitalization, handedness, and sex distribution. Patients with unipolar depressive disorders are typically older than schizophrenics, and the depressives’ mean age of 32 years (nine years greater than that of the schizophrenics) is consistent with that which is commonly found among inpatient psychiatric samples. Periodic assessments of the PSE syndrome measures yielded acceptable levels of inter-rater reliability over time, with most major values exceeding .70. Initial reliability studies of PSE syndromes were based on 25 patients (13 of which were videotaped recordings of interviews), from which seven raters

36

M. E Frazier, M. L. Silverstein, and L. Fogg TABLE 1 Subject Characteristics Schizophrenia (n=52)

Age (in years) Education (in years) Seu (male) Handedness (dextral) Length of current hospitalization

(in days)

Major Depression (n=39)

M

SD

M

23.07 11.85 32 42 106.19

7.29 1.21 (61.4%) (80.8%) 67.20

32.05 12.58 19 34 103.28

SD

12.60 1.20 (48.71%) (87.0%) 42.71

assigned scores to 20 symptoms. Intraclass correlations coefficients havioral ratings were .72 for videotaped and .66 for live interviews. er, the kappa coefficients exceeded .90 for syndrome classifications.

Gender and Medication

for beHowev-

Distributions

There were 30 schizophrenics (61.5%) and 19 depressives (48.7%) who were male, x1(1)=0.72, n.s. There were 31 schizophrenics (59.6%) receiving neuroleptic medication, and 23 depressives (59.0%) on tricyclic antidepressants. For schizophrenics, the dosage level of neuroleptics at time of testing was converted to standardized units of chlorpromazine (Davis, 1976). Mean dosage for schizophrenics was 692.3 mg/day. Dosage level for each patient in the medicated major depression subgroup was compared with the average dose mg/day findings of Gerson (1983) and then cross-referenced with the Daily Dosage Range Table of DiMascio & Shader (1970). Dosage levels in mg/day for these depressives were within normal limits.

Procedures All subjects received the Luria-Nebraska Neuropsychological Battery (LNNB) which was administered in the standard manner (Golden, Purisch, & Hammeke, 1985). Test administration typically occurred between the 21st and 28th days of hospitalization, thus allowing the patients’ psychiatric condition to stabilize at a level permitting satisfactory cooperation with test instructions and requirements. The LNNB is a neuropsychological test battery derived from the concepts and methods for examination of the functional organization of the cerebral cortex, as proposed by the Soviet neuropsychologist, A. R. Luria (1973). This instrument consists of 269 items which comprise eleven major clinical scales and four lateralization scales for the assessment of left and right hemisphere dysfunction. The raw scores on each of the lateralization scales

Lateraked

Dysfunction

37

were converted to T-scores, with a mean of 50 and a standard deviation of 10. Higher scores are indicative of greater levels of impairment. The present study examined performance on the four LNNB lateralization scales: left hemisphere sensorimotor (LH), right hemisphere sensorimotor (RH), left hemisphere empirical scale (L*), and the right hemisphere empirical scale (R*). The LH and RH scales reflect motor and tactile-kinesthetic functions primarily, while the L* and R* scales represent cognitive and perceptual skills related to the higher cortical processes of the secondary and tertiary association areas of the left and right cerebral hemispheres.

RESULTS Neuropsychological performance of the schizophrenic (Sz) and major depression (MD) subjects was evaluated by a multivariate repeated measures analysis of variance (MANOVA) design with groups, gender, and medication status as between subjects factors, and the four LNNB lateralization measures (LH, RH, L*, R*) were treated as repeated measures within subjects. This procedure permits examination of interaction effects of hemisphere (left, right) and type of scale (sensorimotor, empirical) with each other as well as with diagnosis, gender, and medication status. The mean Tscore values for the diagnostic groups by gender are presented in Table 2, and mean T-scores for groups by medication status are reported in Table 3. There were no statistically significant between factors main effects, and the only significant between-subjects interaction was for groups x gender (F(1, 83)=5.22, p< .03). By treating this 2 x 2 interaction as a four-level TABLE 2 T-Scores on the Luria-Nebraska Lateralization

Group Schizophrenia Male (n=32) M SD Female (n =20) M SD Major Depression Male (n = 19) M SD Female (n = 20) M SD

Left Hemisphere

Right Hemisphere

Scales

Left Hemisphere (empirical)

Right Hemisphere (empirical)

45.59 10.46

47.62 11.69

54.16 14.35

50.47 12.87

44.45 10.69

43.80 8.71

48.25 12.14

47.60 10.17

42.31 8.89

44.74 11.42

44.10 7.38

43.31 9.57

50.15 11.79

51.60 14.42

52.95 13.04

53.35 12.39

38

M. E Frazier, M. L. Silver-stein, and L. Fogg TABLE 3 T-Scores on the Luria-Nebraska Lateralization Scales: Diagnostic Groups and Medication Status

Group Schizophrenia Medicated (n = 3 1) M SD Non-medicated (n=21) M SD Major Depression Medicated (n=23) A4 SD Non-medicated (n = 16) M SD

Left Hemisphere

Right Hemisphere

Left Hemisphere (empirical)

Right Hemisphere (empirical)

44.64 9.06

45.87 11.79

53.71 12.33

51.68 11.79

45.90 12.44

45.57 9.21

49.09 15.45

45.95 11.44

46.04 11.84

47.87 14.89

47.04 10.67

48.70 14.23

46.81 10.22

48.81 11.12

50.94 12.45

48.19 8.49

one-way analysis, post hoc Tukey comparisons were performed on each of the four lateralization scales. The results of the contrasts indicated that significant differences could be attributed to higher scores for the female MDs on the R* scale. In addition, a strong but marginal trend in the same direction was found for the L* scale. A second marginal trend was found for the female MDs to obtain more elevated scores than male MDs on the LH and RH scales. Finally, the male Sz had higher L* scores relative to male MDs, but there were no other indications of a male MD superiority compared to male Sz, nor did significant differences occur on any lateralization measures between male and female Sz. These data are shown in Table 2. There was a main effect of type of measure (F(1, 83)=8.98, p< .004) indicating the empirical scales to be more elevated than the sensorimotor scales. This is confounded by a significant interaction of groups x medication status x measure (F(1, 83)=4.78, p< .03). From Table 3, it is clear that this interaction can be attributed to higher scores for the Sz receiving medications. Medicated Sz exhibited higher T-scores (53.77 and 51.68) on the two empirical scales, L* and R*, respectively. The other significant interactions were for hemisphere x type of measure (F(1, 83)= 10.27, p-c .002) and gender x hemisphere x type of measure (F(l) 83)=5.43, p< .02). The hemisphere x type of measure interaction indicates that the L* scale is elevated relative to the other lateralization scales. This effect is confounded by the three-way interaction which indicates that the L* scale is higher than the LH scale, and that this effect is more characteristic of male patients.

Luteralized Dysfunction

39

To control for the potential effects of handedness on gender- and medication-influenced lateralization scale scores, the MANOVA was also performed using the dextral subjects in each group only (Sz: n=42, MD: n=34). Essentially identical results were obtained, especially for the major effects noted above: groupsxgender (F(1, 68)=4.12, p< .05), hemispherex type of measure (F(l) 68) =6.02, p < .02), and gender x hemisphere x type of measure (F( 1, 68) = 5.02, p < .03). The previously significant group x medication status x type of measure interaction emerged as a trend when sinistrals were excluded from the analysis (F(1, 68)=3.05, p< .08), but this may be attributable to the corresponding loss in power rather than a dextral bias. In addition, two trends in the total sample MANOVA reached statistical significance in the MANOVA on dextrals: hemisphere x gender X medication status (F(l) 68)=4.51, p< .04) and type of measure xmedication status (F(1, 68)=4.29, p< .04). In the latter case, the means continue to indicate that it is the Sz on medications who show the elevated L* and R* scores, but the absence of the significant groups x type of measurexmedication effect in the present analysis suggests the possibility that the effect of medication status is partially attributable to proportionately more sinistrals receiving antipsychotic medications relative to dextrals. The second new interaction, hemisphere x gender x medication status, was examined further by post hoc Tukey tests, which indicated that the effect was due primarily to greater left hemisphere elevations among unmedicated females in comparison to unmedicated males. Apparently, this effect was attenuated by the inclusion of sinistrals in the main MANOVA run on the total sample. Considering the entire set of significant MANOVA results, female MDs are more elevated on the L* and R* scales relative to male MDs, and Sz on neuroleptics are more elevated on the L* scale relative to Sz not on neuroleptics. Further, medication status seems not to affect performance of MDs, regardless of gender, and for both cerebral hemispheres and both types of measures. Finally, the L* scale is more affected than either the LH or RH scales for both diagnostic groups regardless of medication status, and more distinctively for males.

DISCUSSION Using the LNNB, the findings reported above indicate that gender differences either influence or are associated with some forms of lateralized neuropsychological performance, specifically complex cognitive-perceptual skills rather than sensorimotor abilities. It appears, however, that sex differences alone do not account for lateralized differences, and further, differences between right and left hemisphere measures do not reflect diagnostic group differences in a uniform manner. Flor-Henry (1976) has reported

40

M. E Frazier, M. L. Silverstein, and L. Fogg

differences between schizophrenics and affective psychoses in prominence of lateralized dysfunction on neuropsychological tests, however Taylor and Abrams (1983) could not confirm these findings. Although the sex distribution of males and females in these two studies is unknown, the data reported above indicate that it is the interaction of gender with diagnosis which may account for the sex difference in schizophrenic and affective disorders. These findings imply that when cerebral lateralization differences occur in different psychopathological disorders, they are more characteristically gender-related for depressives but not for schizophrenics. Thus, there was no significant left hemisphere disadvantage for schizophrenics which was distinctly gender-related. It is also noteworthy that this gender-related deficit is not confined solely to a disturbance of the right hemisphere, since evidence for bilateral involvement is also present. It is not clear, however, whether this finding is more unique to the LNNB in comparison with other neuropsychological approaches which are not as influenced by verbal skills as the LNNB. The influence of type or complexity of Iateralization measure is also apparently important in understanding the performance of the schizophrenics, despite the fact that gender-related differences in lateralization are not apparently present among the schizophrenics. Here, medication status affects schizophrenics’ performance, whereas for depressives, medication status appears to have a relatively minor role. The data indicate that the relatively more complex L* and R* scales are both elevated among the schizophrenics relative to the LH and RH scales, however this effect is largely attributable to those schizophrenics receiving antipsychotic medications. Although at first glance, this finding might seem contrary to expectation, it becomes more understandable when considered from the standpoint that worse performance in the medicated schizophrenic subgroup might not reflect the expected normalization of performance, but rather the fact that these schizophrenics are a more severely disturbed group of patients for whom normalization of performance is limited or constrained by the level of severity of overall psychiatric disturbance. Heaton and Crowley’s (1981) review of 12 studies concluded that continued administration of neuroleptic drugs to schizophrenic patients results in few significant changes in test performance. In contrast, schizophrenics who are not administered psychotropic medications are usually less severely ill and consequently less in need of such treatment. Further, this interpretation would be equally applicable to male and female schizophrenics. The elevated L*/R* scores in the context of more normal LH/RH scores also suggest that the effect of medication status on neuropsychological performance may be more selective rather than global in extent. The present findings are consistent with the literature which concludes that evidence exists for primarily bilateral rather than unilateral dysfunction

Literalized Dysfunction

41

in schizophrenia and depression. The hemisphere interactions with gender indicate that gender is associated with a greater degree of bilateral dysfunction in depression, particularly for complex cognitive-perceptual skills rather than simple sensorimotor abilities, such that it is the female depressives who display greater levels of dysfunction relative to male depressives. For schizophrenics, on the other hand, complex cognitive-perceptual functions are also disturbed bilaterally, relative to sensorimotor skills, but there is no apparent gender-related disadvantage. This view does not totally contradict Flor-Henry’s (1976) findings, since although his data noted predominant left or right hemisphere dysfunction in schizophrenia and depression, respectively, the data also noted bilateral disturbances. Further, Seidman’s (1983) review of cerebral lateralization studies concludes that the weight of the evidence is more supportive of bilateral rather than unilateral brain dysfunction in psychiatric disorders. Another consideration relevant to the presence of right and left hemisphere dysfunction among depressives has to do with the question of the etiology of cerebral disturbance in psychiatric conditions. Recent findings have indicated neurointegrative abnormalities reflected by increased impaired smooth pursuit eye movements among first degree relatives of schizophrenic probands as well as greater than chance concordance rates among monozygotic twins of schizophrenics (Holzman & Levy, 1977) and ventricular enlargement in 20-35 % of first episode schizophrenics (Weinberger, DeLisi, Perman, Targum & Wyatt, 1982). These findings suggest the possibility that brain dysfunction, at least in schizophrenia, may occur early in development and in some instances may also have a genetic basis. This consideration is not limited to schizophrenia, since there is also evidence for impaired eye tracking, enlarged ventricles, encephalographic anomalies, as well as other neurobiological disturbances in nonschizophrenic psychiatric disorders. If it is presumed that at least a significant proportion of schizophrenics and depressives acquire brain dysfunction very early in life, or show prominent genetic predispositions to develop brain dysfunction, then the role of plasticity of brain function leading to mixed patterns of cerebral dominance also becomes important to consider. Cerebral reorganization of cognitiveperceptual functions may lead to both partial preservation of the typical hemisphere-dependent processes and incomplete or compromised compensatory processes in that cerebral hemisphere which is not typically involved in a given skill acquisition. This could produce, therefore, an apparent bilateral behavioral deficit even though the underlying mechanisms for cognitive-perceptual processes remain at least relatively lateralized. Still other considerations relevant to the present findings concern questions about the sensitivity of the LNNB, particularly since the severity of both right and left hemisphere deficits is quite modest on the LNNB in this sample. Previously, Moses and Golden (1980) reported lower T-scores in

42

M. E Frazier, M. L. Silverstein,

and L. Fogg

non-brain-damaged schizophrenics on the LH and RH scales compared to neurological patients, and their schizophrenics’ T-scores were more than 12 points greater than those in the present study. Puente, Heidelberg-Sanders, and Lund (1982) compared brain-damaged and non-brain-damaged schizophrenics on LNNB variables, and their LH and RH T-scores were similar to those reported here, but only for their non-brain-damaged schizophrenics. In contrast, the brain-injured schizophrenics obtained LH and RH scores which were higher, and almost as elevated as the comparable non-braindamaged schizophrenics’ scores in the Moses and Golden (1980) study. It appears, therefore, that the LH and RH scores of the schizophrenics studied in the present sample are lower than those of several other investigations reported in the literature. Since independent classifications of impaired and nonimpaired cerebral dysfunction using this particular schizophrenic sample have identified approximately 40% of the schizophrenics as impaired on the LNNB (Silverstein & Arzt, 1985; Strauss & Silverstein, 1986), the differences between our low T-scores relative to those reported in some other studies can not be accounted for by diminished clinical severity in this sample. Thus, sampling differences across studies must be taken into account, and appropriate caution is advised considering that sample characteristics may be uniquely applicable to the present findings. Further, it is important to note the possibility of focal injuries or subcortical abnormalities which may be present but are not well-represented in the LNNB lateralization scales. The cerebral dysfunction displayed by the schizophrenics and major depression patients was represented in both hemispheres. From Luria’s theory of brain function, mental activity is the product of a complex functional system affected by a combination of concertedly working brain units (Luria, 1973). He argues that it is false to assume that these units perform activities independently of each other. The bilateral findings reported above are consistent with Luria’s views. REFERENCES Boklage, C. E. (1977). Schizophrenia, brain asymmetry development, and twinning: Cellular relationship with etiological and possible prognostic implications. Blologrcul Psychiatry, 12.19-35. Bruder, G. E., & Yozawitz, A. (1979). Central auditory processing and lateralization in psychtatric patients. In J. Gruzelier & P. Flor-Henry (Eds.), Hemispheric asymmetries offunction in psychopathology. Amsterdam: ElsevierINorth Holland Biomedical Press. Davis, J. M. (1976). Comparative doses and costs of antipsychotic medication. Archives of General Psychiatry, 33, 858-861. DiMascio, A., & Shader, R. (1970). Clinical handbook ofpsychopharmacy. New York: Science House. Flor-Henry, P. (1974). Psychosis, neurosis and epilepsy: Development and gender-related effects and their aetiological contributions. British Journal of Psychiatry, 124, 144-150.

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