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Lateral ventricular enlargement associated with persistent unemployment and negative symptoms in both schizophrenia and bipolar disorder
Psychiatrv Research, 12, l-9
Elsevier
Lateral Ventricular Enlargement Associated With Persistent Unemployment and Negative Symptoms in Both Schizophrenia and Bipolar Disorder Godfrey D. Pearlson. David J. Garbacz, William J. Raymond Received
December
R. Breakey,
Hyo S. Ahn, and
DePaulo 28. 1983; revised
version received
March 28, 1984; accepted
April3,
1984.
Abstract. Forty-six patients with schizophrenia or bipolar disorder and 46 individually matched normal volunteers underwent computed tomographic (CT) scans of the head. The ventricular-to-brain ratio was strongly associated with persistent unemployment and negative symptoms in both patient groups. Previous findings of relative lateral ventricular enlargement in a proportion of schizophrenic and bipolar patients were also replicated. Implications of the relationship between CT changes
and chronic
unemployment
among
the patients
are discussed.
Key Words. Computed tomography, ventricular-to-brain ratio, negative toms, schizophrenia, bipolar illness, chronic unemployment.
symp-
Since 1976 reports have appeared demonstrating computed tomographic (CT) changes in some schizophrenic and affectively ill patients when compared with controls (Johnstone et al., 1976; Weinberger et al., 1979; Pearlson and Veroff, 1981; Andreasen et al., 19820, 19826; Nasrallah et al., 1982a, 19826; Standish-Barry et al., 1982; Scott et al., 1983). Although the etiology of the nonspecific structural changes evidenced on CT scans remains unknown, their presence in schizophrenic patients is associated with several historical and clinical variables. These include poor premorbid scholastic and social adjustment (Weinberger et al., 19806); neuropsychological deficits, e.g., on the Luria-Nebraska Battery (Golden et al., 1980); poor response to neuroleptic drugs (Weinberger et al., 1980a); and a relatively greater number of negative as opposed to positive schizophrenic symptoms (Crow, 1980; Andreasen and Olsen, 1982). The present study examined ventricular-to-brain ratio (VBR) in relationship to employment and negative symptoms in young patients with schizophrenia and bipolar affective disorder as compared to age- and sex-matched normal volunteers. We chose to examine employment as a variable because it is easily documented, and because previous studies suggested a possible relationship between employment and ventri-
Godfrey D. Pearlson.
M.A., M.B., B.S., is Assistant Professor; David J. Garbacz, M.A., is Research R. Breakey, M.B., B.Ch.. M.R.C. Psych., and J. Raymond DePaulo, M.D., are Associate Professors, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. Baltimore, MD. Hyo S. Ahn, M.D., is Assistant Professor, Department of Neuroradiology, Johns Hopkins University School of Medicine, Baltimore, MD. (Reprint requests to Dr. G.D. Pearlson. Dept. of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Meyer 279. 600 N. Wolfe St.. Baltimore, MD 21205. USA.) Assistant;
01651781:84
William
$03.00 0 1984 Elsevier Science Publishers
B.V
2
cular
changes
tive disorder
in both (Pearlson
schizophrenia
(Andreasen
and Olsen,
1982) and bipolar
affec-
et al., 1984).
Methods Subjects were chosen from the first 60 patients between 18 and 40 years of age meeting the study criteria. The sample consisted of 19 schizophrenic (I I men, 8 women) and 27 manic-depressive (12 men, 15 women) patients who met DSM-III (American Psychiatric Association, 1980) criteria for schizophrenia and bipolar major affective disorder, respectively. All patients had been hospitalized for their illness at least once previously, and were currently undergoing inpatient or outpatient treatment at the Henry Phipps Psychiatric Clinic. The outpatients attended medication maintenance clinics. Four patients were dropped from the study because l-year followup led either to reclassification of the original diagnosis or to the discovery of exclusion factors. Patients were selected from the remaining pool of 26 schizophrenic and 30 bipolar patients as explained below. Normal control subjects were recruited from full-time employees of the Johns Hopkins Hospital and their relatives; all had been continuously employed for at least the 12 months before CT scan, and none had a personal history of psychiatric hospitalization. Exclusionary criteria for both patients and control subjects were any history of central nervous system (CNS) illness, head injury that had caused unconsciousness, headaches of sufficient severity to have led to medical consultation, heavy use of alcohol or street drugs, oral steriod use in the preceding 3 months, loss or gain of 25% or more of original body weight in the last I2 months, or current pregnancy. All participants scored 24 or above out of a possible 30 on the Mini-Mental State Examination (Folstein et al.. 1975) to screen out dementing processes or low IQ. and all were fully right-handed on Annett’s handedness questionnaire (Annett, 1970). For inclusion in the study, information regarding current and past employment was obtained by interviewing the patients and their current therapists, and by chart review. Current employment was reassessed at a single time point on all patients by direct interview in one IO-day period. All patients were considered employed who had been employed continuously for the previous 6 months, up to and including the reassessment period. Patients who had been partially employed in the last 6 months (e.g., attending college 1%day per week, or in volunteer employment 1day per week) were excluded from the study. This exclusion criterion eliminated 7 of 26 schizophrenics, and 3 of 30 bipolar patients. Two groups remained, one of which had been employed in the previous 6 months, and one of which had not. Of the latter group, the majority had not worked in the last 2 years, and among the schizophrenics, 8 of the 13 currently unemployed had never held any job for as long as 6 continuous months. Control subjects were individually matched for sex and age (within 3 years) with patients. We were able, in addition, to match for race in 70% of cases. The current presence or absence of negative symptoms (Andreasen, 1982; Andreasen and Olsen, 1982) was rated between acute exacerbations of illness by a single observer who was unaware of either the VBR values or the experimental hypothesis, by chart review, interview with the patient and the patient’s current therapist, and telephone interview with a close relative of the patient. Some items (identified by an asterisk) were assessed using the definitions of identical items in the Krawiecka Scale (Krawiecka et al., 1977). We counted any such negative symptom as present only if the patient scored a 3 or 4, the two most severe categories on the Krawiecka scale. The following items were assessed: (1) Poverty of speech.* (2) Apathy: therapist’s and family assessment using criteria of energy and initiative. (3) Poor personal hygiene: therapist felt patient’s frequency of changing attire, washing, and grooming were low for appropriate social class as judged by appearance and odor. (4) Emotional flattening.* (5) Absence of friends: patient has no close friends and avoids making any. (6) Asexuality: rated on patient’s having lost interest in, enjoyment of, or participation in sexual activities. Nonenhanced head scans were performed on the AS & E Model 0500 scanner (512 x 512 matrix) by the same technician employing a slice thickness of IO mm with cuts IO mm apart. Patients and control subjects were scanned on the same occasions. and CTcuts were taken at the
3 same angle relative to the canthomeatal
line, and using the same scanner settings. The slice passing through the widest portion of the bodies of the lateral ventricles was chosen to be rated. Randomly mixed patient and control scan pictures were assigned a number, enlarged to approximately life-size on an overhead projector, and traced onto paper. VBRs were then assessed on these tracings using a computer-linked planimeter by a single operator, who was unaware of the subjects’ identities. Statistical analyses included Student’s I test (paired when comparing patients with matched controls), x2 test with Yates’ correction (where appropriate), and Pearson product-moment correlation.
Results The 19 schizophrenic patients had a mean age (+ SD) of 28.8 ? 5.8 years; for the 27 affective patients, this value was 30.8 f 6.7 years; and for the two groups of normal control subjects, values were 29.7 f 5.3 and 30.7 + 7.6, respectively. As predicted, VBR for the total schizophrenic group (see Table 1) was significantly larger than the control group VBR (paired f 1.88, df 18, lp < 0.05, one-tailed). The VBR for the bipolar patients was significantly larger (paired t = 2.41, df= 26, p < 0.0 125, one-tailed) than the VBR of paired normal controls (see Table 1). When VBR was examined in the employed vs. unemployed patients, significant differences emerged (see Table 1). Unemployed patients from both diagnostic groups had VBRs significantly larger than their controls and employed fellow patients. Employed patients’ VBR values were not different from those of controls. As shown in Table 1, the mean VBR of the unemployed schizophrenic patients (n = 13) was significantly larger (paired t 4.1, df 12,~ < 0.005, two-tailed) than that of controls, while for employed schizophrenics (n 6) mean VBR was not different from that of controls (paired t 0.8, df = 5). The 19 unemployed bipolar patients also had a mean VBR significantly larger (paired t 3.52, df= 18, p < 0.005, two-tailed) than that of controls; the VBR value for the eight employed bipolar patients was not signiftcantly different from the control value (paired t = 0.9, df= 7). Age did not explain these differences between employed and unemployed patients. The schizophrenics’mean ages were 29.1% 6.9 years(unemployed) and 28.3 f 3.5 years (employed). Corresponding values for affective patients were 30.2 * 7.4 and 32.1 * 4.7 years, respectively. These values were not significantly different from each other within each diagnosis. Race and sex were similarly examined. Analyses (~2 with Yates’ correction) of race (black vs. white) and of sex vs. employment status failed to show significant effects of these variables in either diagnostic group. When VBR values were calculated for each sex and race within diagnosis, in every case the unemployed group had a larger mean VBR than the corresponding employed group. As differences had already been established between patients and normal controls matched on several significant measures, a five-way analysis of variance was performed on all 46 patients to assess the effects of age, sex, race, diagnosis, and employment status on VBR. The main effect of employment was significant (F= 10.5, &= 1, p < 0.003). F values were less than I for the other main effects, none of which reached significance. None of the interactions were significant. Negative symptom scores were calculated for each patient from the six items mentioned previously. As shown in Table 2, mean scores were 2.5 f 2.1 for the schizophrenic group and 1.4 f 1.5 for the bipolar group. q
q
q
q
q
q
q
4 Table
1. Mean
status.
VBR
values
and comoared
Employed Schizophrenics
in = 61
for each
to those
group
examined
of COrreSDOndiIW
matched
patients
patient
Unemployed
4.5 ? 2.4 11.6-7.9) NS
in = 13)
by employment controls Total patients
patients
7.0 k 2.4 12.9 - 10.51 ***
(n = 19)
6.2 k 2.6 *
Matched normal, employed controls
(n = 61
5.3 k 1 .a 11.8-6.51
In = 131
3.9 2 1.9 (1.9 - 8.31
(n = 191
4.5 2 1.9
Bipolars
jn = 8)
3.6 k 2.4 (0.1 - 8.01 NS
In = 19)
7.9 * 3 10.2 - 12.01 ***
(n = 27)
6.6 f 3.4
4.3 + 2.6 (2.1 - 8.3)
(n = 191
4.8 t 2.1 (1.3 - 7.7)
In = 271
Matched normal, employed controls
in = 8)
**
4.75 t 2.1
Values shown are mean -CSD; ranges are given in parentheses. Significant valuesforpaired (two-tailed,.
ttestsareasfollows:‘pc0,05ione-tailed,;
“p
rone-tailed);
“‘p
Pearson’s product-moment correlations of VBR vs. negative symptom scores were + 0.50 @ < 0.05) for schizophrenic patients, and + 0.40 @ < 0.05) for bipolar patients. For schizophrenic patients (see Table 2) negative symptom score values were higher for those with large (2 1 SD of control mean) as compared to normal ventricles (t 1.83, df 17, p < 0. I, two-tailed). For bipolar patients, a similar trend was seen (t = 0.83, df 25,~ = NS). Negative symptom scores were not related to duration of illness. We compared the negative symptom scores of persistently unemployed patients with those of their employed fellows within diagnosis. Scores were markedly higher for unemployed schizophrenic patients (t = 3.24, df = 17,~ < 0.005, two-tailed). A similar trend was seen for bipolar patients (t 1.9, df = 25,~ < 0. I, two-tailed). These findings support our hypothesis that negative symptoms and persistent unemployment are associated phenomena in our patients. To assess the concurrent validity of our rating for negative symptoms, scores on the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1982) were compared to our negative symptom scores. A single rater blind to the experimental hypothesis, who had not been involved in the original assessments, was trained in the use of the SANS. He was able to interview and rate I I of 19 schizophrenics (58%) and 16 of the 27 bipolars (59%). Pearson correlation coefficients between scores on our own rating scale and those on the SANS for these individuals were + 0.63 (p < 0.05) for schizophrenic patients, and + 0.68 @ < 0.01) for bipolar patients. q
q
q
q
Discussion
The findings in this study confirm those of other workers demonstrating lateral ventricular enlargement on CT scan in young schizophrenic and bipolar patients. We
Values for t tests (two-tailed)
Significant
NS
* 1.1 ? 1.5
1.6 Il.7
* p c 0.1; ** p c 0.005.
(n = 141
(fl = 10)
are as follows:
1.6 -t 1.5
in = 131
Bipolars
3.322.1
(n = 9)
Schizophrenics
in = 191
in = 13)
1.7 t 1.6
3.4 lr 1.9
*
tt
(n = 6)
(n = 61
0.6 + 0.7
0.7 + 1.0
Table 2. Negative symptom scores (mean k SD) in _~ the schizophrenic and bipolar patients Normal ventricles Unemployed patients Employed patients Enlarged ventricles
(n = 27)
(n = 19)
1.4 * 1.5
2.5 f. 2.1
Total
6 additionally demonstrate that this CT change is significantly associated with persistent unemployment and the presence of negative symptoms in both groups. In schizophrenic patients Andreasen et al. (1982a) have demonstrated a relationship between lateral ventricular enlargement and the presence of relatively more negative and fewer positive schizophrenic symptoms, a finding previously noted by Crow (1980). A unique feature of the current study is the demonstration that negative symptoms also occur in bipolar affective disorder (although less than in schizophrenics), where they are associated with the same CT abnormalities seen in schizophrenic patients with predominantly negative symptoms. Chronic unemployment, a likely marker for more severe illness. provides a fair degree of discrimination between those patients with and without lateral ventricular enlargement in both diagnoses, and may well be a consequence of the presence of negative symptoms. These findings are reminiscent of those of earlier pneumoencephalographic studies. which also reported an association between ventricular enlargement and chronic course, lowered social competence, and poor prognosis in manic-depressive or schizophrenic patients (Huber, 1957; Nagy, 1963; Haug, 1962; Huber et al., 1975). Conclusions from these results must be tempered by methodological limitations. Our method of selecting our patient population has the limitation that we chose to exclude partially employed patients. This exclusion criterion eliminated a significant proportion of the schizophrenic patients, almost 25% of the initial group. The group of subjects in partial employment had a mean VBR close to that of the employed schizophrenic patients (5.2 + 2) and hence similar to that of the normal control group. For the schizophrenic group, the elimination of these partially employed patients exaggerates the proportion of patients with ventricular enlargement. The advantage of our selection method is that it enabled us to compare patients at either end of the employment spectrum. The majority of our bipolar patients attend a lithium maintenance clinic; as reported elsewhere, in a separate analysis of data on the same bipolar group (Pearlson et al., 1984), nearly all of them suffer from delusions and; or hallucinations when ill and can be considered from that perspective to have a severe form of the illness. Targum et al. (1983) have demonstrated an association between the presence of delusional symptoms and cerebral ventricular enlargement in major depressive disorder. Our bipolar patients may therefore have a higher prevalence of ventriculomegaly than would a random selection of bipolar patients. Actual employment records would have ensured greater accuracy in data collection, but would be extremely difficult to collect in practice. The simultaneous blind rating of VBR in patients and control subjects on a single occasion helps to strengthen our findings. A larger subject population might have demonstrated our findings more clearly. There has been recent controversy over the prevalence of lateral ventricular enlargement and other CT abnormalities among patients suffering from schizophrenia. While Golden et al. (1980) and Weinberger et al. (1979) have reported that a high proportion of their patients suffering from schizophrenia demonstrate these abnormalities, Jernigan et al. (1982) and Benes et al. (1982) were not able to demonstrate significant differences from normal controls; Andreasen et al. (19826) have demonstrated an intermediate prevalence. In addressing these disparities, Luchins (1982) points out that discrepancies between studies are most likely ascribable to clinical
7 differences in the populations studied such as the presence of negative symptoms, poor premorbid adjustment, poor response to neuroleptic medications, and the presence of neuropsychiatric abnormalities. As noted by Luchins (1982), those patients studied by Weinberger et al. (1979) and Golden et al. (1980) included a greater proportion of those who were extremely dysfunctional. They had chronic symptoms and a poor response to conventional treatments, as opposed to the more functional patients studied by Jernigan et al. (1982). The current study supports Luchins’ suggestion in that two subpopulations appear to emerge within schizophrenia; additionally we demonstrate a similar phenomenon in bipolar illness. Within each DSM-llldiagnostic group in our study, the relationship between lateral VBR and chronic unemployment was not explained by age, sex, or race differences or by whether patients were currently taking neuroleptics. There are several models for considering the links between lateral ventricular enlargement, unemployment, negative symptoms, and major mental illness. It is plausible that increased VBR is a marker for negative symptoms that is independent of major psychiatric illness. Alternatively, increased VBR, regardless of its cause, could predispose an individual to develop a major psychiatric illness, could be an index of the severity of such an illness, or could be the consequence of a basic pathophysiological (e.g., infectious, genetic, biochemical, traumatic) factor. Such a factor may be manifested both as cerebral hypoplasia (or atrophy) and as the characteristic clinical symptoms of psychosis. Alternatively, ventricular enlargement could represent an independent preexisting trait that predisposes individuals to greater functional impairment only if they are later affected by a major psychiatric illness. Finally, the association may be the net result of several different interactions like those suggested above. Of relevance to our finding is the association between “negative” schizophrenia and unemployment noted by Andreasen and Olsen (1982). Their study contrasted schizophrenics with predominantly positive symptoms with those who had predominantly negative symptoms. Fifty-five percent of their (18) patients with predominantly positive symptoms were currently employed, in contrast to 6% of their (16) patients with mainly negative symptoms. This was a statistically significant difference, one associated with a significant difference in VBR between the populations. Obtaining and maintaining employment is a crude but meaningful index of a person’s basic social skills. The findings reported in this study demonstrated a correlation between an anatomical characteristic of the brain, the VBR, and this specific index of social effectiveness. Because our chronically unemployed patients were not clinically demented but seemed to lack motivation and persistence, we conclude that their employment difficulties most likely stem from a dimension of their illnesses closely related to negative symptoms. Crow (1980, 1982) has argued that there are two components of the schizophrenic disease process, one neurochemical and one structural, and that these are associated with different psychopathological symptoms. The current study adds support to this view, and suggests that a similar relationship also applies in bipolar disorder. Ax (1970) using psychophysiological measurements, examined emotional learning deficits in patients suffering from schizophrenia. He demonstrated a deficient aptitude
for emotional learning not only in patients suffering from schizophrenia, but also in “skid row” habitues and in the chronically unemployed, i.e., in persons who presumably had a life history of consistently low social motivation. Impairment in psychophysiological conditioning scores correlated significantly in this study with “poor speech, thought disorganization, and poor affect.” Ax (1970) claimed that his “skid row” subjects showed no abnormalities in physical, neurological, or psychiatric examination. Nothing is known about the cerebral morphology of subjects with these psychophysiologic characteristics. In conclusion, we have found persistent unemployment and negative symptoms to be significantly associated with lateral ventricular enlargement in both schizophrenic and bipolar patients. Although the origin and ultimate significance of this brain finding remains unclear, there is an obvious need to continue examining the historical and clinical characteristics of psychiatric patients with enlarged cerebral ventricles. Psychophysiologic measures might be usefully added to some of these studies. CT scan studies on nonmentally ill vagrants who are chronically unemployed are also warranted. Acknowledgments. This research was supported by a Johns Hopkins University Institutional Research Grant (to G.D.P.). Computational assistance was received from CLINFO sponsored by NIH Grant #5MOIRR35-20. The following persons helped with critical reviews of the manuscript: P.R. McHugh, R.G. Robinson, G. Nestadt, P.V. Rabins, and J.R. Lipsey.
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Elsevier
Lateral Ventricular Enlargement Associated With Persistent Unemployment and Negative Symptoms in Both Schizophrenia and Bipolar Disorder Godfrey D. Pearlson. David J. Garbacz, William J. Raymond Received
December
R. Breakey,
Hyo S. Ahn, and
DePaulo 28. 1983; revised
version received
March 28, 1984; accepted
April3,
1984.
Abstract. Forty-six patients with schizophrenia or bipolar disorder and 46 individually matched normal volunteers underwent computed tomographic (CT) scans of the head. The ventricular-to-brain ratio was strongly associated with persistent unemployment and negative symptoms in both patient groups. Previous findings of relative lateral ventricular enlargement in a proportion of schizophrenic and bipolar patients were also replicated. Implications of the relationship between CT changes
and chronic
unemployment
among
the patients
are discussed.
Key Words. Computed tomography, ventricular-to-brain ratio, negative toms, schizophrenia, bipolar illness, chronic unemployment.
symp-
Since 1976 reports have appeared demonstrating computed tomographic (CT) changes in some schizophrenic and affectively ill patients when compared with controls (Johnstone et al., 1976; Weinberger et al., 1979; Pearlson and Veroff, 1981; Andreasen et al., 19820, 19826; Nasrallah et al., 1982a, 19826; Standish-Barry et al., 1982; Scott et al., 1983). Although the etiology of the nonspecific structural changes evidenced on CT scans remains unknown, their presence in schizophrenic patients is associated with several historical and clinical variables. These include poor premorbid scholastic and social adjustment (Weinberger et al., 19806); neuropsychological deficits, e.g., on the Luria-Nebraska Battery (Golden et al., 1980); poor response to neuroleptic drugs (Weinberger et al., 1980a); and a relatively greater number of negative as opposed to positive schizophrenic symptoms (Crow, 1980; Andreasen and Olsen, 1982). The present study examined ventricular-to-brain ratio (VBR) in relationship to employment and negative symptoms in young patients with schizophrenia and bipolar affective disorder as compared to age- and sex-matched normal volunteers. We chose to examine employment as a variable because it is easily documented, and because previous studies suggested a possible relationship between employment and ventri-
Godfrey D. Pearlson.
M.A., M.B., B.S., is Assistant Professor; David J. Garbacz, M.A., is Research R. Breakey, M.B., B.Ch.. M.R.C. Psych., and J. Raymond DePaulo, M.D., are Associate Professors, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine. Baltimore, MD. Hyo S. Ahn, M.D., is Assistant Professor, Department of Neuroradiology, Johns Hopkins University School of Medicine, Baltimore, MD. (Reprint requests to Dr. G.D. Pearlson. Dept. of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Meyer 279. 600 N. Wolfe St.. Baltimore, MD 21205. USA.) Assistant;
01651781:84
William
$03.00 0 1984 Elsevier Science Publishers
B.V
2
cular
changes
tive disorder
in both (Pearlson
schizophrenia
(Andreasen
and Olsen,
1982) and bipolar
affec-
et al., 1984).
Methods Subjects were chosen from the first 60 patients between 18 and 40 years of age meeting the study criteria. The sample consisted of 19 schizophrenic (I I men, 8 women) and 27 manic-depressive (12 men, 15 women) patients who met DSM-III (American Psychiatric Association, 1980) criteria for schizophrenia and bipolar major affective disorder, respectively. All patients had been hospitalized for their illness at least once previously, and were currently undergoing inpatient or outpatient treatment at the Henry Phipps Psychiatric Clinic. The outpatients attended medication maintenance clinics. Four patients were dropped from the study because l-year followup led either to reclassification of the original diagnosis or to the discovery of exclusion factors. Patients were selected from the remaining pool of 26 schizophrenic and 30 bipolar patients as explained below. Normal control subjects were recruited from full-time employees of the Johns Hopkins Hospital and their relatives; all had been continuously employed for at least the 12 months before CT scan, and none had a personal history of psychiatric hospitalization. Exclusionary criteria for both patients and control subjects were any history of central nervous system (CNS) illness, head injury that had caused unconsciousness, headaches of sufficient severity to have led to medical consultation, heavy use of alcohol or street drugs, oral steriod use in the preceding 3 months, loss or gain of 25% or more of original body weight in the last I2 months, or current pregnancy. All participants scored 24 or above out of a possible 30 on the Mini-Mental State Examination (Folstein et al.. 1975) to screen out dementing processes or low IQ. and all were fully right-handed on Annett’s handedness questionnaire (Annett, 1970). For inclusion in the study, information regarding current and past employment was obtained by interviewing the patients and their current therapists, and by chart review. Current employment was reassessed at a single time point on all patients by direct interview in one IO-day period. All patients were considered employed who had been employed continuously for the previous 6 months, up to and including the reassessment period. Patients who had been partially employed in the last 6 months (e.g., attending college 1%day per week, or in volunteer employment 1day per week) were excluded from the study. This exclusion criterion eliminated 7 of 26 schizophrenics, and 3 of 30 bipolar patients. Two groups remained, one of which had been employed in the previous 6 months, and one of which had not. Of the latter group, the majority had not worked in the last 2 years, and among the schizophrenics, 8 of the 13 currently unemployed had never held any job for as long as 6 continuous months. Control subjects were individually matched for sex and age (within 3 years) with patients. We were able, in addition, to match for race in 70% of cases. The current presence or absence of negative symptoms (Andreasen, 1982; Andreasen and Olsen, 1982) was rated between acute exacerbations of illness by a single observer who was unaware of either the VBR values or the experimental hypothesis, by chart review, interview with the patient and the patient’s current therapist, and telephone interview with a close relative of the patient. Some items (identified by an asterisk) were assessed using the definitions of identical items in the Krawiecka Scale (Krawiecka et al., 1977). We counted any such negative symptom as present only if the patient scored a 3 or 4, the two most severe categories on the Krawiecka scale. The following items were assessed: (1) Poverty of speech.* (2) Apathy: therapist’s and family assessment using criteria of energy and initiative. (3) Poor personal hygiene: therapist felt patient’s frequency of changing attire, washing, and grooming were low for appropriate social class as judged by appearance and odor. (4) Emotional flattening.* (5) Absence of friends: patient has no close friends and avoids making any. (6) Asexuality: rated on patient’s having lost interest in, enjoyment of, or participation in sexual activities. Nonenhanced head scans were performed on the AS & E Model 0500 scanner (512 x 512 matrix) by the same technician employing a slice thickness of IO mm with cuts IO mm apart. Patients and control subjects were scanned on the same occasions. and CTcuts were taken at the
3 same angle relative to the canthomeatal
line, and using the same scanner settings. The slice passing through the widest portion of the bodies of the lateral ventricles was chosen to be rated. Randomly mixed patient and control scan pictures were assigned a number, enlarged to approximately life-size on an overhead projector, and traced onto paper. VBRs were then assessed on these tracings using a computer-linked planimeter by a single operator, who was unaware of the subjects’ identities. Statistical analyses included Student’s I test (paired when comparing patients with matched controls), x2 test with Yates’ correction (where appropriate), and Pearson product-moment correlation.
Results The 19 schizophrenic patients had a mean age (+ SD) of 28.8 ? 5.8 years; for the 27 affective patients, this value was 30.8 f 6.7 years; and for the two groups of normal control subjects, values were 29.7 f 5.3 and 30.7 + 7.6, respectively. As predicted, VBR for the total schizophrenic group (see Table 1) was significantly larger than the control group VBR (paired f 1.88, df 18, lp < 0.05, one-tailed). The VBR for the bipolar patients was significantly larger (paired t = 2.41, df= 26, p < 0.0 125, one-tailed) than the VBR of paired normal controls (see Table 1). When VBR was examined in the employed vs. unemployed patients, significant differences emerged (see Table 1). Unemployed patients from both diagnostic groups had VBRs significantly larger than their controls and employed fellow patients. Employed patients’ VBR values were not different from those of controls. As shown in Table 1, the mean VBR of the unemployed schizophrenic patients (n = 13) was significantly larger (paired t 4.1, df 12,~ < 0.005, two-tailed) than that of controls, while for employed schizophrenics (n 6) mean VBR was not different from that of controls (paired t 0.8, df = 5). The 19 unemployed bipolar patients also had a mean VBR significantly larger (paired t 3.52, df= 18, p < 0.005, two-tailed) than that of controls; the VBR value for the eight employed bipolar patients was not signiftcantly different from the control value (paired t = 0.9, df= 7). Age did not explain these differences between employed and unemployed patients. The schizophrenics’mean ages were 29.1% 6.9 years(unemployed) and 28.3 f 3.5 years (employed). Corresponding values for affective patients were 30.2 * 7.4 and 32.1 * 4.7 years, respectively. These values were not significantly different from each other within each diagnosis. Race and sex were similarly examined. Analyses (~2 with Yates’ correction) of race (black vs. white) and of sex vs. employment status failed to show significant effects of these variables in either diagnostic group. When VBR values were calculated for each sex and race within diagnosis, in every case the unemployed group had a larger mean VBR than the corresponding employed group. As differences had already been established between patients and normal controls matched on several significant measures, a five-way analysis of variance was performed on all 46 patients to assess the effects of age, sex, race, diagnosis, and employment status on VBR. The main effect of employment was significant (F= 10.5, &= 1, p < 0.003). F values were less than I for the other main effects, none of which reached significance. None of the interactions were significant. Negative symptom scores were calculated for each patient from the six items mentioned previously. As shown in Table 2, mean scores were 2.5 f 2.1 for the schizophrenic group and 1.4 f 1.5 for the bipolar group. q
q
q
q
q
q
q
4 Table
1. Mean
status.
VBR
values
and comoared
Employed Schizophrenics
in = 61
for each
to those
group
examined
of COrreSDOndiIW
matched
patients
patient
Unemployed
4.5 ? 2.4 11.6-7.9) NS
in = 13)
by employment controls Total patients
patients
7.0 k 2.4 12.9 - 10.51 ***
(n = 19)
6.2 k 2.6 *
Matched normal, employed controls
(n = 61
5.3 k 1 .a 11.8-6.51
In = 131
3.9 2 1.9 (1.9 - 8.31
(n = 191
4.5 2 1.9
Bipolars
jn = 8)
3.6 k 2.4 (0.1 - 8.01 NS
In = 19)
7.9 * 3 10.2 - 12.01 ***
(n = 27)
6.6 f 3.4
4.3 + 2.6 (2.1 - 8.3)
(n = 191
4.8 t 2.1 (1.3 - 7.7)
In = 271
Matched normal, employed controls
in = 8)
**
4.75 t 2.1
Values shown are mean -CSD; ranges are given in parentheses. Significant valuesforpaired (two-tailed,.
ttestsareasfollows:‘pc0,05ione-tailed,;
“p
rone-tailed);
“‘p
Pearson’s product-moment correlations of VBR vs. negative symptom scores were + 0.50 @ < 0.05) for schizophrenic patients, and + 0.40 @ < 0.05) for bipolar patients. For schizophrenic patients (see Table 2) negative symptom score values were higher for those with large (2 1 SD of control mean) as compared to normal ventricles (t 1.83, df 17, p < 0. I, two-tailed). For bipolar patients, a similar trend was seen (t = 0.83, df 25,~ = NS). Negative symptom scores were not related to duration of illness. We compared the negative symptom scores of persistently unemployed patients with those of their employed fellows within diagnosis. Scores were markedly higher for unemployed schizophrenic patients (t = 3.24, df = 17,~ < 0.005, two-tailed). A similar trend was seen for bipolar patients (t 1.9, df = 25,~ < 0. I, two-tailed). These findings support our hypothesis that negative symptoms and persistent unemployment are associated phenomena in our patients. To assess the concurrent validity of our rating for negative symptoms, scores on the Scale for the Assessment of Negative Symptoms (SANS) (Andreasen, 1982) were compared to our negative symptom scores. A single rater blind to the experimental hypothesis, who had not been involved in the original assessments, was trained in the use of the SANS. He was able to interview and rate I I of 19 schizophrenics (58%) and 16 of the 27 bipolars (59%). Pearson correlation coefficients between scores on our own rating scale and those on the SANS for these individuals were + 0.63 (p < 0.05) for schizophrenic patients, and + 0.68 @ < 0.01) for bipolar patients. q
q
q
q
Discussion
The findings in this study confirm those of other workers demonstrating lateral ventricular enlargement on CT scan in young schizophrenic and bipolar patients. We
Values for t tests (two-tailed)
Significant
NS
* 1.1 ? 1.5
1.6 Il.7
* p c 0.1; ** p c 0.005.
(n = 141
(fl = 10)
are as follows:
1.6 -t 1.5
in = 131
Bipolars
3.322.1
(n = 9)
Schizophrenics
in = 191
in = 13)
1.7 t 1.6
3.4 lr 1.9
*
tt
(n = 6)
(n = 61
0.6 + 0.7
0.7 + 1.0
Table 2. Negative symptom scores (mean k SD) in _~ the schizophrenic and bipolar patients Normal ventricles Unemployed patients Employed patients Enlarged ventricles
(n = 27)
(n = 19)
1.4 * 1.5
2.5 f. 2.1
Total
6 additionally demonstrate that this CT change is significantly associated with persistent unemployment and the presence of negative symptoms in both groups. In schizophrenic patients Andreasen et al. (1982a) have demonstrated a relationship between lateral ventricular enlargement and the presence of relatively more negative and fewer positive schizophrenic symptoms, a finding previously noted by Crow (1980). A unique feature of the current study is the demonstration that negative symptoms also occur in bipolar affective disorder (although less than in schizophrenics), where they are associated with the same CT abnormalities seen in schizophrenic patients with predominantly negative symptoms. Chronic unemployment, a likely marker for more severe illness. provides a fair degree of discrimination between those patients with and without lateral ventricular enlargement in both diagnoses, and may well be a consequence of the presence of negative symptoms. These findings are reminiscent of those of earlier pneumoencephalographic studies. which also reported an association between ventricular enlargement and chronic course, lowered social competence, and poor prognosis in manic-depressive or schizophrenic patients (Huber, 1957; Nagy, 1963; Haug, 1962; Huber et al., 1975). Conclusions from these results must be tempered by methodological limitations. Our method of selecting our patient population has the limitation that we chose to exclude partially employed patients. This exclusion criterion eliminated a significant proportion of the schizophrenic patients, almost 25% of the initial group. The group of subjects in partial employment had a mean VBR close to that of the employed schizophrenic patients (5.2 + 2) and hence similar to that of the normal control group. For the schizophrenic group, the elimination of these partially employed patients exaggerates the proportion of patients with ventricular enlargement. The advantage of our selection method is that it enabled us to compare patients at either end of the employment spectrum. The majority of our bipolar patients attend a lithium maintenance clinic; as reported elsewhere, in a separate analysis of data on the same bipolar group (Pearlson et al., 1984), nearly all of them suffer from delusions and; or hallucinations when ill and can be considered from that perspective to have a severe form of the illness. Targum et al. (1983) have demonstrated an association between the presence of delusional symptoms and cerebral ventricular enlargement in major depressive disorder. Our bipolar patients may therefore have a higher prevalence of ventriculomegaly than would a random selection of bipolar patients. Actual employment records would have ensured greater accuracy in data collection, but would be extremely difficult to collect in practice. The simultaneous blind rating of VBR in patients and control subjects on a single occasion helps to strengthen our findings. A larger subject population might have demonstrated our findings more clearly. There has been recent controversy over the prevalence of lateral ventricular enlargement and other CT abnormalities among patients suffering from schizophrenia. While Golden et al. (1980) and Weinberger et al. (1979) have reported that a high proportion of their patients suffering from schizophrenia demonstrate these abnormalities, Jernigan et al. (1982) and Benes et al. (1982) were not able to demonstrate significant differences from normal controls; Andreasen et al. (19826) have demonstrated an intermediate prevalence. In addressing these disparities, Luchins (1982) points out that discrepancies between studies are most likely ascribable to clinical
7 differences in the populations studied such as the presence of negative symptoms, poor premorbid adjustment, poor response to neuroleptic medications, and the presence of neuropsychiatric abnormalities. As noted by Luchins (1982), those patients studied by Weinberger et al. (1979) and Golden et al. (1980) included a greater proportion of those who were extremely dysfunctional. They had chronic symptoms and a poor response to conventional treatments, as opposed to the more functional patients studied by Jernigan et al. (1982). The current study supports Luchins’ suggestion in that two subpopulations appear to emerge within schizophrenia; additionally we demonstrate a similar phenomenon in bipolar illness. Within each DSM-llldiagnostic group in our study, the relationship between lateral VBR and chronic unemployment was not explained by age, sex, or race differences or by whether patients were currently taking neuroleptics. There are several models for considering the links between lateral ventricular enlargement, unemployment, negative symptoms, and major mental illness. It is plausible that increased VBR is a marker for negative symptoms that is independent of major psychiatric illness. Alternatively, increased VBR, regardless of its cause, could predispose an individual to develop a major psychiatric illness, could be an index of the severity of such an illness, or could be the consequence of a basic pathophysiological (e.g., infectious, genetic, biochemical, traumatic) factor. Such a factor may be manifested both as cerebral hypoplasia (or atrophy) and as the characteristic clinical symptoms of psychosis. Alternatively, ventricular enlargement could represent an independent preexisting trait that predisposes individuals to greater functional impairment only if they are later affected by a major psychiatric illness. Finally, the association may be the net result of several different interactions like those suggested above. Of relevance to our finding is the association between “negative” schizophrenia and unemployment noted by Andreasen and Olsen (1982). Their study contrasted schizophrenics with predominantly positive symptoms with those who had predominantly negative symptoms. Fifty-five percent of their (18) patients with predominantly positive symptoms were currently employed, in contrast to 6% of their (16) patients with mainly negative symptoms. This was a statistically significant difference, one associated with a significant difference in VBR between the populations. Obtaining and maintaining employment is a crude but meaningful index of a person’s basic social skills. The findings reported in this study demonstrated a correlation between an anatomical characteristic of the brain, the VBR, and this specific index of social effectiveness. Because our chronically unemployed patients were not clinically demented but seemed to lack motivation and persistence, we conclude that their employment difficulties most likely stem from a dimension of their illnesses closely related to negative symptoms. Crow (1980, 1982) has argued that there are two components of the schizophrenic disease process, one neurochemical and one structural, and that these are associated with different psychopathological symptoms. The current study adds support to this view, and suggests that a similar relationship also applies in bipolar disorder. Ax (1970) using psychophysiological measurements, examined emotional learning deficits in patients suffering from schizophrenia. He demonstrated a deficient aptitude
for emotional learning not only in patients suffering from schizophrenia, but also in “skid row” habitues and in the chronically unemployed, i.e., in persons who presumably had a life history of consistently low social motivation. Impairment in psychophysiological conditioning scores correlated significantly in this study with “poor speech, thought disorganization, and poor affect.” Ax (1970) claimed that his “skid row” subjects showed no abnormalities in physical, neurological, or psychiatric examination. Nothing is known about the cerebral morphology of subjects with these psychophysiologic characteristics. In conclusion, we have found persistent unemployment and negative symptoms to be significantly associated with lateral ventricular enlargement in both schizophrenic and bipolar patients. Although the origin and ultimate significance of this brain finding remains unclear, there is an obvious need to continue examining the historical and clinical characteristics of psychiatric patients with enlarged cerebral ventricles. Psychophysiologic measures might be usefully added to some of these studies. CT scan studies on nonmentally ill vagrants who are chronically unemployed are also warranted. Acknowledgments. This research was supported by a Johns Hopkins University Institutional Research Grant (to G.D.P.). Computational assistance was received from CLINFO sponsored by NIH Grant #5MOIRR35-20. The following persons helped with critical reviews of the manuscript: P.R. McHugh, R.G. Robinson, G. Nestadt, P.V. Rabins, and J.R. Lipsey.
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