Brain ventricular size and CSF monoamine metabolites in an adolescent inpatient population

Psychiatry Research, 16, 87-94

87

Elsevier

Brain Ventricular an Adolescent W.

Size and CSF Monoamine Inpatient Population

Stanley Jennings, Jr., S. Charles Schulz, Robert M. Hamer, and Robert 0. Friedel

Received

Nedathur

Metabolites

in

Narasimhachari,

October 29, 1984; revised version received June 6, 1985; accepted July 5, 1985.

Abstract. The cerebrospinal fluid monoamine metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (SHIAA), were compared with ventriclebrain ratios (VBRs) in a group of adolescent inpatients who were divided into psychotic and nonpsychotic groups. HVA, SHIAA, and VBR did not differ significantly between the two groups. There were no significant relationships between these variables in the nonpsychotic group. Psychotic adolescents, however, displayed significant negative correlations between VBR and HVA, and between VBR and SHIAA. The relationship between VBR and monoamine metabolites appears to occur in psychoses other than schizophrenia, is present early in the course of illness, and probably does not represent a dilutional effect. Key Words. Ventricle-brain ratio, homovanillic schizophrenia, psychosis, adolescent inpatients.

acid, 5-hydroxyindoleacetic

acid,

Attempts to define the pathophysiology of schizophrenia have been stimulated by the recent use of computed tomography (CT) to evaluate cerebral pathology. A number of studies have described or reviewed ventricular enlargement (Johnstone et al., 1976, 1978; Maser and Keith, 1983; Roberts, 1983; Weinberger et al., 1983), and concluded that these findings are significant and clinically relevant. Ventricular enlargement has also been correlated with poor response to antipsychotic medications (Weinberger et al., 1980a), poor premorbid social adjustment (Weinberger et al., 19806), and negative symptomatology (Johnstone et al., 1976; Rieder et al., 1979). It is present in some teenage schizophrenic patients (Schulz et al., 1983~). Ventricular enlargement is widespread, but not universally present in schizophrenia, suggesting that a distinction might be made between groups within that diagnosis based on CT results. More recently, several studies have compared monoamine metabolites in the cerebrospinal fluid (CSF) to CT measurements. Potkin et al. (1983) found decreased 5-hydroxyindoleacetic acid (SHIAA) concentrations in schizophrenic patients with enlarged ventricles. Van Kammen et al. (1983) found decreased homovanillic acid

W. Stanley Jennings, Jr., M.D., Nedathur Narasimhachari, Ph:D.,and Robert M. Hamer, Ph.D,are in the Department of Psychiatry, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA. Dr. Narasimhachari is also in the Department of Pharmacology, and Dr. Hamer is in the Department of Biostatistics. S. Charles Schulz, M.D.. is in the Department of Psychiatry, University of Pittsburgh School of Medicine. Pittsburgh, PA. Robert 0. Friedel. M.D., is Medical Director, Charter Westbrook Hospital, Richmond, VA. (Reprint requests to Dr. S. C. Schulz, Western Psychiatric Institute and Clinic, 381 I O’Hara St., Pittsburgh, PA 15213, USA.) 0165-1781~85;

$03.30 @ 1985 Elsevier Science Publishers

B.V

88 (HVA) activity in a group of schizophrenic patients with increased ventricle-brain ratios (VBRs) or cortical atrophy as compared to those without atrophy signs. Nyb’ack et al. (1983) measured HVA, SHIAA, and 3-methoxy-4-hydroxyphenylglycol (MHPG) in a group of predominantly schizophrenic inpatients. Compared to a control population of healthy volunteers, the psychotic patients with ventricular enlargement had significantly decreased HVA and SHIAA, thus confirming the findings of van Kammen et al. (1983) and Potkin et al. (1983). The decreased monoamine concentrations do not appear to have been due to dilutional effects of increased ventricular volume, as this relationship was not present in controls in the study of Nybick et al. (1983). These previous studies comparing VBR and CSF monoamines have been in predominantly or exclusively schizophrenic populations. However, there is evidence that enlarged ventricles occur in other psychoses. Pearlson and Veroff (198 I), as well as Nasrallah et al. (1982), found abnormal VBRs in bipolar patients compared to controls. Targum et al. (1983) and Luchins et al. (1984) found enlarged ventricles in delusional as compared to nondelusional depression. Rieder et al. (i983) found ventricular enlargement in patients with bipolar affective disorder and schizoaffective disorder that was comparable to the enlargement found in the schizophrenic population after correction for age difference. Following the strategy of our group’s previous experiments, we decided to investigate these variables in patients near the onset of their illness and in those not previously medicated. This investigation was undertaken to determine whether the relationship between ventricular enlargement and depressed CSF HVA and SHIAA could be demonstrated in a heterogeneous adolescent population. Methods The subjects were 38 (29 male, 9 female) patients with an age range of 12-18 (mean 15.6, SD 1.4) years, admitted to the Adolescent Psychiatry Service at the Medical College of Virginia Hospital between January 1980 and July 198 I. Four had previous psychiatric hospitalizations, and five had previous neuroleptic exposure (three personality disorder; one major affective disorder, unipolar); the remainder had never been treated with psychotropic medication. None of the patients included in the study had taken medications within 4 weeks of admission. Three patients with personality disorder diagnoses had a previous history of mild (no loss of consciousness) head trauma (VBR range I .4-6.1, mean 3.0). One patient each with diagnoses of schizophrenia and borderline personality disorder had a history of seizure disorders, and the latter had been previously treated with carbamazepine and primidone. Two patients were removed from the study because of chronic and recent steroid exposure, which has been associated with ventricular enlargement (Bentson et al., 1978). Also included in the study were one case each of surgically corrected pulmonic stenosis, history of pancreatitis, and history of Rocky Mountain spotted fever. Diagnosis on each patient was made by the attending psychiatrist (R.O.F.) on the adolescent team using DSM-III (American Psychiatric Association, 1980) criteria with a team case conference approach. Lumbar punctures were performed on all patients in the study within 2 weeks of admission by the psychiatric resident of the service, generally at 8:00 a.m. The fourth aliquot, including the sixth through the eighth cc, was immediately delivered to the Biochemistry Laboratory (N.N.), where it was frozen at -40°C. All patients received a regular hospital diet. HVA and SHIAA were measured by high performance liquid chromatography with electrochemical detection (LC-EC) (Narasimhachari et al., 1982). The coefficient of variation for HVA values was 3.3%

89 and for SHIAA was 3.7%. Cranial CT scans were performed on 32 patients with a second generation Delta Scanner using a 256 x 256 matrix. Calculation of VBR was by the method of Weinberger et al. (1979a, 1979b). The CT scan section with the largest ventricular area was chosen, and blinded to identifying information. The lateral ventricular area was then measured using a K + E planimeter, model #6200 15. The area encompassed by the inner table of the skull was also measured. The ratio of ventricular to intracranial areas made up the VBR. Patients were divided into psychotic (n = 21) and nonpsychotic (n = 18)diagnostic subgroups on discharge. Psychotic discharge diagnoses were made in all cases in which gross psychotic symptoms were present during hospitalization. (See Table 1 for diagnostic distribution.) The VBRs were compared with those of a control group of adolescents that had been established for a previous study. The scans of the schizophrenic patients and adolescent controls were measured by both a psychiatrist (S.C.S.) and neuroradiologist (J. Gehl). A correlation between their measurements of r = 0.89 (p = 0.0001) was found (Schulz et al., 1983~).

Table 1. Frequency of psychotic and nonpsychotic inpatient sample (n = 39) Psychotic

diagnosis

(n = 21)

diagnoses in an adolescent

Nonpsychotic

Schizophrenia

9

Borderline

Reactive

4

Attention

2 2

Mental

Schizotypal/schizoid

2

Major affective

1

Substance

1

Learning

psychosis

Major affective Atypical

disorder

with psychosis

psychosis

Schizoaffective

disorder

Major affective

disorder,

Schizophreniform

bipolar

disorder

(n = 18)

diagnosis

personality deficit

disorder

14

disorder

6

retardation1

4 3

disorder,

unipolar

2

abuse, ETOH

2

disability

1

1. Mean IQ sccre 74. None with specific retardation syndrome.

Results The mean both

(? SD) VBR

the nonpsychotic

(5.88 f 4.19) of the psychotic patients

Fig. 1. Ventricle-brain

group

(4.29 * 2.49) and the control

ratios in teenaged psychiatric

those

of

(2.74 f 2.4) (Fig.

1).

was larger group

than

patients

j

PSYCHOTIC

NONPSYCHOTIC

(n = 16)

(n = 141

CONTROLS in=16'

I

Mean ventricle-brain ratio IVBR) + SEM displayed. The psychotic group mean VBR was significantly higher than the control group mean ip < 0.051, but not significantly different from the nonpsychotic patient group.

90 Analysis of variance revealed a significant difference between the means (Fz4.00, df= 2,~ 0.025). Further analysis by t test demonstrated that mean VBR of the psychotic patient group was significantly larger than that of the control group (t = 2.76, p = 0.009), but not that of the nonpsychotic patients (t = 1.2, p = 0.22). The mean (k SD) CSF HVA of the group with psychosis (47.25 + 28.1 ng/ml) was nonsignificantly lower than that of the nonpsychotic adolescents (63.85 f 40.32 ng/ml) (see Fig. 2). There was also no difference between the two groups on SHIAA, as the mean (* SD) CSF SHIAA concentration of the psychotic group was 24.0 f 14.1 ng/ ml compared to 16.6 * 7.9 ng/ml for the nonpsychotic patients (see Fig. 3). q

Fig. 2. CSF homovanillic acid in teenaged psychiatric patients

Fig. 3. CSF SHIAA in psychotic nonpsychotic teenagers

I

t

19

P

NS

vs.

-I

i

-I PSYCHOTIC (n=201

NONPSYCHOTIC (n=lt31

PSYCHOTIC (rl=19)

Mean + SEM.

NONPSYCHOTIC ln=ls)

Mean + SEM. 5HIAA = 5-hydroxyindoleacetic

acid.

There were no significant correlations among age, VBR, HVA, and SHIAA in the nonpsychotic patients. In the psychotic patients, significant negative correlations were found between VBR and HVA (Fig. 4), and between VBR and SHIAA (Fig. 5). These Fig. 4. Correlation of CSF HVA with VBR in psychotic teenagers (n = 16) 12OL 110-O Q

IOO-

1

8 "56 P\0"25 . SCHIZOPHRENIC

Fig. 5. Correlation of CSF 5HIAA with VBR in psychotic teenagers (n = 15)

PATIEN'S

:

01 VENTRICLE-BRAIN

RATIO (VBRI

A significant negative correlation between CSF HVA Ihomovanillic acid) and VBR (ventricle-brain ratio1 was found in the 16 psychotic patients Ir = -0.56, o
2

4

1

/

6

8

1 10

12

14

VENTRICLE-BRAIN

16

18

20

I

RATIO (VBR)

When a l-tailed test of significance was used to evaluate the relationship of CSF 5HIAA i5-hydroxyindoleacetic acid1 to VBR (ventricle-brain ratio), a significant negative correlation was found I r = -0 45. p < 0.045, l-tailed testl.

91 results and those reported by Nyt&k et al. (1983) demonstrate a similar degree of correlation in the variables studied (Table 2). A trend toward significance (p 0.11) is noted in the correlation between age and VBR for the psychotic group. q

Table 2. Correlations of selected Nyback et al. (1983)

variables

as compared

Nonpsychotic Nyback et al. Type

of sample

Normal

controls

with the results of Psychotic

This study Nonpsychotic

Nyback et al. Schizophrenic

This study Various

psychoses

inpatients 43

14-18

26

15-20

19-43 (27)

12-18 (15.8)

17-44 (28)

13-18 (15.3)

VBR vs. age

0.402

0.16

0.24

0.40

VBR vs. I-WA

0.15

0.21

-0.413

-0.563

VBR

n

Age

range

(mean)

Correlations

0.16

0.09

-0.402

-0.454

HVA vs. age

0.14

0.24

0.28

0.30

HVA vs. 5HIAA

0.14

0.11

0.791

0.25

vs. 5HlAA

1. p < 0.001

2.p < 0.01. 3. p < 0.05. 4. D < 0.09.

Discussion. The relationship between CT scan measurements and monoamine metabolites has not been previously reported in an adolescent inpatient population. However, the results are comparable to those of Nybick et al. (1983) and others, despite significant differences between samples. This article adds further evidence that a relationship exists between ventricular enlargement and decreased monoamine neurotransmitter activity. This finding is of particular interest because of the patients’ relative lack of neuroleptic exposure compared to the methodology of medication washout. The relationship reported is probably not simply a result of a dilutional effect, as it does not exist in the psychiatric inpatient group in our study or the control group of Nybick et al. (1983). It is possible that a relationship between CSF monoamines and VBR in the nonpsychotic patients was lacking because their VBRs were nearly normal and the standard deviation was less than that of the psychotic patient group. It should be pointed out, however, that the range of the VBR for the nonpsychotic patient group was 1.4-10.3. The relationship is probably not specific for schizophrenia, but instead may be present in schizophrenia spectrum and affective disorders, provided that psychotic symptoms exist. This study’s use of nonpsychotic inpatients for comparison provides a control for milieu factors, including the stresses surrounding hospitalization, which cannot be approximated with normal controls. The failure to demonstrate VBRmonoamine relationships in the sample of behaviorally disordered but nonpsychotic patients suggests that these relationships are related to the psychotic state rather than to a particular diagnosis.

92 Crow (1980) has argued for the division of schizophrenia into two types based on the presence of positive or negative symptoms. Negative symptoms have been correlated with increased VBR and could be considered characteristic of a deficit state. Negative symptoms are not reproducible with amphetamines (Angrist et al., 1980) are generally not responsive to neuroleptics (Weinberger et al., 1980a, 1980b; DeLisi et al., 1983; Schulz et al., 19836) and thus might not be secondary to increased dopamine activity. Defects in smooth pursuit eye tracking (Weinberger and Wyatt, 1982), neuropsychological testing (Johnstone et al., 1976; Donnelly et al., 1980; Golden et al., 1980), and premorbid adjustment (Weinberger et al., 1980b), are also thought to correlate with increased VBR and negative symptoms in schizophrenia. Alterations of cerebral activities leading to decreased CSF levels of HVA and SHIAA might also be added to the list of distinctions, and may be considered to be potential biochemical correlates of these abnormalities. For instance, the low HVA in those patients with large ventricles may be a clue to this subgroup’s relative lack of response to neuroleptics. In addition, further CSF studies coupled with more advanced scanning techniques such as magnetic resonance imaging could lead to a localization of the monoamine deficit. It is important to reiterate the never-medicated status of this group at this point, because the results of the experiment are probably not secondary to a depolarization of dopaminergic neurons secondary to long-term neuroleptic treatment. Although it is well documented that ventricular size increases with age, the relationship between age and VBR would not be expected to be a factor in such a limited age range as encompassed by this study. The correlation was low as expected (r 0.16) in the nonpsychotic group. The correlation (r 0.40) and trend toward significance in the psychotic group may suggest that is some psychotic adolescents the rate of increase in VBR is abnormally high during the teenage years. The subgroup (n 6) of schizophrenic patients in the psychotic group showed an unexpectedly high correlation (r = 0.87, p < 0.02) between age and VBR. The question of whether enlarged ventricles are present perinatally or, instead, occur at around the time of illness onset could be an important clue in the etiology of schizophrenia. Rapid ventricular enlargement during the teenage years might result from a response to an as yet undetermined insult to the brain, whereas congenital enlargement would suggest genetic or maternal environmental causes. More study to define the onset and course of ventricular enlargement in various psychiatric populations is thus indicated. q

q

q

References Psychiatric Association. DSM-III: Diagnostic and Statistical Manual of Mental 3rd ed. APA, Washington, DC (1980). S. Differential effects of amphetamine and Angrist. B., Rotrosen, J., and Gershon, neuroleptics on negative vs. positive symptoms in schizophrenia. Psychopharmacology, 72, 17 (1980). Bentson, J.R., Reza, M., Winter, J., and Wilson, G. Steroids and apparent cerebral atrophy on computed tomography scans. Journal of Computer Assisted Tomography, 2, 16 (1978). Crow, T.J. Molecular pathology of schizophrenia: More than one disease process? British American

Disorders.

Medical

Journal,

280,66

(1980).

93 DeLisi, L.E., Schwartz, C.C., Targum, S.D., Brynes, S.M., Spoor, E.C., Weinberger, D.R., and Wyatt, R.J. Ventricular brain enlargement and outcome of acute schizophreniform disorder. Psychiatry Research, 9, 169 (1983). Donnelly, E.F., Weinberger, D.R., Waldman, I.N., and Wyatt, R.J. Cognitive impairment associated with morphological brain abnormalities on computed tomography in chronic schizophrenic patients. Journal of Nervous and Mental Disease, 168,305 (1980). Golden, C.J., Moses, J.A., Zelazowski, R., Graber, B., Zatz, L.M., Horvath, T.B., and Berger, P.A. Cerebral ventricular size and neuropsychological impairment in young chronic schizophrenics. Archives of General Psychiatry, 37,619 (1980). Johnstone, E.C., Crow, T.J., Frith, C.D., Stevens, M., Kreel, L., and Husband, J. The dementia of dementia praecox. Acta Psychiatrica Scandinavica, 57, 395 (1978). Johnstone, E.C., Frith, C.D., Crow, T.J., Husband, E. J., and Kreel, L. Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancer II, 924 (1976). Luchins, D.J., Lewine, R.R.J., and Meltzer, H.Y. Lateral ventricular size, psychopathology, and medication response in the psychoses. Biological Psychiatry, 19, 29 (1984). Maser, J.D., and Keith S.J. CT scans and schizophrenia-Report on a workshop. Schizophrenia

Bulletin,

9, 265 (1983).

Narasimhachari, N., Boadle-Biber, M.C., and Friedel, R.O. A critical evaluation of LC-EC for the simultaneous determination of 5HT, SHIAA and HVA in biological samples using CC-MS for validation. Research Communications in Chemistry, Pathology, and Pharmacology,

37,413

(1982).

Nasrallah, H.A., McCalley-Whitters, M., and Jacoby, C.G. Cerebral ventricular enlargement in young manic males. Journal of Affective Disorders, 4, 15 (1982). Nyback, H., Berggren, B.M., Hindmarsh, T., Sedvall, G., and Wiesel, F.A. Cerebroventricular size and cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy volunteers. Psychiatry Research, 9, 30 I (1983). Pearlson, G.D., and Veroff, A.E. Computerized tomographic scan changes in manicdepressive illness (letter to the editor). Lancet, II, 470 (1981). Potkin, S.G., Weinberger, D.R., Linnoila, M., and Wyatt, R.J. Low CSF 5-hydroxyindoleacetic acid in schizophrenics with enlarged ventricles. American Journal of Psychiatry, 140,21

(1983).

Rieder, R.O., Donnelly, E.F., Herdt, J.R., and Waldman, 1.N. Sulcal prominence in young schizophrenic patients: CT scan findings associated with impairment on neuropsychological tests. Psychiatry Research, 1, I (1979). Rieder, R.O., Mann, L.S., Weinberger, D.R., van Kammen, D.P., and Post, R.M. Computed tomographic scan in patients with schizophrenia, schizoaffective disorder and bipolar affective disorder. Archives of General Psychiatry. 40, 735 (1983). Roberts, J.K.A. Brain structure and function in the schizophrenias: A neurobehavioral approach. Psychiatric Journal of the University of Ottawa, 8, 67 (1983). Schulz, S.C., Koller, M.M., Kishore, P.R., Hamer, R.M., Gehl, J.J., and Friedel, R.O. Ventricular enlargement in teenage patients with schizophrenia spectrum disorder. American Journal

of Psychiatry,

Schulz, ventricular

140, 1592 (1983~).

S.C., Sinicrope, P., Kishore, P., and Friedel, R.O. Treatment enlargement in young schizophrenic patients. Psychopharmacology

response Bulletin,

and 19,

510 (19836).

Targum, S.D., Rosen, L.N., DeLisi, L.E., Weinberger, D.R., and Citrin, C. Cerebral ventricular size in major depressive disorder: Association with delusional symptoms. Biological Psychiatry, 18, 329 (1983). van Kammen, D.P., Mann, L.S., Sternberg, D.E., Scheinin, M., Ninan, P.T., Marder, S.R., van Kammen, W.B., Rieder, R.O., and Linnoila, M. Dopamine-P-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy. Science, 220,974 (1983).

94

Weinberger, D.R., Bigelow, L.B., Kleinman, J.E., Klein, S.T., Rosenblatt, J.E., and Wyatt, R.J. Cerebral ventricular enlargement in chronic schizophrenia: An association with poor response to treatment. Archives of General Psychiatry, 37, 11 (1980~). Weinberger, D.R., Cannon-Spoor, E., Potkin, S.G., and Wyatt, R.J. Poor premorbid adjustment and CT scan abnormalities in chronic schizophrenia. American JournalPsychiatry, 137, 1410 (1980b).

Weinberger, D.R., Torrey, E.F., Neophytides, ventricular enlargement in chronic schizophrenia.

A.N.,

and Wyatt,

Archives

of General

R.J.

Lateral

Psychiatry,

cerebral 36, 375

( 1979a).

Weinberger, D.R., Torrey, E.F., Neophytides, ties in the cerebral cortex of chronic schizophrenic

A.N., and Wyatt, R.J. Structural abnormalipatients. Archives of Genernl Psychiatry, 36,

935 (19796).

Weinberger, D.R., Wagner, R.L., and Wyatt, R.J. Neuropathological studies of schizophrenia: A selective review. Schizophrenia Bulletin, 9, 194 (1983). Weinberger, D.R., and Wyatt, R.J. Cerebral ventricular size: A biological marker for subtyping chronic schizophrenia. In: Hanin, I., and Usdin, E., eds. Biological Markers in Psychiatry and Neurology. Pergamon Press, New York, p. 505 (1982).