13

Psychiatry Research, 43: 13-21 Elsevier

CSF Corticotropin Releasing Hormone, Somatostatin, and Thyrotropin Releasing Hormone in Schizophrenia Csaba M. Banki, Lajos Karmacsi,

Garth Bissette, and Charles B. Nemeroff

Received November 12,1991; revised version received February 24.1992; accepted March 22.1992. Abstract.

Cerebrospinal fluid (CSF) corticotropin releasing hormone (CRH), somatostatin (SRIF), and thyrotropin releasing hormone (TRH) were measured by specific radioimmunoassay methods in 86 patients who met DSM-III-R

criteria for schizophrenia or schizophreniform disorder and in 30 neurologic controls. The multivariate CSF peptide concentration was significantly different in patients compared with controls, but none of the individual variable differences reached statistical significance when analyzed separately. There were no significant CSF neuropeptide differences among patients with various schizophrenic subtypes. Neither global severity of illness nor individual symptoms were correlated with CSF neuropeptide concentrations. Although schizophrenic patients showed a pattern of mildly lower SRIF and TRH levels in their CSF, together with a weak tendency for higher CSF CRH values, these peptide changes did not appear to be specifically related to the core features of schizophrenia. Key Words. Neuropeptides, cerebrospinal fluid.

psychoendocrinology,

schizophreniform

disorder,

Schizophrenia is a common and severe psychiatric disorder that affects 0.6-0.9s of the population in most countries (Jablensky and Sartorius, 1988). It often takes a chronic course and is a major cause of psychiatric disability. Although schizophrenia presents with such variability of symptoms, course, and outcome that its concept was once depicted as “impossible” (van Praag, 1976), it does appear to have a core symptom complex formulated in sets of standard diagnostic criteria such as DSMIII-R(American Psychiatric Association, 1987); consequently, it is generally considered to be a meaningful clinical entity with largely unknown etiology and pathogenesis (Crow, 1982; Stevens, 1982). With the advent of clinical neuropeptide studies in human diseases, there have been several reports on alterations of peptide substances in schizophrenia. Postmortem brain tissue studies, as well as cerebrospinal fluid (CSF) measurements, occasionally found significant differences between peptide concentrations in patients

Csaba M. Banki, M.D., Ph.D., is Head, Department of Psychiatry, Regional Neuropsychiatric Institute, Nagykallo, Hungary. Lajos Karmacsi, M.D., is Senior Psychiatrist, Regional Neuropsychiatric Institute, Nagykallo, Hungary. Garth Bissette, Ph.D., is Director, Laboratory of Psychoneuroendocrinology, Department of Psychiatry, Duke University Medical Center, Durham, NC. Charles B. Nemeroff, M.D., Ph.D., is Professor and Chairman, Department of Psychiatry, Emory University School of Medicine, Atlanta, GA. (Reprint requests to Dr. C.M. Banki, P.O. Box 37, H-4321 Nagykallo, Hungary.) 0165-1781/92/%05.00

@ 1992 Elsevier Scientific

Publishers

Ireland

Ltd.

14 and controls, but the findings often could not be confirmed. For example, somatostatin (SRIF) was found to be decreased (Bisette et al., 1986), unchanged (Doran et al., 1986), or increased (Gerner, 1984) in various schizophrenic patient groups. Another neuropeptide, neurotensin, was found to be very low in the CSF of a subgroup of schizophrenic patients (Widerlov et al., 1982) while it was reported to be markedly elevated in the frontal cortex of individuals who had suffered from chronic schizophrenia (Nemeroff et al., 1983). There is some evidence that the hypothalamic-pituitary-adrenal axis may also be dysfunctional in at least some schizophrenic patients. Although many studies that have reported dexamethasone nonsuppression in schizophrenia may be methodologically flawed (Carroll, 1985) the remaining ones still indicate a significant abnormality (Arana et al., 1985). In an earlier study (Banki et al., 1984) we found a very high rate of dexamethasone nonsuppression in catatonic, but not paranoid, schizophrenic subjects. The adrenocorticotropic hormone (ACTH) and cortisol responses to a corticotropin releasing hormone (CRH) challenge were reported to be normal in one study (Roy et al., 1986); on the other hand, we observed moderately but significantly elevated CSF concentrations of CRH in a group of actively psychotic schizophrenic women (Banki et al., 1987). The thyroid axis may also be involved: Thyroid stimulating hormone (TSH) responses to synthetic thyrotropin releasing hormone (TRH) have sometimes been found to be blunted in schizophrenia (Loosen, 1985) and blunted TSH responses predicted a good therapeutic response to haloperidol in another study (Langer et al., 1986). Both CRH and TRH possess marked behavioral effects that could account for at least some symptoms of positive or negative schizophrenia (Nemeroff et al., 1984~; Griffiths, 1985). However, the relatively scarce data and the controversial nature of the findings do not permit any definite conclusions about the putative role of these, and other, neuropeptides in schizophrenia (Bissette and Nemeroff, 1988; Loosen and Banki, 1988). To extend the existing data base on CSF neuropeptide concentrations in schizophrenic patients and to examine the relationship between clinical variables and CSF peptide levels, we measured three neuropeptides (CRH, TRH and SRIF) simultaneously in a moderately large group of actively psychotic individuals in a collaborative study between Hungary and the United States.

Methods Subjects. Schizophrenic patients of both sexes (n = 86) were investigated as inpatients in a regional psychiatric hospital in Hungary. All subjects had been recently admitted through the regular referral system (i.e., without any specific patient recruitment) from a catchment area with a population somewhat above 500,000. All patients showed active psychotic symptoms at admission. Inclusion required a D&U-III-R diagnosis of either schizophrenia (n = 73)or schizophreniform disorder (n = 13). Table 1 presents pertinent characteristics of the patients and controls. Controls (n = 30) were female inpatients from a neurologic unit at the same hospital. They did not have a DSWZZZ-R psychiatric disorder at the time of the study (and did not report a family or personal history of major psychotic or affective disorders in a personal interview). They received treatment for peripheral neurologic disorders (migraine headache, musculoskeletal, or other neuralgias) but were drug free at the investigation and had not been treated with neuroleptics, antidepressants, lithium, or carbamazepine for at least 2 weeks; in fact, 24 of them had never received such drugs.

15 During an initial hospital period (2-5 days), all patients and controls underwent a detailed physical, neurologic, and laboratory examination, including an electrocardiogram, 16-channel electroencephalogram, and chest and skull x-ray. All subjects who showed clinical or laboratory signs of significant medical, endocrinologic, or central nervous system disease (such as Parkinson’s disease, epilepsy, or Huntington’s chorea) or who had a history of such an illness were excluded. In addition, we did not include subjects with definite alcohol or other substance abuse and women with a possible pregnancy or within 6 months after childbirth. Altogether 11 schizophrenic and 16 control subjects were investigated but excluded by these criteria. Unfortunately, hormone determinations were not available in this study. Schizophrenic patients were diagnosed by two of us (C.M.B. and L.K.), on subsequent days, on the basis of DSM-III-R criteria; only concordant diagnoses were accepted. The psychometric evaluation included the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1988) the Scales for the Assessment of Positive and Negative Symptoms (SAPS [Andreasen, 19861 and SANS [Andreasen, 19821) and the Global Assessment of Functioning (GAF) from the DSM-III-R Axis V. All patients denied the use of neuroleptics, antidepressants, lithium, carbamazepine, or hormone-containing drugs within 2 weeks before admission; 23 patients had apparently never been treated with major psychotropic substances. During the initial period, patients received only minor doses of benzodiazepines or chlomethiazole when necessary to control agitation or anxiety, or to promote sleep; in 14 cases, however, the early administration of a sedative neuroleptic, chlorprothixene, could not be avoided. Procedures. Lumbar punctures were performed at 9-10 a.m. on days 3-5 of hospitalization following an overnight fast and bedrest (without any specific food restrictions) with patients in a sitting position, at the fourth lumbar intervertebral space. The first 10 ml of CSF were collected in a plastic tube without preservative and immediately frozen to -70 “C and stored in the dark until transported, by air and on dry ice, to the United States for peptide analysis. Nor complication of the lumbar puncture procedure was observed in any subject, apart from a mild and transient headache in a few individuals. All samples were coded, and the code was not revealed to the laboratory until all samples were processed. CRH and SRIF were analyzed in two assays, and TRH was processed in a single assay at Duke University Medical Center. Sensitive and specific radioimmunoassay procedures were used (see Nemeroff et al., 19846; Bissette et al., 1986; Banki et al., 1988). All samples were run in duplicate, and the results were expressed as pg/ml peptide. Specifically, all intra-assay and interassay coefficients of variation for all three procedures remained below 10%. Table 1 presents the background variables analyzed in the study. Schizophrenic subtypes were defined according to DSM-III-R criteria, and the psychometric variables used were the total BPRS score, its four major factor scores (thought disorder, withdrawal, suspiciousness, anxiety/depression), the global SANS and SAPS scores, and the current GAF score (assessed, when possible, after an additional interview with a resident family member). Because all three peptide variables had skewed distributions, we used log-transformed peptide data for statistical analysis (univariate analysis of variance [ANOVA], multivariate analysis of variance [MANOVA], and multivariate analysis of covariance [MANCOVA]). Pearson’s correlation coefficients were computed between the variables, and the effects of the clinical and psychometric variables on the CSF neuropeptides were tested by multiple regression analyses. All statistical procedures were performed according to standard methods (Dillon and Goldstein, 1984); in particular, Wilk’s lambda values were transformed to approximate F statistics when MANOVA results were reported.

Results Table

2 presents

mean

phrenic/schizophreniform

CSF

of CRH, SRIF, and TRH in schizoand controls. Although none of the individual

concentrations

patients

16

Table 1. Clinical and demographic characteristics of schizophrenic patients and controls Schizophrenia Sex, M/F

0130

38.8 f 10.6 (18-68)

Age (yr) Weight (kg)

44.6 + 10.6 (28-70)

68.1 f 14.5 (40-100)

Height (cm) Number

Controls

37149

of hospitalizations

62.9 xt 11.9 (41-84)

164.2 f 9.5 (148-180) 4.1 f 3.1 (l-l 8) (median: 3)

157.9 -t 4.5 (148-165) -

First onset (yr)

8.0 + 6.7 (l-26) (median: 6)

-

Episode

(wk)

6.0 f 5.5 (2-l 2) (median: 4)

-

Current

GAF

23.4 rt 7.9 (1 O-46)

Global SANS Global SAPS

-

1.6 + 1.4 (O-4)

-

4.0 f 0.9 (2-5)

-

44.8 f 6.1 (28-58)

Total BPRS

-

Note. Data are presented as mean f SD; the range is given in parentheses. GAF = Global Assessment of Functioning. SANS = Scale for the Assessment of Negative Symptoms. SAPS = Scale for the Assessment of Positive Symptoms. BPRS = Brief Psychiatric Rating Scale.

variable differences reached the 5% level of statistical significance, the MANOVA was significant (F= 3.24; df = 3, 112; p < 0.025). Both SRIF and TRH levels tended to be reduced in patients(F= 3.56; df= 1, 114;p=O.O61, and F= 3.55; df= 1, 114; p = 0.062, respectively), while CRH showed a nonsignificant tendency rather to increase (Table 2). Since the schizophrenic group contained both sexes but all controls were women, we compared the female schizophrenic patients with the controls. The results were almost identical to those for the total group of patients (MANOVA: F = 3.81; df= 3, 75; p = 0.014; the means for the female patients were: CRH, 52.6 + 20.2; SRIF, 24.0 + 9.7; TRH, 2.5 + 1.7).

Table 2. Neuropeptide concentrations (pg/ml) in the cerebrospinal fluid of schizophrenic patients and controls Corticotropin (CRH) Somatostatin Thyrotropin (TRH)

Schizophrenia

Controls

54.3 f

47.0 f

releasing hormone

(SRIF)

22.7 (12-152)

25.4 + 12.4 (4.4-81)

7.9 (27-61)

30.0 + 11.9 (5.6-67)

releasing hormone 3.0 zlz 2.4 (0.1-14.5)

3.7 +

2.9 (1.1-16.6)

Note. Data are presented as mean f SD, the range is given in parentheses. The difference is significant by multivariate analysis of variance: Wilks’ lambda = 0.920, p < 0.025. None of the univariate differences reached the 5% level of statistical significance (CRH: p > 0.33, SRIF: p = 0.09).

Because of significant differences in the background variables (sex, age, and body height) between schizophrenic patients and controls, we tested the group differences after the effects of the first four variables in Table 1 were covaried by a MANCOVA procedure; the differences between schizophrenic patients and controls did not decrease but in fact slightly increased (F= 3.23; df = 4, 111; p = 0.015). There was no statistically significant difference among the schizophrenic subtypes

17 regarding their CSF neuropeptide concentrations (Table 3). The mean age of the paranoid subgroup was significantly higher (41.7 f 10.1 years) than that in the other patients (33.7 f 9.8 years), and body weight and height were also inhomogeneous among the subgroups. Again, partialing out the effects of sex, age, body weight, and height did not change the statistical homogeneity of the schizophrenic subgroups, regarding their CSF peptide levels (F = 0.38; df = 12, 209; p > 0.96). Table 3. Neuropeptide concentrations (pg/ml) in the cerebrospinal fluid of four subtypes of schizophrenic disorders Thyrotropin Corticotropin releasing releasing hormone Somatostatin hormone SD

Mean

SD

Mean

SD

53.3

25.0

24.6

12.6

2.9

2.3

52.9

20.2

26.7

12.5

3.8

3.0

59.6

23.6

24.2

9.3

1.9

0.4

57.3

14.4

28.0

13.5

3.5

2.4

Mean Paranoid

(n = 55)

Disorganized Catatonic

(n = 12)

(n = 6)

Schizophreniform

(n = 13)

Note. The difference among the subgroups was not statistically significant by multivariate analysis of variance: Wilks’ lambda = 0.953, p > 0.90.

We examined the effects of previous number of hospitalizations, time from first onset, duration of present psychotic episode, and current GAF on the three CSF peptide concentrations (Table 4): none of the multiple regression analyses yielded significant results. These regressors explained only 2% of CRH, 8% of SRIF, and < 10% of TRH variance in the CSF. Table 4. Multiple regression analysis of three cerebrospinal fluid neuropeptides with clinical variables as predictors HOSP

ONSET

DUR

GAF

CRH

0.00

-0.00

0.11

R2

-0.10

0.017

> 0.83

SRIF

0.19

-0.02

-0.11

0.18

0.077

>0.15

TRH

0.18

-0.31

0.05

0.16

0.095

> 0.08

P

Note. CRH = corticotropin releasing hormone. SRIF = somatostatin. TRH = thyrotropin releasing hormone. HOSP = number of hospitalizations. ONSET = time from first onset. DUR = duration of present episode. GAF = current Global Assessment of Functioning score. The first four columns are (rounded) standard p coefficients.

The psychometric variables (BPRS and its factors, SANS, and SAPS) were also found to show almost no relationship to the CSF concentrations of the three neuropeptides (Table 5); they explained only 1% of the CRH, 3% of the SRIF, and 12% of the TRH variance. Only a single /3 coefficient was statistically significantless than could be expected by chance alone. There was no significant difference between the neuropeptide results of the 14 patients who received single doses of chloprothixene (50 mg) before the lumbar puncture and of those who received no neuroleptic medication (F= 0.37; df = 3,82; p > 0.77). Twenty-eight patients received either benzodiazepines or chlormethiazole before the lumbar puncture, while 44 patients remained completely drug free during the initial period: the latter two groups showed no neuropeptide differences (F= 0.32;

18

Table 5. Psychopathometric variables and cerebrospinal fluid neuropeptides: Multiple SANS SAPS

BPRS

THD

SUS

WD

A/D

R*

p

CRH

0.01

0.01

-0.18

0.06

0.06

0.13

-0.00

0.019

> 0.98

SRIF

-0.14

-0.07

-0.10

-0.05

0.13

0.28

0.04

0.053

> 0.73

TRH

-0.28

-0.11

0.1 1

0.132

> 0.12

N&e. SANS BPRS WD =

0.03

-0.27

-0.08

-0.03

CRH = corticotropin releasing hormone. SRIF = somatostatin. TRH = thyrotropin releasing hormone. = Scale for the Assessment of Negative Symptoms. SAPS = Scale for the Assessment of Positive Symptoms. = Brief Psychiatric Rating Scale, and its factors: THD = thought disorder, SUS = suspiciousness, withdrawal, A/D anxiety/depression.

df = 3, 68; p > 0.81). Contrasting the 23 “drug-naive” (i.e., never-medicated) schizophrenic/ schizophreniform subjects with the rest of the patients again revealed no significant difference (F = 0.50; df = 3,82; p > 0.68). The neuropeptide means of the 44 patients who received no drugs at all were almost identical to those of the total schizophrenic group (CRH: 55.3 + 26.8, SRIF: 25.3 * 13.4, TRH: 3.1 + 2.5; see Table 2). Finally, to test the possible effects of storage, transport, and other timerelated factors, we examined the CSF peptide results from the six subsequent shipments (from 1987 through 1990; the shipments did not represent separate assays): no significant difference emerged (F = 0.26; df = 15, 216; p > 0.99).

Discussion Despite the statistically significant multivariate difference of CSF neuropeptides in schizophrenia/ schizophreniform patients vs. controls, we believe that this finding must be interpreted with extreme caution. The overlap between the individual values of patients and controls was large for all three peptides (see ranges in Table 2) and the mean differences were too small (15% for CRH, 18% for SRIF, and 23% for TRH) to be biologically meaningful. Levels of CRH in CSF were previously found to be similar to control values in patients with schizophrenia (Nemeroff et al., 1984b). In a previous article (Banki et al., 1987), we observed a significant elevation of CSF CRH in acutely ill schizophrenic patients; on closer observation, that result was mainly due to only three markedly elevated individual values. Both the control and the schizophrenic means were comparable in the two studies (controls: 47.0 vs. 40.3 pg/ml; patients: 54.3 vs. 57.8 pg/ml). More important, the lack of significant correlations between CSF CRH and the background, clinical, or psychometric variables makes it unlikely that CSF CRH concentrations are related to the disorder itself or to some of its essential features. It must be remembered, however, that little is known about CRH concentration in brain tissue in schizophrenia; the origin of CRH found in the lumbar CSF is unclear; and it is yet to be determined whether the concentration of CRH in CSF reflects CRH content or release in the brain (Bissette and Nemeroff, 1988; Widerlov, 1988). SRIF has been found to be reduced in the CSF in various neurologic and psychiatric conditions, suggesting the nonspecificity of the findings (Rubinow et al., 1984; Nemeroff et al., 1987); some authors have speculated that SRIF decrease might indicate global cognitive impairment or a general neuronal dysfunction. Though

19 CSF SRIF concentrations tended to be lower in schizophrenic patients in the present and the overlap with control values was study, the decrease was moderate, considerable; therefore, we believe that this small mean decrease has no clear biologic significance. Our SRIF values were uniformly lower than those from other laboratories (Rubinow et al., 1984), perhaps because we did not use acidic preservatives; however, this did not affect intergroup differences. Again, the remarkable lack of correlation between CSF SRIF and several clinical variables (e.g., subtypes, positive and negative symptom clusters, and BPRS factors) argues against the extensive involvement of SRIF in the pathogenesis of schizophrenia. To date, little information has been reported about CSF TRH values in psychiatric patients, and we are not aware of any specific report on schizophrenic patients. CSF TRH may be elevated in major depression (Banki et al., 1988) and may be normal in psychotic mania. Brain TRH was reported to be reduced in the frontal cortex of schizophrenic patients (Nemeroff and Bissette, 1985); in another study, no difference in the TRH concentration in the amygdala was found between schizophrenic subjects and controls (Biggins et al., 1983). However, this latter sample was small (n = 7), and the clinical descriptions were unsatisfactory. As in the case of CRH, TRH is widely distributed in the central nervous system (Griffiths, 1985), and it is not known which region contributes most to the lumbar TRH content. At present, CSF neuropeptide concentrations must be viewed as a rough and global marker of the overall peptide production within the central nervous system. In conclusion, despite the minor but significant differences of neuropeptide concentrations between schizophrenic and control subjects, we interpret this study as predominantly negative; this conclusion is essentially based on the lack of relationship between the peptide levels and the clinical, psychometric variables. It must be noted, however, that the absence of lumbar CSF neuropeptide markers does not mean that neuropeptides are not involved in schizophrenia: Profound regional, or even global, alterations may exist without measurable abnormalities in the CSF. Further research (e.g., in vivo visualization of neuropeptides or their receptors) may elucidate a role of neuropeptides in the pathogenesis of schizophrenia. References American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd ed., revised. Washington, DC: American Psychiatric Press, 1987. Andreasen, N.C. Negative symptoms in schizophrenia: Definition and reliability. Archives of General Psychiatry, 39:784-788, 1982. Andreasen, N.C. Evaluation of positive and negative symptoms in schizophrenia. Psychiatry & Psychobiology, 2: 108-12 1, 1986. Arana, G.W.; Baldessarini, R.J.; and Ornsteen, M. The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Archives of General Psychiatry, 42:1193-1204, 1985. Banki, C.M.; Arat6, M.; and Rihmer, Z. Neuroendocrine differences among subtypes of schizophrenic disorder. Neuropsychobiology, 11: 174-177, 1984. Banki, C.M.; Bissette, G.; Arat6, M.; and Nemeroff, C.B. Elevation of immunoreactive CSF TRH in depressed patients. American Journal of Psychiatry, 145:1526-1531, 1988. Banki, C.M.; Bissette, G.; Arat6, M.; O’Connor, L.; and Nemeroff, C.B. CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. American Journal of Psychiatry, 144:873-877, 1987.

20 Biggins, J.; Perry, E.K.; McDermott, J.R.; Smith, LA.; Perry, R.H.; and Edwardson, J.A. Postmortem levels of thyrotropin-releasing hormone and neurotensin in the amygdala in Alzheimer’s disease, schizophrenia and depression. Journal of Neurological Sciences, 58: 117122, 1983. Bissette, G., and Nemeroff, C.B. The role of neuropeptides in the pathogenesis and treatment of schizophrenia: In: Nemeroff, C.B., ed. Neuropeptides in Psychiatric and Neurological Disorders. Baltimore: John Hopkins University Press, 1988. pp. 49-75. Bissette, G.; Widerlov, E.; Walleus, H.; Karlsson, I.; Eklund, K.; Forssman, A.; and Nemeroff, C.B. Alterations in CSF concentrations of somatostatin-like immunoreactivity in neuropsychiatric disorders. Archives of General Psychiatry, 43:1148-l 154, 1986. Carroll, B.J. Dexamethasone suppression test: A review of contemporary confusion. Journal of Clinical Psychiatry, 46: 13-24, 1985. Crow, T.J. The biology of schizophrenia. Experientia, 38: 1275-1279, 1982. Dillon, W.R., and Goldstein, M. Multivariate Analysis: Methods and Application. New York: John Wiley & Sons, 1984. Doran, A.R.; Rubinow, D.R.; Roy, A.; and Pickar, D. CSF somatostatin and abnormal response to dexamethasone administration in schizophrenic and depressed patients. Archives of General Psychiatry, 43:365-369, 1986. Gerner, R.H. Cerebrospinal fluid cholecystokinin and bombesin in psychiatric disorders and normals. In: Post, R.M., and Ballenger, J.D., eds. Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins, 1984. pp. 388-392. Griffiths, E.C. Thyrotropin-releasing hormone: Endocrine and central effects. Psychoneuroendocrinology, 10:225-235, 1985. Jablensky, A., and Sartorius, N. Is schizophrenia universal? Acta Psychiatrica Scandinavica, 78(Suppl. 344):65-70, 1988. Langer, G.; Koinig, G.; Hatzinger, R.; Schonbeck, G.; Resch, F.; Keshavan, MS.; and Sieghart, W. Response of thyrotropin to thyrotropin-releasing hormone as predictor of treatment outcome. Archives of General Psychiatry, 43:861-868, 1986. Loosen, P.T. The TRH-induced TSH response in psychiatric patients: A possible neuroendocrine marker. Psychoneuroendocrinology, 10:237-260, 1985. Loosen, P.T., and Banki, CM. The use of nonopiate neuropeptides as diagnostic tools in psychiatric and neurological disorders. In: Nemeroff, C.B., ed. Neuropeptides in Psychiatric and Neurological Disorkrs. Baltimore: John Hopkins University Press, 1988. pp. 18-48. Nemeroff, C.B., and Bissette, G. Involvement of non-opioid peptides in the pathogenesis of neurological and psychiatric disorders: Evidence from CSF and postmortem studies. Progress in Clinical and Biological Research, 1921333-341, 1985. Nemeroff, C.B.; Kalivas, P.W.; Golden, R.N.; and Prange, A.J. Behavioral effects of neurotensin, substance P and other neurohypothalamic hypophysiotropic hormones, peptides. Pharmacology and Therapeutics, 24: l-56, 1984a. Nemeroff, C.B.; Walsh, T.J.; and Bissette, G. Somatostatin and behavior: Prechnical and clinical studies. In: Reichlin, S., ed. Somatostatin. New York: Plenum Press, 1987. pp. 157-167.

21 Nemeroff, C.B.; Widerliiv, E.; Bissette, G.; Walleus, H.; Karlsson, 1.; Eklund, K.; Kilts, C.D.; Vale, W.; and Loosen, P.T. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science, 226: 1342-1344, 19846. Nemeroff, C.B.; Youngblood, W.W.; Manberg, P.J.; Prange, A.J.; and Kizer, J.S. Regional brain concentrations of neuropeptides in Huntington’s chorea and schizophrenia. Science, 221:972-975, 1983. Overall, J.E., and Gorham, D.R. The Brief Psychiatric Rating Scale (BPRS): Recent developments in ascertainment and scaling. Psychopharmacology Bulletin, 24:97-100, 1988. Roy, A.; Pickar, D.; Doran, A.; Wolkowitz, 0.; Gallucci, W.; Chrousos, G.; and Gold, P. W. The corticotropin-releasing hormone stimulation test in chronic schizophrenia. American Journal of Psychiatry, 143: 1393-1397, 1986. Rubinow, D.R.; Gold, P.W.; Post, R.M.; Ballenger, J.C.; and Cowdry, R.W. Somatostatin in patients with affective illness and in normal volunteers. In: Post, R.M., and Ballenger, J.C., eds. Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins Company, 1984. pp. 369-387. Stevens, J.R. The neuropathology of schizophrenia. Psychological Medicine, 12:695-710, 1982.

van

Praag,

H.M.

About

the impossible

concept

of schizophrenia.

Comprehensive

Psychiatry, 17:481-497, 1976.

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