low levels of somatostatin in human csf mark depressive episodes

16
Psychoneuroendocrinology, Vol. 9. No. 3, pp. 233 -248, 1984. 0306-4530/8453.00 + 0.00 Printed in Great Britain. © 1984 Pergamon Press Ltd. LOW LEVELS OF SOMATOSTATIN IN HUMAN CSF MARK DEPRESSIVE EPISODES o HANS AGREN* and GUDMAR LUNDQVISTt *Department of Psychiatry and tDepartment of Clinical Chemistry, University Hospital, S-751 85 Uppsala, Sweden (Received 27 April 1983; in final form 20 December 1983) SUMMARY Somatostatin-like immunoreactivity was measured in the cerebrospinal fluid (CSF) of 85 in- patients with current or recent episodes of major depressive disorders, diagnosed according to Research Diagnostic Criteria (RDC) as assessed with the Schedule for Affective Disorders and Schizophrenia (SADS). Several biopsychiatric tests were run during the same week of investigation. Results indicate low levels of CSF somatostatin to be a state marker for episodes of depression characterized by sad appearance, feelings of tiredness, insomnia, and subjective inability to acknowledge any external precipitants for the depression. CSF somatostatin was negatively related to platelet monoamine oxidase (MAO) activity; MAO activity appeared to account better for the degree of melancholic features than did somatostatin. The ratio between 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in CSF also correlated negatively with somatostatin. A positive relationship was noted between CSF xanthine and somatostatin. There was a highly significant curvilinear correlation between CSF somatostatin and serum TSH concentrations, but no correlations between CSF somatostatin and serum GH or prolactin, or with plasma cortisol before or after dexamethasone. SOMATOSTATIN is a cyclic tetradecapeptide (MW 1640 daltons) that inhibits the release of growth hormone (GH) from the pituitary (Vale et al., 1975). The name "panhibin" has been suggested to emphasize its powerful inhibitory function in a number of systems, including TSH release (McCann, 1982). Somatostatin-like immunoreactivity is widely distributed in rat brain (Brownstein et al., 1975; Kobayashi et al., 1977). In a post-mortem study on humans, Eckernas et al. (1978) found rather high concentrations of somatostatin in the neostriatum, while the highest levels were localized in the hypothalamus and in the medial part of the amygdaloid complex. S¢rensen (1982) studied human brain material obtained during neurosurgical operations of twelve patients and found somatostatin- positive cell bodies to be widely distributed and present in all cortical layers and in all areas studied (frontal, parietal and temporal). Cell bodies were numerous in the cortex, especially in layer I, where somatostatin fibers were in close contact with other cells. Very large somatostatin cells with long fibers were found throughout the subcortical white matter. Somatostatin- and avian pancreatic polypeptide (APP)-like immunoreactivities were reported by Vincent et al. (1982) to coexist in the rat forebrain (neocortex, hippocampus, and other areas) and, at least in the peripheral nervous system, somatostatin has been shown to occur in some sympathetic noradrenergic neurons (HOkfelt et al., 1977). The importance of the somatostatin system is demonstrated by the finding of this peptide in all regions of the fetal rat brain as early as 14 days post-mating (McGregor et al., 1982). o Correspondence to be addressed to H. Agren, NIMH, Bldg. 10, Room 4S239, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20205, U.S.A. 233

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Page 1: Low levels of somatostatin in human CSF mark depressive episodes

Psychoneuroendocrinology, Vol. 9. No. 3, pp. 233 - 2 4 8 , 1984. 0 3 0 6 - 4 5 3 0 / 8 4 5 3 . 0 0 + 0.00 Printed in Great Britain. © 1984 Pergamon Press Ltd.

L O W L E V E L S O F S O M A T O S T A T I N I N H U M A N C S F

M A R K D E P R E S S I V E E P I S O D E S o

HANS AGREN* a n d GUDMAR LUNDQVISTt

*Department of Psychiatry and tDepartment of Clinical Chemistry, University Hospital, S-751 85 Uppsala, Sweden

(Received 27 April 1983; in final form 20 December 1983)

SUMMARY

Somatostatin-like immunoreactivity was measured in the cerebrospinal fluid (CSF) of 85 in- patients with current or recent episodes of major depressive disorders, diagnosed according to Research Diagnostic Criteria (RDC) as assessed with the Schedule for Affective Disorders and Schizophrenia (SADS). Several biopsychiatric tests were run during the same week of investigation. Results indicate low levels of CSF somatostatin to be a state marker for episodes of depression characterized by sad appearance, feelings of tiredness, insomnia, and subjective inability to acknowledge any external precipitants for the depression. CSF somatostatin was negatively related to platelet monoamine oxidase (MAO) activity; MAO activity appeared to account better for the degree of melancholic features than did somatostatin. The ratio between 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in CSF also correlated negatively with somatostatin. A positive relationship was noted between CSF xanthine and somatostatin. There was a highly significant curvilinear correlation between CSF somatostatin and serum TSH concentrations, but no correlations between CSF somatostatin and serum GH or prolactin, or with plasma cortisol before or after dexamethasone.

SOMATOSTATIN is a cyclic tetradecapeptide (MW 1640 daltons) that inhibits the release of growth hormone (GH) from the pituitary (Vale et al., 1975). The name "panhibin" has been suggested to emphasize its powerful inhibitory function in a number of systems, including TSH release (McCann, 1982). Somatostatin-like immunoreactivity is widely distributed in rat brain (Brownstein et al., 1975; Kobayashi et al., 1977). In a post-mortem study on humans, Eckernas et al. (1978) found rather high concentrations of somatostatin in the neostriatum, while the highest levels were localized in the hypothalamus and in the medial part of the amygdaloid complex. S¢rensen (1982) studied human brain material obtained during neurosurgical operations of twelve patients and found somatostatin- positive cell bodies to be widely distributed and present in all cortical layers and in all areas studied (frontal, parietal and temporal). Cell bodies were numerous in the cortex, especially in layer I, where somatostatin fibers were in close contact with other cells. Very large somatostatin cells with long fibers were found throughout the subcortical white matter. Somatostatin- and avian pancreatic polypeptide (APP)-like immunoreactivities were reported by Vincent et al. (1982) to coexist in the rat forebrain (neocortex, hippocampus, and other areas) and, at least in the peripheral nervous system, somatostatin has been shown to occur in some sympathetic noradrenergic neurons (HOkfelt et al., 1977). The importance of the somatostatin system is demonstrated by the finding of this peptide in all regions of the fetal rat brain as early as 14 days post-mating (McGregor et al., 1982).

o Correspondence to be addressed to H. Agren, NIMH, Bldg. 10, Room 4S239, National Institutes of Health,

9000 Rockville Pike, Bethesda, MD 20205, U.S.A.

233

Page 2: Low levels of somatostatin in human CSF mark depressive episodes

234 HANS AGREN and GUDMAR LUNDE)VI~,'I

Somatostatin-like immunoreactivity is measurable in the cerebrospinal fluid (CSF) of primates and humans. Several studies have concluded that the origin of CSF somatostatin is extra-hypothalamic (Berelowitz et al . , 1981, 1982; S~rensen et al. , 1981). Findings of reduced levels of CSF somatostat in in various clinical disorders thus are of particular interest, in view of the potential of tracing extra-hypothalamic or even cortical peptide derangements in these disorders. Low levels of CSF somatostat in have been reported as an irreversible abnormali ty in patients with Parkinson 's disease (Dupont et al. , 1982), and reversibly low levels have been reported in patients with multiple sclerosis during relapse (Serensen et a l . , 1980). A distinct reduction was found in patients with Alzheimer's disease and mixed dementias (Wood et al . , 1982), and decreases have been reported in patients with anorexia nervosa and depression (Gerner & Yamada, 1982). Low levels in depressives also were reported by Post et al. (1982), who reported the serotonin reuptake inhibitor zimelidine to significantly increase CSF somatostatin. Rubinow et al. (1983) found clearly lower CSF somatostat in levels in 47 affectively disordered patients compared to 39 normal volunteers. A negative correlation of CSF somatostat in with CSF 5-hydroxyind.oleacetic acid (5HIAA) and CSF noradrenalin was found in a subsample of 17 patients.

The present study was prompted by the heuristic value that could be attached to any demonstrated connection between pathological behavior, known brain regulatory systems, and a widely distributed brain peptide like somatostat in that is localized in the cortex and other areas crucially involved in behavior and mood regulation. Relations with other well-researched psychobiological markers in depression such as CSF monoamine metabolites, platelet MAO activity, and endocrine measures such as plasma cortisol, TSH, GH, and prolactin and the TSH, G H and prolactin responses to T R H would enhance a theoretical understanding of their regulation. Any relation with indices of brain purinergic function as measured by CSF levels of xanthine and hypoxanthine would increase knowledge in a novel area. Is there a special quality to a psychiatric expression of decreased brain somatostat in activity? I f CSF levels are low in depression, what affective symptoms covary with somatostatin? What clinical value do blood measures of hormones like TSH, that is partly controlled by somatostatin, have in assessing central somatostatin function? These questions were addressed in the present study of 85 affective patients forming part of a comprehensive ongoing Uppsala study on the psychobiology of depression.

METHODS Patients

Eighty-five patients were diagnosed as having major depressive disorders according to the Research Diagnostic Criteria (RDC), as assessed with the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott & Spitzer, 1979). Of 73 patients with a distinctly episodic illness, 21 were at their worst during the week of investigation, 27 had experienced the peak of their present depression between two weeks and two months before investigation, and for 25 the peak had occurred more than two months before. Twenty-two patients scored less than 12 on the Hamilton Rating Scale for Depression for the present week (extracted from the SADS) (Endicott et al., 1981) and thus were out of their recent depression. Fifty-five were unipolar depressives, 23 were bipolar II and only six were bipolar I. Fifty-six were primary depressives, of whom 21 were pure, six were spectrum and eight were sporadic unipolars, according to the classification ofWinokur et al. (1978). Among the 28 secondary depressives, seven had suffered from alcoholism, 13 had generalized anxiety disorder, nine had panic disorder, four had phobic disorder, seven had obsessive - compulsive disorder, and one was an antisocial personality. There were no cases of schizophrenia and only two cases of schizoaffective disorder, but eight had

Page 3: Low levels of somatostatin in human CSF mark depressive episodes

DEPRESSIVE EPISODES AND SOMATOSTATIN 235

schizotypal features. Nine patients were psychotic. The mean number of depressive symptoms in the RDC checklist for major depressive disorder (minimum criterion is 3) was 6.0 + 1.4 (S.D.). The mean number of earlier depressive episodes was 11.2 (range, 0 to more than 100). Other descriptive patient data on a similar patient sample have been reported earlier (~gren & Wide, 1982).

All patients were hospitalized on a research ward for at least five days. They Were free from any antidepressant or neuroleptic medication for a minimum of 10 days before lumbar punctures, although the great majority were off these drugs for a considerably longer time. Thirty patients had not taken benzodiazepines for many weeks before investigation; 32 used it daily but irregularly on demand; and 22 were on a regular daily benzodiazepine schedule.

CSF sampling Lumbar punctures (LP) were performed in the lateral recumbent position in a standardized fashion (at 0800 to

0900 hr, patient bedresting and fasting since midnight, always 13 ml withdrawn and mixed well). To the portions set aside for peptide analyses were added 400 KIE Trasylol per ml (Bayer, Leverkusen). CSF was rapidly frozen at - 20°C and stored for varying lengths of time at - 70°C until assay. Samples were thawed at + 4°C. Portions for analysis of monoamine metabolites were sent frozen within one week after sampling by mail to L. Svennerholm at St. J0rgen's Hospital, GOteborg.

Analysis o f CSF somatostatin Somatostatin-like immunoreactivity in CSF was measured with a solid phase radioimmunoassay (Lundqvist et

al., 1980), with somatostatin antibodies coupled to microcrystalline cellulose. The antiserum used, R 141, is well characterized with respect to reactivity against different parts of the somatostatin molecule (Arimura et al., 1978) as well as to the lack of immunoreactivity against other peptides in the CNS and the gastrointestinal tract. Tyr-l-somatostatin (Beckman, Geneva) was used for iodination by the lactoperoxidase method, and synthetic somatostatin (Beckman, Geneva) was used for standards. Parallelism between CSF somatostatin from various dilutions of CSF samples and the standard curve was taken as evidence of the identity between the synthetic standard and CSF somatostatin.

Other analyses CSF monoamine metabolites were analyzed in GOteborg by a method described elsewhere (Andersen et al.,

1981). Analyses of serum and plasma hormones were performed as described in detail elsewhere (Agren & Wide, 1982). The dexamethasone suppression test (DST) performed two to three days after the LP used dexamethasone (1 mg p.o.) given at 2300 hr, with plasma samples for cortisol drawn at 0800, l l00 and 2300 hr before dexamethasone, and at 0800, 1100, and 2000 hr the day after. The TRH test was always performed at least a day and a half before dexamethasone was administered and two to three hours post-LP. Serum TSH was drawn before and 30 min after an injection of TRH (200 ~tg i.v.); serum GH and prolactin were analyzed in the same blood samples by L. Wide using routine radioimmunoassay methods at the Department of Clinical Chemistry of our hospital. Platelet monoamine oxidase (MAO) activity was measured by L. Oreland at Department of Pharmacology, Umdi University, as described by ~gren & Oreland (1982). Analysis of the CSF purine metabolites hypoxanthine and xanthine has been detailed elsewhere (Niklasson et al., 1983; .g, gren et al., 1983). L. Terenius measured CSF endorphins (fractions l and II) by radioreceptorassay (~gren et aL, 1982).

Statistical analysis All data were processed by a mainframe computer (IBM 4341) at the Uppsala University Computing Center

using SAS (Statistical Analysis System, Inc.) procedures (Correlation, Frequency, General Linear Models, Stepwise Regression and Plot). Statistical problems encountered in correlating many variables with each other have been discussed elsewhere (,~gren, 1981; Agren & Wide, 1982; Agren, 1983). The ANCOVA method employed to adjust biological and symptom variables to the same sex ("intersex"), age (40 years), height (170 cm) and weight (67 kg) has been detailed elsewhere (Agren, 1983).

RESULTS

T h e m e a n v a l u e _+ S . D . o f C S F s o m a t o s t a t i n in t h e 85 p a t i e n t s was 16.7 _ 5 .5 p g / m l .

B a s e d o n m u l t i p l e r e g r e s s i o n a n a l y s i s , s o m a t o s t a t i n c o r r e l a t e d n o n s i g n i f i c a n t l y w i t h t h e

p a t i e n t s ' sex, age , h e i g h t a n d w e i g h t ( v a r i a n c e in s o m a t o s t a t i n a c c o u n t e d f o r b y t h e s e f o u r

p r e d i c t o r s w a s o n l y 4 . 2 % ) . N e v e r t h e l e s s , t h e i n d i v i d u a l p r e d i c t o r c o e f f i c i e n t s ( t h e b

v a l u e s ) w e r e u s e d t o a d j u s t s o m a t o s t a t i n leve ls t o a se t p a t i e n t c o n d i t i o n w i t h s a m e sex,

Page 4: Low levels of somatostatin in human CSF mark depressive episodes

o

236 HANS AGREN and (-iUI)MAR LUNDQVISI

age, height and weight. The distributions of raw and adjusted somatostatin levels are shown in Fig. 1.

0 r -

== o"

u.

._,=

rc

CSF Sornatostat in ( n -85 )

an 16.6

SD 5.4

an 16.3

pg/ml

in 16.7

SD 5.5

in 16.0

FIG. 1. Distributions and means of somatostatin in CSF of 85 depressive patients. The distribution of raw values is not significantly different from a Gaussian one (Kolmogorov- Smirnov D = 0.099, p = NS), while the distribution of values adjusted to same sex, age, height and weight of patients is significantly non-Gaussian

(D = 0.106, p = 0.016).

Severity of depression Correlating both raw and adjusted somatostatin values with various clinical measures

of depression revealed highly significant relationships. Table I demonstrates lower CSF values in the more severe depressions, especially as judged by the GAS (Global Assessment Scale, included in the SADS; the lower the rating the more handicapping the illness). Clearly significant correlations also were found with the Endogeneity subscale of the SADS, implying less CSF somatostatin in the more endogenous patients. Similar significances were obtained when the somatostatin measure was dichotomized, with the upper quartile ( 7 5 - 1 0 0 percentiles) contrasted against the lower quartile ( 1 - 2 5 percentiles). However, the correlation with the Endogeneity subscale appeared to be due to the strong correlation between the Endogeneity and GAS scores, since partiatling out the influence of the GAS scale from the correlation between somatostatin and Endogeneity reduced the r value to around zero. On the other hand, partialling out the influence o f Endogeneity from the link between somatostatin and GAS weakened the significance but did not abolish it (adjusted values: rSOM:GA s = 0.343, n = 85, p = 0.0013; rSOM:GAS:EN D = 0.238, n = 85, p = 0.027). Confining the analysis to only those 30 patients who were completely drug-free at investigation revealed unchanged correlations between somatostatin and the GAS scores (with GAS for past week: r = 0.543, n = 30, p = 0.0028). A conclusion would be that lower somatostatin levels characterize any severe depression, not only those with melancholic features.

Phase of depression Correlations between somatostatin and depth o f depression were stronger with severity

measures for the past week (the week preceding investigation) than fo r the worst week (the peak depressive week during the current or recent depression), as shown in Table I. Table

Page 5: Low levels of somatostatin in human CSF mark depressive episodes

DEPRESSIVE EPISODES AND SOMATOSTATIN 237

TABLE I. NEGATIVE CORRELATIONS BETWEEN SOMATOSTATIN IN CSF AND SEVERITY OF DEPRESSION (IN EACH "CELL", UPPER FIGURE IS PEARSON'S LOWER FIGURE 1S SIGNIFICANCE LEVEL)

Somatostat in Somatostat in Somatostat in lowest (0) vs

raw adjusted highest (1) values values quartile

(n = 85) (n = 85) (n = 42)

Hamil i ton scores for past week

Hamil ton scores for worst week

GAS scores for past week

GAS scores for worst week

Endogeneity sub-scale past week

Endogeneity sub-scale worst week

Raw - 0.236 0.030

Adj - 0.196 - 0.312 0.072 0.044

Raw - 0.186 0.088

Adj -0 .137 - 0 . 1 8 4 NS NS

Raw 0.378 0.0004

Adj 0.343 0.409 0.0013 0.0072

Raw 0.303 0.0048

Adj 0.262 0.346 0.016 0.025

Raw - 0.277 0.010

Adj - 0.257 - 0.377 0.018 0.014

Raw - 0.246 0.023

Adj - 0.234 - 0.290 0.031 0.063

Raw values: values not adjusted to same sex, age, height and weight. Adjusted values: adjusted to same sex, age, height and weight.

II shows increasing somatostatin levels the longer the time between the worst week and investigation. The same result is demonstrated in Table III for a nonparametric analysis, which indicates significantly more patients having somatostatin levels below the median if the worst week was close to investigation. This can be taken as indirect evidence of a relationship between CSF somatostatin levels and depressive phase.

Perception of stressful events One SADS item (No. 222) assesses patients' subjective conviction of stressful events as

being causally related to the precipitation of their illness, on a scale from 1 to 4 (1: no such

Page 6: Low levels of somatostatin in human CSF mark depressive episodes

o 238 HANS AGREN and GUDMAR LUNDQVISr

TABLE II . SOMATOSTATIN LEVELS IN C S F (pg/ml) IN 73 PATIENTS WITH DISTINCTLY EPISODIC COURSE OF DEPRESSIVE EPISODES, SPLIT FOR TIME LAPSED BETWEEN WORST WEEK OF PRESENT OR RECEN'f

DEPRESSION AND WEEK O'F INVESTIGATION

Time Adjusted lapsed CSF somatostat in

(months) n (pg/ml _+ 1 S.D.)

0 4,+42 Ia i t 0 . 5 - 2 27 15.2 ~ 5.3 ¢ c

b > 2 25 18.8 ± 5.8

t-Tests with equal variances: a NS; b t = 2.35, d.f. = 50, p = 0.023; c t = 2.62, d ~ = 44, p = 0.012.

TABLE 111. SOMATOSTATIN LEVELS IN CSF SPLIT INTO TWO GROUPS: LOWER QUARTILE ( 1 - 2 5 PERCENTILES; < 12.5 pg / ml , n = 2 0 ) AND UPPER QUARTILE (75 - - I00

PERCENTILES: ~> 20.4 pg /ml , n = 18)

Time Adjusted Adjus ted lapsed CSF somatosta t in CSF somatosta t in

(months) (< 12.5 pg/ml) (> 20.4 pg/ml)

0 7 3

0 . 5 - 2 8 4

> 2 5 11

x2= 5.09, d,f. --2, p < 0.05.

relation, 4: convinced of such relation). Table IV shows significantly more patients in the group with somatostatin levels in the lower quartile to be not clearly aware of any stressful event, and the opposite for patients in the upper quartile. Interestingly, there was no similar correlation with degree of stressful events as rated more or less objectively by the clinician.

TABLE IV. PATIENTS' CONVICTION THAT STRESSFUL EVENTS WERE CAUSALLY RELATED TO THE

DEVELOPMENT OF DEPRESSIVE EPISODE IN RELATION TO CSF SOMATOSTATiN LEVELS

Adjusted CSF somatosta t in (number o f patients)

In lower In upper quartile quartile

(< 12.5 pg/ml) (> 20.4 pg/ml)

Aware o f no stressful event o r

believes event was possibly related to the episode (SADS item 222, scores 1 - 2)

Subjective conviction that event was most likely o r a lmos t certainly related to the episode (SADS item 222, scores 3 - 4 )

15 7

4 12

X2 with Yates ' correction: for continuity = 5.29, d.f. = 1; p = 0.021. Fisher 's exact probability test: p = 0.0088.

Page 7: Low levels of somatostatin in human CSF mark depressive episodes

DEPRESSIVE EPISODES AND SOMATOSTATIN 239

Stepwise multiple regression with depressive symptoms Somatostat in was univariately correlated (using Pearson r) with over 100 depressive

SADS items, rated both for past week and for worst week of current or recent depression. In order to avoid obvious pitfalls like accepting Type II statistical errors as significant

o correlations, a random split-half methodology as described elsewhere (Agren, 1981, 1983; Agren & Wide, 1982) was used. Only 10 symptoms were retained for further analysis based on the following criteria: (1) a univariate correlation of p < 0.13 in the whole sample, and (2) a retained r value in both split-halves, with the weakest r not less than 30°7o of the r value in the undivided sample. After adjustment to the same sex, age, height and weight of patients, these 10 symptoms showed very minor changes in their correlations with adjusted somatostatin. The 10 adjusted symptoms were entered as predictor variables in a stepwise regression analysis with somatostatin as the predicted variable. A maximum R ' improvement technique (Draper & Smith, 1981, p. 307) selected an optimal combinat ion of depressive characteristics. Table V shows the final result:

TABLE V. SOMATOSTATIN IN CSF AND THREE DEPRESSIVE SADS ITEMS: TRI- AND UNIVARIATE CORRELATIONS (n = 85)

(ALL MEASURES ADJUSTED TO SAME SEX, AGE, HEIGHT AND WEIGHT OF PATIENTS)

Trivariate regression SADS items Range b F p

Univariate correlation r p

Depressed appearance 1-6 - 1.35 6.43 0.013 -0.325 0.0024

Subjective feeling of lack of energy or fatigue past week l - 6 - 0.88 4.05 0.048 - 0.283 0.0088

Insomnia worst week l -6 -0.68 3.56 0.063 -0.188 0.085

+25.7

Statistics for trivariate regression: R 2 = 0.191 ; F = 6.30; d.f. = 3,80; p = 0.0008.

"depressed appearance" particularly, but also "subjective feeling of lack of energy" and " i n s o m n i a " were negatively related to somatostat in levels, together accounting for 19070 of its variance (p < 0.001 for this trivariate regression). Testing this set of predictors on the completely drug-free subgroup of 30 patients disclosed an unchanged or even higher degree of variance accounted for (R ~ = 0.330; F = 4.10; d.f. = 3,26; p = 0.017). Thus, our depressed patients with low CSF somatostat in levels looked sad, felt tired and did not sleep well.

Correlations with monoamine metabolites The CSF levels of monoamine metabolites in these patients have been reported earlier

(Agren & Wide, 1982). Table VI lists univariate correlations between CSF somatostat in and the CSF dopamine metabolite homovanillic acid (HVA), the noradrenalin metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), and the serotonin metabolite 5-hydroxyindole- acetic acid (5HIAA), both for the raw values and for the values adjusted to same sex, age, height and weight. Results are shown both for the whole sample and split for the affective

Page 8: Low levels of somatostatin in human CSF mark depressive episodes

240 HaNS AGREN a n d GUDMAR LUNDQVIST

TABLE VI. CORRELATIONS BETWEEN SOMATOSTA'FIN AND MONOAMINE METABOLITES IN C S F

CSF monoamine metabolite

C S F somatostatin

All Bipo la r s U n i p o l a r s (n = 85) (n = 29) ~n = 55) l" r r

P P P

H V A

0 .082 0 .219 0 .021 Raw NS NS NS

A d j 0 .103 0 .255 0 .047 NS NS NS

M H P G

0.121 0 .111 0 .123 Raw NS NS NS

0.102 0 .044 0.125 A d j NS NS NS

5 H I A A

0 .152 0 .067 0 .162 Raw NS NS NS

O. 169 0 .029 0 .204 A d j NS NS NS

M H P G / H V A

- 0 .215 - 0 .162 - 0 . 2 2 9 Raw 0 .048 NS 0 .092

A d j - 0 .263 - 0 .244 - 0.271 0 .015 NS 0 .045

subtypes unipolar/bipolar depression. Only the ratio MHPG/HVA (adjustment was performed after division by subtype) demonstrated a significant and negative correlation with somatostatin (adjusted values: r= 0.263, n=85 , p=0.015) , that was strongest among unipolar patients even though the r values were quite similar in both diagnostic subgroups. Figure 2 (with n = 84) shows this relationship graphically. Benzodiazepine medication was unimportant in this connection, since the correlation coefficient among the 30 completely drug-free patients was unchanged (r= -0 .265) .

Correlation with serum TSH The mean (_ 1 S.D.) serum TSH in the 85 patients was 2.38 _+ 0.75 mU/l (range,

0 . 7 - 4.4 mU/1) The mean TSH increase on TRH stimulation was 7.2 +_ 7.7 mU/1 (range, 0 . 7 - 5 9 . 6 mU/l) . No patient showed any evidence of thyroid disorder (serum triiodothyronine was analyzed in 49 cases: mean 1.79 _ 0.32 nmol/l; range, 1.11 -2 .50; reference interval 1 . 4 - 3.2 nmol/l).

CSF somatostatin correlated significantly alut positively only with serum TSH (linearly between adjusted values: r = 0.307, n = 85, p = 0.0043; stronger in unipolars), but much weaker with the TSH inc.xe~.se following TRH stimulation (between adjusted values: r=0.214, n=85 , p=0.050) . Figure 3 illustrates a parabolic regression between somatostatin and TSH. As explained in the figure legend, curvilinearity (the squared

Page 9: Low levels of somatostatin in human CSF mark depressive episodes

DEPRESSIVE EPISODES AND SOMATOSTATIN 241

1 . 6 -

1 U.

t..) .E 0.8

~ o.6-

~ 0.4 +

~ 0.2.

0 0

• : e

o

• • o o

o o I - ~ e

o • ~ I t • ° • - • • • c

t'o 2'0 +o C S F Somatostatin, pg/ml

FIG. 2. Negative linear correlation between the ratio MHPG/HVA in CSF and CSF somatostatin. Regression for whole group (n = 84; line symbol ):r= -0.263, p=0.015. Unipolars only (symbols • and - - ) : r = - 0.27 l, n = 55, p = 0.045. Bipolars only (symbols C) and . . . . . ): r = - 0.244, n -- 29, NS. Thus, the r value is quite similar in both the unipolar and bipolar groups as compared with the undivided sample. Both variables

are adjusted to same sex, age, height, and weight.

5"

4-

E 3 . I I -

1-

• • 0 /

• • O ] e o • /

\ • o • ~ ° o

. . . . . . . . o , : Z \ ' ~ % 0 0 • • • / 0 • -

. • 2 .

• o •

8 . , 9 . 0 o o e" o

O Q

0 0 1'0 2'0 30

CSF Somatostat in, pg/ml

FIG. 3. Correlations between serum TSH and CSF somatostat in. Unipolar depressives (n = 46) have symbols • and - - ; bipolars (n = 29)-0 and - - - - . Regression line for whole group . Both measures are adjusted to same sex, age, height, and weight. Univariate correlation: Whole group: r = 0.307, p =0.0043. Unipolars: r=0 .328 , p = 0 . 0 1 4 . Bipolars: r=0 .242 , NS. Parabolic regression (shown in picture): Whole group R 2 =0.207; F = 10.71; d.f . =2,82; p=0 .0001 (SOM: F = 7 . 6 7 , p=0 .0070 ; SOM*SOM: F = 11.68, p=0 .0010) . Unipolars: R2=0.211; F = 6 . 9 3 ; d . f .=2 ,52 ; p=0 .0021 (SOM: F = 4 . 1 2 , p = 0 . 0 4 8 ; SOM*SOM: F = 6 . 7 7 . p=0 .012) Bipolars: R 2 = 0.209; F = 3.43; d.f. = 2,26; p = 0.048 (SOM: F = 3.92, p = 0.058; SOM*SOM: F = 4.94, p = 0.035). Thus, the correlations in the whole group are retained after splitting by affective subdiagnosis, and the squared somatostat in term is always more important than the simple one, demonstrat ing a significant curvilinearity.

s o m a t o s t a t i n t e rm) is in i t se l f s ign i f i can t , a n d m o r e so t h a n the l inear r e l a t i o n ( the s imp le

s o m a t o s t a t i n t e rm) . S o m a t o s t a t i n a c c o u n t e d fo r a b o u t 21070 o f the v a r i a n c e in T S H

(R ' = 0 .207; F = 10.71; d.f. = 2,82; p = 0.0001). D i v i d i n g the s a m p l e in to uni - a n d b i p o l a r s

r e su l t ed in v i r t u a l l y iden t i ca l p a r a b o l i c curves . T h e s a m e r e l a t i o n s h i p was f o u n d in the

d r u g - f r e e g r o u p (R 2 = 0.197).

Negative correlation with platelet MA 0 activity A s ign i f i c an t n e g a t i v e c o r r e l a t i o n e m e r g e d b e t w e e n p la t e l e t M A O ac t iv i ty a n d C S F

s o m a t o s t a t i n ( b e t w e e n r a w va lues : r - - - 0 .293, n = 68, p = 0 .015; b e t w e e n a d j u s t e d va lues :

Page 10: Low levels of somatostatin in human CSF mark depressive episodes

2 4 2 H A N S ,~GREN a n d GL/DMAR LUNDQVIST

r = - 0 . 2 6 1 , n = 68, p = 0 . 0 3 1 ) . In the d rug- f ree g roup the same re la t ionship held (raw values: r = - 0.324).

Positive correlation between depressive scores and both CSF somatostatin and platelet MA 0 activity

Figure 4 shows a th ree -d imens iona l over la id g raph o f p la te le t M A O act ivi ty and C S F s o m a t o s t a t i n levels co r re l a t ed with bo th Endogene i t y and G A S scores dur ing the week p reced ing inves t iga t ion . The stat is t ics a re given in the f igure legend. The slopes o f the border l ines be tween the " t e r r a c e s " o f the regress ion surfaces c lear ly demons t r a t e tha t Endogene i t y scores were m o r e re la ted to M A O than to soma tos t a t i n , whi le G A S scores were a b o u t equa l ly re la ted to bo th .

T 0.30,

'|0.20 _~'~

o.lo

GAS S c o r e s - Endogenlit y Scores . . . . . . . . . .

< 4 0 45 5 0 55 eo

>4o ""'"" ~ " ~ ; " .- ! / / '

_ . J _ 25 <20

1() 20 30 CSF Somatostatin, pg/ml

S5

: 7 0

FIG. 4. Computer-generated contour plot of bivariate correlations between scores of GAS (Global Assessment Scale, lower values more handicapping illness) and Endogeneity scores (higher values -- more melancholic features) for the week preceding investigation, and CSF somatostatin (x axis) and platelet MAO activity (y axis). On z axis are drawn "terraces" of the two overlaid regression surfaces. No significant interactions were found between somatostatin and MAO in accounting for either GAS or Endogeneity. Raw values were used; adjustment to same sex, age, height and weight produced minimal changes. Regressions: GAS = 44.4 ÷ 1.1 SOM - 64 MAO [R2=0.265; F= 11.72; d.f. =2,65; p=0.0001; F values for individual predictors: SOM (F= 13.88), MAO (F=3.47)1. Endogeneity = 28.4-0.6 SOM + 69 MAO [R2=0.184; F=7.34; d.f. =2,65; p = 0.0013; F values for individual predictors: SOM iF= 5.25), MAO (F= 5.13)]. Thus, platelet MAO activity

accounts better for endogeneity than does CSF somatostatin.

Positive relationship with CSF xanthine M e a n C S F levels (+ 1 S.D.) o f the pur ine me tabo l i t e s xan th ine and h y p o x a n t h i n e were

1.80 _ 0.49 lxmol/1 and 2.36 _ 0.73 ~tmol/ l , respect ively. There was a highly s igni f icant co r re l a t ion be tween xan th ine and s o m a t o s t a t i n (raw values: r = 0.292, n = 80, p = 0.009; ad jus t ed values: r = 0 . 2 8 8 , n = 8 0 , p = 0 . 0 1 ) . As shown in Fig. 5, the re la t ionsh ip was s t ronger a m o n g the b ipolars . The x a n t h i n e - soma tos t a t i n l ink was equa l ly s t rong in the comple t e ly d rug- f ree g r o u p o f pat ients ( r = 0 . 4 3 6 , n=30, p = 0 . 0 1 8 ) . N o l ink be tween s o m a t o s t a t i n and C S F h y p o x a n t h i n e was found (raw values: r= 0.056, n = 80, p = NS).

Apparent negative link with benzodiazepme intake There was a s t rong, direct co r r e l a t i on be tween C S F s o m a t o s t a t i n levels a n d

o p e r a t i o n a l l y r a t ed benzod iazep ine in take (scale 0 - 3 ) (r= -0.418, n= 82, p = 0 . 0 0 0 1 ) .

Page 11: Low levels of somatostatin in human CSF mark depressive episodes

DEPRESSIVE EPISODES AND ~OMATOSTATIN 243

B

o E

==

c c~ x

$

• o ~ ° ° ° • o

/ • o o • o o |

0 10 2'0 a0 CSF Somatostatin, pg/ml

Fz6. 5. Linear correlation between CSF concentrations of xanthine and somatostatin. Regression for whole group (n = 80; line symbol ): r = 0.288, p = 0.010. Unipolars only (symbols • and - - ) : r= 0.189, n=52, NS. Bipolars only (symbols ( ) and . . . . . ): r=0.521, n=27, p=0.0053. Thus, the strongest and significant correlation is accounted for by the bipolar patients. Both variables are adjusted to same sex, age,

height and weight of patients.

However, actively depressed patients consumed more benzodiazepines than those already improved at investigation. A nonparametric correlation between time lapsed from worst week of current or recent depression to day of investigation (divided in three groups as in Tables II and III) and rated benzodiazepine intake revealed a highly significant link (~2= 16.45, d.f. = 6, p = 0.012; and with benzodiazepine ratings 0 and 1 lumped together due to a very small number of l's: 22= 14.96, d.f. = 4,/9<0.005). As expected, the lowest intake was found among those already improved. The relation between benzodiazepine intake and somatostatin disappeared when only those patients who experienced their depressive peak during the week of investigation were taken into account (r=0.040, n = 20, NS), nor was it found among those with their worst week between 0.5 and two months before testing ( r = - 0 . 2 9 0 , n=26, NS). Thus, the correlation between benzodiazepine intake and somatostatin appears to be explained by the suggested depressive state-dependence of somatostatin.

No correlations with CSF endorphins Radioreceptorassayed levels of CSF endorphins (fractions I and II) were unrelated to

CSF somatostatin (r values close to zero). Details concerning the endorphin analyses and data can be found elsewhere (,~gren et al., 1983).

No obvious relationship with plasma cortisol No significant correlations existed between CSF somatostatin and plasma cortisol

measures at six time-points during dexamethasone tests, performed on a subsample of patients. The highest r value was obtained between somatostatin and postdexamethasone cortisol at 1100 hr (adjusted values: r = 0.213, n = 45, p = 0.16). Nor did any relationship become evident if only completely drug-free patients were considered (n = 22). Means and other data on cortisol can be found elsewhere (Agren & Wide, 1982).

Page 12: Low levels of somatostatin in human CSF mark depressive episodes

244 [Lx~. AGRI:N and (.iL D~.b\R Lt.NL~Q\ ~sl

N o correlat ions with s e rum G H and prolact in

The mean serum GH level (_+ 1 S.D.) on 21 patients was 2.2 ___ 1.6 txg/l (range, 0.5 7. l I~g/1). The mean serum protactin on 20 patients was 5.4 __. 3.8 ~tg/1 (range, 0.7- t5.6 ~tg/l). Thirty minutes after injection of 200 ~tg TRH, the mean GH change was 0.7 _ 1 .~ ~tg/l (range, - 1.1 to 5.0 ~tg/1), and the mean prolactin increase was 40.8 + 28.7 ~tg/l (range, 4.4 to 92.5 t~g/l). No relationships were found between CSF somatostatin and any of the above measures, even after logarithmic transformations of the data.

DISCUSSION

Our levels of CSF somatostatin-like immunoreactivity (mean _+ S.D.: 16.7 _+ 5.5 pg/ml) in 85 patients with major depressive episodes are lower than those reported by others focusing on other patient groups. Since we do not have any healthy controls for comparison, we can only discuss intrasample differences. Two studies from the same Danish laboratory have found quite high CSF somatostatin levels: 95 pg/ml in 11 patients with active multiple sclerosis (S¢~rensen et al., 1980); 88 pg/ml in 39 Parkinsonian patients and 147 pg/ml in 29 healthy controls (Dupont et al., 1982). Lower values, but still higher than ours, have been reported by Wood et al. (1982) (21 pg/ml in 11 patients with Alzheimer's dementia, 52 pg/ml in 32 healthy controls). Levels between 40-65 pg/ml were reported by Post et al. (1982), and Rubinow et al. (1983) reported 35.5 +_ 4.0 pg/ml for 25 depressed patients, 62.8 _+ 6.4 pg/ml for 39 normal volunteers, and 54.7 _ 5.6 pg/ml for 15 improved depressives. Gerner & Yamada (1982) found levels corresponding well with ours: 23 pg/ml in 29 healthy controls, t5 pg/ml in 28 depressives and 20 pg/ml in 23 women with anorexia nervosa. The differences among laboratories are most likely related to varying immunological activities of the standard preparations used. Varying specificities of antibodies against somatostatin also may have contributed.

There was no significant correlation of somatostatin with sex, age, height or weight of the patients. The absence of any link to body height argues against the suspicion that a major portion of somatostatin measured in lumbar CSF might originate in the spinal cord (a high concentration caudally in the dorsal horns in the rat spinal cord was reported by Stine et al., 1982).

A tentative result of this study is that currently depressed patients have lower CSF levels of somatostatin than patients already improved at the time of investigation and that depressives with lower values are characterized by key depressive features such as looking sad, feeling tired, not sleeping well and not recognizing any obvious external reasons why they feel the way tl~y do. Both the negative correlation found here between CSF somatostatin and platelet MAO activity and the connection between higher levels of MAO and the melancholic symptom of early morning awakening reported earlier (Agren & Oreland, 1982), as well as a more handicapping depression (lower GAS scores), suggest a covarianee between somatostatin and MAO in accounting for depressive episodes (Fig. 3).

Another link between somatostatin levels and monoamine-related indices was the negative relation with the ratio MHPG/HVA in CSF, suggesting the peptide to be somehow involved in a balance between catecholaminergic systems. Rubinow et al. (1983) found a negative relationship between somatostatin and noradrenalin in CSF. A modulatory role of both dopamine and noradrenalin in the regulation of hypothalamic

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DEPRESSIVE EPISODES AND SOMATOSTATIN 245

somatostatin has been proposed by Negro-Vilar et ~al. (1978) using in vitro experiments and by Torres et al. (1982) doing in vivo depletion studies in rats. Further, Garcia-Sevilla et al. (1978) found somatostatin administered intracerebroventricularly (i.c.v.) to stimulate monoaminergic neurons, both synthesis and utilization of dopamine, noradrenalin and serotonin. However, no CSF monoamine or monoamine metabolite has been successfully correlated with severity or phase of depressive episodes. It is conceivable that somatostatin represents a state marker of depression, and if so it may be intimately involved in the pathogenesis of depression. Oaae might view the status of monoaminergic neurons as influencing the phenomenological expression of a depression, since higher levels of, for example, CSF 5HIAA and HVA were seen in patients with more melancholic

o features and a better outcome (Agren, 1981). Are melancholic features the typical expression of a depressed patient with well-functioning monoaminergic systems (non-low CSF monoamine metabolites and/or high MAO activity)? Only a longitudinal study would support or disprove this hypothesis.

The absence of any clearcut relation between postdexamethasone plasma cortisol levels and CSF somatostatin may be interpreted in at least two ways. To be noted is that dexamethasone was always administered at least a day and a half after LP. First, the two putative indices of depressive phase might have different degrees of inertia, i.e. positive dexamethasone suppression tests (DSTs) might persist longer than lowered somatostatin. Second, if the DST is positive mainly in depressives with melancholia (Carroll et al., 1981) and low somatostatin were to be found in any major depressive insomniac looking sad and feeling tired, then a possible correlation between the two in a subset of depressed patients would not be discernible in a more heterogenous sample,

The curvilinear correlation between serum TSH and CSF somatostatin might be interpreted in the light of other studies. In our protocol, TRH was given two to three hours after LP. Somatostatin not only inhibits the release of GH, but it also can inhibit the stimulated secretion of TSH, and, in vitro, high concentrations of TRH cannot overcome a somatostatin block (Vale et al., 1975). A study of neonatal rats has suggested somatostatin to influence TSH ontogenetically before TRH (Oliver et al., 1982). Neonatal exposure of rats to propylthiouracil, resulting in mild adult hypothyroidism, was shown to permanently impair brain function, manifested in part by increased content of somatostatin in several brain areas, significantly so in hypothalamus, hippocampus and cortex (Kato et al., 1982). Another line of research related to TSH has been studies on thermoregulation and oxygen consumption. Somatostatin, like other neuropeptides, produces hypothermia, and TRH was able to antagonize this effect (Morley et al., 1982). Somewhat conflicting evidence was given by Brown (1982), who found the somatostatin analog ODT8-SS, given to rats i.c.v., to increase oxygen consumption and to reverse bombesin-induced hypothermia, probably by increasing body metabolism. This is in line with results by Moldow & Hollander (1981), who found that exposure of rats to cold stress prior to sacrifice increased the release of somatostatin from dispersed hypothalamic cells. Thus, several types of data support the notion that somatostatin and TSH may be negatively and positively correlated with each other in different somatostatin ranges, i.e. display a curvilinear relationship. The "disturbing" factor might well be TRH.

That CSF xanthine was positively associated with somatostatin, at least in bipolar patients, may be of particular interest since there is some evidence that purinergic

Page 14: Low levels of somatostatin in human CSF mark depressive episodes

246 HANS ,~GREN and GUDMAR LUNDQVIS7

mechanisms affect somatostatin release. Robbins et al. (1982) found cyclic AMP and theophyllamine to stimulate somatostatin release in cultured rat cortical cells. This, in fact, returns attention to monoamine systems, since Niklasson et al. (1983) have shown CSF xanthine as well as hypoxanthine to be highly significantly positively correlated with both CSF HVA and 5HIAA.

The negative association between benzodiazepine intake and CSF somatostatin is most readily explained by the fact that benzodiazepines are typically consumed more during the worst phase of a depression; the link between the two was absent if the analysis considered only those patients investigated when they were at their worst. Also, no statistical correlation between somatostatin and other variables discussed in this paper disappeared when only completely drug-free'patients were taken into account. However, any possible relationship between benzodiazepine effects and somatostatin mechanisms should not be dismissed. It is pertinent to compare this link with a similarly negative one found between benzodiazepine intake and CSF xanthine (Agren et al., 1983), However, this study also presented evidence to regard xanthine as a state-dependent variable.

In conclusion, there is reason to believe that the cyclic neuropeptide somatostatin, which is distributed widely in the brain and measurable in the CSF (mainly of extra- hypothalamic origin), is involved in the regulation of mood. The widespread occurrence of this peptide in the cerebral cortex (Serensen, 1982) would bring cortical peptidergic derangements in depression into focus for future research. Pept ide- peptide coexistence in cortical cells (Vincent et al., 1982) deserves close attention. Somatostatin appears to interact with other neurotransmitter systems, for example the monoamines, that are most likely involved in the phenomenological expression of depression. CSF somatostatin is curvilinearly related to serum TSH levels, but in such a complex way that simple TSH analyses may be of only moderate clinical value in assessing somatostatin activities. Evidence has been presented for regarding somatostatin as a state marker of depressive episodes. True longitudinal studies are mandatory to further elucidate the meaning of CSF somatostatin as a variable dependent on depressive state.

This study was supported by the Swedish Medical Research Council [grant 6355 to H..~. and 4534 to G.L.), the Swedish Medical Society (the SOderstrOm-KOnig Hospital Foundation), and the Fredrik and Ingrid Thuring Foundation.

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