Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia

Psychiarry Research. 15, 28 l-292

Elsevier

Cerebrospinal Metabolite

Fluid Monoamine and Monoamine Concentrations in Melancholia

Alec Roy, David Pickar, Markku Steven M. Paul

Linnoila,

Allen R. Doran, Philip Ninan, and

Received January 15, 1985; revised version received May 9, 1985; accepted June lo, 1985.

Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were nonsuppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors. Abstract.

q

Key Words. Depression, 4-hydroxyphenylglycol.

dopamine,

metabolites,

dexamethasone,

3-methoxy-

Since the catecholamine hypothesis of affective disorders was initially described (Bunney and Davis, 1965; Schildkraut, 1965), there have been many clinical studies examining monamine metabolites in cerebrospinal fluid (CSF) in order to assess central aminergic function in depression. This literature has recently been extensively reviewed (Post et al., 1980; Zis and Goodwin, 1982; Jimerson and Berrettini, in press). Several studies have found no significant differences between depressed patients and various control groups in the CSF levels of the dopamine (DA) metabolite homovanillic acid (HVA) (Bowers et al., 1969; Roos and Sjiistrom, 1969; Mendels et al., 1972; Takahashi et al., 1974; Subrahmanyam, 1975), others have found lower levels (van Praag and Korf, 1971; Banki, 1977; .&berg et al., 1984), and still others have reported lower CSF HVA levels only in patients with psychomotor retardation (Papeschi and McClure, 1971). Several studies using the probenecid technique have

Alec Roy, M.D., David Pickar, M.D., Allen R. Doran, M.D., and Steven M. Paul, M.D., are in the Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, MD. Markku Linnoila, M.D., Ph.D., is in the Laboratory of Clinical Studies, DICBR, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD. Philip Ninan, M.D., is in the Department of Psychiatry, Emory University School of Medicine, Atlanta, GA. (Reprint requests to Dr. A. Roy, Section on Clinical Studies, NIMH, Bldg. 10, Rm. 4N-214, 9000 Rockville Pike, Washington, DC 202051000, USA.) 016%1781/85/$03.30

0 1985 Elsevier Science Publishers

B.V.

282 also reported lower probenecid-induced accumulations of CSF HVA in depressed patients, suggesting decreased DA turnover in depression (Roos and Sjostrom, 1969; Korf and van Praag, 1971; Sjostrom, 1973). CSF levels of the serotonin metabolite 5hydroxyindoleacetic acid (SHIAA) have been reported to be unchanged (Bowers et al., 1969; Papeschi and McClure, 1971; Goodwin et al., 1973; Sjostrom, 1973) decreased (Ashcroft et al., 1966; van Praagand Korf, 1971; Coppen et al., 1972; Takahashi et al., 1974; Banki, 1977), or distributed bimodally in depressed patients (Asberg et al., 1976). Low probenecid-induced accumulations of CSF SHIAA have been found in some (Korf and van Praag, 1971; Sjostrom, 1973; van Praag et al., 1973; Banki, 1977) but not all studies (Berger et al., 1980). Studies of CSF levels of norepinephrine in depression have also yielded conflicting results (Post et al., 1973; Christensen et al., 1980) while the levels of the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) have been reported to be unchanged (Wilk et al., 1972; Vestergaard et al., 1978; Agren, 1980; Berger et al., 1980; Oreland et al., 1981) decreased (Post et al., 1973; Subrahmanyam, 1975) or increased (Jimerson et al., 1983; Koslow et al., 1983). Possible explanations for the many discrepancies in CSF studies among various laboratories include differences in analytical methodology, heterogeneity in diagnostic subgroups, differences in conditions under which controls were studied, and other clinical and methodological variables reviewed by Post et al. (1984). The majority of studies on CSF monoamines and/or metabolites in depressed patients have reported CSF levels on only one or two of the three major monoamine systems. Only the study of Berger et al. (1980) simultaneously examined the levels of five monoamines and/or their major metabolites. In the present study, we examined CSF levels of HVA, conjugated or unconjugated dihydroxyphenylacetic acid (CONJDOPAC and DOPAC), dopamine sulphate (DAS04), norephinephrine (NE), SHIAA, and MHPG in patients meeting the DSM-ZUcriteria (American Psychiatric Association, 1980) for major depressive episode with and without melancholia and dysthymic disorder. Thus, values of the various CSF monoamines and/or their metabolites were examined both in relation to each other and with and between depressive subtypes. Methods Subjects. Twenty-eight depressed inpatients of the 4-East Clinical Research Unit of the National Institutes of Health Clinical Center participated in a study of CSF amine and amine metabolites. The patients were diagnosed on the basis of a clinical interview using DSM-III criteria. Fifteen patients received the diagnosis of major depressive episode with melancholia (MEL), eight received the diagnosis of major depressive episode only (MDE), and the remaining five patients were diagnosed as having dysthymic disorder. Within the overall group of MDE patients, 19 were unipolar and 4 were bipolar patients. The Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960) global anxiety and depression ratings (Bunney and Hamburg, 1963), and the Brief Psychiatric Rating Scale (Overall and Gorham, 1962) were completed for each patient by a physician trained in their use. A total HRSD anxiety score was obtained by summing scores on HRSD items 10 and 1I (psychic and somatic anxiety) and a total HRSD subjectively reported insomnia score by summing HRSD items 4,5, and 6 (initial, middle, and delayed insomnia). Patients followed a low monoamine, alcohol-free, and caffeine-restricted diet for at least 2

283

weeks before study. Those who were psychotropic medications slowly withdrawn medications and medication free at least weeks before lumbar puncture (LP). LPs were performed between 8:30 a.m. and 9:00 a.m. with the patients in the lateral decubitus position. All patients had fasted and been at bedrest since midnight before the LP. The first 10 ml of CSF was collected as a pool and placed on ice at bedside, subsequently aliquotted, and then frozen at -80°C until the time of assay. CSF was assayed using high performance liquid chromatography with electrochemical detection (HPLC-EC) (Scheinin et al., 1983, 1984; Seppala et al., 1984) for levels of NE, MPHG, SHIAA, HVA, DOPAC, CONJDOPAC, and DAS04. CSF levels were not corrected for age or height. Two days after the LP, the dexamethasone suppression test (DST) was performed in the 15 MEL and 8 MDE patients using the method of Carroll et al. (1981). Blood for cortisol determinations was drawn at 4 p.m. on the day before an 11p.m. dose of dexamethasone (1 mg) and again at 4 p.m. and 1 1 p.m. on the following day. Cortisol determinations were performed using a radioimmunoassay (Diagnostic Products Corporation). A maximum postdexamethasone cortisol value > 5 PgYc identified dexamethasone nonsuppressors. The data were analyzed using nonparametric statistical methods; group comparisons were by the Wilcoxon rank sum test and correlations by the Spearman rank order correlation.

Results The demographic patient

group

and clinical

data

is predominantly

Table 1. Demographic

for the patients

female

and contains

studied

Mean Range 46

(years)

Female Male Age on onset of first-ever depressive

episode

medication

Total

duration

HRSD

affective episodes depressive free

of disorder

depression

Bunney-Hamburg

(weeks) (years)

score depression

BPRS anxiety/depression BPRS withdrawal/retardation subscale BPRS = Brief Psychiatric episode.

score

subscore

35-66

Mean Range

Mean

42.6

37.8

26-64

7

4

1

1

1

7.6

15-60 2-40

37.5 2.25

14-48

27.2

O-6

N/A N/A

s/4-21

9.3

l-24

7

2-39

12.4

2-78

13.5

14.4

l-38

5.3

2-39

N/A

27.9

21-36

21.3

15-30

a.8

6.78

(months)

Time

1. The None

of

Dysthymic disorder (n = 5)

MDE (n = 8)

14

34

episode

Number of previous Duration of present

in Table

male patients.

data and clinical ratings MDE with melancholia (n = 15)

Age

are shown

only three

10

a

5.6

10.5

a.8

7

5.9 Rating Scale. HRSD = Hamilton

4.3 Rating Scale for Depression.

Range 22-58

i a-42

3-39 7-10

3.8 MDE= majordepressive

MDEwith melancholia patients had asignificantly higher mean HRSD scorethan MDE patients (p
subscores

284

the patients had delusions. shown in Table 2.

The levels of the CSF variables

for individual

patients

are

Table 2. CSF monoamine and monoamine metabolite data (pmoles/ml) for depressed patients ranked in the 3 diagnostic subtypes by their total HRSD depression score HRSD DST Patient Aae Sex score result

CONJHVA

DOPAC

DOPAC

DAS04

NE

MHPG 5HlAA

Melancholies 1

62

F

21

NS

78

0.89

1.4

2.7

0.98

57.3

56

2

48

F

23

NS

74

1.14

2.3

5.4

0.86

40.7

56

3

37

F

23

S

126

1.41

2.2

4.3

0.63

44.5

69

41

41

F

23

NS

63

1.04

1 .a

3.6

0.50

50.0

79

5

58

F

24

NS

45

1.14

2.2

4.1

0.85

62.8

67

6

35

F

25

S

39

0.90

1.2

2.3

0.71

25.2

42

7

66

M

25

NS

114

0.98

3.2

11 .l

1.63

60.4

77

a

37

F

26

NS

75

0.97

2.2

3.5

0.24

38.8

76

9

44

F

30

s

125

1.11

1 .o

2.3

0.50

38.4

a7

101

40

F

30

S

46

1.02

1.2

2.6

0.44

34.6

64

11

60

F

32

NS

130

1.02

1.4

6.3

0.39

37.6

125

12

42

F

32

NS

150

i .a0

2.8

3.5

0.47

49.9

137

13

49

F

33

NS

245

3.40

5.0

2.7

1.20

88.1

133

141

35

F

35

NS

170

2.13

3.6

a.5

0.83

67.8

111

15

36

F

36

S

175

1.53

3.3

3.7

0.75

38.6

126

110.33

1.37

2.32

4.44

0.73

48.98

87.00

58.35

0.67

1.10

2.49

0.35

16.02

31.22

Mean SD

Major depressive episode 1

53

F

15

NS

312

2.30

4.7

5.5

0.53

53.5

138

2

53

F

16

NS

46

0.87

1 .a

5.5

0.34

37.1

42

3

58

F

16

NS

154

1.41

3.3

5.9

0.28

43.1

a2

41

26

F

la

S

182

1.92

2.6

3.2

0.87

41.5

120

5

36

F

20

S

337

2.58

4.9

3.4

1.02

51.5

153

6

27

F

26

NS

93

1.52

2.2

3.0

1.05

43.1

77

7

31

F

29

S

191

3.21

3.4

3.4

1.07

40.4

125

a

47

M

30

S

138

1.43

2.8

3.6

1.19

41.5

70

Mean

181.62

1.9

3.2

4.2

0.70

43.9

loo.8

SD

100.1

0.75

1 .l

1.21

0.3

5.6

38.5

Dysthymic disorder 1

34

F

7

S

120

1.25

2.1

1.9

0.18

33.0

a1

2 3

49 18

M ru

a 9

s s

106 273

0.91 2.51

3.9 5.7

3.4 4.7

0.53 0.49

45.0 34.2

76 127

4

26

F

10

NS

la5

2.44

2.8

3.9

0.53

44.3

95

5

58

F

10

S

176

2.68

4.1

13.7

0.37

41.8

a4

172.0

1.96

3.72

5.52

0.42

39.66

92.6

0.81

i .3a

4.69

0.15

5.67

20.45

Mean SD

66.04

DST = Dexamethasone suppression test; NS = nonsuppression and S = suppression. HRSD = Hamilton Rating Scale for Depression. HVA = homovanillic acid; DOPAC = dihydroxyphenylacetic acid; CONJDOPAC = conjugated dihydroxyphenylacetic acid; DAS04= dopaminesulphate; NE= norepinephrine; MHPG =3-methoxy4-hydroxyphenylglycol; and 5HIAA = 5-hydroxyindoleacetic acid. 1. Bipolar patient.

285 The diagnosis of melancholia was associated with low levels of each of three dopamine metabolites. MEL patients (n 15) had lower levels of CSF HVA in comparison with non-MEL patients with MDE (n = 8) @ < 0.05) (Table 2, Fig. 1). As these groups differed not only with regard to the presence of melancholia but also as to severity of depression as quantified by the HRSD (Table I), the eight melancholic patients who had the lowest scores on the HRSD (MEL patients l-8, Table 2) were chosen as a subgroup of melancholic patients who, despite melancholic features, had similar depression severity to MDE patients (HRSD total scores: mean + 23.8 + 1.6 vs. 21.3 f 6.0, respectively, NS). This subgroup of MEL patients had significantly lower levels of CSF HVA @ < 0.03) DOPAC @ < 0.02), and CONJDOPAC 0, < 0.03) than the MDE patients. When all MEL patients and all non-MEL patients (MDE + dysthymic disorder, n 13) were compared, MEL patients again showed significantly lower levels of CSF HVA @ < 0.02) DOPAC (p < 0.05) and CONJDOPAC (p < 0.03) than nonmelancholic patients (Fig. 1). q

q

Fig. 1. Major depressive episode (MDE) with melancholic patients vs. nonmelancholic depressed patients on CSF levels of HVA, DOPAC, and CONJDOPAC 0

-

.

0

0

3-

mo-

6-

0 MELANCHOLIA 0 MDE ALONE 0 DYSTHYMIC DISORDER 0

0

a-

t

o

8 i

“yy””

.

co 0

*_*. 8 0

”

l-

0

NoNM~~NlcjHoLlC e

HOMOVANILLIC

ACID IHVA)

MELANCHOUC N = 15

NONMELANCHOUC N = 13

DIHYDROXYPHENYLACETIC ACID (DOPACI

f

MEIANCHOLIC N = 15

NONM~Ly~Wlc

CONJUGATED OIHYDROXYPHENYLACETIC ACID ICONJDOPAC)

By nonparametric Wilcoxon rank sum test, MDE with melancholic patients had significantly lower levelsof CSF, HVA, DOPAC. and CONJDOPAC than all nonmelancholic depressed patients in = 13 I ip < 0.02, p < 0.05. and ~~0.03, respectively) and significantly lower levels of CSF HVA than MDE without melancholia patients (n=8) lp < 0.05).

As might be expected from the results showing that the eight MEL patients with lowest HRSD scores had the most significant differences when compared with the severity-matched MDE patients, within the MEL group itself, more severely ill patients had higher levels of DA metabolites. This is reflected in the MEL group by direct correlations between both CSF HVA and DOPAC and total HRSD scores (rl= 0.64,~ < 0.01, and I,= 0.53,~ < 0.05, respectively); and between CSF HVA and

the BPRS average score (v, = 0.66, p < 0.01).Further, in MEL patients, the total HRSD subjectively reported insomnia score related to CSF HVA (rq= 0.59,p< 0.02). No significant differences were found between MEL and non-MEL patients with regard to levels of CSF SHIAA. In the MEL patients, however, SHIAA was related to severity of depression as reflected by a correlation with the total HRSD scoie (rs= 0.75, p < O.Ol),with global depression (r, 0.57, p < 0.03) with the BPRS average score (rs= 0.71,~ < O.Ol), the BPRS anxiety/depression subscale score (rs= 0.58,~ < 0.03), and the total HRSD insomnia score (rr= 0.59, p < 0.05). CSF NE and MHPG were not significantly related either to the diagnosis of melancholia or to measures of severity of depression, although for all depressed patients CSF NE correlated to the total HRSD anxiety score (r, = 0.42, p < 0.03). The number of months of the current depressive episode correlated in the total group and in MEL patients with CSF HVA (rs= 0.40,~ < 0.06 and rs= 0.54,~ < 0.05, respectively). There were no significant relationships between the number of previous episodes of affective disorder and any of the CSF variables. q

Relationship to the DST. DST nonsuppression was found in 10 of 15 melancholies (66.7%) and 14 of 23 MDE patients (60.9%). DST nonsuppression was associated with higher levels of CSF MHPG in comparison to DST suppression. This was found for the total 23 MDE patients (p < 0.025) as well as for the 15 MEL patients (p < 0.025) (Fig. 2). There were no significant differences between nonsuppressors and suppressors with regard to the CSF levels of NE or any of the other CSF measures. Fig. 2. Comparison of MHPG MAJOR

of DST nonsuppressors

DEPRESSIVE N=23

EPISODE

and suppressors

on CSF levels

MELANCHOLICS N=15

._ Dexamethasone Non-Suppressors N = 14

‘t = 2.78, “t

= 2.56,

df = 20, p < 0.025. df = 13. /I < 0.025

Dexamethasone

Dexamethasone

Dexamethasone

suppressors N=9

Non-Suppressors N=lO

Suppressors N=5

287 Interrelationship Between Biochemical Measures. For the total group of depressed patients, statistically significant relationships were found among the CSF dopamine metabolites, HVA, DOPAC, and CONJDOPAC; DAS04 was only weakly related to CONJDOPAC (Table 3). Further, each of the DA metabolites, but not DAS04, was correlated with levels of CSF SHIAA; CSF NE was significantly related only to CSF MHPG (Table 3). Similar results emerged when the diagnostic subgroups were considered separately. Of particular note was the high correlation between CSF HVA and SHIAA in MEL patients (n = 15) (r, 0.83, p < O.OOl), in patients with MDE only (n = 8) (rs= 0.98,~ < O.OOOl), in dysthymic disorder patients (n= 5) (rs= l.O)and the relationship between CSFNEand MHPG(r,= 0.64,p
Table 3. Spearman intercorrelations of CSF monoamine centrations in total group of 28 depressed patients DOPAC HVA

r,0.86 p < 0.0001

DOPAC CONJDOPAC DAS04 NE

CONJDOPAC

DASO4

and metabolite con-

NE

MHPG

BHIAA

0.77

0.19

0.18

0.21

0.87

0.0001

0.33

0.36

0.27

0.0001

0.73

0.12

0.26

0.25

0.76

0.0001

0.53

0.18

0.20

0.0001

0.37

0.26

0.41

0.63

0.049

0.17

0.03

0.0003

-0.13

0.24

0.10

0.52

0.21

0.60

0.49

0.05

0.007

0.79

MHPG

0.21 0.29

HVA = homovanillic

acid; DOPAC = dihydroxyphenylacetic acid; CONJDOPAC = conjugated phenylaceticacid; NE=norepinephrine; MHPG=3-methoxy-4-hydroxyphenylgylcol;and5HIAA=5-hydroxyindoleacetic acid.

dihydroxy-

Discussion In the present study we have observed significantly lower levels of three dopamine metabolites-HVA, DOPAC, and CONJDOPAC-in the CSF of MEL patients in comparison to a mixed group of MDE or dysthymic disorder patients. That this difference is not solely related to severity of depression but rather to the syndrome of melancholia is supported by the similar results that emerged when a severity-matched subgroup of MEL patients was compared with MDE patients. Differences between MEL and non-MEL depressed patients were unique for the DA metabolites; levels of CSF SHIAA, NE, and MHPG were each unrelated to the MEL/non-MEL distinction. Other studies have reported low levels of CSF HVA in patients with endogenous depression (van Praag et al., 1975; Asberg et al., 1984). Van Praag et al. (1975) found that among patients with endogenous depression, it was only patients with psychomotor retardation who showed a significantly lower accumulation of CSF HVA after probenecid. Our failure to find this relationship may be due to our

288 use of the HRSD to measure psychomotor retardation compared to specially designed scales used by van Praag et al. (1975) and Banki et al. (198 1). That diminished dopaminergic function may be involved in the pathophysiology of depressive illness is also suggested by the transient mood-elevating properties of DA agonists such as L-dopa, bromocriptine, and amphetamine (van Praag and Korf, 1975; Waehrens et al., 1981; Jimerson and Post, 1984), by the efficacy of some antidepressants with DA reuptake inhibition or agonist effects (e.g., nomifensine, piribedil) (van Sheyen et al., 1977; Post et al., 1978) or by the effects of antidepressant treatments on DA turnover in depression (Linnoila et al., 1983~). Further, preclinical data suggest that antidepressants decrease the sensitivity of brain DA autoreceptors (Serra et al., 1979; Antelman and Chiodo, 198 1; Lee and Tang, 1982). The consistent pattern of results that we found for the three DA metabolites, each of which is dependent upon the enzyme monoamine oxidase for its formation and the acid transport mechanism for transport out of CSF, suggests that we reliably measured dopaminergic activity. The fact that CSF DAS04 levels were neither related to diagnostic groupings nor to the other three DA metabolites supports the notion that this conjugated form of the parent amine is an independent reflection of DA metabolism. In the present study, we did not observe significant differences in levels of CSF SHIAA between MEL and non-MEL patients, although the relatively small sample size may have contributed to this apparent discrepancy, since mean levels tended to be lower in MEL patients. Further, the CSF levels of SHIAA were significantly correlated to those of HVA, a finding consistent with many other reports (Gottfries et al., 1969; Wode-Helgodt et al., 1977; Sedvall et al., 1980; Agren, 1983; Linnoila et al., 19836) and thus suggestive of either a common regulatory mechanism or transport system (Pradhan and Bose, 1978). In our MEL patients, both HVA and SHIAA were positively correlated with measures of severity (including subjective reports of sleep disturbance). Relationships between levels of HVA and SHIAA and severity measures have been previously observed in some, but not all studies in which this was examined (Papeschi and McClure, 197 1; Agren, 1980). Banki et al. (198 1) and Agren (1980), for example, have respectively reported positive associations between CSF HVA and SHIAA and insomnia in depressed patients. We also observed higher levels of CSF HVA in patients with a longer duration of current depressive episode and in a previous study found higher levels of CSF HVA and SHIAA in depressed patients who had experienced a significant life event during the 6 months before hospital admission (Roy et al., in press a). Thus, in our study this apparently paradoxical finding (i.e., higher levels of HVA were found in patients with greater severity within the diagnostic group having overall lower levels) may be due in part to the stress of being ill for a mean of 6.8 months and in part to an interaction between life stress preceding the illness and the underlying biology of the illness itself. Alternatively, the same underlying neurobiological process responsible for the symptom-related increase in CSF HVA/ SHIAA may over a period of weeks or months result in a depletion of these monoamines, thus accounting for the overall decrease in the MEL patients. Two findings regarding the CSF levels of NE and MHPG emerged in our study. First, we observed a significant correlation between levels of CSF NE and anxiety

289

symptoms quantified by the HRSD, a finding consistent with the report of Post et al. (1984) in which levels of CSF NE were related to nurses’ ratings of anxiety and with other studies relating anxiety symptoms to sympathetic nervous system tone as reflected by levels of plasma NE (Wyatt et al., 197 1; Roy et al., in press b). Second, we observed significantly higher levels of CSF MHPG in DST nonsuppressors than DST suppressors in both the total group of patients with MDE and in those with melancholia. Since MHPG readily crosses from plasma to CSF and exists in these compartments in equilibrium (Jimerson et al., 198 1; Kopin et al., 1983) our finding is consistent with reports of higher levels of plasma MHPG (Jimerson et al., 1983; Roy et al., submitted for publication) and NE (Roy et al., in press 6) in DST nonsuppressors. In our study, CSF NE was unrelated to DST response, despite an observed correlation with CSF MHPG. Although the origin of CSF NE is largely unknown, and may be partly from sympathetic vascular innervation, it is unlikely to arise from the periphery, thus supporting the idea that peripheral noradrenergic sympathetic hyperactivity (but not central) is more closely related to abnormalities in the hypothalamic-pituitaryadrenal (HPA) axis in depression. In summary, in the present study, we have observed a significant decrease in CSF DA metabolites in MEL compared with non-MEL depressed patients. The good correlation between CSF HVA and SHIAA and depressive symptoms raises the possibility that an increase in brain DA and/or serotonin activity is related to state factors such as the severity of depression. The overall decrease in CSF HVA in the MEL group as a whole may indicate a chronic effect of the illness. The concurrent measurement of several DA metabolites adds further credibility to our findings that decreased CSF levels of DA metabolites occur in depression with melancholia. Finally, our findings support other data suggesting a relationship between the central nervous system and peripheral sympathetic nervous system and anxiety, and an association between hyperactivity of peripheral sympathetic activity and HPA axis dysfunction. Acknowledgment.

secretarial

The authors

thank Jean Colison for statistical

help and Andrea Hobbs for

services.

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