Symptom profiles of biological markers in depression: A multivariate study

Psychoneuroendocrinology,Vol. 15, No. 1, pp. 29-37,

1990

0306-4530/90 $3.00 + 0.00 ©1990 Pergamon Press pie

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SYMPTOM PROFILES OF BIOLOGICAL MARKERS IN DEPRESSION: A MULTIVARIATE STUDY MICHAI~LMAES,I LEO MAES,2 and EDUARDSUY1 1Psychiatric Center St. Jozef, Munsterbilzen, and 2Laboratoryfor Analytical Chemistry, CTL, Ghent, Belgium (Received I March 1988; in final form 7August 1989)

SUMMARY The dexamethasone suppression test (DST), the thyrolropin releasing hormone (TRH) test, and the ratio of plasma L-tryptophan to competing amino acids (L-TRP/CAA)were studied in relation to the 21 items of the Hamilton Depression Rating Scale (HDRS) in 123 depressed patients categorized according to DSM-III. The relationships between the biological data and the items or item clusters of the HDRS were assessed by multivariate analyses. The psychopathological correlates of increased postdexamethasone cortisol and decreased thyroid stimulating hormone (TSH) responsivity to TRH were middle and delayed insomnia and weight loss. The symptom correlates of decreased availability of LTRP to the brain were psychic anxiety, depersonalization, obsessions and paranoid symptoms. Core depressive symptoms, i.e. depression, loss of interest, feelings of guilt and suicidal thoughts, were not related to the biological markers. INTRODUCTION THE DEXAMETHASONESUPPRESSIONTEST (DST), thyrotropin releasing hormone (TRH) test and the ratio of plasma L-tryptophan (L-TRP) to the sum of amino acids known to compete for the same cerebral uptake mechanism (CAA) have been the subject of considerable research. In 40-60% of major depressives an abnormal DST occurs (Carroll, 1982; Feinberg & Carroll, 1984; Maes et al., 1986a), which indicates hypothalamo-pituitary-adrenal (HPA) axis overdrive (Holsboer et al., 1984). A blunted thyroid stimulating hormone (TSH) response to TRH is another consistently reported abnormal finding in major depression (Loosen & Prange, 1982) indicating some dysfunction of the hypothalamo-pituitary-thyroid axis (Loosen & Prange, 1982). The L-TRP/CAA ratio, regarded as an index of the availability of L-TRP to the brain (M611er, 1985), had been found to be decreased in major depressive patients (Joseph et al., 1984; Maes et al., 1987a). Serotonin synthesis in the brain depends upon the availability of L-TRP (Femstr6m, 1984). Van Praag et al. (1975) advocated the "dissection" of psychiatric syndromes to investigate the biological correlates of specific symptom profiles. The psychopathological correlates of an abnormal DST have been delayed insomnia, retardation, psychic anxiety, loss of insight and obsessions-compulsions (Nasr et al., 1983), anxiety, anergy and sleep disturbances (Reus, 1982), appetite and weight loss (Zimmerman et al., 1984), suicide (Coryell & Schlesser, 1981), somatic complaints (Kasper & Beckmann, 1983), and anxiety and depressed mood (Bryer et al., 1983). The symptom profiles of a blunted TSH-response to TRH have not been thoroughly examined; /~gren (1981) reported that the TSH responses to TRH were positively related to obsessiveCorrespondenceto be addressed to: Dr. M. Maes, PsychiatricCenter St. Jozef, Abdijstraat 2, B-3751 Munsterbilzen, BELGIUM. 29

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M. MA~ et al.

compulsive symptoms. The symptom profiles of reduced availability of L-TRP to the brain have been anxiety and somatization (Joseph et al., 1984), agitation (Curzon et al., 1979), anorexia and suicidal thoughts (Banki et al., 1981), and depressed mood, neuromuscular symptoms, anxiety, agitation and catatonia (Lehmann, 1972). The present study investigated the psychopathological correlates of disturbances in the DST, TRH-test a n d the availability of L - T R P in the same group of patients. The D S T and the LT R P / C A A ratio have been reported elsewhere (Maes et a l . , 1986a; 1986b) SUBJECTS The subjects were 123 depressed patients consecutively admitted to the Psychiatric Center between 1 August 1983 and 3 December 1984. The patients were categorized into two subgroups according to the DSM-III (American Psychiatric Association, 1980): minor depression (Williams & Spitzer, 1982), including dysthymic disorder (300.40), atypical depression (296.82) and adjustment disorder with depressed mood (309.00), and major depression (296.X2, 296.X3, 296.X4). Diagnoses were made by two clinicians and were accepted when agreement was reached. Patients with a coexisting atypical depression and some other major psychiatric disorder, bipolar patients, and patients with substance use disorders were excluded. The 21-item version of the Hamilton Depression Rating Scale (HDRS) (Hamilton, 1960) was completed four to five days after admission to hospital. Fifty-eight patients were drug-free for at least 14 days before admission. The others had taken benzodiazepines, antidepressants and/or low doses of neuroleptics (e.g. flupentixol <3 mg/day, promazine <50 mg/day). Patients who had taken higher antipsychotic dosages of neuroleptics were not included. After admission, 68 subjects did not receive any medication; the others were given benzodiazepines (<40 mg diazepam equivalents per day). Medical, laboratory (blood and urine analysis, liver and kidney function tests, sedimentation rate and leukocytes) and neurobiological (EEG) investigations showed no major pathologies. All patients were clinically euthyroid. Carroll's (1982) exclusion criteria for patients were applied in order to avoid false positive and false negative test results in the DST. METHODS The blood samplings for the determination of the biological data were performed three to six days after admission of the patients to hospital. The TRH test was performed the day prior to the DST. The amino acids L-TRP, valine and leucine were determined on fasting (10 hr) serum samples taken at 0800h. The amino acid assay was performed by liquid chromatography on a 5 Ixm ODS phase. Precolumn derivatization was performed with orthopdialdehyde, and fluoremetric detection was performed at ~xclr=360 nm; ~MIS=425 nm (Turnell & Cooper, t982). The inter-assay coefficients of variation were: L-TRP: 7% (mean=41 10-6 mole/L, n=16), valine: 3.5% (mean= 195 10.6 mole/L, n--16), and leucine: 4.5% (mean= 183 10-6 mole/L, n= 16). The L-TRP/CAA ratio was calculated as the ratio between L-TRP and the sum of valine+leucine, multiplied by 100 (Maes et al., 1987a). Samples for the determination of serum cortisol were taken at 0800h after oral administration of dexamethasone (1 mg) at 2300h the previous day. The plasma cortisol determination was by a commercial enzyme immunoassay with double antibody separation of free and bound antigen (Endab Cortisol RIA kit, Immuno Tech. Corp., Cambridge, MA). The inter-assay coefficient of variation was 12% (mean = 8 pg/dL, n = 60). During the TRH-test, patients were kept in bed. After an overnight fast, TRH (200 I.tg) (Roche) was administered (IV) over 30 sec at 0800h. Blood samples for the determination of TSH were taken before (basal TSH), 20 and 60 min after the injection. The Amax TSH response was calculated as the peak minus the basal TSH value. TSH was determined by a Beckton-Dickinson automatized commercial radioimmunoassay method. The interassay coefficient of variation was 7% (mean=7.2 txIU/mL,n = 12). Statistical Analysis The independence of two classification systems and the frequency distribution of the variables were checked by means of the Z2 test. Relationships between variables were assessed by means of Pearson's product moment and point biserial correlations, stepwise multiple regression, and canonical correlation analysis. To test the difference between sample means, Student's t-test, the Mann-Whitney U-test, analysis of variance (ANOVA), analysis of covarianee (ANCOVA), and linear discriminant analysis (LDA) were used. The classification results of the LDA were assessed by means of the K-statistic for nominal scales (Cohen, 1960). If the results were not normally distributed, appropriate transformations were used. The significance level was set at tx=0.05 (two tailed).

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31

RESULTS

Descriptive Statistics Table I lists the demographic data of the 123 patients. There were no significant differences in sex ratio between the DSM-III subgroups. Major depressives were significantly older than minor depressive patients. There were no significant differences in drug state among the depressive categories. The frequency distribution of post-dexamethasone cortisol (logarithmic transformation), Amax TSH (square root transformation), the L-TRP/CAA ratio, age and HDRS approached a Gaussian distribution.

TABLE I. DEMOGRAPHICDATAFOR THE 123 DEPRESSIVE PATIENTS

Diagnostic Categories Minor Depression (300.40, 296.82, 309.00 Major Depression (296.X2, 296.X3, 296.X4) Total Depressive Sample

Drug State* BZ DF No/Yes Yes/No

Sex Ratio Age (years) Index Male:Female m e a n + S D

md

13:31

39.5 + 12.0

21/23

19/25

MD

22:57

47.5 + 12.4t

47/32

39/40

T

35:88

44.7 + 12.8

68/55

58/65

* BZ indicates use of benzodiazepines the day before testing (no or yes); D F indicates length of drug-free period before admission to hospital (->two weeks, yes or no). t Significantly different from rod, t = 3.47, p = 0.0007.

Table II shows the intercorrelation matrix for the HDRS, the biological data, age and gender. The HDRS score was significantly related to the DST results, the L-TRP/CAA ratio and age. Age was positively related to the DST and negatively to Amax TSH.

TABLE II. INTERCORRELATIONMATRIXFOR THE HDRS, BIOLOGICALVARIABLES, AGE AND SEX IN 123 DEPRESSIVE PATIENTS DST Amax TSH L-TRP/CAA Age Sex

HDRS*

DSTt

0.40c -0.08 -0.30¢ 0.24B 0.03

0.01 -0.21A 0.21a 0.01

Amax TSH§ L-TRP/CAA v

0.06 -0.24B -0.09

-0.05 -0.06

* HDRS=21-item Hamilton Depression Rating Scale score. t D S T = 0 8 0 0 h post-dexamethasone cortisol value. § A m a x T S H = peak T S H value minus pre-TRH baseline value. v L - T R P / C A A = tryptophan (Valine + Leucine) ratio. Ap < 0.05, Bp < 0.01, Cp < 0.001, without Bonferroni correction for the 15 correlations.

Age

-0.06

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M. MAESet al.

TABLE III. MEAN H A M I L T O N

D E P R E S S I O N SCALE SCORE, P O S T - D E X A M E T H A S O N E CORTISOL V A L U E , AMAX T S H AND L - T R P / C A A RATIO (_+SD) IN MINOR AND M A J O R DEPRESSION.

Group

md MD T

0800h postdexamethasone

Amax TSH

HDRS

cortisol (gg/dL)

(glU/mL)

L-TRP/CAA x 100

19.6 -+ 3.2 26.7 _+5.5* 24.2 __5.9

1.75 _+2.35 7.88 + 7.57+ 5.69 -- 6.87

7.35 + 4.70 6.39 -- 4.09 6.74 +_4.33

16.34 _+3.26 14.35 + 3.79§ 15.07__3.72

md/MD/T and other abbreviations: see Tables I and II. * significantly different from md, p < 0.0001 by t-test. 1 significantly different from md, p < 0.001 by t-test. § significantly different from md, p < 0.01, by t-test.

Table 111 displays the HDRS and biological data. Patients with major depression were significantly more depressed and showed significantly increased post-dexamethasone cortisol and significantly decreased L-TRP/CAA ratio compared to minor depressives. These differences remained significant after correcting for age and drug state (use of benzodiazepines the day before testing and the length of drug-free period before admission to hospital) by ANOVA. DST Post-dexamethasone cortisol was significantly positively correlated with late insomnia (afterpcorrection by the Bonferroni method; van Knippenberg & Siero, 1980). By multiple regression, 26.3% of the variance in the DST results could be explained by middle insomnia, psychic anxiety, hypochondriasis, loss of weight and diurnal variation (F=7.2; df=5,87; p < 10-3). DST nonsuppressors exhibited significantly higher scores on late insomnia, loss of weight and diurnal variation, compared with DST suppressors (cortisol>3.5 p.g/dL; Maes et al., 1986a). Table IV lists the results of the linear discriminant analysis with the 21 HDRS items as independent variables and the DST nonsuppressors versus the suppressors as the two groups. Late insomnia and loss of interest were the significant discriminating variables. Amax TSH There were no significant correlations between Amax TSH and any of the 21 HDRS items after p-correction. Up to 10.6% of the variance in Amax TSH could be accounted for by the regression on middle insomnia and obsessional symptoms (F=4.2; df=2,87; p<0.05). Patients with a blunted TSH response (Amax TSH<5.0 p.IU/mL) had significantly greater weight loss than patients with a normal response. Retardation, loss of weight and loss of libido were significant discriminating variables between the two groups (Table IV). L-TRP/CAA ratio The L-TRP/CAA ratio was significantly positively correlated with paranoid symptoms (after p-correction). Up to 20.7% of the variance in the ratio could be explained by the multiple regression on diurnal variation, depersonalization, paranoid and obsessional symptoms (F=6.7; df=4,87; p < 10-3). The more severe these symptoms, the lower was the L-TRP/CAA ratio. Patients with a reduced availability of L-TRP (L-TRP/CAA<0.145; Maes et al., 1986b) were significantly discriminated from those with a higher ratio (Table IV). Psychic anxiety and depersonalization were the discriminating variables. Age, sex and drug state (use of benzodiazepines the day before testing and the length of drugfree period before admission) were entered in the statistical analyses; there were no significant effects on the above-mentioned results.

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SYMPTOMPROFILESOF BIOLOGICALMARKERS

T A B L E IV. L I N E A R DISCRIMINANT ANALYSIS CLASSIFICATION RESULTS W I T H T H E 2 1 - H D R S ITEMS AS I N D E P E N D E N T VARIABLES.

Number PredictedGroup Membership of

Percent 1c-Statistic Correctly for Nominal

Cases

in Group I

in Group 2

Classified

Scales

DST Suppressors (1) DST Nonsuppressors (2)*

76 47

57 (75.0%) 15 (31.9%)

19 (25.0%) 32 (68,1%)

72.4%

0.423A

TSH Nonblunters (1) TSH Blunters (2)t

73 50

51 (69.9%) 19 (38.0%)

22 (30,1%) 31 (62.0%)

66.7%

0.317B

Normal L-TRP/CAA ratio (1) Reduced L-TRP/CAA ratio (2)§

68 55

53 (77.9%) 25 (45.5%)

15 (22.1%) 30 (54.5%)

67.5%

0.3338

*Nonsuppressors: 0800hpost-dexamethasonecortisol->3.5pg/dL. t Blunters: AmaxTSH <5 p.IU/mL. §ReducedL-TRP/CAAratio: <0.145.

Ap<0.001, 8/9<0.01.

The canonical correlation analysis results are listed Table V. The biological data were entered as dependent variable, and the 21 HDRS items, age and drug state were entered as independent variables. There were two canonical correlations derived. The first (r=0.55) was between DST results and Amax TSH, and age, middle and late insonmia, loss of weight and paranoid symptoms. The second canonical correlation (r=0.52) was between DST results and the L-TRP/CAA ratio, and delayed insomnia, agitation, psychic anxiety, diurnal variation, depersonalization and obsessional symptoms.

T A B L E V. C A N O N I C A L CORRELATION ANALYSIS B E T W E E N THE BIOLOGICAL DATA A N D T H E 21 H D R S ITEMS, A G E A N D D R U G STATE.

Loadings Variables Dependent variables DST results Amax TSH ratio L-TRP/CAA

Independent variables depressed mood guilt suicide insomnia, initial insomnia, middle insomnia, delayed work and interests retardation agitation anxiety, psychic

Loadings

CVI* CV2* Variables

CVI* CV2*

Independent variables 0.71 - 0 . 6 1 (continued) -0.58 -0.14 anxiety, somatic 0.27 0 . 8 7 gastrointestinal symptoms somatic symptoms, general genital symptoms 0.21 -0.19 hypochondriasis 0.06 0 . 0 8 loss of weight -0.05 -0.08 loss of insight 0.02 0 . 0 2 diurnal variation 0.40 -0.25 depersonalization 0.47 -0.39 paranoid symptoms -0.06 -0.14 obsessional symptoms 0.28 -0.05 DF* 0.15 -0.39 BZ* 0.03 -0.55 Age*

-0.05 0.22 0.04 -0.16 0.21 0.59 -0.18 0.31 -0.21 -0.45 -0.32 0.25 0.34 0.41

-0.31 -0.00 -0.11 -0.24 -0.25 -0.16 -0.33 -0.50 -0,37 -0.31 -0,41 0.05 0.12 -0.14

*CV=canonical variates;DF=length of drug-freeperiod before admission to hospital;BZ=use of benzodiazepinesthe day priorto testing. Significantloadings(>0.350)are underlined.

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M. ~

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DISCUSSION

The results of the present study indicate that post-dexamethasone cortisol values were related to the vegetative component of the HDRS, i.e. middle and delayed insomnia, weight loss and diurnal variation. DST nonsuppressors were significantly differentiated from suppressors by late insomnia, weight loss and diurnal variation, in agreement with Zimmerman et al. (1985), who found that vegetative symptoms (middle and late insomnia and diurnal variation) discriminated DST nonsuppressors from suppressors. Our results are also in agreement with these of/~gren (1981), Reus (1982) and Zimmerman et al. (1984), who found that weight loss and insomnia were characteristics of DST nonsuppressors. However, our results are in contrast with those of Brown and Quails (1981) and Nasr et al. (1983), who found that suppressors exhibited more weight loss, hypochondriasis and diumai variation compared to nonsuppressors. Gmnhaus et al. (1985), on the other hand, found no relationship between DST nonsuppression and serf-reported diurnal variation of mood or early morning awakening. In the present study we found no significant relationship between the DST results and any of the core depressive symptoms, i.e. depressed mood, feelings of guilt, suicidal thoughts or loss of interest. These results are at variance with those of Coryell and Schlesser (1981), who found that an abnormal DST was a predictor of suicide. We found that the principal psychopathological correlates of a blunted TSH response to TRH were middle insomnia and weight loss. Goodwin et al. (1988) also found that a blunted TSH response was related to weight loss. We found Amax TSH to be positively related to obsessional symptoms, which concur with the findings of/~gren (1981). The major symptom profiles of a reduced L-TRP/CAA ratio were paranoid and obsessional symptoms, psychic anxiety, depersonalization and diurnal variation, and are in accordance with the findings of Lehmann (1972) and Joseph et al. (1984). We believe that the discrepancies reported in the literature on the psychopathological correlates of the DST might be caused either by differences in the selection of the patient samples or by differences in the choice of statistical methods. Some investigators (Brown & Quails, 1981; Nasr et al., 1983; Gmnhaus et al., 1985) selected patients with endogenous major depression; relationships between biological data and clinical variables might be considerably weakened by selection of only one subgroup within the full depressive sample. There is no reason to believe that the DSM-III subgroups of minor depression, simple major depression and major depression with melancholia or with psychotic features are not a clinical or a biological continuum (Maes et al., 1987b; 1988a). In some of the above-mentioned studies the statistical methods were less than optimal, e.g. without p-correction for multiple comparisons (van Knippenberg & Siero, 1980). Multivariate approaches have been recommended to analyze the complex relationships between biological data and clinical profiles (Demel et al., 1973;/~,gren, 1981). Kasper and Beckmann (1983) examined the relationship between biological data and HDRS factors, but it is not clear how they computed these factors. /~gren (1981), Nasr et al. (1983) and Zimmerman et al. (1984) used linear discriminant analysis or multiple regression analysis, two multivariate techniques which also were used in the present study. Some investigators (Bech et al., 1981; Bech, 1984) advocate the use of logistic models to deal with problems that can arise from stochastic dependency in the case of traditional statistical analysis. In the present study we also included a canonical correlation analysis, which is well suited to determine the maximum relationship between two sets of variables. The biological data could be divided in two components which were related to distinct symptom profiles. The first component, the DST and Amax TSH, was related to age and to the vegetative cluster of the HDRS, i.e. weight loss and middle and delayed insomnia. Others have observed that positive DSTs increase and

SYMPTOMPROPn.ESOFBIOLOOICAL MARKERS

35

TSH responsivity to TRH decreases with age (Extein et al., 1981; Lewis et al., 1984). The vegetative symptom cluster is regarded as a hallmark for disturbances in the hypothalamus (Ordy, 1977; Saleem, 1984), which are posited to be of pathophysiological relevance for abnormal DSTs and TRH tests (Loosen & Prange, 1982; Holsboer et al., 1984). The second component consisted of the DST and the L-TRP/CAA ratio, which were related to agitation, psychic anxiety, depersonalization, obsessional symptoms, diurnal variation and delayed insomnia. Maes et al. (1987a; 1988b) observed that the L-TRP/CAA ratio was significantly negatively correlated with DST results. Consequently, our findings suggest that the DST reflects two distinct patterns of dysfunction in the HPA axis. The first is linked to reduced TSH responsivity to TRH, possibly reflecting hypothalamic symptoms. The second is related to a reduced availability of L-TRP, possibly symptoms indicative of anxiety (agitation, psychic anxiety, depersonalization, obsessional symptoms) and disturbances in circadian rhythms (diurnal variation, delayed insomnia). In the present study, the use of benzodiazepines in low doses did not affect either the results of the biological tests or the severity of the individual HDRS items. This is in agreement with the data of Muller and Wollert (1975) with reference to the availability of L-TRP, the data of Carroll et al. (1981) with respect to the DST, and with the findings of Kjellman et al. (1985) with reference to sedative effects on the TRH test. Widlocher et al. (1983) found that treatment with very high doses of benzodiazepines led to a slight improvement in the HDRS, which was apparent eight days after starting treatment. In our study, much lower doses of benzodiazepines were used, and the HDRS score was determined four to five days after admission. Furthermore, patients who were drug-free for at least two weeks before admission did not differ from those who had taken drugs until starting the wash-out period. Consequently, there were no major effects of the drag state of the patients on our results. In conclusion, the psychopathological correlates of disturbances in the DST and TRH test were the vegetative symptoms of depression. The symptom profile of reduced L-TRP availability was psychic anxiety, paranoid and obsessional symptoms, depersonalization and diurnal variation. Core depressive symptoms, including depressed mood, feelings of guilt, suicidal ideation and loss of interest, were not related to the biological data.

Acknowledgements: We are indebted to ACC, Statistical Center, Heverlee, Belgium, for providing help and to Dr. M.J.A.J.M. Hoes, Ph.D., M.D., University of Nijmegen, The Netherlands, for discussion of the text. The authors express their appreciation to Mrs. M. Maes for secretarial support. REFERENCES /~gren H (1981) Biological markers in major depressive disorders: a clinical and multiple study. Acta Universitatis Upsaliensis, Abstracts of Uppsala Dissertations from the Faculty of Medicine, 405. American Psychiatric Association (1980) Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (DSM-III). APA, Washington DC. Banki CM, Molnar G, Vojnik M (1981) Cerebmspinal fluid amine metabolites, tryptophan and clinical parameters in depression. J Affect Disord 3:91-99. Bech P (1984) The instrumental use of ratio scales for depression. Pharmacopsychiatry 17: 22-28. Bech P, Allerup P, Gram LF, Reisby N, Rosenberg R, Jacobsen O, Nagy O (1981) The Hamilton Depression Scale: evaluation of objectivity using logistic models. Acta Psychiatr Scand 63: 290-299. Brown WA, Quails CB (1981) Pituitary-adrenal disinhibition in depression: markers of a subtype with characteristic clinical features and response to treatment? Psychiatry Res 4:115-128. Bryer JB, Borrelli DJ, Matthews EJ, Kornetsky C (1983) The psychological correlates of the DST in depressed patients. Psychopharmacol Bull 4: 633-637. Carroll BJ (1982) The dexamethasone suppression test for melancholia. Brit J Psychiatry 140: 292-304. Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF, James NW, Kronfol Z, Lohr N, Steiner M,

36

M. M~a~set al.

De Vigne JP, Young E (1981) A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch Gen Psychiatry 38: 15-22. Cohen J (1960) A coefficient of agreement for nominal scales. Educ Psychol Meas 20: 37-46. Coryell M, Schlesser MA (1981) Suicide and the dexamethasone suppression test in unipolar depression. Am J Psychiatry 138:1120-1121. Curzon D, Kantamaneni BD, Lader MH, Greenwood MH (1979) Tryptophan disposition in psychiatric patients before and after stress. Psychol Med 9: 457-463. Demel I, Gordesch J, Katschnig H, Poldinger W, Scheiber V, Sint P (1973) Multivariate procedures in the statistical analysis of psychic and somatic symptoms in depression. Psychother Psychosom 22:121-130. Extein I, Pottash ALC, Gold MS (1981) The thyrotropin releasing hormone test in the diagnosis of unipolar depression. Psychiatry Res 5:311-316. Feinberg M, Carroll BJ (1984) Biological markers for endogenous depression. Effect of age, severity of illness, weight loss and polarity. Arch Gen Psychiatry 41: 1080-1085. Fernstr~SmJD (1984) Tryptophan availability and serotonin synthesis in rat brain: effects of experimental diabetes. In: Schlossberger HG, Kochen W, Linzen B, Steinhart H (Eds) Progress in Tryptophan and Serotonin Research. Walter de Gruyter, New York, pp 161-172. Goodwin GM, Fairburn CG, Keeman JC, Cowen PJ (1988) The effects of diet and weight loss upon the stimulation of thyrotropin (TSH) by thyrotropin-releasing hormone (TRH) and suppression of cortisol secretion by dexamethasone in men and women. J Affect D isord 14:137-144. Grunhaus L, Flegel P, Carroll BJ, Greden JF (1985) Self-reported diurnal mood changes, early morning awakening and the dexamethasone suppression test in endogenous depression. JAffectDisord 8: 1-7. Hamilton M (1960) A rating scale for depression. JNeurol Neurosurg Psychiatr 23: 56-61. Holsboer F, Muller OA, Doerr HG, Sippel WG, Stalla GK, Gerken A, Steiger A, Boll E, Benkert O (1984) ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression. Psychoneuroendocrinology 9: 147-160. Joseph MG, Brewerton TD, Reus VI, Stebbins GT (1984) Plasma L-tryptophan/neutral amino acid ratio and dexamethasone suppression in depression. Psychiatry Res 11: 185-192. Kasper S, Beckmann H (1983) Dexamethasone suppression test in a pluridiagnostic approach: its relationship to psychopathological and clinical variables. Acta Psychiatr Scand 68: 31-37. Kjellman BF, Ljunggren JG, Beck-Friis J, Wetterberg L (1985) Effect of TRH on TSH and prolactin levels in affective disorders. Psychiatry Res 14: 353-363. Lehmann J (1972) Mental and neuromuscular symptoms in tryptophan deficiency: a review with special reference to mental symptoms in a selected material of carcinoid patients. Acta Psychiatr Scand (Suppl) 237. Lewis DA, Pfohl B, Schlechte J, Coryell W (1984) Influence of age on the cortisol response to dexamethasone. Psychiatry Res 13: 213-220. Loosen PT, Prange AJ (1982) Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review. Am J Psychiatry 139: 405-416. Maes M, De Ruyter M, Hobin P, Suy E (1986a) The dexamethasone suppression test, the Hamilton depression rating scale and the DSM-III depression categories. J Affect Disord 10: 207-214. Maes M, De Ruyter M, Hobin P, Suy E (1986b) The diagnostic performance of the L-tryptophan/competing amino acids ratio in major depression. Acta PsychiatrBelg 86: 257-265. Maes M, De Ruyter M, Hobin P, Suy E (1987a) Relationship between the dexamethasone suppression test and the L-tryptophan/competing amino acids ratio in depression. Psychiatry Res 21: 323-335. Maes M, De Ruyter M, Suy E (1987b) Prediction of subtype and severity of depression by means of dexamethasone suppression test, L-tryptophan/competing amino acids ratio, and MHPG flow. Biol Psychiatry 22: 177-188. Maes M, De Ruyter M, Claes R, Suy E (1988a) Self-rated depression in relation to DSM-III classification: a statistical isolinear multiple components analysis. Acta Psychiatr Scand 77: 27-33. Maes M, De Ruyter M, Claes R, Suy E (1988b) Sex-related differences in the relationships between self-rated depression and biological markers. JAffectDisord 15:119-125. M611er SE (1985) Tryptophan to competing amino acids ratio in depressive disorder: relation to efficacy of antidepressive treatments. Acta PsychiatrScand (Suppl) 325. Muller WE, Wollert U (1975) Benzodiazepines: specific competitors for the binding of L-tryptophan to human serum albumin. Arch Pharmaco1288: 17-27. Nasr SJ, Pandy G, Altman EG, Gibbons R, Gaviria FM, Davis JM (1983) Symptom profiles of patients with positive DST: a pilot study. BiolPsychiatry 18: 571-574. Ordy JM (1977) Neuroendocrinology and psychiatric drugs. In: Schoolar JC, Claghorn JL (Eds) Kinetics of Psychiatric Drugs. Brunner-Mazel, New York, pp 90-126. Reus VI (1982) Pituitary-adrenal disinhibition as the independent variable in the assessment of behavioral symptoms. Biol Psychiatry 17:317-326.

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Saleem PT (1984) Dexamethasone suppression test in depressive illness: its relation to anxiety symptoms. BritJ Psychiatry 144: 181-184. Turnell D, Cooper J (1982) Rapid assay for amino acids in serum or urine by precolumn derivatization and reversed phase liquid chromatography. Clin Chem 28: 527-531. van Knippenberg A, Siero F (1980) Multivariate Analyse. Van Loghum-Slaterus, Deventer. van Praag HM, Korf J, Lakke JMWF, Schut T (1975) Dopamine metabolism in depressions, psychoses and Parkinson's disease: the problem of the specificity of biological variables in behavior disorders. Psychol Med 5: 138-145. Widlocher D, Lecrubier Y, Le Coc Y (1983) The place of anxiety in depressive symptomatology. Brit J Clin Pharmacol 15: 171-179. Williams JBW, Spitzer RL (1982) Research diagnostic criteria and DSM-III: an annotated comparison. Arch Gen Psychiatry 39: 1283-1289. Zimmerman M, Pfohl BM, Coryell WH (1984) Appetite and weight change and the dexamethasone suppression test. Biol Psychiatry 19: 923-928. Zimmerman M, Stangl D, Coryell W (1985) The research diagnostic criteria for endogenous depression and the dexamethasone suppression test: a discriminant function analysis. Psychiatry Res 14: 197-208.