Plasma -tryptophan/neutral amino acid ratio and dexamethasone suppression in depression

Psychialfr Research. 11 , 185-192 Elsevier

1St in. 982). esce01

185

PlasmaL-Tryptophan / Neutral Amino Acid Ratio and Dexamethasone Suppression in Depression Marsha ll S. Joseph, Timothy D . Brewerton, Victor I. Reus, and Glenn T. Stebbins Recei,·ed June 14, 1982; revised version received November 28, 1983; accepTed January 9, 1984.

Abstract. We exa mined the ratio of plasmaL-tryptop han (L-TRP) to other neutral ammo acids ( AA) in normal controls and depressed patients undergoing a dexa methsone suppression test (DST). The L-TRP / NAA ratio discriminated controls from patients; however, there was no difference in the mean L-TRP / NAA ratio between DST suppressors and nonsuppressors. The cortisol level measured at l600h postdexamethasone and the L-TRP/ NAA ratio were positively correlated. The l600h postdexamethasone cortisol levels accounted for 24% of the variance of Hamilton Depression Rating Scale (H DRS) scores. The inclusion of L-TRP I NAA ratios with l600h postdexamethasone cortisol levels in a multiple regression equation resulted in an increase in this value and accounted for 65 % of the variance in H D RS scores. The finding suppo rts the use of multivariate biological models in depression. Key Words. L-Tryptophan, dexamethasone, cortisol, depression.

The dexamethasone suppression test (DST) is an established biological marker for majo r dep ressive diso rder that subdivides patients into those with or without evidence for hypot hala mic-pituitary-adrenal (HP A) disinhibition (Carroll et al., 198 1). HPA disin hibition is useful in the clinical management of psychiatric disorders as a diagnostic ind icator a nd predictor of response to antidepressant medications (Carroll, 1982). The ratio of fasting plasma L-tryptophan (L-TRP) to the five other neutral amino acids (~ AA) is another potential biological marker for depressive diso rder with promising clinical utility. A low L-TRP / NAA ratio is reported to discriminate depressed patients from normal controls (DeMyer et al., I 981 ). Patients with a low L-TR P N AA ratio have a better a ntidepressa nt response to oral L-tryptophan (Moller et al., 1980), imipramine (Moller et al., 198 I), and amitriptyline (Moller et al., 1983) than patients with a high ratio·. In addition, other investigators have noted that lithium decreases plasma levels of isole ucine, leucine, and va line, and have suggested that the decrease in co mpeting amino acids may be the mechanism for lithium's enhancement of bram serotonin level (Leighton et al., I 983). It has been well established in animals that the ratio of plasma L-TRP to the other NAA co mpeti ng for blood-brain transport, rather than the absolute value of either

AI the time t his research was carried out. MarshallS. J oseph, M.D. (deceased), Timothy D. Brewerton, M. D .. \'tclor 1.. Reus. M.D .. and Glenn T . Stebbins. B.A., were in the Department of Psychiatry, Univers it~ of California School of Medicine. San Francisco, CA. (Reprint requests to Dr. V.I. Reus, Langle~ Porter ;-,'europsychiatric Institute. University of California, San Francisco, 40 1 Parnassus Ave., San Francisco. CA 94143. USA.) 01 65- 1781 84 S03.00 ~ 1984 Elsevier Science Pub lishers B.V.

186

free or total plasma L-TRP, is the best determinant of the amount of tryplCIDballf!i.. transported into the brain and thus of brain serotonin concentration (Fernstrom etaJ. 1973). The plasma L-TRP JN AA ratio may therefore identify subgroups of depr patients with alterations in serotonin metabolism. Despite a considerable body of da._ implicating a regulatory interaction between the serotonergic system and the HPA axis, it is unknown to what extent, if any, the plasma L-TRP JNAA ratio overlaps will the DST results in depressed patients. Serotonin precursors are known to stimulate the HPA axis, presumably by increasing central serotonin function. There a re several reports showing an increase ift cortisol following administration of L-TRP in healthy volunteers (Woolf and Lee. 1977; Hyyppa et al., 1979; Modlinger et al., 1980). Serotonin itself appears to be involved primarily in the control of the circadian fluctuations in corticosteroid concentration. The effects of serotonin on the corticosteroid response to stress are inconsistent, with no clear relationship described (Krieger, 1978). Both stress and pharmacologic changes in corticosteroids have a variable effect on brain serotonin ( Krieger, 1978). Hydrocortisone can shunt tryptophan away from central serotonin synthesis and toward the peripheral kynurenine pathway by the induction of hepatic tryptophan pyrolase (Green and Curzon, 1968). However, corticosterone also increases tryptophan hydroxylase activity, the rate-limiting step in serotonin synthesis, and thereby may increase central serotonin function (Rastogi and Singhal, 1978). With the above interrelationships in mind we compared concurrent plasma L· TRP/ NAA ratios and DST results in depressed patients.

Methods Subjects were inpatients at the Langley Porter Neuropsychiatric Institute who met DSM-1/1 criteria for major depressive disorder (American Psychiatric Association, 1980). All were otherwise in good health and had been withdrawn from all medications for a t least I week. Two patients had been withdrawn from tricyclic antidepressant medication 2 weeks before entry in the study. Shortly after admission, trained nurse raters completed the Hamilton Depression Rating Scale ( H DRS) ( Hamilton, 1960) a nd the Brief Psychiatric Ra ting Scale (BPRS) (Overall and Gorham, 1962). All ratings were confirmed independently by a staff psychiatrist. Pa tients completed t he Beck Depression Inventory (BDI) (Beck et al. , 196 1). Norma l controls were recruited from the ward staff. All were without medical or diagnosable psychiatric disorders. H DRS a nd BPRS scores were obtained on a ll co ntrols. During the first week of hospitalization, the patients, who were on a standard ward diet, underwent a dexamethasone suppression test (DST) according to the method described by Carroll et al. ( 1981 ). On day I, a n 0800h fast ing blood sample was obtained for determination of plasma cortisol and the neutral amino acids L-TRP. tyrosine, isoleucine, leucine, phenylalanine, a nd va line. At 2330h patients received dexamethasone, I mg orally. On day 2 blood was obtained at 1600 a nd 2300h for d etermina tion of plasma cortisol. Any patient with a postdexamethasone cortisol va lue > 5 J.tg/ dl was considered a nonsuppressor. An 0800h fasting blood sample ( 12-hour fast) was obtained from normal controls for determination of N AA levels. The average duration between psychometric assessment and blood sampling was approximately 36 hours, a nd no patient showed a significant devia tion in clinical symptomatology during this period. Subjects were entered into the study on a consecutive admission basis with the exception of the last two subjects , who were recruited on the basis of prestudy DST results. In both cases, results oft he study DSTwere consistent with the subject's previous response. Eight suppressors,

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187 i ht nonsuppressors. and.eight normal controls matche~ for a~e and sex were selected before elg od drawing. As shown m Table I , there were no stgntftcant dtfferences between suppressors b ~ nonsuppressors o n any psychometric scale. Normal controls had a mean HDRS score of2.3 : nsD 1.6 and a mean BPRS score of 23 ± SD 2.4, both significantly lower tha n patient va lues.

Ta ble 1. Sex, age, HDRS, BPRS, and 801 comparisons between patients and c o ntrols (mean ± SO) v ariabl es Male/female Age years ) HDRS BPRS BDI

Suppressors

Nonsuppressors

Cont rols

3/ 5 45 ± 17 27.8 ± 5.6 42.8 ± 8.5 17.1 ± 6.3

3/ 5 42 ± 13 34.6 ± 8.3 48.8 ± 15.2 11 .5 ± 7.4

3/ 5 42 ± 16 2.25 ± 1.61 23 ± 2.41

1. p < 0 001 l two-tailed t test).

All blood was obtained in heparinized tubes and stored at -70°C. Plasma cortisol was measured by fluorometric liquid chromatography by the method of Gotelli et a!. ( 198 1). Plasma NAA were measured by high performance liquid chromatography (Lee, 1974) by Bioscience Laborato ries. Van Nuys, California. The L-TRPI NAA ratio was calculated by dividing the plasma L-T RP by .the sum ?fth~ other five amino acid levels and was expressed as a perce ntage. Subjects were dtchotomtzed mto depressed versus normal and suppressor versus nonsuppressor groups. Group comparisons of behavioral and neurochemica l data were made by the independent groups 1 test. Correlations were determined by calculation of either the Pearson r or multi ple R2. Values reported are mean± standard deviation. Significance was set at the level of p < 0. 05 (two-tailed). However, the probability statements accompanying simultaneously used tests should not be considered exact levels but rather as descriptive indicators of the relative significance between different findings. A forced entry multiple regression (Statistical Package for the Social Sciences Update 7-9) was perfo rmed on each psychometric scale (dependent variable) using first the 1600h postdexamethaso ne cortisol level and then the L-TRP / NAA ratio (independent variables). The 1600h postdexa methasone cortisol level was used because it is the most easily obtained estimation of HP A disinhibition, especially in an outpatient setting. The order of inclusion was selected to answer the specific question of what additional information (variance accounted for) is obtained by measuring the L-TRP1N AA ratio in depressed patients already undergoing a DST. The change in R 2 after the inclusion of the L-TRP I NAA ratio was used to assess the importance of this second variable.

Res u lts Bet w ee n- and Within-Group Compariso ns. The results of total tryptophan and L-TR P/ NAA ratio in patient groups and controls are given in Table 2. Both significantly discri minated patients from controls. Neither the mean of the total nor that of the L-T RP / NAA ratio was different between suppressors and nonsuppressors. There was no difference in the mean level of any other N AA between controls and patients or between suppressors and nonsuppressors. The total tryptophan level was negatively corre lated with age in controls (r = -0. 74, p < 0.05). The L-TRP I NAA ratio showed a weak negative correlation with age (r = -0.56) in controls. There was no correlation between either total tryptophan or the L-TRPI NAA ratio and age in patients. There was no correlation in the depressed group between L-TRP I NAA ratio and eit her 0800h baseline cortisol or the 2300h postdexamethasone cortisol, but the

188 Table 2. Total plasma L-TRP and L-TRP/NAA ratio In patients and controls (mean ± SO)

Subjects Controls (n = 8 ) All patients (n = 16 ) Su ppressors (n = 8 ) Nonsuppressors ( n = 8)

Total L-tryptophan (J.LM/dl) 4.38 ± 1.60 3.13±0.721 3.00 ± 0.762 3.25 ± 0.71

L-Tryptophan/ neutral amino acids 10.21 ± 6.96 ± 6.65 ± 7.27 =

4.52 2.141 2.572 1.72

1. p < 0.02 ( t-test differen ce from controls. two-tailed ). 2. p < 0.05 (I- test difference from controls. two-tailed).

L-TRP I N AA ratio was positively correlated with 1600h postdexamethasone cortisol < 0.04). The finding is consistent with a number of other studies which have shown that the 1600h postdexamethasone value more sensitively discriminates subtle alterations in pituitary-adrenal dysregulation than either the 0800h predexamethasone or 0800h postdexamethasone values, presumably because the latter are more directly confounded by the pulsatile, circadian release system (Carroll, 1982; Coryell et a!., 1982; Halbreich et a!., 1982). Although there was no difference in the lTRP I NA A ratio between the suppressor and nonsuppressor groups, a significant association with the L-TRP / NAA ratio can be demonstrated when HPA activation (i.e., operationally defined as the 1600h postdexamethasone cortisol level) is considered as a continuous variable. Specifically, those two markers share a common variance of 27% (r = 0.52; p < 0.04). This correlation could not be accounted for by either age or sex.

(r = 0.52,p

Behavioral and Neurochemical Correlations. Table 3 shows the correlations between each psychometric scale, the L-TRP / NAA ratio, and the 1600h postdexamethasone cortisol value. With the exception of a negative correlation with the cognitive disturbance subscale of the HDRS, the L-TRP I NA A ratio did not correlate with any indicator of severity of illness. In contrast, the 1600h postdexamethasone cortisol level correlated positively with the total HDRS score and the anxietysomatization subscale on the HDRS and the anxiety-depression subscale on the BPRS. Prediction of Depressive Severity. When the 1600h plasma cortisol level and the L-TRP I N AA ratio are entered together into a multiple regression equation with each psychometric scale as a dependent variable, there is an improvement in the ability of these markers to predict severity of illness. There are significant R 2 values for total HDRS scale, the HDRS anxiety-somatization and cognitive disturbance subscales, the BPRS thought disturbance and activation su bscales, and the BDI score. Most important, the increase in R 2 between cortisol a lone and cortisol plus the LTRP I NA A ratio (t:.R 2) is significant. The last column in the table specifically demonstrates the statistical advantage of including tryptophan in the equation. Table 4 demonstrates the effect of dichotomizing the variables into suppressors versus nonsuppressors by DST and high versus low L-TRPI NAA ratio (split at the

189

rnedian value). Altho ugh . the small n's in each cell preclude statistical analysis. it ca n be

een that t he three patients whose results parallel co ntro l values (OST suppressors AA ratio) are the least depressed with the lowest HDRS scales. The ot her cells appea r roughly equal.

~vith a high L-TRP I

Table 3. Percent variance (R 2) of HDRS, BPRS, and BDI accounted for by the L-TRP/NAA ratio, 1600h postdexamethasone cortisol level (Cort), and combination of both in a multiple regression equation (CortiL-T RP) L-TRP/ NAA IP

Cort IP

CortiL-TRP IP

tH P Cort & CortiL-TRP

HDRS (total) Anxiety-somatization Cognitive disturbance Retardation

0.086 0.008 0.284 1 0 .051

0.239 1 0.311 1 0.015 0.117

0.6512 0.5073 0.5033 0.340

0.41 2 2 0.1961 0.488 2 0.223

BPRS (total) Anxiety-depression Anergy Thoug ht disturbance Activation

0.043 0.009 0.113 0.058 0.016

0.11 7 0.299 1 0.001 0.187 0.224

0.32 0 0.348 0.169 0.4843 0.414 1

0.203 0.050 0.168 0.296 1 0.190

BDI (total)

0.046

0.168

0.418 1

0.2501

Ratings

1. p < 0 .05. 2. p < 0 .005. 3. p < O.Q1.

Table 4. HDRS by dexamethasone suppressor vs. nonsuppressor and L- TRP/ NAA ratio (high vs. low) Dexamethason e suppression test

(

L-TRP/ NAA

Suppressor

Nonsuppressor

Low1

Mean = 30.8

Mean = 33.7

so = 4 .8

so = 8.4

n =5

n =3

Mean = 22.7

Mean = 35.2

so = 1.2

so = 9 .2

n=3

n =5

(

(

High 1

( I

1. High and low groups split at the median.

D iscussion

t

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I

T hese data confi rm reports indicating a lower L-TRP I NAA ratio in depressed patients co mpared to no rma l controls. In depressed patients undergoing a DST, we fo und no significa nt di ffe rence between the mean plas ma total L-TRP or L-TRPJ NAA rat io in su ppressors compared to nonsuppressors. We selected the 1600h postdexa methaso ne cortisol and the L-TRP/ NAA ratio as the best va riables representing HPA disinhibi-

190 tion and central serotonin activity, respectively, and found a weak positive correlatio between these two variables. Although this correlation is significant, a commO: va riance of 27% cannot be considered a redundant measure. Although there are no other reports linking the L-TRP I NAA ratio and postdexamethasone cortisol levels, Davis et a!. ( 1981) report a lack of correlation between cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and postdexamethasone plasma cortisol levels, while Trask man eta!. ( 1980) find only a weak correlation between CSF 5-HIAA and CSF cortisol. However, the relationship between the plasma L-TRP j NAA ratio and CSF 5-HIAA has not been definitely established. Plasma cortisol has been negatively correlated with plasma total tryptophan in post-partum patients (Handley et al., 1980) and patients with Cushing's syndrome (Kelly et al., 1980); however, these dissimilar patient groups make comparisons to our st ud y difficult. We found the 1600h postdexamethasone cortisol levels correlated with the severity of illness. An association between H P A disinhibition and degree of depression has been noted by other investigators (Carroll, 1972; Stokes et al., 1975; Davis et al., 1981· Reus, 1982). There was no correlation between the L-TRP / NAA ratio and overall severity of illness. This conflicts with DeMye r et al. (1981) who found lower LTRP / NAA ratios when patients were most depressed clinically. Several studies using total plasma tryptophan (rather than the L-TRP / N AA ratio) showed no or little correlation with psychometric scales for depression (Handley eta!., 1980; Kelly et al., 1980; Hoes et al., 1981). We found that 65% of the variance in H DRS scores could be accounted for by the combination of the L-TRP/ NAA ratio and l600h postdexamethasone cortisol levels. The significant increases in the R 2 values after the inclusion of the L-TRP / NAA ratio in the multiple regression equation indicate that it is useful in improving the prediction of illness, both in severity and nature. These markers seem to code best for an agitated depression (Curzon et al., 1979; Reus, 1982) as demonstrated by the combination of HDRS subscales anxiety-somatization and cognitive distu rbance and BPRS subscales thought disturbance and activation. The HDRS subscale retardation and the BPRS su bscale anergy are notably unaffected by either marker. A likely mechanism underlying the increase in total HDRS R 2 may be the role of the L-TRP / N AA ratio as a "statistical suppressor" variable (see Cohen and Cohen, 1975, for a more extensive discussion of "traditional" or " classical" suppression). Although the L-TRP / NAA ratio and 1600h postdexamethasone cortisol share 27% of the variance, the relative lack of any shared variance between the L-TRP f N AA ratio and the HDRS would suggest that L-TRP / NAA removes that cortisol variance which does not correlate with the HDRS (cortisol /3-coefficient = 0.88; L-TRP/ NAA Pcoefficients= -0.75). T hus the improved R 2 appears to be the result oft he excl usion of a subgroup of cortisol values which do not have psychometric correlates. A similar relationship between HPA disinhibition, serotonin activity, and HDRS scores was recently reported by Davis eta!. ( 1981). In their article, postdexamethasone plasma cortisol levels were significantly correlated with HDRS scores and accounted fo r 22% of the variance. Adding postprobenecid CSF 5-HIAA levels to postdexamethasone plasma cortisol values improved the relationship to severity of depression

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191 and accounted for 52% of the variance in the HDRS. The hypothesis that the L-TR P N AA ratio and DST identify independent abnormalities is further supported by a recent s~udy w_hic_h noted that the ~STan~ a me~surement ~f platelet s_erotonin upta ke identtfied s1gmficantly more pat1ents w1th maJor depressiOn than e1ther test alone (M eltzer et al., 1983). Measurement of the L-TRP / NAA ratio is expensive and not widely available, in contradistinction to the DST. Our data provide a rationale for obtaining the LTRP t NAA ra tio in addition to the DST. The reliability of the L-TRP / NAA ratio may be increased by either repeat sampling or a longer fasting period to compensate for daily fluctuations in levels. Although the size of our sample precludes definitive statements regarding se rotonin and HPA disinhibition in depression, this study supports multivariate approaches to biological markers for depression. Acknowledgment. The authors thank the nursing staff of the Inpatient Treatment &

Research Service for their assistance in the execution of this study, and Natasha Page Carroll, A. Richard Corso. and the G rants Management Unit for their assistance in the preparation of this article. The research reported was supported in part by training grant #5-R32-M H- 15091 and Biomedical Research Support Grant #2-S07-RR-05755.

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