neutral amino acid ratios in obsessive-compulsive patients with and without depression

PSYCHIATRY RESEARCH Psychiatry Research 69 (1997) 9-1.5

Plasma tryptophan levels and tryptophan/neutral amino acid ratios in obsessive-compulsive patients with and without depression Laura Bellodi”, Stefano Erzegovesi, Laura Bianchi, Valentina Lucini, Roberta Conca, Adelio Lucca Department

of Neuropychiatric Sciences, Istituto Scientifico Ospedale San Raffaele, University of Milan School of Medicine, Via Luigi Prinetti 29, 20127 Milan, Italy

Received 27 December 1995; revised 18 July 1996; accepted 4 November 1996

Abstract We have studied fasting plasma tryptophan (TRP) levels and tryptophan/large neutral amino acid (TRP/LNAA) ratios in 12 patients with obsessive-compulsive disorder (OCD) and 12 patients with OCD and a coexisting current diagnosis of major depressive disorder (OCD-MDD). Assessments were made at baseline and after 6 weeks of treatment with fluvoxamine. OCD-MDD patients had significantly lower baseline TRP levels and TRP/LNAA ratios than OCD patients. After 6 weeks of fluvoxamine treatment, OCD-MDD patients had significant increases in plasma TRP and TRP/LNAA ratio, whereas OCD patients had non-significant decreases. Our data suggest that a major depressive syndrome could be a state variable affecting the changes in plasma TRP and TRP/LNAA ratio in OCD 0 1997 Elsevier Science Ireland Ltd. patients. Keywords:

Tryptophan;

Amino

acids; Serotonin;

Fluvoxamine

1. Introduction reuptake inhibisymptoms in

patients with obsessive-compulsive disorder (OCD) led to the ‘serotonin hypothesis’ of OCD (Goodman et al., 1989a; Pigott et al., 1990; Barr et al., 1992; Smeraldi et al., 1992). Recent studies with 5HT agonists and/or antagonists as pharmacological probes (Zohar et al., 1987; Hollander

* Correspondence author. Tel.: + 39 2 26433315; fax: + 39 2 26433265; e-mail: [email protected].

et al., 1992) have provided additional support for the role of the S-HT system in the pathogenesis

serotonin (5HT) obsessive-compulsive

The fact that

tors

reduce

01651781/97/$17.00 PIlSO165-1781(96)02961-7

6 1997 Elsevier Science

Ireland

Ltd. All rights reserved.

IO

L. Bellodi et al. /Psychiatric

and treatment of OCD. On the other hand, several studies (Maes and Meltzer, 1995) have indicated that alterations in central nervous system serotonin (5HT) function may be involved in the pathophysiology of depression. The synthesis of brain serotonin requires dictary intake of its precursor, the essential amino acid L-tryptophan (TRP). Several reports have shown that both an increase and a decrease of dietary and plasma tryptophan lead to corresponding changes in brain TRP and 5-HT levels in several animal species (Fernstrom and Wurtman, 1971a; Yuwiler, 1973; Pardridge, 1979; Curzon, 1981; Moja et al., 1989). Moreover, all the large neutral amino acids (i.e. valine, isoleucine, leucine, tyrosine, phenylalanine, and tryptophan) are transported across the blood-brain barrier by the same transport system, so that there is a competition amongthe six amino acids for the carrier protein. Thus, it has been suggested that the molar ratio of TRP to the sum of the other five large neutral amino acids (TRP/LNAA ratio) might be a better indicator of central 5-HT levels than basal plasma TRP (Fernstrom and Wurtman, 1972: Fernstrom, 1992). Fasting plasma TRP concentration and TRP/LNAA ratio, as peripheral indicatorsof central S-HT levels, have been assessed in OCD and mood disorders. As for depressed patients, the ma,jority of results (DeMyer et al., 1981; Joseph et al., 1984; Cowen et al., 1989; Lucca et al., 1992) demonstrated significantly lower plasma TRP levcls and TRP/LNAA ratios than in normal controls. III addition, TRP/LNAAs ratio was considered as a biological predictor for antidepressant therapeutic response (Moller et al., 1990: Lucca ct al.. 1994). On the other hand, the few data about OCD patients showed that basal levels of plasma TRP and TRP/LNAA ratio were not significantly different from those of normal controls (Lucca et al., 1992). We undertook the present preliminary study to determine whether the presence of a depressive syndrome might act as a factor in the variation of baseline plasma TRP levels and TRP/LNAA ratios in a new sample of OCD patients. In addition, to look for possible differences between OC‘D patients with and without a depressive syn-

Research 69 (1W7) Y-15

drome, we studied the effects of a standardized pro-serotonergic pharmacological treatment on plasma TRP levels and TRP/LNAA ratios. 2. Methods 2.1. Subject5

Twenty-four patients (6 men and lb: women) were consecutively recruited from the Anxiety Disorders Clinical and Research IJnit at San Raffaele Hospital, Milan, from March 1995 to July 1995. All patients met DSM-IV (American Psychiatric Association, 1994) diagnostic criteria for obsessive-compulsive disorder (OCD) andhad been drug-free for at least 3 weeks, No subject had received fluoxetine within 5 weeks of testing. Twelve (50%) patients had a coexisting current diagnosis of major depressive disorder (OCDMDD) and were considered as a separate group. The subtypes of OCD-MDD patients were coexisting major depressive disorder, recurrent (1 1 patients, 5 with melancholic features) and major depressive disorder, single episode (1 patient). All ‘pure’ OCD patients had a negative lifetime history for mood disorders. No other diagnoses were made. Exclusion criteria were: renal, hepatic and/or thyroid abnormalities, indicated by anamnesis and routine analyses, other serious general medical conditions, and body weight 20% above or below the ideal weight. Both oral and written informed consents were obtained from all patients before their enrollment in the study. 2.2. Clinical assessment All patients underwent a clinical evaluation for Axis I disorders, The Italian version of the Diagnostic Interview Schedule-Revised (DIS-R) (Robins et al., 1989) was routinely administered by a resident in psychiatry (V.L.), trained in the use of the instrument. The data collected were scored by a computer program (Marcus et al., 1990) and then modified according to DSM-IV criteria where appropriate.

L. Bellodi et al. /Psychiatric Research 69 (1997) 9-15

11

To quantify baseline OCD symptom severity, we used the Yale Brown Obsessive-Compulsive Scale (Y-BOCS) (Goodman et al., 1989b,c), which is sensitive to and selective for changes in severity of OCD symptoms. To quantify baseline depressive symptoms, the 21-item Hamilton Depression Rating Scale (HDRS) was used (Hamilton, 1960).

MDD) and Time (changes between the 2 time points sampled - TO and Tl). The interaction of Group X Time was also considered. Paired t-tests (Nie et al., 1986) were used as post-hoc tests for plasma TRP levels and TRP/LNAA ratios before and after treatment. Results are presented as mean + S.D.

2.3. Procedure

3. Results

All the subjects were placed on a standard diet 2 days before testing. The diet employed had 1800 kcal, subdivided in iipids (23%), proteins (22%,), and carbohydrates (5.5%). The approximate daily amount of tryptophan was 0.6 g. At OS:00 h (TO), following an overnight fast, a blood sample was drawn and Y-BOCS and HDRS were administered. Then, all patients began standardized treatment with fluvoxamine, according to an open design, following this schedule:

3.1. Characteristics of the sample

Demographic and clinical characteristics of the sample are summarized in Table 1. We found statistically significant differences between the two groups (OCD vs. OCD-MDD) in baseline depression scores (HDRS total score: 11.67 _t 5.88 vs. 24.17 k 4.28. F = 28.21; df = 1,23; P = 0.000). No other significant differences were found.

.

3.2. Plasma TRP levels and TRP/LNM

l

.

days 1-8: 50 mg, at bedtime, days 5-9: 100 mg, at bedtime, days 10-14: 150 mg (50 mg at 08:OOh and 100 mg at bedtime).

From day 15 onwards, the daily dosage could be increased to a maximum of 300 mg according to the drug’s tolerability and clinical efficacy. After 6 weeks of treatment (Tl) a second blood sample was drawn and Y-BOCS and HDRS were again administered to all patients. Total plasma amino acid levels were determined as previously described (Lucca et al., 1992). 2.4. Data analysis The chi-square test (Nie et al., 1986) was used to compare sex differences between the two groups (OCD vs. OCD-MDD). One-way analysis of variance (ANOVA) (Nie et al., 1986) was used to compare the demographic and clinical characteristics of the two groups. Results from plasma TRP levels and TRP/LNAA ratios before and after treatment were analyzed by ANOVA for repeated measures (Dixon, 1990). The main effects considered were Group (OCD vs. OCD-

ratios

Baseline plasma TRP levels in OCD vs. OCDMDD patients were 74.42 + 12.04 and 57.83 k 12.25 pmol/l, respectively. Both baseline TRP levels and TRP/LNAA ratios were significantly different between the two groups (F = 11.19; df = 1,23; P = 0.003 and F = 4.60; df = 1,23; P = 0.043). The ANOVA for repeated measures used to assess changes in total plasma TRP levels revealed a significant Group X Time interaction (F = 6.15; df = 1,22; P = 0.021). Considering TRP/LNAA ratio as a dependent variable, there was also a significant Group X Time interaction (F = 5.94; df = 1,22; P = 0.023). As shown in Figs. 1 and 2, fluvoxamine treatment was associated with a significant increase in plasma TRP levels in OCD-MDD patients. Conversely, in OCD patients, the decrease was not significant. In fact, post-hoc t-tests for paired data showed significant increases in OCD-MDD patients after treatment (t = - 2.43, df = 11, P = 0.033 for TRP values; t = - 3.23, df = 11, P = 0.008 for ratio values) and non-significant decreases for OCD patients (t = 1.38, df = 11, P = 0.195 for TRP values; t = 0.69, df = 11, P = 0.505 for ratio values).

L. Bellodi et al. /Psychiatric Research 69 (lW7/ Y-15

12 Tablc I Characteristics

of the sample

(N = 24) OCD (N = 12)

OCD-MDD

(N = 12)

_._~ Sex (M/F) Age (years) Education level (years) Onact OCD (years) Onset MDD (years) Y-BO(‘S score TO Y-BW‘S score TI HDKS score TO IIDRS SCOW TI TRP level TO ( ~mol/l) TRP level Tl ( pmol/l) Sum 01 LNAAs TO ( pmol/l) Sum of LNAAs Tl ( Fmol/l) TRP/LNAA ratio TO TRP/LNAA ratio Tl

2; IO VI.42 * IO.%2 lll.X2 * 4.5 I 22.92 ri_ I I If)

4/x JO.67 f 14.09 11.27 k 2.94 195x * 6.13 26.00 15.93 Il.67 7.33 74.42 66.75 6 14.67 615.50 0.120 0.1 I3

“F‘ ~1 35.42; df = 1,23; P = 0.000. “F 11.19; df = 1,23: P = 0.003. ‘F ~~0.93; df = 1.23; P = NS. “I: 4.hO: df = 1.23; P = 0.033. Y-HO(‘S. Yale-Brown Obsessive-Compulsive LNAAs. large neutral amino acids; TRP/LNAA Kc\ults are presented as mean f S.D.

* 8.06 * 6.36 * 5.X8” i_ 3.61 k 12.04” t 17.96 k 140.66’ k 175.92 * 0.017d * 0.037

27.3’

x t‘: 0’

?j.5S

t h.7S

I’J.33 + IO.70 z-1.17 t 1.7s” I I .zi I 3 hi T7.X.X -+ 11.75”

6rl.V 5h4.08 52’1.92 0.103 0. I25

Scale; HDRS, Hamilton ratio. tryptophan/large

DepressIon Rating Scale neutral amino acid ratio.

; t * + ‘r

IJ.5X

I IJ.hl’ 7x.37 0.02lI” 1).022

(?I-ltcm):

T.W.

rrvl)tophan:

. .

90

: .

80

,go / 80

: 70 !

i =o

170

. . . 8

50

40

.

Fig. I. Fluvoxamine treatment was patients, with a non-significant decrease levt:ls.

associated, in plasma

in OCD tryptophan

Fig. 2. FhJvoxdmine treatment was associated. in OCD-MDD patients. with a significant increase in plasma ttyptophan levels.

L. Bellodi et al. /Psychiatric Research 69 (1997) 9-15

3.3. Behavioral ratings

ANOVA for repeated measures applied to total Y-BOCS ratings revealed a significant effect of Time (F = 40.82; df = 1,22; P = 0.0001). For total HDRS ratings, we also found significant effects of Group (F = 22.75; df = 1,22; P = 0.0001) and Time (F = 93.74; df = 1,22; P= 0.0001). There was also a significant interaction of Group X Time (F = 18.52; df = 1,22; P = 0.0003). No other significant main effects or interactions were found. 4. Discussion In our sample, obsessive-compulsive patients with a coexisting diagnosis of major depressive disorder (OCD-MDD) had significantly lower plasma TRP levels than patients with OCD only, whereas the plasma TRP levels of OCD patients were within the range of the normal population. In fact, normal data from our laboratory (29 healthy subjects, all screened for the absence of Axis I and II disorders), showed a mean plasma TRP value of 70.55 k 10.62 pmol/l, not significantly different from OCD subjects and significantly higher than the OCD-MDD subjects (ANOVA with Student-Newman-Keuls test for multiple comparisons: df = 50. OCD vs. OCDMDD: P < 0.05; OCD vs. Healthy: P = NS; Healthy vs. OCD-MDD: P < 0.05). Other reports (Lucca et al., 1992) have suggested that there is a significant effect of a current diagnosis of major depressive episode on basal plasma tryptophan levels and TRP/LNAA ratios, as compared to normal subjects and a small group of obsessivecompulsive patients, with OCD-MDD patients having lower levels, even though not statistically significant, than OCD patients. It is still unclear if total or free plasma TRP levels are more indicative ofcentral tryptophan levels (e.g. Wurtman et al., 1981). A significant correlation, however, was reported in the decrease of free and total tryptophan levels after a mixture devoid of tryptophan (Delgado et al., 1990; Benkelfat et al., 1994). Considering the predictive value of the TRP/LNAA ratio, our data showed that the low-

13

ering of the TRP/LNAA ratio in OCD-MDD subjects seems to be due exclusively to lowered TRP levels, since the sum of the large neutral amino acids was not statistically different between OCD and OCD-MDD subjects. Factors other than a depressive syndrome could have contributed to the different results for different groups, e.g. differences in gender, age, or food intake (Fernstrom and Wurtman, 1971b). In our sample, however, there were no significant differences in gender or age distribution between our two subgroups, and we tried to minimize the influence of dietetic habits by placing all the subjects on a standard diet 2 days before testing. Pharmacological treatment significantly decreased Y-BOCS ratings in both subgroups. OCD-MDD subjects, being more depressed at baseline, had more improved HDRS scores than OCD patients, as evidenced by the significant Group x Time interaction. OCD-MDD patients in our sample had significantly increased plasma TRP levels after a pharmacological treatment with fluvoxamine, which agrees with other reports in the literature (Quintana, 1992; Lucca et al., 1994). This finding is in contrast to that of Celada et al. (19921, who found a plasma TRP concentration in MDD patients unchanged after 6 weeks of fluvoxamine treatment. The most intriguing finding in our study is the different plasma TRP and TRP/LNAA ratio responses to pharmacological treatment of OCD and OCD-MDD patients. We can hypothesize that plasma TRP level and TRP/LNAA ratio might be state variables, sensitive to treatment in OCD patients with a coexisting diagnosis of MDD, but not in patients with OCD only. Thus, our data suggest that a major depressive syndrome could be the state variable that, through a different handling of tryptophan, affects the changes in plasma TRP and TRP/LNAA ratio after pharmacological treatment. On the other hand, the role of plasma tryptophan levels seems not to be significant in OCD patients without a depressive syndrome, as already suggested by two previous studies of tryptophan depletion in OCD (Barr et al., 1994; Smeraldi et al., in press).

L. Beilodi et al. / P_sychiatticResmd~ 69 (lY07) 9-m1.5

I4

Further investigations, with larger numbers ot patients, will be necessary to confirm these preliminary data and see whether low plasma TRP levels and TRP/LNAA ratios are state or trait biological markers of depression in OCD patients.

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