T-lymphocyte concentrations of cholecystokinin-8 and beta-endorphin in eating disorders: II. Bulimia nervosa

ELSEVIER Psychiatry Research 37 (1995) 51-56

PSYCHIATRY

RESEARCH

T-lymphocyte concentrations of cholecystokinin-8 and beta-endorphin in eating disorders: II. Bulimia nervosa

Francesca Brambilla* a, Giampaolo Pernab,

Mirella Brunetta b, Angela Draisci b, Albert0 Peirone b, Paola Sacerdotec, Barbara Manfredi’, Albert0 E. Paneraic

aPsychoneuroendocrine Center, Ospedaie Pini, Milan, Italy bDipartimento Scienze Neuropsichiche. Istituro Scientifico. S. Raffaele. Milan, Italy

CDipariimento Farmacologia Universitb. Milan, Italy

Received 15 June 1994; first revision received 12 December 1994; second revision received 8 May 1994; accepted 26 June 1995

Abstract

Concentrations of cholecystokinin-8 (CCK-8) and /3-endorphin (p-EP) in T-lymphocytes of 26 women with bulimia nervosa (BN) and in 26 age- and sex-matched healthy comparison subjects were measured. Ten patients were then treated with 300 mg/day of tluvoxamine, p.o., and live patients were treated with 300 mg/day of amineptine, p.o., for 4 months. Concentrations of the two peptides were measured again after 1, 2, and 4 months of therapy. Basal CCK-8 values were significantly lower in patients than in healthy subjects. During fluvoxamine therapy, CCK-8 values increased, reaching normal levels by month 4 of treatment. No such increase occurred during amineptine therapy. Baseline /3-EP values were normal in the bulimic patients but had declined by month 4 of fluvoxamine therapy.

Keywords: Bulimia nervosa; Peptides; Amineptine; Fluvoxamine

1. Introduction

The biological basis of the increased hunger, decreased satiety, and craving for carbohydrates

and lipids that characterize bulimia nervosa (BN) are still poorly understood (Kissileff et al., 1986; Nakai et al., 1987; Walsh et al., 1989; Rodin et al., 1990; Hadigan et al., 1992; Rolls et al., 1992).

Changes in the secretory patterns of brain

* Corresponding author, Piazza Grahdi 3, Milan0 20127, Italy; Tel: +39 368 3017420; Fax: +39 2 70122889.

neurotransmitters, neuropeptides, neurohor- mones, and peripheral hormones that are known to regulate eating behavior (Morley et al., 1985;

Morley, 1989) have been tentatively, implicated in the pathogenesis of these abnormal sensations. BN has been hypothetically linked to impairments of central and peripheral secretion of cholecysto-

kinin- (CCK-8), a potent stimulator of satiety and inhibitor of preferential consumption of carbohydrates and lipids, and an inhibitor of endog- enous opioids (&endorphin and dynorphin) that

stimulate hunger and carbohydrate preference (Bartness et al., 1984; Morley et al., 1985; Morley,

0165-1781/95/%09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-1781(95)02674-L

52 F. Brambilla et al. /Psychiatry Research 59 (1995) 51-56

1989; Asin et al., 1992; Beck, 1992; Bednar et al., 1992; Cooper et al., 1992; Lieverse et al., 1993). Data in the literature in this regard, however, are scanty. Cerebrospinal fluid (CSF) CCK-8 levels of BN patients were decreased (Gerner and Yamada, 1982; Brewerton et al., 1992a; Lydiard et al., 1993) and plasma concentrations of the peptides showed little response to a mixed liquid meal (Geracioti and Liddle, 1988). CSF levels of P-endorphin @- EP) were lower than normal, and those of dynorphin were normal in the CSF of bulimic patients (Lesem et al., 1991; Brewerton et al., 1992b). Data for plasma levels of /3-EP were contradictory, being generally lower than normal in bulimic patients, although they were higher than normal in vomiting patients (Fullerton et al., 1986, 1988; Waller et al., 1986; Foss and Trygstad, 199 1). Even though extremely interesting, the data are too scarce to provide clear-cut evidence of the involvement of the two peptides in the etiopathogenesis of BN. Moreover, most of them derive from a transversal examination of BN patients, and their significance remains to be confirmed. Only Foss and Trygstad (1991) followed up their patients and observed a normalization of previously low plasma /3-EP levels after fluoxetine treatment, in parallel with improvement of the bulimic symptomatology. Finally, it must be remembered that plasma levels of &EP reflect only pituitary secretion, which does not parallel cerebral secretion, and that peripheral peptides hardly cross the blood-brain barrier and therefore probably have little significance for the pathogenesis of hunger, satiety, and food selection.

In a preliminary investigation of BN patients. we studied concentrations of the two peptides in T-lymphocytes, a peripheral compartment that is thought to reflect the brain neuronal secretion and regulation of many hormones, including /3-EP and CCK-8 (Kavelaars et al., 1990; Panza et al., 1991; Sacerdote et al., 1991); is of easy and relatively noninvasive access; and allows repeated measurements. In Part I of this report (Brambilla et al., 1995), which focused on patients with anorexia nervosa, of both the restricting (AN-R) and the binging-purging (AN-BP) types, we observed that baseline CCK-8 values were lower than normal and P-EP values greater than normal.

On the assumption that these alterations might mirror similar ones in the central nervous system, we suggested that they could reflect one pathogenetic factor in the modulation of anorexic symptomatology. In a similar vein, we studied the levels of the two peptides in drug-free bulimic patients and then longitudinally during the course of a combined cognitive-behavioral, psychophar- macological, and nutritional therapy. The aim of the study was to determine whether the concentrations of the two peptides were altered in the active phase of the disorder, if they were correlated with specific symptoms, and if they could be modified by treatment in parallel with specific changes in the symptomatology of the eating disorder. Final- ly, by giving antidepressant drugs with selective actions on different central regulatory systems, we hoped to define the specific effect of one or the other neurotransmitter on T-lymphocyte CCK-8 and P-EP concentrations and on peptide- correlated pathological eating behavior.

2. Methods

Twenty-six bulimic women, outpatients of the Center for Eating Disorders of the Department of Science Neuropsichiche Universita, Istituto Scien- titico S. Raffaele, Milan, Italy, entered the study. They were 16-43 years old (mean age = 23, SD = 7.5), with a duration of illness of 1-13 years (mean = 5.8, SD = 4.3), and with a body mass index (BMI) of 18-28 (mean = 21.2, SD = 4.7). Four of them had amenorrhea, which had ranged from 9 months to 6 years in duration at the time of the study, and the others had regular menses. Twenty-six physically healthy women, age- matched to the patients and selected from the hos- pital staff, were used as comparison subjects (the same comparison subjects are described in the AN study reported in Part I; Brambilla et al., 1995).

The diagnosis of BN was based on the Diagnos- tic Interview Schedule, Revised (DIS-R; Robins et al., 1989) in accord with DSM-III-R criteria (American Psychiatric Association, 1987). None of the patients had concomitant Axis I disorders. and only one had a past history of an Axis I disorder (bipolar disorder). None of them had been previously been treated with psychophar-

F. Brambilla et al. 1 Psychiatry Research 59 (1995) 51-56 53

macological drugs; some had had brief trials of various types of psychodynamic treatments without significant amelioration of the disorder. The comparison subjects were also interviewed with the DIS-R to exclude present or past psychopathology, especially eating disorders. In- formed consent was obtained from both patients and healthy subjects. Criteria for exclusion from the study were the same used for AN patients (see Part I). The nutritional counseling and the cognitive behavioral therapy followed the guidelines reported in the study of AN patients (Brambilla et al., 1995).

Ten of the 26 BN patients were given 300 mgday fluvoxamine, p.o., for 4 months, and live received 300 mg/day amineptine, p.o., for 4 months. Fluvoxamine was chosen because of its mainly serotonergic stimulating activity; serotonin (5hydroxytryptamine, 5-HT) increases satiety and inhibits carbohydrate and lipid craving (Morley, 1987; De Bellis et al., 1993). Amineptine was chosen for its mainly dopaminergic stimulating activity, since dopamine (DA) inhibits hunger (Of- fenmahier et al., 1977; Leibowitz, 1986). The function of both neurotransmitters has been reported to be decreased in BN patients (Kaye et al., 1984, 1991; Brewerton et al., 1986; Jimerson et al., 1988, 1992).

During the 4 months of treatment, the patients were monitored with the Eating Disorder Inven- tory (EDI; Garner et al., 1983) and the Bulimic In- vestigatory Test (BITE; Henderson and Freeman, 1987) for their eating pathology, and with the Hamilton Rating Scales for Depression (HRSD; Hamilton, 1960) and Anxiety (HRSA; Hamilton, 1959). BMI was calculated before treatment began

and then after 1, 2, and 4 months of treatment. CCK-8 and fi-EP concentrations in T-lymphocytes were measured at the same intervals (for pro- cedures, see Brambilla et al., 1995).

The statistical evaluation included analysis of variance (ANOVA) and repeated measures ANOVA.

3. Results

Basal concentrations of CCK-8 in T-lymphocytes were significantly lower (pg/lO cells) in BN patients than in comparison subjects (BN: mean = 24.9, SD = 14.9; comparison subjects: mean = 47.7, SD = 21.3; F = 20.1; d’= 1, 50; P < O.OOOl), while those of P-EP (pg/lO cells) did not differ in the two groups (BN: mean = 27.6, SD = 12.7; comparison subjects: mean = 25.0, SD = 12.1; P = NS). Administration of fluvoxamine (Table 1) was followed by significant rises in CCK-8 values after 2 months (F = 12.0; df = 1, 9; P = 0.007) and 4 months of therapy (F = 7.6; df = 1, 6; P < 0.01). ANOVA for repeated measures revealed a significant effect of time (F = 3.8; df = 3, 18; P < 0.03). Levels of fi-EP had decreased after 4 months of fluvoxamine therapy (values at 4 months vs. basal values: F = 20.4; df = 1, 6; P = 0.004, by ANOVA), but repeated measures ANOVA showed no significant effect of time. Ad- ministration of amineptine (Table 2) did not change mean CCK-8 and fi-EP values at any measurement point during the treatment period, and repeated measures ANOVA did not reveal a significant effect of time.

Fluvoxamine therapy did not alter depression and anxiety levels or ED1 scores except for the

Table 1 T-lymphocyte concentrations of cholecystokinin-8 and B-endorphin in fluvoxamine-treated patients with bulimia nervosa

Baseline Month I Month 2 Month 4

Mean SD Mean SD Mean SD Mean SD

Cholecystokinin-8 (pg/lO cells) 20.6 13.1 27.3 24.6 31.0 12.8** 41.7 49.2* B-Endorphin @g/l 0 cells) 31.8 13.4 36.8 23.0 23.7 20.8 12.3 4.3***

Note. Treatment levels vs. basal levels: *P = 0.01; **P = 0.007; l **P = 0.002.

54 F. Brambilla et al. /Psychiatry Research 59 (1995) 51-56

Table 2 T-Lymphocyte concentrations of cholecystokinin-8 and fl-endorphin in amineptine-treated patients (pg/lO x 6 cells)

Baseline Month 1 Month 2 Month 4

Mean SD Mean SD Mean SD Mean SD

Cholecystokinin-8 18.6 9.0 31.8 20.6 47.2 28.8 42.1 26.2 fl-Endorphin 31.1 10.5 34.5 40.1 30.9 31.5 27.9 28.3

cluster related to “fear to grow,” which was revealed by repeated measures ANOVA to have improved significantly by month 4 of treatment (F= 5.6; df = 3, 21; P = 0.006). Repeated measures ANOVA indicated that BITE scores for symptoms (F = 4.0; df = 3, 21; P = 0.02) and severity (F= 8.7; df = 3, 21; P = 0.001) improved significantly during treatment. A trend toward a decrease was found for binging (baseline: mean = 4.1, SD = 0.3; posttreatment: mean = 2.7, SD = 0.7) and vomiting (baseline: mean = 3.2, SD = 0.8; posttreatment: mean = 2.2, SD = 0.9).

Repeated measures ANOVA showed that amineptine significantly improved BITE symptom (F = 4.9; df = 3, 9; P = 0.03) and severity scores (F = 4.5; df = 3, 9; P = 0.03). By month 4 of treatment, anxiety also showed improvement (F = 11.36; df = 1, 3; P = 0.043), but repeated measures ANOVA was not significant. Depression and ED1 scores did not change significantly. Bing- ing (baseline: mean = 4.0, SD = 0.3; posttreatment: mean = 3.0, SD = 0.9) and vomiting (baseline: mean = 4.6, SD = 0.7; posttreatment: mean = 3.5, SD = 0.6) showed a trend toward improvement). BMI was normal both before and after treatment.

4. Discussion

Even though preliminary, our data may suggest some hypotheses about the link between CCK-8 and &EP concentrations in T-lymphocytes and BN. The finding of significantly lower than normal CCK-8 concentrations in our patients suggests that the levels of the peptide are reduced in all the biological compartments of BN patients, and not only in CSF and in plasma, as already reported in

the literature (Gerner and Yamada, 1982; Geracioti and Liddle, 1988; Brewerton et al., 1992a; Lydiard et al., 1993). As a consequence, the low values observed in the different studies cannot be a chance finding unrelated to BN, but may be an expression of a generalized reduced secretion of the peptide, possibly pathogenetically involved in the development and course of the disease. This hypothesis is further supported by the observation that treatment of the BN patients with fluvoxamine resulted in a significant increase of CCK-8 values in parallel with significant improvement of BITE scores. At the moment, we can only suggest, but have not yet demonstrated, that the generalized impairment of CCK-8 concentrations observed by us and others is responsible for, or at least linked to, the psychopathology of BN. The fact that amineptine significantly improved BITE and anxiety scores but did not change CCK-8 values casts doubts on the hypothesis that impairments of the peptide concentrations are somehow involved in the pathogenesis of BN, unless we further hypothesize that the phenomenon is mediated by the 5-HT system, with CCK-8 and 5-HT exerting reciprocal regulatory effects (Cooper et al., 1992) and not by the DA system.

The concordant reductions of CCK-8 concentrations in CSF and T-lymphocytes support the hypothesis that the secretion of the peptide in the two compartments is regulated similarly, and therefore that T-lymphocyte levels of the peptide may be used in humans as a mirror of the secretory pattern of the hormone in the brain under normal and pathological conditions (Kavelaars et al., 1990; Panza et al., 1991; Sacerdote et al., 1991). It is interesting to mention, at this point, that the T- lymphocyte CCK-8 concentrations are similarly

F. Brambilla et al. /Psychiatry Research 59 (1995) 51-56 55

lower than normal in both AN-R and AN-BP patients, as well as in BN patients, which suggests that this alteration might be a common basic pathology for eating disorders in general, indepen- dent of the dominant form of symptomatology.

T-lymphocyte @EP concentrations were normal in our patients, did not change during amineptine therapy, and were reduced only at the end of the fluvoxamine treatment. This would suggest that the opioid is not directly involved in the eating pathology of BN. The literature includes reports of decreased &EP concentrations in CSF and of normal or increased concentrations in plasma (Fuller- ton et al., 1986, 1988; Waller et al., 1986; Foss and Trygstad, 1991; Lesem et al., 1991; Brewerton et al., 1992b). The contrasting results between our study and those of the others could be due either to differences in the selection of subjects or to the fact that concentrations of P-EP in T-lymphocytes may not reproduce exactly the secretory pattern of brain or the concentrations in plasma.

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The low values of CCK-8 in our patients might be an expression of lowered central secretion of 5 HT, since the neurotransmitter is a natural stimulator of CCK-8 (Cooper et al., 1992) and CCK-8 concentrations increased during fluvoxamine but not amineptine therapy. The data for /3- EP, however, do not support this interpretation; 5- HT is also a natural stimulator of /3-EP (Morley, 1982; Petraglia et al., 1984), but basal /3-EP concentrations were not reduced in our patients and did not increase during fluvoxamine therapy.

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As mentioned before, our data are preliminary, the population examined is small, the follow-up period has encompassed only 4 months of treatment, and it is therefore difficult to validate a possible involvement of CCK-8 and /3-EP in the development and course of BN or at least of some of its symptoms. However, we believe that our protocol of investigation, which we are now apply- ing to a larger group of patients for a longer period of time, may be an easy and reliable tool for future investigations of the biological bases of BN.

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T-lymphocyte concentrations of cholecystokinin-8 and beta-endorphin in eating disorders: II. Bulimia nervosa