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CSF Oxytocin and Vasopressin Levels after Recovery

from Bulimia Nervosa and Anorexia Nervosa,

Bulimic Subtype

Guido K. Frank, Walter H. Kaye, Margaret Altemus, and Catherine G. Greeno

Background: When ill, people with eating disorders have

disturbances of the neuropeptides vasopressin and


Methods: To avoid the confounding effects of the ill state,

we studied women who were recovered (more than 1 year,

normal weight, and regular menstrual cycles, no bingeing

or purging) from bulimia nervosa (rBN) or binge eating/

purging–type anorexia nervosa (rAN-BN), and matched

healthy control women.

Results: Vasopressin was elevated in rAN-BN and showed

a trend towards elevation in rBN. In rBN, elevated

cerebrospinal fluid vasopressin may be related to having a

lifetime history of major depression. In comparison,

cere-brospinal fluid oxytocin was normal in recovered subjects,

but elevated levels in some rBN might be related to birth

control pill use.

Conclusions: These data confirm and extend the

possibil-ity that elevated cerebrospinal fluid vasopressin may be

related to the pathophysiology of eating disorders, and/or

a lifetime history of major depression. Biol Psychiatry

2000;48:315–318 © 2000 Society of Biological Psychiatry

Key Words: Anorexia nervosa, bulimia nervosa,

oxyto-cin, vasopressin, major depression, obsessive– compulsive




ulimia nervosa (BN), a disorder of unknown etiology

that has its onset in young women, is characterized by

binge eating followed by compensatory methods to

pre-vent weight gain (American Psychiatric Association

1994). Most commonly, women with BN maintain a

normal weight. Bulimic symptoms also occur less

com-monly in people with the binge eating/purging type of

anorexia nervosa (AN-BN). People who are ill with BN

and AN-BN have a similar range of comorbid symptoms

(Garfinkel et al 1995) and a wide variety of

neuroendo-crine disturbances (Kaye et al 1998a), which could be a

consequence of central nervous system neuropeptide

dys-regulation. For example, altered concentrations of

oxyto-cin (OXT) and vasopressin (AVP) have been found in

people with eating disorders (EDs) (Demitrack et al 1990,

1992; Gold et al 1983a).

OXT and AVP are produced in the hypothalamic

supraoptic and paraventricular nucleus and are released

peripherally via pituitary projections to the

neurohypoph-ysis, and also centrally directed into the brain (Swaab et al

1993). Central and peripheral OXT and AVP are

indepen-dently regulated (Geiner et al 1988), with the peripheral

activities of these peptides best known. AVP controls

free-water clearance of the kidney, whereas OXT

pro-motes uterine contraction and milk let-down. In the brain,

these peptides are long-acting neuromodulators and exert

complex behavioral effects. OXT administration to rats

disrupts memory consolidation and retrieval, whereas

AVP administration enhances memory function. In animal

models, OXT has anxiolytic actions, whereas AVP has

anxiogenic effects (Liebsch et al 1996; McCarthy et al

1995). Thus, in several ways the effects of OXT appear to

be reciprocal to the effects of AVP. In terms of EDs, these

neuropeptides are of interest because they influence

feed-ing behavior (Burlet et al 1990; Olson et al 1991) and have

also been implicated in obsessional behaviors (Leckman et

al 1994) and depression (Gjerris et al 1985).

It is not known whether alterations in OXT or AVP are

a consequence of pathologic eating or malnutrition, or if

they are premorbid traits that contribute to a vulnerability

to develop EDs. Determining whether abnormalities are a

consequence or a potential antecedent of pathological

feeding behavior is a major question in the study of EDs.

It is impractical to study people with EDs prospectively,

because of the young age of onset and difficulty in

premorbid identification of people who will develop this

illness. Therefore, we studied women who were recovered

for more than a year from BN or AN-BN. Any persistent

psychobiological abnormalities might be trait-related and

might potentially contribute to the pathogenesis of the


From the Department of Psychiatry, University of Pittsburgh, School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania (GKF, WHK, CGG) and the Department of Psychiatry, Cornell University Medical College, New York, New York (MA).

Address reprint requests to Walter H. Kaye, M.D., University of Pittsburgh, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, E-724, Pittsburgh PA 15213.

Received June 10, 1999; revised December 28, 1999; accepted January 3, 2000.


Methods and Materials

Thirty-three women who had previously met DSM-IV criteria for an ED were recruited: 23 women recovered from BN (rBN), and 10 subjects recovered from binge eating/purging–type AN (rAN-BN). The rBN women had never had AN. Recovered ED subjects were compared to 17 female normal control subjects (NC), who were recruited through advertisements in local news-papers and who were without lifetime psychiatric or major medical illnesses. In the year before the study, all participating subjects had to maintain a body weight of.90% average body weight (%ABW) (Metropolitan Life Insurance Company 1959), have regular menstrual cycles; have not binged, purged, or engaged in restrictive eating patterns; and have not met criteria for substance-related disorders. None of the subjects had a current major depressive episode. Current depressive symptoms were assessed with the Hamilton Depression Rating Scale (HDRS; Hamilton 1967) and current obsessive and compulsive symptoms with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS; Goodman et al 1989). All subjects completed a 7-day diary at home, in which they listed individual food items consumed, portion sizes, and exercise frequency. This informa-tion was used to confirm the presence of relatively normal dietary intake. Subjects were free of medication for 6 weeks prior to the study and gave informed consent.

A lumbar puncture (LP) for obtaining cerebrospinal fluid (CSF) samples without preservative was performed during the early follicular phase by methods previously described (Kaye et al 1998b). CSF OXT and AVP assays were performed by radioimmunoassay also as previously described (Altemus et al 1994). A modified version of the Schedule for Affective Disor-ders and Schizophrenia-Lifetime Version (SADS-L) was used for assessment of lifetime axis I diagnoses (Kaye et al 1998b). Three NC, two rAN-BN, and nine rBN women were taking birth control pill (BCP) at the time of the study.

One-way analysis of variance (ANOVA) and Tukey’s post hoc test were used to investigate three group comparisons. Analysis of covariance (ANCOVA) was applied for confounding vari-ables. Two-way ANOVA investigated possibly interacting inde-pendent within-group factors when all cells were filled; other-wise stepother-wise regression was applied. Correlations were assessed

by Spearman correlation coefficients. For statistical analyses, the SPSS (Chicago) software package was used (Barcikowski 1984).


The three subject groups (Table 1) were of similar ages.

Current %ABW was lower in rAN-BN compared to rBN

women, and as expected, there were significant

differ-ences in high and low lifetime %ABW. ED subjects had a

similar age of onset of their ED.

The three subject groups had similar CSF OXT values;

however, CSF AVP concentrations were significantly

elevated in the rAN-BN compared to NC, and tended to be

higher compared to rBN women (p


.06, Tukey’s post

hoc test). When the three groups were combined, age was

significantly associated with CSF AVP (r


.43, p



Separate ANCOVAs with age as covariate showed that

CSF AVP in the rAN-BN was significantly higher than for

NC subjects [F(1)


12.1, p


.002], or rBN [F(1)






A series of exploratory analyses was done in rBN

subjects to determine whether depression or obsessive–

compulsive disorder (OCD) or other factors were related

to neuropeptide levels. The rAN-BN group was not

analyzed because of their small cell sizes. rBN with a

lifetime history of OCD had higher CSF OXT

concentra-tions (n


5, 7.74


2.0 pmol/L) than did rBN subjects

without a lifetime OCD diagnosis (n


16, 5.89



pmol/L, p


.05). In addition, rBN with a lifetime history

of major depressive disorder (MDD) had higher CSF AVP

concentrations (n


17, 6.50


2.0 pmol/l) than did rBN

without a lifetime MDD diagnosis (n


4, 5.63



pmol/L, p


.03). Neither CSF AVP or OXT was related

to current depression or OCD symptoms in rBN. To

determine whether BCP use contributed to these findings,

a stepwise regression analysis was done. This showed that

elevated CSF OXT in rBN was mainly related to BCP

Table 1. Comparison of Study Subjects on Demographic Variables and Cerebrospinal Fluid Oxytocin and Vasopressin

Recovered normal weight

% average body weight (%ABW) 111610a 101

610b 105

67.5 4.9 .01

Maximum lifetime %ABW 123611a 120

619 11069b 5.5 .00

Minimum lifetime %ABW 9568a 69

68b 96

68a 43.3 .00

Age of onset of eating disorder (years) 16.263 14.862.4 — 1.6 .22

Length of recovery (months) 38.7625 26.8619 — 1.8 .19

Hamilton Depression Rating Scale 7.466.6 (18) 7.964.8 (9) 4.163.6 (14) 4.5 .15

Yale Brown Obsessive Compulsive Scale 9.467.4a(18) 9.6

67.6a(9) 2.6

63.8b(14) 5.2 .01

Oxytocin pmol/L 6.3761.79 7.3262.22 6.2661.95 1.1 .35

Vasopressin pmol/L 0.7460.20 0.8960.17a 0.66

60.13b 5.3 .01

Values are mean6SD.

p,.05 foravs.b(Tukey’s post hoc test).

316 BIOL PSYCHIATRY G.K. Frank et al


intake (t


3.2, p


.005) but not to a lifetime history of

lifetime OCD (t


1.1, p


.3); however, birth control use

had no effect on CSF AVP (t


0.87, p


.40) as the

relationship of CSF AVP and a history of MDD (t





.03) remained significant.


These data confirm and extend the possibility that long-term,

recovered eating disorder subjects with bulimic-type

symp-toms have increased CSF AVP. Previous studies (Demitrack

et al 1990; Gold et al 1983a) found elevated CSF AVP levels

in ill and recovered subjects with eating disorders but

subgrouping by types of eating behavior was not done.

This study raises the possibility that elevated CSF AVP

is particularly associated with depressive symptoms. Such

questions were not asked in previous studies of people with

eating disorders. The small size of subject groups after

segregating by ED type and Axis I diagnosis limits our power

to investigate the interactions of these diagnoses and AVP.

Other studies have found elevated CSF AVP in people with

lifetime MDD who were not currently depressed (Sorensen et

al 1985), whereas other studies suggest reduced CSF AVP

levels in depression (Gold et al 1983b). We also found that

CSF AVP was associated with age. We are not aware of a

study in humans investigating age as a covariate for this

peptide; however, age was related to the circadian pattern of

CSF AVP in an animal study (Jolkkonen et al 1986).

As a group, recovered subjects had normal CSF OXT

levels. These data, however, raise a question of whether

CSF OXT is related to a lifetime history of OCD or BCP

use. CSF OXT has not been previously measured in

recov-ered ED subjects. People with OCD have been reported to

have both normal (Altemus et al 1999) and elevated levels of

CSF OXT (Leckman et al 1994). Studies in animals suggests

that peripheral administration of gonadal steroids can alter

brain OXT mRNA; however, changes in CSF OXT or AVP

have not been found (Amico et al 1990; Insel et al 1997;

Parry et al 1991). In terms of limitations, the small size of the

recovered ED groups makes segregation by diagnosis or BCP

problematic. Thus, these preliminary data raise interesting

questions, but replication is needed in a larger sample.

Supported in part by grants from the National Institute of Mental Health (No. 2 R01 MH 42984-04, “The Neurobiology of Feeding Behavior in Bulimia”), the Children’s Hospital Clinical Research Center, Pittsburgh, Pennsylvania (No. 5M01RR00084), and the Christina Barz-Foundation, Du¨sseldorf, Germany.


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Table 1. Comparison of Study Subjects on Demographic Variables and Cerebrospinal Fluid Oxytocin and Vasopressin


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