Clonidine stimulation in anorexia nervosa: Growth hormone, cortisol, and beta-endorphin responses

P.s_vchiatry Research, 20, 19-3 I Elsevier

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Clonidine Stimulation in Anorexia Nervosa: Growth Hormone, Cortisol, and Beta-Endorphin Responses

Francesca Brambilla, Mario Lampertico, Laura Sali, Franc0 Cavagnini, Cecilia Invitti, Maurizio Maggioni, Carlo Candolfi, Albert0 E. Panerai, and Eugenio E. Miiller

Abstract. Clinical and biochemical findings link anorexia nervosa (AN) and primary affective disorders (PAD). Clonidine. an a2-adrenoceptor agonist, has been shown to blunt growth hormone (GH) response and greatly lower plasma cortisol m PAD patients. We examined the (iH, cortisol, and P-endorphin (/3-EP)

responses to an acute clomdme challenge( 150 c(g i.v. as a bolus) before and after 30 days of treatment with desmethylimlpramine in 14 women with AN. Both before and after treatment, the AN patients showed normal plasma GH and cortisol responses. but an Increased plasma P-EP response. The increased p-EP response in

AN was independent of weight and depressive symptomatology. Our data indicate that a>-adrenoceptors involved in the control of GH and adrenocorticotropic hormone are not altered in AN. The increased P-El’ response may indicate elevated opioid activity in the hypothalamo-pituitary system of AN patients.

Key Words. Anorexia nervosa. clonidine, growth hormone. cortisol, P-endorphin

Data in the literature suggest that a norepinephrine (NE) deficiency is present in the central nervous system (CNS) of patients with anorexia nervosa (AN). Plasma and urinary levels of NE and NE metabolites are low during the active phase of the disease and normalize after weight recovery (Hoes, 1977; Halmi et al., 1978; Winokur, 1978; Gross et al., 1979; Darby et al., 1980; Gerner and Gwirtsman, 1981; Gwirtsman and Gerner, 1981; Riederer and Toifl, 1981; Biederman et al., 1984). This would suggest that the NE deficiency is related to weight loss or lack of some specific food compo- nent. Reduced cerebrospinal fluid (CSF), plasma. and urinary levels of NE have been found after fasting or acute starvation in normal humans (Palmblad et al, 1977; Gross et al.. 1979) but not in patients with cancer-induced starvation (Riederer and Toifl, 1981). In AN, a shortage of essential amino acids could lead to an NE deficiency. However, plasma levels of tyrosine, the precursor of NE, have been reported to be both normal and low (Gross et al., 1979; Gerner et al., 1984). Moreover, NE turnover, which has been found to be reduced in CSF after probenecid administration in the active phase of AN, does not normalize after weight recovery (Kaye et al., 1980), and no significant correlation has been observed between the amount of weight lost/ re-

Francesca Brambilla. M.D., is Head. Psychoendocr-me Center. Ospedale Pslchiatrico Pini, Milan. Marlo Lampertico. M.D.. IS Head. and Laura Sali, M.D.. is Resident. Second Medical Division, Ospedale Generale. Saronno. France Cavagnini, M.D., and Cecilia Inkitti. M.D., are m Climca Medica Il. IJnlver- sit& Milan. Mauri/lo Maggloni. M.D.. IS at VillaZuchi. Catate. Carlo Candolfi. M.D., isat Centro Analisi. Mowa. Albert0 E. Panerai. M.D., and Eugenlo E. MUer, M.D., are Professorb. lstituto Farmacologia, IJmverslt& Milan. (Reprint requests to Prof. F. Brambilla, Ospedale Psichiatrico PIni. Via lppocrate 45, Mllano. Italy.)

Ol65-1781/87/$03.50 @ 1987 El. sevier Science Publishers B.V.

gained and NE or 3-methoxy-4-hydroxyphenylglycol (MHPG) levels (Halmi et al., 1978; Winokur, 1978; Gross et al., 1979; Gerner and Gwirtsman, 198 I; Gwirtsman and Gerner, 1981). These contrasting data suggest that an NE deficiency might be related not only to food deprivation but also to the psychopathology that is at the basis ofthe disorder. Along this line, it has been suggested that AN may bear some relationship to primary affective disorders (PAD) (Crisp and Stonehill, 1973; Cantwell et al., 1977; Halmi et al., 1979; Winokur, 1980; Gwirtsman and Gerner, 1981; Eckert et al., 1982). Reduced brain, CSF, and urinary NE metabolites have been found in PAD patients in some but not all studies (Birkmayer and Riederer, 1975; Schildkraut, 1978; van Praag, 1982; Manberg et al., 1985). In both depression and AN, however, the significance of blood or urinary catecholamine levels in relation to CNS secretion and psychopathology is obscured by the large peripheral production of the amines. An indirect method of evaluating central NE function, including NE production and receptor sensitivity, is through the study of hormonal responses to the NE agonist clonidine. Clonidine is a presynapticipostsynaptic a,-receptor agonist, whose administration increases growth hormone (GH) and decreases adrenocorticotropic hormone-cortisol secretion in normal subjects (La1 et al., 1975; Lanes et al., 1983). In PAD patients the GH response to clonidine is blunted (Matussek, 1980; Boyer et al., 1982; Charney et al., 1982; Siever et al., 1982; Johnson, 1983) while the cortisol decrease in response to clonidine has been found to be either more pronounced or similar to that in controls (Matussek, 1980; Boyer et al., 1982; Johnson, 1983; Sieveret al., 1984). Because ofthe hypothesized similarities between AN and PAD, we used the clonidine challenge test to investigate the NE receptor sensitivity of AN patients.

Acute administration of clonidine elevates plasma P-endorphin (P-EP) concentrations in rats through an activation of cY-adrenergic receptors at the level of both the CNS and the anterior-pituitary (Pettibone and Mueller, 198 I). Therefore, we decided to measure plasma P-EP levels after clonidine in AN subjects. We then administered desmethylimipramine (DM I), a tricyclic antidepressant acting mainly on the noradre-

nergic system. Our main goal was to discover whether changes in mood would parallel changes in receptor sensitivity and, hence, in neuroendocrine responses, independ- ently of weight recovery.

Methods

Fourteen female patients with AN, aged 15-40 years, were studied (see Table I for clinical data). All patients met the major criteria for AN of Feighner et al. (1972). Six patients, however, had weight losses <25% of ideal body weight (according to the Metropolitan Life Insurance Company), which has been proposed as a cutoff value for the diagnosis. We mcluded these patients because they were in the process of steadily losing weight and had all the psychopathological characteristics of the disease~~especially the anorectic behavior that has been proposed by Feighner et al. (1972) and Halmi et al. (1979) to be the hallmark of the disease.

The DSM-III diagnosis of PAD (American Psychiatric Association, 1980) was excluded in the AN patients after examination by two psychiatrists. All the patients were hospttahzed during the neuroendocrine tests, before starting therapy, and after 30 days of treatment. During the other periods of study, patients lived at home. The patients were allowed a free choice of diet throughout the study. Average caloric intake before treatment was approximately 800 calories. Accurate measurement of caloric intake was not possible, however, because of the propensity 01 some patients to hide food or induce postprandial vomiting. Patients had not had any type of treatment for at least I month before the study.

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The first clonidine test was performed before therapy began. At 0830h a butterfly needle was inserted into a forearm vein and kept patent by saline infusion. Clonidine (150 pg diluted in IO ml of saline) was infused over l-2 minutes at 0900h. Heparinized blood samples for GH and cortisol assays, as well as blood treated with EDTA and Trasylol(lOO0 U/ml) for p-EP assays, were obtained at 0900h immediately before the clonidine infusion and then at I5,30,45,60,90. and 120 minutes after it. Twenty-four hours later, the same test was repeated with saline infused instead of clonidine. Blood samples were immediately centrifuged, and the plasma was stored until assay at -20°C.

DMI was then administered orally to 12 of the 14 patients (two refused the therapy) three times a day for 30 days, at dosages of 1.5 mg/ kg body weight for the first I5 days and increasing to 2 mg/ kg body weight for the next I5 days. Blood DM I levels were assayed before therapy and then every 7 days during therapy to ensure compliance. After 30 days of therapy, the patients repeated the clonidine and saline tests as described above.

As a control, seven age-matched healthy female subjects received the clonidine and saline tests once. They were not hospitalized and arrived at the research unit by OXOOh after an overnight fast. They rested in bed before starting the tests at 0900h.

Cortisol was measured by radioimmunoassay (RIA) with a kit from Byk-Gulden (Italy). GH was also measured by RIA according to the method of Schalch and Parker (1964). p-EP levels were assayed by the method of Panerai et al. (1983). with high performance liquid chromato- graphy (HPLC) being used to separate p-EP from /3-lipotropin (/3-LPH). /?-EP was then assayed radioimmunologically. p-EP antibody against human p-EP-C terminal was obtained rn rabbits after conjugation with albumin. The cross-reactivity against human /3-EP was 1000/b and that against rat /3-EP was ICY& which suggests that the antibody is specific for the last fiveamino acids of the molecule. No cross-reactivity against met-enkephalin, leu-enkephalin, OI- endorphin, y-endorphin, and A-endorphin was present. DMI levels were assayed by HPLC according to the method of Schmidt (198 I). The psychological status of the patients before and after 30 days of therapy was monitored by the Wechsler Rating Scale (WRS) for depression (Wechsler et al., 1983) and the Zung Self-Rating Scale (ZRS) (Zung and Durham, 1965). T he ANlS Rating Scale (ARS) (Fichter and Keeser, 1980) was used to assess anorectic symptomatology. Data were analyzed by analysis of variance.

Table 1. Characteristics of Datients with anorexia nervosa

Patient

8

9

10

11

12

13

14

he 18

29

17

29

19

22

21

15

29

24

19

35

40

20

Duration Duration Height Before After Before After amenorrhea anorexia (cm) therapy therapy therapy therapy

2.0 2.0 160. 37.0 39.0 29.6 25.9

8.0 9.0 161 46.0 47.0 17.7 15.9

1.0 4.0 160 35.0 34.6 33.0 34.2

1.6 13.0 150 38.8 42.0 12.5 7.7

2.0 2.0 162 41.6 43.9 23.0 18.7

4.0 6.0 160 30.0 30.5 43.9 43.0

2.9 3.0 160 39.0 40.0 27.1 25.2

0.7 0.8 164 47.5 51.0 12.0 5.7

11.0 11.0 153 40.0 40.5 22.5 21.5

1.2 1.2 170 47.5 49.0 20.5 18.1

1.0 1.6 158 42.0 42.5 17.8 17.4

11.0 11.0 161 35.0 34.0 40.6 42.4

1.6 2.6 160 28.3 54.1

0.8 1.0 162 40.5 25.8

Weight (kg) VO Below IBW

Note. IBW = Ideal body weight. Age (yearsI. Duration of amenorrhea Iyears. months'. Duration of anorexia (years, monthsl.

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Results

DM I therapy was associated with a modest weight gain (0.5-3.5 kg) (Table 1) in 11 of the 12 patients treated. Measurement of DMI blood levels cornfirmed patients’ compliance and good absorption of the substance. No marked individual variations were present in serum levels of DMI, which ranged between (mean + SE) 39.6 ? 9.9 ng; ml at 7 days and 98.2 + 21.8 ngi ml at 21 days (plateau levels).

Psychological Data. The WRS and ZRS (Fig. I) revealed that before therapy all patients had depressive symptomatology of variable severity (mean f SE = 72.2 ? 4, WRS; 48.1 k 3.2, ZRS). At 30 days of therapy, there was a nonsignificant decrease in mean (+ SE) scores on both scales (WRS = 61.6 * 4.3; ZRS = 42.7 f 3.4). When each patient was considered individually, however, we observed a clear-cut decrease in WRS and ZRS scores for the five patients who had the most severe depressive symptomatology (Table I, patient nos. 1,3,4, 10, I I). For the total sample, depression was absent or mild at 30 days of treatment in 10 cases and persisted only in two patients (nos. 2, 12).

Fig. 1. Global values of ratings scales before and after DMI therapy in

131

72

61

anorectic patients

Wachrlcr

80

48

42

fung 160

66

47

Anir

Note. DMI : desmethylimipramine. Before therapy, n = 14. after therapy, n 12. Data are presented as mean IT SE.

No significant correlation was observed between weight reduction before therapy and the effect of DM I treatment. The ARS results were dubious because the responses seemed rather unreliable. However, a trend toward improvement was observed with this scale too (mean ? SE = 47.6 * 72 VS. 56.0 f 9.3).

GH Secretion. Before therapy, GH levels (Fig. 2) were normal in 10 patients (I. l-4.7 ng/ ml; Table 1, patient nos. 2-8, IO- I I, 14) and elevated in 4 (8.0, 13.5,8.6,6.8 ng/ ml;

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patient nos. 1,9, 12, 13, respectively). The mean (+ SE) GH value was 4.6 20.9 ng: ml. Baseline values in controls ranged from 0.7 to 4.3 ngi ml (I .6 ?r 0.3). The difference between patients and controls is significant @ < 0.01).

Clonidine administration (Fig. 2) induced GH increases in all patients, with peaks between I5 and 120 minutes after the stimulation (mean peak value for the group at 30 minutes). GH increments from baseline ranged from I.8 to 20.5 ng; ml (mean + SE = 10.5 * 1.7 ngiml).

At 30 days of therapy, baseline GH values were normal in all patients (0.8-4.9; mean ? SE = 3.9 + 0.6 ng;ml). Nevertheless, GH values in patients were still significantly higher than those in controls (JI < O.Ol), and no significant difference was observed in the baseline GH values of patients before and at 30 days of therapy. Clonidine stimulation induced GH increases in all the patients, with peaks occurring between 30 and 90 minutes (mean peak value at 30 minutes). GH increments ranged from 2.2 to 30.2 ng:‘ml (9.2 + 2.2 ngj ml).

Fig. 2. Growth hormone responses to clonidine stimulation in anorectic patients before and after DMI therapy and in controls

nglml - AN before therapy

----. AN after therapy

:::::::: ‘....... Controls M k SE

# 15’ 30’ 45’ 60’ 90 120’ illI”.

Note DMI - desmethylimipramine. Anorectlc patlents before therapy in 14 -solId Ilne; anorectlc pattents

after therapy n = 12 i-dashed Ilne, controls n 7 s-dots Data are presented as mean L SE

Clonidine administration in controls induced GH increases, which peaked between 30 and 90 minutes (mean45 minutes) and ranged from I. I to 18.7 ng: ml (8.8 f 1.4). No statistically significant differences were observed between GH responses in controls and patients either before or at 30 days of treatment. There were also no significant differences between GH responses in patients before and at 30 days of therapy. Saline administration did not induce GH increases in either patients or controls.

24

Cortisol Secretion (Fig. 3). Before therapy, baseline cortisol levels were normal in 13 patients (10.0-26.0 ng/ml; patient nos. I-12, 14) and slightly elevated in l(28.0 ngiml; patient no. 13). The mean (* SE) value for the whole group was 16.7 k 1.7 ng; ml.

Clonidine administration was followed by lowering of plasma cortisol, with nadir values occurring between 30 and 120 minutes (mean = 60 minutes). Plasma cortisol decrements following clonidine ranged from 2.6 to 14.0 ng/ml (7.8 f 0.9 ngjml).

At 30 days of therapy, baseline cortisol levels were normal in all 12 patients treated (mean k SE = 15.3 f 2.5 ng/ml), but no significant difference was observed between cortisol values before and at 30 days of therapy. Clonidine administration was followed by plasma cortisol decrements, with nadir values occurring between 15 and 120 minutes (mean at 60 minutes). Plasma cortisol decrements ranged from I .2 to 20.5 ng/ ml (6.0 k 1.6 ng/ ml), and no significant differences were observed between cortisol decrements before and at 30 days of treatment.

Saline administration to patients before therapy was followed by plasma cortisol decrements, with nadir values occurring between 45 and 120 minutes (mean at 120 minutes). Plasma cortisol decrements ranged from 3.5 to 16. ng; ml (mean t SE = 7.4 k I .8 ng/ ml). No significant difference was observed between decrements obtained after clonidine and after saline administration, either before or at 30 days of treatment.

Fig. 3. Cortisol responses to clonidine stimulation and saline in anorectic patients before and after DMI therapy and in controls

lo:1 : *. : rw : . . . . . . ..,

10. 1

-i-_ *h;

-a I

0 15’3cv45’6v w 1rno 15’ w 45’ 60’ w 1m(Y 15’ 3cr 45’ w w 1m min. min. min.

Nore. DMI = desmethylimipramine. Response to clomdine-solld line, responsetosaline-dashed Ilne. Anorec- tic patients before therapy in = 14~; anorectlc patlentsaftertherapy,n= 121;controls’n=71. Dataarepresented as mean f SE

AN before therapy AN after therapy

11 . . . I

I ngiml m

I

In controls, baseline plasma cortisol values ranged from 8.7 to 18.5 ng/ ml (mean + SE = 13.3 k 1.6 ng/ml) and no significant difference was observed between basal cortisol values of patients and controls. Clonidine administration in controls induced decrements, with nadir values occurring between 90 and 120 minutes (mean at 90 minutes). Plasma cortisol decrements ranged from 4.6 to 8.7 ng/ ml (mean + SE q 6.6 +

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0.9 ng/ ml). After saline administration, nadir values occurred between 30 and 120 minutes (mean at 120 minutes). Plasma cortisol decrements ranged from I. I to 10.4 ngj ml (mean f SE = 4.8 + 1.6 ngj ml). No significant differences were observed between cortisol responses to clonidine in patients before or at 30 days, responses to saline in patients and controls, and responses to clonidine and to saline in patients and controls. Subtraction of plasma cortisol levels after saline from those after clonidine, both in patients and controls, did not affect the nonsignificant difference existing between data for the two groups.

fi-Endorphin (Fig. 4). Before therapy, basal /3-EP levels were elevated in three patients (995.7, 281.0, 81.4 fmole/ ml; patient nos. 2, 4, I I) and normal in the others (5.5-55.7 fmole; ml). The mean (* SE) value for the group was 58.7 f 24. I fmole; ml.

Clonidine administration induced an increase in plasma P-EP levels in all but two patients (nos. 2, 14) who showed a decrease in the levels of the peptide. Peak /3-EP levels occurred between 15 and 60 minutes (mean at 30 minutes) and nadir values at I5 and 120 minutes. Plasma P-EP increments ranged from 4.5 to 481. I fmole/ml, and decrements were 12.5 and 16.8 fmole/ ml. The mean (5 SE) plasma P-EP increment for the group was 168.2 * 58.4 fmole/ ml.

At 30 days of therapy, basal P-EP levels were still elevated in two patients (127.9, 97.8 fmole/ ml; patient nos. 2,4) and normal in the others (5.0-16. I). The mean (+ SE) value for the whole group was 33.4 f 17.6 fmolejml.

Fia. 4. B-EndorDhin resDonses to clonidine stimulation in anorectic patients iefo;e and aiter DMI’therapy and in controls

fmoliml

300

250

200

150

1W

a0

tielore therapy

:

I I ml/ml

300

250

200

150

100

80

0 15’ 3(Y 4(y My w im -AN EBz ;OJ;;OLS (BEFORE Ill,“.

THERAPY)

Note. DMI = desmethylimipramine. Ii-Endorphin responses to clonidlne I” anorectlc patlents 6ol1d lme and controls {dots ). Anorectic patients before therapy (n = 14 I; anorectic patients after therapy, n = 12 I, controls n 7~. Data presented are as mean 2 SE.

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No significant difference was observed between basal /?-EP levels before and at 30 days of therapy. Clonidine administration induced increments in plasma /3-EP levels in all the patients, with peaks occurring between I5 and 60 minutes (mean at 60 minutes). increments ranged from 8.6 to 495.0 fmole; ml (mean * SE = 298.3 ? 68.7 fmole, ml).

Basal P-EP levels of controls ranged from 22.3 to 58.6 fmole/ ml (mean + SE = 4 I .6 + 5.2). No significant difference was observed between /3-EP levels of patients, either before or at 30 days of therapy, and those of controls. Clonidine induced increments in all the controls, with peak levels occurring between 45 and 90 minutes (mean at 60 minutes). Increments ranged from 7.6 to 166.9 fmole/ml. The mean (2 SE) value for the group was 60.3 * 20.3 fmolel ml. Saline administration was not associated with /?-EP increases in either patients or controls.

Statistical analysis revealed that /?-EP increments of patients before therapy were not significantly different from those of controls. When the two patients whose P-EP levels were actually suppressed after clonidine were excluded from the evaluation, however, the difference between patients and controls became significant (II < 0.01). No significant difference was observed between values of patients before and at 30 days of treatment.

No significant correlations were observed between basal levels of GH, cortisol. or P-EP and absolute weight or o/o weight reduction from ideal body weight, either before or at 30 days of therapy. Similarly, no significant correlations were observed between GH, cortisol, or /3-EP responses to clonidineadministration and absolute weight or(;; weight reduction from ideal body weight, either before or at 30 days of therapy. No correlation was observed between P-EP responses to clonidine and depression scores before or at 30 days of therapy, or o/ti reduction from pretreatment depression scores at 30 days of treatment.

Side Effects, Clonidine administration induced only mild drowsiness in both patients and controls. Mean blood pressure for the group ranged from I28 * 9180 * 7 at 0 time, with a decline at 15-30 minutes after clonidine administration to 107 + IO/ 7 I f 7 and return to preinjection levels at 45 minutes. No constant variations were observed in pulse rates.

Discussion

GH responses to clonidine of AN patients were not significantly different from those of controls, suggesting that the adrenergic receptors involved in the control of GH secretion were not subsensitive. Thus, findings in AN patients contrast with those in PAD patients, who show a blunted GH response to clonidine. Since we did not use a weight-adjusted dose of clonidine in AN patients, it is possible that, due to their weight deficiencies, they received a proportionally higher dose of clonidine than controls. This would result in a hyperstimulation of the a,-adrenoceptors masking an underly- ing subsensitivity. Note, however, that in PAD patients, who frequently lose weight during depressed phases, the dose of clonidine used was never weight-adjusted and the subsensitivity in each patient was independent of the absolute weight or c/o weight reduction.

After clonidine, patients and controls had the same decrements in plasma cortisol

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levels, which did not differ from those observed after saline injections in either group. Our data on the effect of clonidine on plasma cortisol are not consistent with those of La1 et al. (1975) and Lanes et al. (1983). but confirm those of Siever et al. (1984). who observed no effect of clonidine on cortisol secretion in normal subjects. Siever et al. (1984) reported significantly higher decrements in cortisol plasma levels after clonidine in PAD patients than in controls--a finding we did not observe in our AN subjects. Neither the blunted GH increase nor the excessive cortisol decrease after clonidine reported in PAD patients was observed in our AN patients, suggesting that the sensitivity of (postsynaptic?) a,-adrenoceptors involved in GH and adrenocorticotropic hormone (ACTH) secretion is normal. Interestingly, the affinity of prei postsynaptic adrenoceptors for clonidine is reduced in starved animals (Spyra and Pirke. 1982).

Although DMI improved depressed mood in our subjects, it did not change the pattern of GH and cortisol responses to clonidine. Administration of DMI and amitriptyline did not affect the blunted GH response.to clonidine of PAD patients in the report of Charney et al. (1982). while according to Checkley et al. ( 198 I). it induced a nonsignificant enhancement of the response. Our data, as well as those reported in the literature, suggest that treatment with tricyclic antidepressants in PAD and AN does not alter a,-adrenoceptor sensitivity, while it does in normal animals (Charney et al., 1981).

In view of the derivation of ACTH and /3-EP from the same parental molecule, pro-opiomelanocortin (Guillemin et al., 1977) and the apparently similar mechanism subserving /3-EP and ACTH release (Krieger et al., 1978), it is difficult to explain why clonidine administration in both patients and controls failed to alter plasma cortisol levels while increasing /3-EP levels. Obviously, direct measurement of plasma ACTH after clonidine administration is needed to investigate this point further.

Whatever the mechanism(s) responsible for the divergent P-EP and cortisol responses to clonidine may be, the higher secretion of P-EP after clonidine in AN patients than controls indicates either an enhanced sensitivity of the a,-adrenoceptors involved or an intrinsically higher functioning of the “downstream” located cortico- tropin releasing factor/P-EP system. We believe the latter possibility is more likely because (I) the GH response to clonidine gives no indication of an increased (Y?- adrenoceptor responsiveness and (2) treatment with DMI, a drug that alters noradrenergic neurotransmission, failed to modify &EP responsiveness to clonidine.

An increased primary CRF production from the hypothalamus of AN patients might explain the excessive plasma /3-EP increases after clonidine. In the rat, it has been shown that clonidine increases plasma /3-EP and intracerebro-ventricular injection of phenoxybenzamine blocks the drug-induced increase (Pettibone and Mueller, 1981). An alternative, but not mutually exclusive, possibility would be that of an increased /3-EP function. Evidence exists in the literature suggesting a higher than normal level of CNS /3-EP activity in AN. Pickar et al. (198 I) and Kaye et al. (1982) reported high basal levels of opioid-like material in the CSF of active anorectics which normalized after weight recovery. In a previous study, we observed elevated basal levels of plasma p-EP in a group of AN patients, but no correlation with weight loss/recovery (Brambilla et al., 1985). In the present study, only a few patients had frankly elevated basal plasma fi-EP levels, but a striking increase was noted after stimulation. An indirect index of increased opioid-like secretion in AN was provided

28

by the data of Moore et al. (198 I), who observed significant weight gain in AN patients treated with I-I I week infusions of naloxone, an opioid antagonist. Similarly, Bara- nowska et al. ( 1984) observed that a single administration of naloxone was followed by a significant increase in P-EP-like substances in AN but not in normal subjects, while ACTH and cortisol levels were unchanged. Opioids are reportedly involved in appetite and body weight regulation (Margules et al., 1978; Kryriakides et al., 1980) and intraventricular injection of B-EP increases appetite in satiated rats (Kenny et al., 1978).

What is the significance of this neuroendocrine alteration for the psychopathology of AN is hard to say. Recall that plasma P-EP reflects pituitary P-EP activity, and it is presently unknown how the latter mirrors opioid activity in hypothalamic and extra- hypothalamic sites. Interestingly, no correlation was found between the neuroendocrine alteration and weight loss/recovery or depression. In PAD patients, @EP-like levels in CSF and plasma have been reported to be either increased (Tere- nius et al., 1977; Lindstriim et al., 1978; Brambilla et al., 1981, 1982; Risch, 1982; Brambilla et al., 1983, 1984~. 19846) or normal (Catlin et al., 1981; Naber et al., 1981; Post et al., 1981; Emrich, 1982).

In summary, in cdntrast to findings in PAD patients and starved rats, the respon-

siveness of a,-adrenoceptors involved in GH and, likely, ACTH responses appears to be normal in AN patients after clonidine challenge, suggesting preservation of a hypothalamic NE tonus. The altered fi-EP response to clonidine merits further

investigation.

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Clonidine stimulation in anorexia nervosa: Growth hormone, cortisol, and beta-endorphin responses