PSYCHIATRY

RESEARCH

ELSEVIER Psychiatry Research 69 (1997) 1555162

Noradrenergic receptor sensitivity in obsessive-compulsive disorders: I. Growth hormone response to clonidine

stimulation

Francesca Brambilla”,” , Giampaolo Pernaa, Laura Bellodi”, Cinzia Arancio”, Angelo Bertani a, Giulia Perinib, Christian Carrarob, Franc0 Gavab

“Dipartimento di Scienze Neuropsichiche lJniuersit& Istituto Scientifico H.S. Raffaele, Milano, Ital\ b

Clinica Psichiattica lJniversit6 Padova, Ital\,

Received 16 April 1996; revised 21 November 1996; accepted 16 December 1996

Abstract

In 15 patients with obsessive-compulsive disorder COCD) and in 15 healthy controls postsynaptic a-2-adrenoceptor sensitivity was examined by measuring the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) and to clonidine stimulation. Basal values of GH and somatomedin-C @MD-C) and mean GH responses to GHRH were the same in patients and controls, thus suggesting that a peripheral pathology of the somatotropic axis should not be present. GH responses to clonidine stimulation were blunted in patients suggesting that post-synaptic cY-2-adrenoceptors are subsensitive, possibly due to higher than normal noradrenergic secretion. 0 1997 Elsevier Science Ireland Ltd.

Keywords: Obsessive-compulsive disorder; a-2-Adrenoceptors; Clonidine: Growth hormone-releasing hormone; Growth hormone

1. Introduction

That alterations of the central noradrenergic (NE) system are involved in the pathogenesis of obsessive-compulsive disorder (OCD) has been

* Corresponding author. Centro di Psiconeuroendocrinolo-

gia, Istituto di Scienze Neuropsichiche, Istituto Scientific0

Ospedale S. Raffaele, Via Prinetti 27, Milan0 20127, Italy.

Tel.: + 39 2 26433376; fax: +39 2 70122889.

suggested on the basis of results obtained from

studies in experimental animals and humans. In

animals, increased central NE availability has

been implicated in the mediation of compulsive-

like repetitive behavior (Kokkinidis and Anisman,

1982). In humans, administration of clonidine

(clan), an a-Zadrenoceptor agonist which in-

hibits NE secretion presynaptically, improved the

symptomatology in some OC patients (Knesevich,

1982; Hollander et al., 1988, 1991; Lee et al.,

0165-1781/97/$17.00 0 1997 Elsevier Science Ireland Ltd. All rights reserved

PrlSO165.1781(96)03032-l

156 F. Brambilla et al. /Psychiatry Research 69 (1997) 155-162

1990). However, treatments with antidepressant drugs that act on the serotoninergic (5HT) sys- tem have proved to be more effective than those that act on the NE system (Turner et al., 1985). In addition, acute administration of yohimbine, an a-Znoradrenergic autoreceptor antagonist which increases NE impulse flow and turnover, does not worsen the OC symptomatology (Cederbaum and Aghajanian, 1976, 19771.

Direct biochemical evidence of NE involve- ment in the pathogenesis of OCD is contradic- tory. Basal plasma concentrations of NE and its main metabolite 3-methoxy-4-hydroxy-phenyl-gly- co1 (MHPG) have been reported to be either normal or higher than normal (Siever et al., 1983; Lee et al., 1990; Hollander et al., 1991). The yohimbine-induced stimulated and the clonidine- inhibited MHPG secretions are the same in OC subjects and in controls, while the yohimbine-in- duced cortisol rises may be either normal or increased (Rasmussen et al., 1987; Lee et al., 1990; Hollander et al., 1991). Postsynaptic (u-2- adrenoceptor sensitivity, investigated by the growth hormone (GH) response to acute cloni- dine (clan) or desimipramine administration, is normal or blunted (Siever et al., 1983; Khanna et al., 1988; Hollander et al., 1989, 1991; Lee et al., 1990; Lucey et al., 1992). These contradictory data leave the question of pre-postsynaptic a-2- adrenoceptor sensitivity and, as a consequence, of NE secretion unresolved. We have examined the function of the NE system in a group of OC patients by measuring the postsynaptic a-2- adrenoceptor sensitivity, expressed by the GH response to acute clonidine administration. The downstream process of the GH response to clan administration involves stimulation of the hy- pothalamic postsynaptic cY-2-adrenoceptors and, as a consequence, of growth hormone-releasing hormone (GHRH). GHRH stimulates pituitary GH secretion and, through it, somatomedin-C (SMD-C) production by the liver. In turn, GH and SMD-C inhibit GHRH secretion and the GH response to GHRH stimulation through a feed- back mechanism (Eriksson, 1985). Thus, the GH responses to clonidine stimulation depend on post-synaptic cr-Zadrenoceptor sensitivity and on a correct downstream function of the GHRH-

GH-SMD-C axis. As a consequence, a blunted GH response to clan administration cannot auto- matically be considered to express postsynaptic cY-2-adrenoceptor subsensitivity and, possibly, NE hypersecretion, unless the basal GH and SMD-C levels and GH responses to GHRH have been proved to be normal.

In our patients we examined in parallel the basal concentrations of plasma GHand SMD-C levels and the GH responses to GHRH and to clan stimulation, with the aim of better clarifying the functional aspects of the NE system in a group of patients with OCD.

2. Material and methods

Fifteen patients with OCD, recruited over 1 year at the Anxiety Disorder Clinic and Research Unit of the Dipartimento Scienze Neuro- psichiche, Istituto Scientific0 Ospedale S. Raf- faele, Milano, and at the Clinica Psichiatrica, Universith, Padova, entered the study. They were eight men and seven women, aged 17-60 years (M f S.D. = 34.2 k 10.41, with histories of the disorder of l-22 years’ duration (13.5 + 8.2). The diagnosis of OCD was made with the Diagnos- ticInterview Schedule-Revised (DIS-R), according to the DSM-III-R criteria (American Psychiatric Association, 1987). The controls were seven women and eight men matched for sex and age, selected from the hospital staff, physically healthy and without any lifetime psychiatric disorder ac- cording to DSM-III-R criteria (DIS-R interview). Informed consent was obtained from patients and controls.

Criteria for exclusion from the study for both groups of subjects were physical organic diseases, metabolic and endocrine disorders, immune pathologies, obesity or recent weight loss, brain organic disorders, cerebral trauma, and Axis I and II disorders according to DSM-III-R criteria, apart from OCD in patients.

Before our study, 14 of the 15 subjects had been treated with psychopharmacological drugs, including neuroleptics (haloperidol or phenothi- azines), antidepressants (tricyclic, serotoninergic selective reuptake inhibitors) and benzodi- azepines, as a single drug or as a combination of

F. Brambilla et al. /Psychiatry Research 69 (1997) i.i5- lb-7 1.51

them. Drugs were all stopped from 30 days to 6 1. One-way analysis of variance (ANOVA) to years before starting our study. One patient had analyze baseline levels of the hormones. never been treated. Five OC and five control 2. Two-way ANOVA, to assess possible diff’cr- women were in fertile age and two were post- ences of baseline GH concentrations in rcla-

menopausal. In the two fertile groups, the en- tion to SCY (.s) and diagnosis (d), in which rl docrine studies were always done during the first and s were the grouping factors and GH 6 days of the cycle or in the 3 days immediately basal value was the dependent variable. The preceding the menstrual period, to avoid cycle-re- same analysis was used also to assess possible lated estrogenic fluctuations which could modify differencc>s of AUC, A-max and A-(/;~ for GH the GH responses to the stimulus (Ho et al., response> to GHRH and clan stimulation in 1987). patients kind controls.

The severity of OC symptoms of the patients

was evaluated on the Yale-Brown Obsessive-

Compulsive Scale (Y-BOCS) (Goodman et al., 1989) the day before the hormonal tests.

The GHRH test was performed first, followed

48 h later by the clan test, withsubjects recum- bent, in the morning after 12 h of fasting and 1 h

of bedrest. Smoking and drinking alcohol or cof- fee were not allowed in the 12 h before the tests. At 0X.30, a butterfly needle was inserted into a forearm vein, kept patent by saline infusion. At

OX.30 and 09.00 (time -30 and O), EDTA-anti- coagulated blood was drawn to measure basal

concentrations of GH and SMD-C, and the two values obtained for each hormone were averaged. At OQ.00, GH-RH f I I.Lg/kg body wt.) or clan (IS0 /~.g) were injected i.v. as a bolus, diluted in

IO ml of saline. Blood samples for hormonal assays were drawn at IS-min intervals for 1 h and

at 30-min intervals for another hour, immediately centrifuged and plasma frozen at -20°C until assayed. The cut off for signiticant responses of GH to GHRH or clan stimulation was an in- crcast’ of the hormone concentrations at peak time of more than double the basal levels and an

ahsolutc value at peak time of more than 5 ng/ml.

3. Preliminary ANCOVA for repeated mc;I- sureb, to assess in OC patients the possible

influence of obsessive-compulsive symptoma- tology on severity of hormonal impairments,

in which time (t) was the repeated measure factor. .s was the grouping factor. GH level

was the dependent variable ant! Y-BOCS scores. age or duration of the drug-fret intcr- val were [he covariates.

4. ANOVA for repeated measures. to assess possible differences of the hormonal respon-

ses to the GHRH and clan test in relation to s and rl. in which t was the repeated measure

factor. d and .< were the grouping factor\. 5. Student-, test. 6. Type 2 error. 7. Pearson‘\ coefficient of correlation.

If any significant difference was found by ANOVA or ANCOVA, r-test with Bonferroni’s

correction wits applied post-hoc.

3. Results

Plasma GH concentrations were measured ra-

dioimmunologically with the commercial kits of Sorin (Italy) and those of SMD-C with kits of Nichvlh (USA). after alcohol-HCl extraction of the plasma.

The GH responses to the stimulation tests were evaluated at each point of the curves, as area

under the curves (AUC), h-max (difference between basal and peak values) and a-% (h-max Y 100,~ baseline hormonal values). The statistical analyses were:

Basal values of GH did not differ in OC patients

and controls. on the days of the GHRH or of the clan test (GH-RH day: patients = M :t S.D. = 2.1 i 0.9 ng/ml vs. controls = 1.5 f 0.2 ng/ml: clan day: patientx = 1.8 i_ 0.6 vs. controls = 1.6 i_ 0.2) (Table I). The hormonal values on the 2 days and, on each day. the values at -30 and 0 times were not significantly different from one another in

either group. There were no differences between men and women in either group.

Basal SMD-C levels, expressed as the mean of the values obtained during the GHRH and the

158

Table 1

F. Brambilla et al. /Psychiatq Research 69 (1997) 155-162

GH responses to GHRH and clonidine stimulations in OC patients and controls

Test

GHRH test GH basal AUC A-max A-%

CLON test GH basal AUC A-max A-%

Men Women

Patients Controls Patients Controls

2.5 + 0.7 1.25 + 1.2 1.65 + 1.8 1.75 + 1.5 a 1124.5 + 919.6 858.7 + 902.3 482.3 + 1037.1 979.8 + 935.5 a

19.5 + 14.1 13.6 + 15.6 8.9 + 15.5 13.8 + 14.0 a 2973.4 & 4831.1 2099.1 _+ 2351.5 1500.5 f 3816.2 882.5 f 1213.8 a

2.2 * 0.5 1.1 + 1.1 1.3 f 0.9 2.3 + 2.0 203.2 + 266.2 434.3 + 75.8 81.7 + 143.2 313.9 f 261.1 6

4.7 * 5.1 16.6 + 20.7 1.7 + 2.1 6.5 + 4.1 C

1195.2 f 1676.3 1515.4 f 1880.4 722.1 + 1424.9 389.4 + 380.9 a

Values are expressed as means + standard deviation. Significance of values (Student’s t-test) a: Non-significant; b: F = 9.6, d.f. = 28, P = 0.03; c: = F = 6.73, d.f. = 28, P = 0.02.

clan days, were not significantly different in patients and controls (patients = M + SD. = 216.6 t_ 71.8 ng/ml vs. controls = 197.8 f 78.8 ng/ml). Values obtained on the 2 days and on each day at -30 and 0 times did not differ from one another in either group. There were no dif- ferences between men and women.

Since GH responses to various stimulations

MEN WOMEN

were been reported to differ in male and female subjects (Eriksson, 198.51, we analyzed our results separately for the two genders. GH responses to GHRH stimulation were not significantly differ- ent in patients and controls, at any point on the curves (Fig. 0, as areas under the curves (AUC), A-max or A-% (Table 1). However, it must be mentioned that in 8 of the 15 patients (four

Fig. 1. Growth hormone response to GHRH stimulation in 15 OC patients ( ---_) and in 15 controls (-.-.-I (M f S.D.).

F. Brambilla et al. /Psychiatry Research 69 (1997) 155-162 159

women and four men) and in one control (wo- man), GHRH-induced GH rises were blunted. ANOVA for repeated measures revealed signifi- cant effects of time (F = 17.4, d.f. = 6,15, P = O.OOOOl>, of sex (F = (4.0, d.f. = 1,26, P = 0.009), of time per sex (F = 3.1, d.f. = 6,16, P = 0.007) and of time per diagnosis (F = 2.5, d.f. = 6,16, P = 0.025). Male subjects had significantly higher responses than female ones. Type 2 error for GH responses to GHRH stimulation was > 0.8.

GH responses to clan stimulation were signifi- cantly lower in patients than incontrols, at each point of the curves (Fig. 2), as AUC and A-max, but not A-% (Table 1). ANOVA for repeated measures revealed significant effects of time (F = 21.9, d.f. = 6,16, P = O.OOOOl), diagnosis (F = 5.54, d.f. = 1,26, P = 0.026) and of time per diagnosis (F = 5.53, d.f. = 6,16, P = O.OOOOl), but not of sex.

Mean peak time of GH responses to either GHRH or to clan stimulation was significantly advanced in female but not in male patients com- pared to that of controls (GHRH: t = 3.3, d.f. = 1.12, P = 0.006; clan: t = 2.3, d.f. = 1.12, P = 0.04) There were no correlations between responses of OC patients to GHRH and to clan, expressed as AUC, and age of the patients or duration of drug-free period since the last pharmacological treatment.

4. Discussion and conclusion

The blunted GH responses of our OC patients to clan stimulation suggest that postsynaptic cr-2- adrenoceptors are subsensitive, possibly as a con- sequence of increased NE secretion. The pheno- menon should not be ascribed to a pathology of the downstream basal secretion of GH and SMD- C, whose repeatedly normal concentrations ex- clude that the blunted responses to clan adminis- tration were due to negative feedback on the secretions of hypothalamic GHRH and pituitary GH. The normal mean GH responses to GHRH stimulation, expression of the pituitary soma- totrop receptor sensitivity, also would suggest that a hypophysial pathology is not involved in the blunted GH response to clan. The fact that 8 of the 15 OC patients had lower than normal GHRH-induced GH rises does not disagree with this statement since we observed no correlation between GHRH- and clan-induced GH rises. The reason for these blunted GH responses to GHRH stimulation is not clear. However, since GH rises are reduced in subjects with decreased GHRH secretion, and restored to normal somatotrop ac- tivity after repeated GHRH infusions, and since GHRH secretion is stimulated by noradrenaline

WOMEN

Fig. 2. Growth hormone response to clan stimulation in 15 OC patients (-- -) and in 1.5 controls (6---j (M + S.D.)

160 F. Brambilla et al. /Psychiatry Research 69 (1997) 155-162

(Muller, 1987; Blanchard et al., 1989; Pavia et al., 19931, the blunted postsynaptic cr-2-adrenoceptor sensitivity could be responsible for a lower than normal down-stream transmission of stimuli, re- sulting in reduced GHRH secretion and soma- totrop sensitivity. Alternatively, the blunted re- sponses could be due to increased hypothalamic secretion of somatostatin, which inhibits the GHRH-GH system. In fact, Altemus et al. (1993) observed increased somatostatin concentrations in the cerebrospinal fluid (CSF) of OC patients. However, Roy et al. (1994) observed high plasma levels of antisomatostatin-14 antibodies, which should result in disinhibition of the GHRH-GH secretion. Our protocol of investigation does not allow us to discriminate between these hypothe- ses and does not explain why the blunted respon- ses occur only in some and not all OC patients. Since type 2 error is relatively elevated, thus possibly suggesting that the GH response to GHRH stimulation is not normal, we are now in the process of examining the response in relation to duration and severity of the disorder and to its specific symptomatological aspects in a larger OC population.

The observation that the GHRH-induced GH rises were lower in OC and control women than in men was not unexpected. It is known that gonadal steroids modulate GH secretion, and that men respond to apomorphine or L-dopa-induced catechominergic stimulation with GH rises greater than those of women (Ettigi et al., 1975; Sachar et al., 1975; Shulman et al., 19871.

The blunted clan-induced GH responses of our patients are in line with similar results obtained by Siever et al. (1983) but disagree with the nor- mal responses observed by Khanna et al. (19881, Lee et al. (1990) and Hollander et al. (1991). The reasons for the discrepancy are not clear. It has been suggested that since there is a blunting of the clan-induced GH rises in major depressive disorders (Matussek et al., 1980; Charney et al., 1982; Checkley et al., 1982; Boyer et al., 1982; Siever et al., 1985; Brambilla et al., 1988; Amster- dam et al., 1989; Mitchell et al., 1991) and since OC patients may have depressive comorbidity, this could be the reason for the altered responses

of some and not all OC subjects. Since, however, comorbidity with major depressive disorders, or even with significant depressive symptomatology, was an exclusion criterion for our patients, this cannot be the reason for their blunted GH re- sponses to clan stimulation. There is a pathology of the GHRH-GH-SMD-C axis in subjects with protein malnutrition (Fichter and Pirke, 19841, but our patients had no specific lack of protein consumption. Previous psychopharmacological treatments, in particular with tricyclic antidepres- sant drugs acting mainly on the noradrenergic system, have been reported to downregulate post- synaptic cu-Zadrenoceptors, and this can be observed up to 1 year after the drug is stopped (Schittecatte et al., 1989). However, in our patients we saw no correlation between biochemical im- pairments and the duration of the washout, sug- gesting that this was not a consequence of the pharmacological administration, Another possibil- ity is suggested by the observation that clan pro- motes 5-HT secretion by acting on postsynaptic a-Zadrenoceptors which are located on sero- toninergic neurons (Conway et al., 1990; Mon- geau et al., 1994). Therefore, a reduced 5-HT activity could be responsible for the blunted GH responses to clan stimulation, and it is worth remembering that impairments of the serotonin- ergic system had been repeatedly reported in OCD (Goodman et al., 1990, 1992; Finenberg et al., 1994). However, serotonin has also been re- ported to inhibit NE secretion (Mongeau et al., 1994), and therefore a 5-HT deficiency might reduce presynaptic NE secretion ensuing in post- synaptic a-2-adrenoceptor super- and not subsen- sitivity. Our protocol of investigation does not allow us to discriminate between NE excess and 5-HT deficiency as causes of the blunted GH responses to clan stimulation.

The hypothesis that the blunted GH response to clan stimulation could be due to subsensitivity of the imidazoline 1 (11) receptor in the central nervous system might also be advanced. In fact, clan stimulates GHRH and GH secretion not only by acting on cY-2-adrenoceptors but also on 11 receptors, which are well known to be NE responsive (Bamberger et al., 1995; Garcia-Sevilla

F. Brambilla et al. / Psvchiatry Research t’i9 C 1997) 152 lb1 I h 1

et al., 1996). Again, our protocol of investigation

does not allow us to support or exclude this hypothesis.

The observation that GH responses to the GHRH stimulus showed a sex-linked effect and those to clan stimulation did not is intriguing. At

the moment, the only possible explanation for

this discrepancy is that the two stimuli have dif-

ferent targets, GHRH acting on the hypophyseal somatotrops and clan on the hypothalamic cu-2-

adrenoceptors. The effects of gonadal hormones

on pituitary GH secretion are strongly docu- mentcd. while those on the hypothalamic a-2-

adrenoceptors are more difficult to quantify.

The advanced mean response of GH to either GHRH or clan stimulation of patients when com- pared to those of controls is also intriguing, espe-

cially the fact that the phenomenon seems to occur in women and not in men. We have no

explanation for this, but the data are too consis- tent and statistically significant to be chance end-

ings. At the moment, in agreement with Siever’s

data (19831, we are inclined to suggest that in OCD there is increased central NE bioavailability at the synaptic level, with ensuing postsynaptic

tu-2-adrenoceptor subsensensitivity. The patho- genetic significance of this alteration for the de- velopment and course of the disease and for some

of its symptoms need to be clarified.

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