161

Psychiatry Research, 37: I6 I - 177 Elsevier

Noradrenergic Function in Obsessive-Compulsive Disorder: Behavioral and Neuroendocrine Responses Clonidine and Comparison to Healthy Controls Eric Hollander, Robert Gully, Donald

Nitescu, F. Klein, and

to

Bert R.

Received Abstract. To evaluate noradrenergic (NE) function in obsessive-compulsive disorder (OCD), behavioral, physiological, and neuroendocrine responses to the az-adrenergic agonist clonidine were examined in 18 patients with OCD and 10 healthy subjects. Subjects received single i.v. doses of 2 pgi kg of clonidine administered under double-blind, placebo-controlled, random-assignment conditions. Following clonidine, but not following placebo, patients transiently experienced a significant reduction of obsessions and compulsions. Significant drowsiness and a reduction in anxiety were also noted, but the antiobsessional effect appeared independent of the soporific and antianxiety effects. Growth hormone (GH), cortisol, and 3-methoxy-4-hydroxyphenylglycol responses to clonidine did not differentiate patients from healthy controls. Blood pressure and pulse in response to clonidine did not differ between groups. Improvement in OCD symptoms after clonidine significantly correlated with GH response to clonidine, suggesting specific noradrenergic mediation. This finding lends only partial support for a primary defect of noradrenergic function in OCD. Key Words. Obsessive-compulsive disorder, norepinephrine, disorders, growth hormone, 3-methoxy-4-hydroxyphenylglycol. Obsessive-compulsive of up to 3% (Robins

clonidine,

anxiety

disorder (OCD), a disabling disorder with a lifetime prevalence et al., 1984), may be more common than either schizophrenia or

panic disorder. The prevailing biological model of OCD centers on the role of serotonin (5-hydroxytryptamine; 5HT) in the mediation of obsessions and compulsions (Zohar et al., 1987; Hollander et al., 19880, in press). This model is supported by the superior efficacy of 5HTreuptake blockers in the treatment of OCD (Thor&et al., 1980; Ananth et al., 1981; lnsel et al., 1983; Flament et al., 1985; Volavka et al., 1985; Price et al., 1987; DeVaugh-Geiss et al., 1989; Liebowitz et al., 1989). There is less evidence supporting a role for norepinephrine (NE) in the pathophysiology of OCD. Eric Hollander, M.D., is Assistant Professor of Clinical Psychiatry, College of Physicians and Surgeons of Columbia University, and Director, OCD Biological Studies Program, N.Y. State Psychiatric Institute. Concetta M. DeCaria. M.A.. is Proiect Coordmator, OCD Biological Studies Program. Anca Nltescu. Bert Stover, and Robert Gulley are Data Analysts, N.Y. State Psychiatric Institute. Thomas Cooper, M.A., is Director, Analytical Psychopharmacology Laboratory, N.Y. State Psychiatric Institute. Donald F. Klein, M.D., is Professor of Psychiatry, College of Physicians and Surgeons of Columbia University, and Director of Research, N.Y. State Psychiatric Institute. Michael R. Liebowitr, M.D., is Professor of Clinical Psychiatry, College of Physicians and Surgeons of Columbia University, and Director, Anxietv Disorders Clime, N.Y. State Psychiatric Institute. (Reprint requests to Dr. E. Hollander, OCD Biological Studies Program, N.Y.S. Psychiatric Inst., 722 W. 168 St., New York, NY 10032, USA.) 0165-17g1/91/,$03.50

@ 1991 Elsevier Scientific

Publishers

Ireland

Ltd.

162 In blind comparisons with 5HT reuptake blockers, NE reuptake blockers were not effective in the treatment of OCD (Zohar and Insel, 1987; Leonard et al., 1989). However, the principal metabolite of the antiobsessional agent clomipramine, desmethylclomipramine, is a potent NE reuptake blocker (Asberget al., 1977; Mellstrom and Tybring, 1977). Further, there have been reports that clonidine, an a,-adrenergic receptor agonist, has antiobsessional effects in patients with OCD (Knesevich, 1982) and Tourette’s syndrome (Cohen et al., 1980; Leckman et al., 1985) although this effect may be transitory (Hollander et al., 1988b). Finally, noradrenergic mechanisms have been documented in the production of anxiety (Redmond, 1979) as well as in anxiety (Charney et al., 1984; Charney and Heninger, 1986) and depressive (Siever et al., 1983) disorders-disorders that may be closely related to OCD given the comorbidity (Rasmussen et al., 1986) and overlap of biological markers (Insel et al., 1982a, 19826).

Recent studies have attempted to assess central nervous system (CNS) NE function in OCD with the use of challenge studies that stimulate NE receptors. One study compared response to the a,-receptor antagonist yohimbine (20 mg, p.o.) in 12 patients with OCD and a similar number of controls (Rasmussen et al., 1987). There were no between-group differences in behavioral and 3-methoxy-4-hydroxyphenylglycol (MHPG) responses to yohimbine. However, there was an increased cortisol response to yohimbine in patients compared to controls. Clonidine (2 pgi kg, i.v.), an a,-noradrenergic agonist, has been used as a probe of the NE system. It has primarily a central site of action (Reid et al., 1977; Van Zwieten, 1980), and has been noted to lower blood pressure and plasma MHPG as well as to reduce anxiety and arousal (Charney and Heninger, 1986; Nutt, 1986). Preclinical studies with clonidine demonstrate inhibition of spontaneous firing of noradrenergic neurons in the locus ceruleus (Svensson et al., 1975). Clonidine appears to increase growth hormone (GH) release via direct stimulation of postsynaptic a,-receptors (Eriksson et al., 1982). However, clonidine may have indirect 5HT effects as well (Svensson et al., 1975). The clonidine challenge test has been performed in several patient populations, including panic disorder (Charney and Heninger, 1986; Nutt, 1989; Uhde et al., 1989), major depression (Matussek et al., 1980; Checkley et al., 1986; Siever et al., 1984~; Charney et al., 1983; Horton et al., 1986) schizophrenia (La1 et al., 1983), and alcoholism (Nutt et al., 1988). Single doses of clonidine have been found to decrease ratings of anxiety in patients with panic disorder (Charney and Heninger, 1986; Nutt, 1989; Uhde et al., 1989) major depression (Uhde et al., 1981; Siever et al., 1984~; Siever and Uhde, 1984) and opiate withdrawal (Gold et al., 1978). Administration of i.v. clonidine in patients with OCD has yielded conflicting findings to date. Siever et al. (1983) compared nine patients with OCD with a similar number of normal controls and reported blunted plasma GH response to clonidine, suggesting decreased postsynaptic noradrenergic a,-adrenergic receptor sensitivity. Further, there were higher plasma free MHPG and plasma NE levels at baseline, suggesting increased presynaptic noradrenergic activity. However, a recent study comparing 10 patients with OCD and 13 normal controls did not report betweengroup differences in GH, MHPG, blood pressure, or pulse response to clonidine (Lee et al., 1990). In this study. baseline MHPG levels did not differ, but the maximum

163

number of binding sites (fimax) for tritiated clonidine in platelets was greater in OCD report, we noted a patients than in normal subjects (Lee et al., 1990). In a preliminary decrease in OCD symptoms following clonidine (Hollander et al., 1988~). Lee et al. (1990) reported a decrease in anxiety-related symptoms on the clonidine day, but attributed this to sedative effects of clonidine. Siever et al. (1983) did not systematically assess behavioral response to clonidine. This study was designed to evaluate behavioral, physiological, and neuroendocrine responsivity to the noradrenergic cy,-adrenergic receptor agonist clonidine in patients with OCD and healthy volunteers. Relationships between behavioral, physiological, and neuroendocrine responsivity were also examined. Methods Patients.

All patients met DSM-III-

R

criteria (American Psychiatric Association,

1987) for

OCD. were medically healthy outpatients aged 18-46 years, had been ill for at least 3 years, did not have a primary depressive illness, had a score < 18 on the 17-item Hamilton Rating Scale for Depression (HRSD), had never met criteria for another axis 1 disorder (including panic disorder, social phobia, schizophrenia, paranoid disorder, organic mental disorder, and bipolar disorder), and had not abused drugs or alcohol in the last 6 months. Females, included only if unable to become pregnant or on an acceptable birth control program with a negative pregnancy test, were all premenopausal and were not taking oral contraceptives. All patients were at least 8 weeks drug-free, none had ever received depot antipsychotic medications, and only one had ever received a 5HT reuptake blocker, clomipramine, which was discontinued 9 weeks before the study. Eighteen patients (I3 male, 5 female) with a mean age of 34.2 (SD = 7.6; range = 18-46) years participated in the clonidine and placebo studies. These OCD patients had been ill for 14. I (SD = 10.0; range q 3-38) years; had a severe level of obsessions on the Yale-Brown ObsessiveCompulsive Scale (YBOCS) of 14.0 (SD = 2.4; range = 10-18); a moderate level of compulsions on the YBOCS of 9.6 (SD = 5.3; range O-17); and a moderate to severe level of total OC symptoms on the YBOCS of 23.7 (SD q 6.9; range = 10-30). Depression ratings on the HRSD were 8.4 (SD = 5.9; range q O-18). All six patients from the previous clinical report (Hollander et al., 1988n) are included in the present sample. Healthy Subjects. Healthy subjects were determined to be free of current or past mental disorder on the basis of semistructured psychiatric interview. Family history of psychiatric illness was systematically assessed. One healthy subject had a family history of psychiatric illness, but this subject did not differ from the group on clinical, behavioral, or endocrine measures. None of the controls had any medical illness as determined by physical examination and laboratory tests. No control subject had received any medication for 3 weeks before the study. Ten healthy controls (7 males, 3 females) with a mean age of 32. I (SD = 5.9; range q 25-42) years participated in the studies. They did not significantly differ in age or sex from the patients. Procedures. All studies consisted of single-dose clonidine or placebo administered under double-blind, random-assignment conditions on separate days. After an overnight fast, subjects arrived at the Biological Studies Unit of the New York State Psychiatric Institute at approxtmately 8 a.m. on the study day. Subjects were placed on a low monoamine diet beginning 72 hours before the first procedure and for the duration of the studies to control for the possible effect of tyramine on corttsol and prolactin measurements. Subjects remained at bedrest and in an awake and fasting state for the duration of the procedure. An indwelling i.v. catheter was inserted in a forearm vein at 8:30 a.m., I hour beforedrugadministration. At 9:30 a.m. (0 time), the subject received either placebo or identical challenges with clonidine, meta-chlorophenyl-

164 piperazine (m-CPP), or fenfluramine. The clonidme dose was 2 pgi kg by slow i.v. push. The m-CPP dose was 0.5 mg/ kg, p.o. The fenfluramine dose was 60 mg, p.o.. (Results of the m-CPP and fenfluramine challenge and discussion of serotonergic function m OCD are reported separately [Hollander et al., in press].) The challenges were conducted at intervals 2 48 hours (mean interval between challenges = 7.9 days; mean interval between clonidine and placebo challenges = I I .6 days). Clonidine, m-CPP. and placebo were given in a random, computergenerated, counterbalanced order. while fenfluramine was always administered last because of possible carry-over effects. The procedures for behavioral ratings and medication administration were Identical, and thus the patient and clinical rater remained blind to the given procedure. Medtcation was administered by a psychiatrist, and clinical ratings were performed by a trained research nurse or research psychologist. After a 45min stabilization period, baseline blood samples were collected 15 and 0 min before clonidine or placebo administratton. All blood samples were collected from the i.v. cannula into acid-washed borosilicate glass tubes containing balanced ammonium/potassium oxalate for chenucal assays, or heparin for neuroendocrineassays. Blood pressureand pulse were measured at 30-min intervals during the procedure. After clonidine or placebo administration, blood samples were taken for GH and cortisol levels at 15, 30, 45, and 60 min. The blood-drawing procedures were performed by a separate technician. Behavioral ratmgs were admmistered at -30, 0, 60, 120. and 180 min for all procedures. The rating scale was the Clinician Challenge OC Scale, a 5-point global severity score rated from 0 (none) to 4 (extreme) for obsessions, compulsions, and obsessions + compulsions, on the basis of duration, distress, and ability to control symptoms (developed by W. Goodman, M.D., and available on request from the authors). The rating scale was administered by a trained research nurse or psychologist who was unaware of the challenge medication. During the baseline pertod, each subject was admimstered an OCD checklist, which is a detailed questionnaire regarding numerous dtfferent types of past and current obsessions and compulsions (Goodman et al., 1989~. 1989h). During subsequent OCD ratmgs, the clinical rater referred back to these symptoms in assessing change of OCD symptoms. Because of this detailed checklist, the rater could not be blind to diagnosis, but was blmd to medication. The clinical rater kept a detailed clinical narrative, including any behavioral or side effects during the procedure. In addttion. subject self-ratings were collected at each of the above times using IOO-mm visual analogue scales to evaluate change in mood (depression) and anxiety. These scales were scored (in mm) from the left-hand side of a IOO-mm line to a perpendicular mark made by the subject. The score ranges from 0 (not at all) to 100 (most ever). To evaluate drovvsiness, a clinician-admimstered 5-point analogue scale was given at each of the above times. The scores ranged from 0 (not at all) to 4 (extremely, most ever). Other clinical ratings completed at baseline included the 17-item HRSD (Hamilton, 1960) and the YBOCS (Goodman et al.. 1989~. 19896). Dose, and Route of Administration. Clonidine hydrochloride was obtained from Boehringer lngelheim Pharmaceuticals, Inc.. Ridgefield, CT, in l-ml ampules of 0. I5 mg; ml. The i.v. dose of 2 pg! kg was chosen to rephcate the method of Siever et al. (1983). All subjects received an identical IO-cc infusion at the zero time plus three identical capsules on each procedure day. On the clomdine challenge day, subjects received IO cc of clonidine hydrochloride (2 I_cg/kg) mixed with normal saline by slow i.v. push over a 5-min period, and three placebo capsules. Placebo capsules were prepared by the Pharmacy Department of the New York State Psychiatric Institute. Subjects received three placebo capsules and IO cc of normal saline by slow i.v. push on the placebo challenge day. Drugs,

Methods. Plasma cortisol was assayed by radtotmmunoassay (RIA) Micromedic RIA kit. The intra-assay and interassay coefficients of variation were 4.6%, respectively. Plasma GH was analyzed by a double antibody usmg human GH and primary antiserum donated by the National Pituttary agency. The labeled Biochemical

using the 3. lqb and standard ligand is

165 repurified on the day of assay using a G-100 Sephadex column (Click et al., 1963). Intra-assay and interassay coefficients of variation were 3.17% and 3.75%, respectively. Plasma MHPG was determined by gas chromatography/ mass spectrometry using a modification of the method of Jimerson et al. (198 I). In our hands, this method has intra-assay and interassay coefficients of variation of 3.8% and 5. ITo, respectively. Data Analysis. The effects of clonidine and placebo on behavioral ratings, physiological measures, and plasma cortisol and GH concentrations over time (O-180 min) in patients and controls were evaluated initially by analysis of variance with repeated measures (ANOVAR). Further examinations with paired t tests for within-group comparisons were conducted by subtracting the baseline (0 time) values from the time at which maximal change occurred following drug administration, resulting in a peak change score (peak A t tests). Between-group comparisons (normal controls vs. patients) used ANOVAR and Student’s nonpaired t tests. In addition to peak A r tests, comparisons between normal controls and patients were done by “peak double-a” t tests. This consisted of subtracting, from the maximal change following clonidine, the change following placebo at the corresponding time points, thus obtaining an estimation of the net maximal clonidine effect. Depending on the normality of the distribution of the data, Pearson or Spearman rank-order correlations were calculated to evaluate relationships among the behavioral and neuroendocrine effects of clonidine as reflected by peak changes in patients and normal controls. Correlations between physiological effects and behavioral and neuroendocrine responses were also calculated in this fashion. All levels of significance are based on two-tailed tests. To indicate variance, SDS are provided.

Results Behavioral patients,

Effects

ANOVAR

of Clonidine.

showed

p = 0.003) for postinfusion

Comparing clonidine and placebo within drug x time interaction (F= 11.69; df= 1, 17; (O-180 min) global ratings of OCD (Fig. 1). There was a a significant

Fig. 1. Mean global obsessive-compulsive obsessive-compulsive disorder (OCD)

(OC) ratings in patients with and healthy controls over time O-occ*~oc0n-l8

l -op*cMJ.ocoN.l8

-0.500

4 -60

-30

0

30

60

90

120

Isa

180

Time (Minutes) OCD patients (n = 18 / mdlcated by circles. Healthy controls n = 101 lndlcated by triangles. Clonidine, indicated by open figures, and placebo, Indicated by closed figures, were admlnistered by slow i.v. double-blind, random-assignment conditions.

2 ,+g/kg

I,

push under

significant drug x time interaction for both obsessions (F= 11.78; &‘= 1, 17;~ = 0.003) and compulsions (F = 8.14; df= 1, 17; p = 0.0 1) rated separately. Comparison of peak change of OCD severity demonstrated a significant difference between clonidine and placebo (t = -2.76, p = 0.013). Both obsessions (t -2.50, p = 0.023) and compulsions (l= -2.30, p = 0.035) were significantly less following clonidine compared to placebo. Time to minimum obsessions (150 f 42 min) following clonidine did not significantly differ from time to minimum compulsions (153 * 42 min), and time to minimum obsessions significantly correlated with time to minimum compulsions following clonidine (r = 0.59. n = 18, p 0.01). Thus, obsessions do not decrease before compulsions following clonidine. Since controls by definition had no obsessions or compulsions and thus did not manifest a decrease in symptoms with clonidine, patient-control statistical comparisons are superfluous. q

q

Self-Ratings of Mood and Anxiety. Clonidine did not significantly differ from placebo on self-ratings of anxiety or mood (depression) within patients. Peak A anxiety following clonidine (2 1 * 17) marginally differed from peak a anxiety following placebo (12 + 10; t = 2.00, n 14,~ = 0.066), such that patients became less anxious on clonidine. Peak A mood following clonidine (12 + 14) and placebo (9 * 11) did not significantly differ. Peak change in mood following clonidine did not significantly correlate with peak change in obsessions (r = -0.30, n = 16, p = 0.25) compulsions (r = 0.23, n= 16,p=O.38), or combined obsessive-compulsive (OC) score (r=-0.14, n = 16,~ = 0.60). Likewise, peak change in anxiety following clonidine did not influence peak change inobsessions(r=-O.l6,n= 15,p=0.28),compulsions(r=-0.42,~~ 15,~~ 0.14), or combined OC score (r = -0.30, n = 15, p 0.26). Thus, the effect of clonidine on obsessions and compulsions was independent of concurrent mood and anxiety changes. Since healthy controls by definition did not have significant anxiety or depression, this did not change with clonidine, and patient-control statistical comparisons are superfluous. q

q

clonidine caused significantly Clinician-Rated Drowsiness. Within patients, greater drowsiness than placebo by ANOVAR (F= 50.26; df’= 1, 16;~ = 0.00001) and peak A drowsiness following clonidine (1.9 * 0.8) was significantly greater than that following placebo (0.6 * 0.9; 1 = 6.47, p = 0.0001). However, patients did not differ from controls on clinician-rated drowsiness following clonidine by ANOVAR, and peak ,I drowsiness following clonidine in patients (1.9 + 0.8) and controls (1.2 + 1.4) did not differ. Effect of Drowsiness on OC Ratings. Peak change in drowsiness following clonidine did not significantly correlate with peak change in obsessions (r = -0.02, n 17,p=0.93),compulsions (~=0.09, rz= 17,p=O.72), or combined OCscore(r= 0.16, rr= 17, p = 0.53). In addition, followingclonidine. patients with high drowsiness scores did not significantly differ from those with low drowsiness scores on peak change in OC scores (t -1.04, p = 0.31). The one patient without any drowsiness had an antiq

q

167 obsessional response to clonidine, and the one patient without an antiobsessional response had substantial drowsiness following clonidine. Thus, the effect of clonidine on obsessions and compulsions was not associated with its effect on drowsiness. Other Effects. Of the 18 patients with OCD, by clinician report followingclonidine, 17 had drowsiness, I 1 had dry mouth, IO became less anxious, 7 felt calmer, and 7 had improved mood, whereas 4 felt less happy, 5 felt dizzy, 5 described difficulty in swallowing, 3 had difficulty concentrating. 3 had difficulty speaking, and 2 had a headache. Of the 10 normal controls, by clinician report following clonidine, 9 felt drowsy, 5 felt calmer, 4 had an urge to urinate, 4 had dry mouth, 4 had decreased concentration, 3 had a headache, 3 felt dizzy, 2 were less talkative, and I was less anxious. Physiological Measures. Within patients, a significant drug x time interaction (F= 4.86; df = 7, 84;p=O,OOO)and peak A t test (t=-4.2l,p=O.O01)indicated asigniftcantly greater decrease in systolic blood pressure following clonidine than following placebo (Fig. 2). However, neither diastolic blood pressure nor pulse rate following clonidine significantly differed from placebo by ANOVAR or peak A analyses. When patients were compared with healthy subjects on systolic blood pressure, there were significant main effects for drug (F= 102.4; df = I, 20; p = 0.000 I), time (F= 6.49; df = 7, 14O;p= O.OOOl), and sex (males had greater systolic BP) (F= 4.96; df’= I, 18; p = 0.039) and marginal effects for diagnosis (patients had marginally greater systolic BP) (F= 3.89; df= 1, 20;~ = 0.06). However, the diagnosis x time x drug and the sex x diagnosis x time x drug interactions were not significant. Peak A and peak double-A t tests were also not significant. Thus, systolic blood pressure response to clonidine did not differentiate patients from controls. Fig. 2 summarizes the results over time following clonidine and placebo for systolic and diastolic blood pressure and pulse in patients and controls. Fig. 2. Physiological response to clonidine (2 pg/kg, i.v.) and placebo in 15 patients with obsessive-compulsive disorder (OCD) and 9 healthy controls Systolic

Diastolic

Blol~~~~Pressure

a5

q

-•0caraRx*

Time (uinutt.)

.-.ow clo3uk o-occn w

.-.acO OalB”. o--0rJcO Flu.*

.-.OCD claldln* o--0ccD Pl.x* .--.cm”ldl”. 130

Pulse (s~ot~/uin~k)

l$l,ocooj Pressure

85

140

75

8=8:% Ez”

Time OW..J

.-.ca”va am”!&., O--OcmM mmda

75

lime

(ui~14

Systolic blood pressure response mmHg left , dwstollc blood pressure response, mmHg /, middle #,and pulse response 1beats/mln) right are shown Closed circle represents patients who recewed clonldlne. open circle represents patients who recewed placebo, closed square represents controls who received clonldme, and open square represents controls who received placebo

168 For diastolic blood pressure, there were significant main effects for drug (F= 33.5; Crf= 1,20; p O.OOO),time (F= 4. I I; df’= 7, 140; p = O.OOO),and sex (males had greater diastolic blood pressure) (F = 16.5; dj’ = 1, 18; p = O.OOl), but not for diagnosis. However, the diagnosis x time x drug, sex x diagnosis x time x drug, and peak A and peak double-A t tests were not significant. Thus, patients did not differ from controls in diastolic blood pressure response to clonidine. For pulse, there were significant main effects for diagnosis (patients had faster pulses) (F= 5.12; s'f=I,22;~ = 0.034)and time (F= 3.13; df=7. 154;p=O.O04) but not drug or sex. The diagnosis x time x drug, sex x diagnosis x time x drug. peak ZI and peak double-A I tests were not significant. Thus, patients did not differ from controls in pulse response to clonidine. q

Effects on MHPG. Within patients, ANOVAR revealed a significant effect (F = 1 1.69; L@ = 1, 13; p = 0.004) indicating a greater reduction following clonidine than following placebo. Peak A t test confirmed significantly greater reduction of MHPG following clonidine (-0.4 f 0.4) ing placebo (-0.1 * 0.3; t = -2.44, p 0.03) (Table I). Comparing patients to controls, ANOVAR. peak A, and peak double were not significant (Table 1). Therefore. patients did not differ from MHPG response to clonidme.

drug x time in MHPG this, with a than follow-

q

Table

1. MHPG

effects

of clonidine

Clonidine

and placebo

challenge

Base

Peak

Mean

3.4

3.0

SD

0.5

0.4

Mean

3.1

SD

0.7

A

A analyses controls on

(ng/ml)

Placebo challenge A

Peak double A

Base

Peak

-0.4

3.0

2.9

-0.1

-0.3

0.4

0.4

0.3

0.3

0.4

3.3

0.2

3.4

3.4

0.0

0.2

0.8

0.8

1.0

0.8

0.9

0.8

Patients

Controls

Note. MHPG = 3-methoxy-4-hydroxyphenylglycol

Neuroendocrine Findings. GH. Within patients, ANOVAR

revealed a significant drug x time effect (F= 5.22; a significantly greater GH rise following clonidine than following placebo (Fig. 3). Peak A t test confirmed this, with significantly greater peak increase in GH following clonidine (7.6 + 6.8 ngj ml) than following placebo (0.1 * 3.8 ng/ ml) (t = 3.28, p = 0.005). When patients were compared with controls, there was no significant group x time x drug effect for GH (Fig. 3). Patients (7.6 * 6.8 ng; ml) did not significantly differ from controls (5.5 ? 5.5 ngi ml) on peak GH rise following clonidine or on double-A t test. Thus, patients did not differ from controls in GH response to clonidine. Cortisol. Within patients, a marginal main group effect (F = 2.90; u[f= I, 25; p = 0.10) reflected increased cortisol in patients with OCD compared to normals at for cortisol (Fig. 4) baseline (Fig. 4). There was no significant drug x time interaction df= 4, 64; p = 0.027) indicating

169 Fig. 3. Mean human growth hormone (ng/ml) time-response curve before and after clonidine (2 pg/kg, i.v.) and placebo in 17 patients with obsessivecompulsive disorder (OCD) and 10 healthy controls 0--0t3edimPotintN-17 .-•AoclboPotMN-17 A-AaonigrrbnWN-10

13-

A-APlac&eCatmtN-10

z

ll--

\ F

9--

i!

7--

b

5--

E

%O

0 A-adrenergic receptor function in OCD. Further. changes in physiological measures following clonidine do not influence either behavioral or neuroendocrine response to clomdine. At baseline. patients with OCD had faster pulses than healthy control subjects. Earlier studies with i.v. clonidine in OCD either did not assess physiologtcal responses (Siever et al., 1983) or found that clonidine resulted in similar reductions in blood pressure and pulse in both patients and controls (Lee et al., 1990). However, baseline pulses were more rapid in patients than in controls (Lee et al., 1990). which might be due to greater anxiety, and is consistent with our baseline finding. Following the az-adrenergic receptor antagonist yohimbine, the only significant patient-control difference was a greater increase in standing systolic blood pressure in the patients with OCD. In our study, systolic and diastolic measures were taken in a supine position. Neuroendocrine Effects of Clonidine. Clonidine resulted in a significantly greater increase in plasma GH than did placebo in patients, which is consistent with its central postsynaptic hypothalamic az-adrenergic receptor agonist mechanism of action

173 (Eriksson et al., 1982; Tuomisto et al., 1985; Checkley et al., 1986). However, GH response to clonidine did not differentiate patients with OCD from normal controls. This finding differs from the initial report by Siever et al. (1983) of blunted GH response to clonidine in patients with OCD, but is in agreement with the study of Lee et al. (1990), who did not find between-group differences in GH response to clonidine. This discrepancy might be partially explained by depressive symptoms in the patients, since HRSD scores were higher for patients in the Siever et al. (1983) study (mean = 12.8, range = 5-24) than for patients in our study (mean = 8.4, range = O-18). HRSD scores were not reported in the Lee et al. (1990) study. This is important since depression has been associated with blunted GH response to clonidine (Matussek et al., 1980; Checkley et al., 1981, 1986; Charney et al., 1982, 1983; Siever et al., 1982, 1984~; Horton et al., 1986). Growth hormone response was not reported in the yohimbine study in OCD (Rasmussen et al., 1987). This finding does not support subsensitivity of a,-adrenergic receptor function in OCD, and stands in contrast to the blunted GH response to clonidine reported in major depression (Matussek et al., 1980; Checkley et al., 1981, 1986; Charney et al., 1982, 1983; Siever et al., 1982, 1984~; Horton et al., 1986) panic disorder (Charneyet al., 1986; Nutt, 1989; Uhde et al., 1989) and alcoholism (Nutt et al., 1988). Rather, there is an intriguing suggestion of greater GH response to clonidine in OCD patients (peak double-A = 7.5 ngi ml) compared to controls (peak double-A 4.6 ngiml), although this does not reach statistical significance. Individuals with the most robust GH response to clonidine had the greatest antiobsessional effects, perhaps suggesting these individuals had more intact cy,-adrenergic receptor sensitivity. However, they did not have greater blood pressure responsivity. While the possibility of carry-over effects from the other challenges exists, this would affect clonidine and placebo responses equally, and would make the findings less rather than more robust. Preclinical studies document that NE acts via central postsynaptic receptors to lower plasma cortisol levels (Ganong, 1980; Price et al., 1986). While there is evidence in humans that a,-agonists significantly decrease cortisol release (La1 et al., 1975; Lanes et al., 1983; Siever et al., 19846) we did not find this. Clonidine does not seem to have direct serotonergic effects, since serotonergic stimulation is known to increase, rather than decrease, cortisol secretion (Mueller et al., 1976; Van de Kar and Bethea, 1982). Preclinical studies, however, suggest that clonidine has indirect 5HT effects (Svensson et al., 1975). It has been reported that yohimbine increased cortisol in patients with OCD in comparison to normal controls (Rasmussen et al., 1987). The authors suggested that this supports postsynaptic cY,-adrenergic subsensitivity in OCD. However, we did not see significant cortisol effects with clonidine in OCD patients. Cortisol release is known to increase with moderate or anticipatory anxiety (Hollander et al., 1989, 1990) and thus increased cortisol following yohimbine may have been secondary to the anxiogenic effects of yohimbine in OCD. Since patients with OCD are more anxious and more depressed than normal controls, this may also explain the trend toward a baseline elevation in cortisol in patients with OCD compared to controls in our study as well as in the study of Rasmussen et al. (1987). q

174

Conclusion None of the physiological or neuroendocrine dependent variables differentiated patients with OCD from healthy subjects, which does not support a primary defect of noradrenergic function in OCD. However, clonidine transiently improved OC symptoms, and the extent of this improvement correlated with peak GH response, suggesting noradrenergic involvement in clonidine’s antiobsessional properties. A placebocontrolled trial of chronic transdermal clonidine treatment via adhesive patch in OCD is needed to determine if this antiobsessional effect persists. The authors gratefully acknowledge statistical consultation with Donald Ross, Ph.D., and Jihad B. Saoud, M.S., assistance by Michael Fay, R.N., and Sari Trungold, B.A., and performance of biochemicaland neuroendocrineassays by Hanna Novacenko, M.S., and David Allen. Clonidine hydrochloride was provided by Boehringer lngelheim Pharmaceuticals, Inc., Ridgefield, CT. The authors are grateful for the help of the pharmacy at the N.Y. State Psychiatric Institute. This investigation was supported in part by grants MH-30906. Biomedical Research Support Grants, and Research Scientist Development Award MH-00750 (Dr. Hollander) from the National Institute of Mental Health, Rockville. MD.

Acknowledgment.

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macologJ

Noradrenergic function in obsessive-compulsive disorder: behavioral and neuroendocrine responses to clonidine and comparison to healthy controls.

To evaluate noradrenergic (NE) function in obsessive-compulsive disorder (OCD), behavioral, physiological, and neuroendocrine responses to the alpha 2...
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