A review of GHRH stimulation test in psychiatry

REVIEW ARTICLE A Review of GHRH Stimulation Test in Psychiatry Stacy S. Skate, Maurice W. Dysken, and Charles J. Billington

We critically reviewed controlled investigations of the growth hormone releasing hormone (GHRH) stimulation test in depression, anorexia nervosa, bulimia, panic disorder, schizophrenia, and Alzheimer "s disease. Comparisons of GH responsiveness between patients and controls within each diagnostic category were equivocal and in some cases contradictory. Factors that may contribute substantially to the inconsistent findings within diagnostic categories include (I) the variability of GHRH-simulated GH among control groups; (2) the lack of uniformity in test procedures and outcome measures; and (3) the age and gender of subjects. In addition, the individual reproducibility of the GHRH stimulation test has not been adequately investigated and until the test' s stability within subjects can be determined, the validity of'nterpretations resulting from the GHRH simulation test are in question.

Key Words: Growth hormone releasing hormone (GHRH), growth hormone (GH), depression, eating disorder, panic disorder, schizophrenia, Alzheimer's disease

Introduction Neuroendocrine research in psychiatry has been directed at characterizing neurotransmitter mechanisms of action in healthy individuals, further delineating the pathophysiology underlying psychiatric conditions, discovering biological markers that may provide diagnostic information, and identifying biological indices of treatment response or recovery. Much of this work has involved the use of provocative tests such as the dexamethasone suppression test (DST), the corticotropin-releasing hormone stimulation test, thyrotropin-releasing hormone stimulation tests, and growth hormone stimulation tests. Although provocative tests have been studied extensively in psychiatric conditions, very few provocative tests have been rigorously standardized and adequately validated. One exception is the DST, which has been studied as a biological marker for From the GRECC Program, Minneapolis Veterans Administration Medical Center (SSS. MND, CIBI and the Department of Medicine, University of Minnesota, Minneapolis, MN (CJB). This work was supported by the Department of Veterans Affairs Medical Research. Adressall reprint requests to Stacy Skare. MA, GRECC Program ( I IG), Minneapolis VA Medical Center, One Veterans Drive, Minneapolis, MN 55417. Received August 3 I, 1992; revised November I0, 1993. © 1994 Society of Biological Psychiatry

melancholia. In a 6-year study, Carrall and colleagues ( 1981 ) tested 438 subjects and examined (1) components of the test procedure such as dosage, number, and timing of blood samples; (2) factors that may influence test results such as age, gender, and recent medication use; (3) test response in healthy subjects; and (4) the diagnostic sensitivi_ty and gpec__ificity of the test in comparison to normal controis and patients with other psychiatric diagnoses. G'owth hormone stimulation testing has been a particularly active area of neuroendocrine research in psychiaW¢. For example, Laakmann and colleagues have extensively researched a number of growth hormone challenge tests in healthy adults and depressed patients by using probes such as desimipramine (Laakmann et al 1977; Matussek and Laalcmann 1981), diazepam (Laakmann et al 1982), chlodmipramine (Laakmann et al 1972, 1984, 1977), and a combination of desimipramine and receptor blockers (Laakmalta et al 1986). Interest in growth hormone stimulation testing has risen in the past few years with the availability of synthetic growth hormone releasing hormone (GHRH), a substance identical to naturally occurring GHRH that selectively stimulates growth hormone release (Evans et al 1984: 0006-3223/94/S07.00

250

BIOLPSYCHIATRY

S.S, Skare et al

I~M.36:249=265

Thomer et al 1983). Because of its selectivity GHRH offers a more direct theoretical avenue for investigating GH pathways and may produce more reliable results than previous paradigms. A number of studies have evaluated the GHRH stimulation test in specific psychiatric conditions; however, a comprehensive summary of these findings among psychiatric disorders has yet to be assembled. In addition, methodological features and outcome measures have not been compared across studies. To assess GHRH stimulation test results to date and as a step toward standardization of GHRH stimulation test procedures, we will summarize investigations of the GHRH stimulation test in depression, anorexia nervosa, bulimia, panic disorder, schizophrenia, and Alzheimer's disease. The study methodology and test procedures will be a primary focus and only controlled studies will be reviewed. First, though, we will summarize what is known of the biology of GH and GHRH participation in its regulation.

Biology of GH and GHRH GH is secreted from the anterior pituitary gland under controi of the hypothalamus (Epelbaum 1992; Frohman et al 1992; Muller et al 1991; Zeitler et al 1990). GH system regulation is complex, involving many neurotransmitters and hormonal feedback loops. Principal stimulatory control is by GHRH and principal inhibitory influence is by somatostatin (Figure l). Both peptides travel from hypothalamus to anterior pituitary through a vascular portal system instead of by direct neural connection. GHRH and somatostatin are secreted in pulsatile fashion, with peaks of one normally paired with troughs of the other (Plotsky and Vale 1985; Tannenbaum and Ling 1984). GH itself is secreted pulsatilely in response to these influences. In the periphery, GH produces some actions, such as antagonism of insulin directly, whereas other actions, such as somatic growth, are ,.~.~ae,,..,,~, throu~ tr~pauc I". . . . manufacture of insulin like growth factor 1 (IGF-I; also known as somatomedin-C). GH and IGF-1 provide negative feedback to the pituitary and hypothalamus. Within the hypothalamus, neural activity influencing GH is concentrated in two hypothalamic nuclei: the arcuate and periventricular. Control signals affecting GH are also sent from the limbic system to hypothalamus. At each of these sites, it is probable that a variety of neurotransmitters participate in neuronal regulation that ultimately affects GH through GHRH or somatostatin. Cell bodies synthesizing GHRH are located primarily in the arcuate nucleus (Sawchenko et al 1985), whereas cell bodies synthesizing sornatostatin are primarily located in the periventricular nucleus of hypothalamus (Urman et al 1985). Both types of cells project axons to the median eminence, where the hormones are secreted into the hypothalamic--pituitary portal system. Both of these cell types proba-

Somatostatin-Secreting Periventricular N u c l e u s

/ "
GH ~

Alpha-2 Adrenergie Neurons

GH - Secreting

Pituitary Cells

Figure 1. Interaction of the stimulatory GHRH secreting arcuate nucleus neurons and the inhibitory somatostatin secreting periventficular neurons in the regulation of GH secretion by anterior pituitary cells. Both GHRH and somatostatin are released into the hypothalamic-hypophysial portal system at the median eminence and thereby travel to GH secreting cells in the pituitary. The most firmly established intrahypothalamic regulation, by alpha 2 adrenergic neurons is also shown.

bly also interact directly (Epelbaum 1992), as there is evidence of direct contact between the cell types (Daikoku and Tsumo 1990; Epelbaum 1992; Horvath et al 1989; Liposits et al 1988). In addition, antibody blocking studies show that somatostatin normally blocks GHRH release (Miki et al 1988; Thomas et al 1985). There is evidence for the reciprocal interaction, namely that GHRH activates sornatostatinergic cells in the periventricular nucleus (Katakami et al 1986; Mitsugi et a11990). At the arcuate nucleus, the alpha 2 adrenergic neurotransmitter system appears important in GHRH regulation. Alpha 2 adrenergie receptors have been identified on arcuate nucleus (Sato et al 1989). Inhibition or depletion of catecholamines almost totally suppresses GHRH pulse in rat, and clonidine (an alpha 2 agonist) restores pulses (Durand et al 1977; Eden et al 1979). In humans, the alpha 2 blocker yohimbine lowers GH response to clonidine (.Camanni et al 1989). Another catecholaminergic system involved in GH regulation is the alpha-1 adrenoreceptor, an inhibitory influence that may be located on and increase the activity of the somatostatin-producing cell bodies in the periventficular nucleus (Celia et al 1987). The adrenergic 131 receptor is also inhibitory to GH in pharmacological studies, probably acting through modulation of somatostatinergic neurons (Epelbaum et al 1981). Adrenergic 132 receptors may have effects opposite to the [31 actions (Camanni et al 1989). Dopaminergic pathways also appear to participate in GH regulation within the hypothalamus,

GHRH Testing in Psychiatry

BKX.~YOUA'mY

251

I~4~r~49=~6s

though the specific site for this action is less clear. Dopamine agonists can raise GH levels in humans (though dopamine can also suppress GH in acromegatics, who presumably have control system alterations) (Muller 1987). Cholinergic muscarinic receptors appear to be a means of activating GH release 0Levenston and Cryer 1980). Most likely this action is through inhibition of somatostatin release within the hypothalamus (Locatelli et at 1986). There appear to be actions of several other neurotransmitters at unspecified locations as well, including TRH, serotonin, glucagon neuropeptide, galanin, prostaglandins, and others. It should be noted that despite this desciption, the control pathways explaining many standard stimuli of GH release have not been described: stress, exercise, malnutrition/protein depletion, estrogens; and similarly standard inhibitors of GH release are not understood: obesity, glucocorticoids, increased free fatty acid levels, and medroxyprogesterone. It is likely that the complexity of the control system is greater than so far described. When we measure the response to GHRH, we are assessing the direct pituitary responsiveness to its endogenous releasing factor. GHRH exists in two endogenous forms: GHRH !-44, GHRH 1-40; and a pharmacological agonist: GHRH 1-29. All three of these forms have been used for dynamic testing, and important differences in response based on the molecular form are possible, but have not been shown (Grossman et al 1984; Vance et al 1986). The response to GHRH is clearly different from measuring the GH response to, for example, clonidine because, for the reasons stated above, the clonidine response is more indirect and subject to other influences. Moreover, it should be noted that the influence of agonist and antagonist activity on GH secreting cells prior to administration of exogenous GHRH is not understood and could be potentially relevant. Some investigators infer levels of activity in central controlling neurons based on differences between the GH response to, for instance cionidine, and the response to GP,qH. This indirect knowledge is attractive, but without direct verification is subject to qualification based on our less than complete knowledge of these control systems.

Depression Rationale Growth hormone (GH) responsiveness in depressed patients has been assessed using a variety of provocative agents. A blunted GH response has been reported following administration of insulin (Gruen et al 1975), L-dopa (Mendlewicz et al 1977), D-amphetamine (Langer et al 1976), and clonidine (Matussek et al 1980). Based on these and other reports of GH dysregulation (Jarrett et al 1986; Mendlewicz et al 1985) in depression, Lesch and colleagues (1987) first

reported GHRH stimulation test results in depressed patients and normal controls. Repfications ~ were then canied out by Krishnan et at (1988) and Thomas et al (1989a) who emphasized that GHRH stimulates GH secretion at the level of the pituitary and appears to ~ hypothatamic contro| mechanisms. Severat investigat~t~ L~orporated more than one provocative agent in replication studies (lEriksson et at 1988; Lesch et al 1989a) as a way of not only comparing GH responses but also of testing hypotbeses regarding specific receptor pathways controlling GH release. To extend this research, Peabody and colleagues (1990) compared the GHRH stimulation test response in patients with several different diagnoses.

Studies Lesch and associates (Lesch et al 1987) administered the GHRH stimulation test to 11 patients who met Research Diagnostic Criteria (RDC) (Spitzer et al 1973) for major depressive disorder of the primary endogenous subtype and fulfilled DSM-m criteria (APA 1980) for major depressive episode. A control group of 11 healthy volunteers matched for gender, age, body weight, and ovarian status were studied for comparison. Depressed patients exl~'bited significantly lower basat GH levels (1.1 ± 0.7 versus 2.2 "4" 1.7), increased somatomedin- C (SIn-C) levels (I. 1 -4-0.7 versus 0.6 -+ 0.3), lower Amax GH (Table 1), and lower GH area under the curve (AUC) (Table 1) in comparison to normal controls. GH response was not affected by gender, age, body weight, basal GH or Sm-C level. The magnitude of the GH response was not related to the duration of depressive illness, number of affective episodes, length of current depressive episode, or severity of illness. Eriksson et al (1988) examined the GH response to GHRH and to guanfacine, an alpha2 adrenoceptor agonist, in 13 inpatients (9 men, 4 women) with DSM-III/P,DC diagnoses of major depressive disorder and in 13 age- and gender-ma_cwhedcontrols subjects. Guanfacine was chosen instead of clonidine because of its greater selectivity for the alpha2 adrenergic receptor (Scholtysik et al 1980). No significant group differences were observed in GH response to GHRH or to guanfacine at any of the sample time points. The peak response to both GHRH and guanfacine, however, was greater in depressed patients (Table 1). There was a significant correlation between GHRH- and guanfacinestimulated peak GH within the depressed group (r = 0.94, p < 0.001), the control group (r=O.83,p < 0.01), and for the combined sample (r = 0.82, p < 0.001). Krishnan and associates (1988) measured the GH response to GHRH in 19 patients (11 men, 8 women) with RDC diagnoses of major depression, endogenous subtype, and 19 age- and gender-matchedhealthy volunteers with no history of psychiatric disorders. No significant differences were observed between depressed patients and controls in

S.S. Skaxeet al

Table I. The CHRH

ShIdV

Leschet al. ‘987

E&son et al ‘988*

StimulationTestin Patients with Demession

Diaanosis

n

Meanage 2 SD (range)

Gender 4M.7W

ENDGG DEP

‘I

CTRL

‘I

MAJ DEP

I 1.6 yrs) 11.3 yrs) ‘2.6

4M.7W

‘0

53.2 .; (27-65 49.22 (22-63 46.7 2

‘0

46.3 2 ‘4.4

9M.4W

9M.4W

Infusion time and

GHRH

Gtttcitmc

sampletimes (mitt)

dosage

tlwaaws

9AM:--15.0, ‘5,30, 45.60.90.120

Appr8:SO~ki: -2O,-‘0, 0. IO, 20.30.40, JO. 60 70,80.90

IPak

33.3 wg l(PmittIV

A&OH AWC AtnaxGH AWC GH4S mitt

ENDGG DEP

39.3 r ‘4

“M.aW

24.0 -c 23.6 1346 r 1655 23 + 17(NS)

AmaxGH

‘6-c ‘4 ‘2.8 + ‘[email protected]) ‘2.1 -F ‘[email protected])

50 Ira

peakGH AmaxGH A AWC

7.3 -e 5.3 6.7 2 5.2 339 + 504 @
’ ‘@%

A AWC GH-30

“d’s

‘9

4.5 2 4_0@<0.05) 217 r I53cpCO.Ol)

GH45 tnin

Krishnanetal ‘98Sb

GH O@ml) M=SDCpvaIttc)

9AM:--15.0.15.30.45,

WGH

60,90,120 cTlu

‘9

39.4 ‘c I5

l’M.8W

‘989iv

ENDGG DEP

‘5

49.6 t 9.2

8M,7W

I5

51.’ -c

8.8

8M.7W

Thomasetai I 989ad

ENDGG DEP

Leschet al

‘8

47.9 t ‘7.2

5M. 13W

9AM:-‘5,O. l5,30,45, 60,90,120

lOAM: l5,30,45, 60.90.120

;45 mitt GH--60

‘020 + 1088 14.7 (NS) 1”.6(NS) ‘8.1 (‘US) 19.2 (NS)

g-90 CTRL

I8

45.2 2 ‘7.4

3M.lSW

E-30 ;45 tttin

8.8 9.0 a.9 7.8

GH-60 min

GH-90 min

Peabodyetal 199@

MDD (-TRL

7 6

442’5 462 ‘7

7M

9 AM: -90. -60, -30. 0,15.30,45,60,90, ‘20

6M

’ we

peakGH adj.peakGH peakGH tx’j; lx& GH

20.3 2 21.3 (?) 25.2QKO.05) 37.0 2 30.5 44.6

? = not availabk *Mean GH concenrmtionswere highest for both groups at 45 min and were estimated from a figure. ‘Ihe gmups wee not significantly different at any of the time points. SubjectswhohadaGH levelgreaterthan5 @ml foranyofthe threebaselinesampleswereexcluded Fromtheanalysis(3paticnts, 3conuols). l%eageandgen&rdatapresenled in the table were notadjusted fortheseexclusions. “Tablepresentsr-test findings.Wilcoxon matched-pairssigned-ranktestanalysesam also repotted in the article. cl%e belweengmup differences in A AUC was testedusing the Mann-Whitney U-test. ‘GH valuestquimd log transformationbefore r-testswere performed. l%e actual arithmetic values of GH are presentedin the table. There were no significantdifferences in GH responsebetweengmups at any of the time points. ‘Differences betweengroups were analyzed usingan ANCOVA. on the age-adjustedmeans.

body weight or basal GH levels (0.75 _+0.13 versus 0.66 ? 0.24). GHRH-stimulated peak GH and Amax GH were significantly higher in depressed patients than in controls (Table 1). The Amax GH in depressed patients was greater than that of controls in 14 of the 19 matched pairs. Three depressed patients exhibited marked GH responses to GHRH and when they were excluded from the analyses, along with their matched control subjects, the significant differences in GH response between depressed patients and

controls were no longer observed. The time to peak GH did not differ significantly between patients (48.9 t 32.0) and controls (48.2 It 35.2). There were significant correlations between age and peak GH (r = -0.38, p < 0.02) and body weightandpeakGH(r=-O.54,p=O.OOl);however,gender did not correlate with peak GH response. L.esch and colleagues (1989a) administered GHRH, thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone (CRH) stimulation tests to 15 patients with

GHRH Testing in Psychiatry

RDC~SM-m-R major depressive disorder, endogenous subtype, and to 15 healthy subjects matched for age, body mass index (BMD, gender, and ovarian status. The &AUC for GHRl-l-stimulated GH was significantly lower in depressed patients than in nonnal controls (Table 1). Depressed patients also exhibited significantly lower AAUC values for TRH-stimulated TSH (210 +- 143 versus 571 +_ 314 mU,min/L; U = 31, p < 0.00 ! ) and for CRH-stimulated ACTH (1177 _ 1224 versus 3384 +_ 2506 pg-min/ml, U = 40, p < 0.01); however, the AAUC of CRH-sfimulated cortisol did not differ significantly between groups (10.9 - 5.0 versus 11.8 _+ 6.2 ngmin/L).The only significant relationship observed between neumendocrine responses occurred between ACTH and TSH responses when groups were combined (r, = 0.52,p < 0.01). An additional study by Lesch et al reported findings of patients tested in this study and therefore will not be further reviewed (Lesch et al 1989b). Thomas and associates (1989a) measured GH, TSH, and prolactin (PRL) responses to GHRH in 18 patients who had DSM-III major depressive episode with melancholia and in 18 age- and sex-matched controls. There were no significant differences between groups in basal GH or stimulated GH or AGH at any of the time points (Table 1). There was, however, a trend indicating higher GH levels in the depressed patient group. No significant differences were observed between the groups in basal or stimulated TSH or PRL, although patients exhibited significantly lower serum free 3"3levels than controls (4.79 + .64 versus 5.40 -4- .68). Peabody et al (1990) measured GH responses to GHRI-I in 6 men who were inpatients with RDC major depressive disorder (unipolar), 10 men who or were inpatients with schizophrenia/schizoaffective disorder, and in 6 men who were normal controls. Because of the strong Spearman rank correlation between stimulated peak GH and age (r=--0.70, p < 0.01), stimulated peak GH concentrations were compared using an analysis of covariance (ANCOVA), with age as the covariate. Depressed patients exhibited sig-nificantly lower GH concentrations than normal controls (Table 1). The statistical comparison between unadjusted peak GH values was not presented.

Eating Disorders Rationale Baranowska and colleagues (1986) conducted the first controlled study of GHRH-stimulated GH responsiveness in anorexic women and did so because elevated GH responsiveness to TRH stimulation had been repotted in these patients (Maeda et al 1976; Travaglini et al 1976). Additional work in anorectic patients was carried out by Casanueva et al (1987), who examined the role of estrogen, and De Marinis et al (1988), who focused on the influence of body

a~c ~YctuA~y tg94~,t~205

~3

weight and nutritional status in conWolling the secretion of GHRH-stimulated GH. Several investigators extended these studies by compa.,ing GH release induced by cl~:dine versus GHRH in anorexia (Brambilla et a11989), and by comparing GH release following ~ and Ln.sulininduced hypoglycemia versus GHRH in ~ ( C o i m et al 1990). Rolla and associates (I 990) studied GH responsiveness in anorexic patients and controls during ~ glucose metabolism and during hypoglycemia. The influence of cholinergic pathways on GH regulation was investigated by both Tamai et al (1990) and Rollaet al (1991), who used a selective muscarinic antagonist during the GHRH stimulation test. These studies are summarized below.

Studies Baranowska and associates (1986) measured GH, PRL, and insulin response to GHRH stimulation in six women diagnosed with anorexia nervosa (Feighner et al 1972; Russell 1979) and in six healthy women. GH concentrations were significantly higher in patients with anorexia nervosa than in normal controls 45 rain after GHRH ~ n i s t r a t i o n Gable 2); however, the differences between groups were not statistically significant at any of the other time points. Neither group exhibited changes in PRL or insulin in response to GHRH stimulation. GHRH-stimulated GH responsiveness was examined by Casanueva and colleagues (1987) in eight women diagnosed with RDC anorexia nervosa and six age-matched controls, who were tested with and without tamoxifen, an estrogen receptor blocker. The anorectic patients were tested twice: once with GI-IP,A-I and once with saline, in randomized order, with a minimum of 4 days between tests. Controls were tested three times in the follicular phase of the menstrual cycle, in a fixed order, under the following experimental conditions: (1) GHRH alone; (2) 10 mg oftamoxifen orally every 8 hr for 2 days, with a final dose given 3 hr before G H P ~ admir,~stration, and (3) saline alone. The peak GH response to GHRH in anorectic patients and controis was vLrtually identical (Table 2) and GH concentrations did not differ significantly at any of the individual time points. In addition, no significant differences in GH were observed between tamoxifen-treated controls and anorectic patients or untreated controls (Table 2). Basal GH levels were similar across the three groups. De Marinis and colleagues (1988) administered the GHRH stimulation test to nine women with DSM-[II anorexia nervosa, 14 obese women, and 13 normal women. GHRH stimulation tests were performed under one of the four following test conditions: 9 AMfollowing an overnight fast; 9 AM following a meal 45 rain earlier; 1 PM following a meal at 8 AM; and 1 I'M following a meal 45 rain earlier. Of the 36 subjects, 15 women participated in two test sessions, seven women participated in three test sessions, and two

BIOLPSYCHIATRY t994:36:249~.-~

S.S. Skate et al

Table 2. The G H R H Stimulation Test in Patients with Anorexia, Bulimia, and Panic Disorder Study

Diagnosis

Baranowskaetal Anorexia 1986"

Casanueva et al 1987

DeMarinisetal 1988~

Brambillaetal 1989

Coiroetal 199@

Rolla et al 1990~

Tarnai et al 1990'

Rolla el al 1991/

n 6

Mean age ± SD (range) 20±? (18-27 yrs)

Gender 6W

CTRL

6

29 -+ ? (25-31 yrs)

6W

Anorexia

8

8W

CTRL

6

'> [ 15-24 yrs] ?

Anorexia CTRL Anorexia CTRL Anorexia CTRL Anorexia CTRL Anerexia

7 8 5 5 5 5 5 5 21

CTRL

10

6W

Bulimia

7

(15-30yrs) (22-27 yrs) (15.-30yrs) (22-27 yrs) (15-30yrs) (22-27yrs) (15-30yrs) (22-27yrs) 19.9 ~- 4.4 ( 14-35 yrs) 20.6-+5A ( 15-33 yrs) 29.0-- 3.7

CTRL

7

30.6-+4.5

7W

Anorexia

6

16.3 - 2,2 ( 13-19 yrs)

6W

CTRL

5

16.4 - 2,2 (13-19yrs)

5W

Anorexia

9

19.1 -+ 3,6 (15-25 yrs)

9W

CTRL

6

20.1 4-0,7 (19-21 yrs)

6W

Anorexia Acute phase Anorexia Recovery Phase AED

5

5W

7

CTRL

7

17.6 ± 1.4 ( 16-19 yrs) 17.0 -+ 1.9 (14-20 yrs) 1 6 . 0 - 2.7 (13-20yrs) 17.8-+-1.3 ( 15-20 ~ )

8

7W 8W 5W 5W 5W 5W 5W 5W 21W

Infusion time and sample times (min) 9AM:-30,0,15,30, 45,60,90, 120

10:45 AM: - 15.0. 15. 30, 45, 60 GHRH alone Tamoxifen + GHRH 9AM:-15,0.15,30, 60. 90(fasting) 9AM:-15.0. 15,30 60, 90 (after meal} I PM:-15,0, 15,30, 60,90(fasting) I PM:-15,0, 15,30, 60,90(aftermeal) 9AM:O, 15,30,45, 60,90, 120

GHRH dosage

0.75tt.g/kg GH--3Omin GH--45 rain GH--60min GH--90 min G H - - 3 0 rain GH--45 rain GH--60min G H - - 9 0 rain ! ttf,/kg peakGH I ttg/kg 50ttg 50ttg 50txg 50ttg 1 ttg/kg

10W 7W

8W 7W 7W

Outcome measures

8:30AM:0, 15,30, 45,6O,9O, 120

! ttg/kg

Appr. I I AM: -30; 0; saline or glucose at 30,60,90, 120~then GHRH at 5, 15,30,45, 60,90,120

I ttg/kg

Appr. 9 AM: saline or P Z P a t - 15, 0, 30, 60, 90, 120

I ~g/kg

Appr. 11 AM: -30: 0; saline at 30, 60, 90, 120; then GHRH or PZP+GHRH at 5, 15, 30,45,60.90, 120

1 p,g/kg I ttg/kg

peak GH peak GH peak GH peak GH peak GH peakGH peak GH peakGH peak GH peakGH A max GH AUC A max GH AUC GH--15 rain G H - - 3 0 min GH---45 rain GH---60 rain G H - - 9 0 min G H - - I 5 min GH--30 min GH---45 rain GH----60 rain GH--90 min Salpeak GH Sal A AUC GlucpeakGH Glue AAUC Sal peakGH eotAAUC Gluc peak GH Gluc A AUC Sal A max Sal AUC PZP A max FZP AUC Sal A max Sal AUC PZP A max FZP AUC Sal A AUC PZPAAUC Sal A AUC PZP A AUC Sal A AUC PZP A AUC Sal A AUC PZP A AUC

GH (ng/~l) M ~ SD (p value) 48(NS) 70 (p
27(NS) ! 2 (NS} 25 9 7 3 28.2 ~ 14.4(NS) 28. i ± 24.5 35.6 _+ 23.8 (NS) 53.2 -+ 20.4 (NS) 52.8 -+ 15.8 28 (?) 18 21 (?) 17 35 (?) 12 3 4 . 6 +- 19.3 (p<0.01) 186.0 _+91.6 (p<0.01) 8.4 -'- 5.4 48.5 _ ! 8.7 17.5 _ 4.5 17.0_+ 4.0 I 0.0 -+ 2.5 5.5 -+ 2.5 2.5 -+ 2.5 ! 6.0 + 2.5 15.5 _+ 2.5 9.0 -+ 2.0 4.5 -+ 2.0 1.5 _ 2.5 415-+--27.4(?) 3 0 -+ 1.9 (p<0.02) 52.1 -+ 18.9(?) 4.6 - !.4 (p
( Continued on thefollowing page)

GHRH Tes~:ngin Psychiatry

n ~ . PSVCtUATtV

255

t ~,3¢~249~2f~

Table 2. ( Continaedfrom previouspage ) Study Ralloportetal 1989s

Diagnosis PANIC

n

Mean age ±SD(range)

Gender

Ii

30.4-*- 13.4

4M, TW

Infusion time end sample times (nun) 8:30AM:-30,-15,0, 15,30,45,60.75o90o

GHRH dosage I Ixg/kg

106,120

Tanceretal 1993 t

CTRL

II

30.2____.12.7

4M, TW

PANIC

13

4M,9W

CTRL

20

33+-9 (20-.44) 3 0 ± 10 (20--44)

Appr. 10AM:0, 15, 30. 45, 60

13M, T W

! Fg/kg

Outcome

GH(ngtml)

me~aes

M~_SD{pv~)

AGH--15 mi_.n 2.6"*-5.7 (p<0.05) A G H - - 3 0 rain !.9 ~ 4.9 (p<0:03) A G H - - 4 5 rain 13 (NS) A C ~ min 0.3 (NS) A G H m 7 5 m i n 0.1 (NS) A G H - - 9 0 min 0.8 (NS) A G H - - I $ m i n II~--. 13.1 A G H m 3 0 m i n 13.1 "" 15.6 AGH---45 rain 11.8 A G H - - 6 0 rain II.0 A G H ~ 7 5 rain 9_5 A G H - - 9 0 m i n 5.4 A max GH 5.5 ± 8,0(p<0.03) AUC 188 "*"301 (.o<0.02) A max GH 8.0 ~ 5.9 AUC 2 9 4 ± 271

? : not available .The GH concenlrations in the table were estimated from a figure. The only significant difference in GH mspot~e between groups occurred at 45 rain. *The age ranges reported were taken from the total number of subjects in each group, not f n ~ the actual number of sub~'ls participating in each of the experimemal conditions. Peak GH values other than the 9 AMcondition requiring an overnight fast were approximated from figures. Statistical comparison of these vahmswes~ nr~ reported. "The GH values( _+SD) reported in the table were estimated from a figure. Timbulimia and controlsgroupswere not significantly different in OH response (repeated messures ANOVA). "Group comparisonsbetween peakG H levelswere not ~ A A U C me exp~ssed as l~g,120min.ml-~. ,Max A and AUC values for the saline condition wen: estimated from figure~ ~-or the FLP+GtlRH condition, PZP was administered 5 rain before GHRH. Data were log-transformed for analysis. sTbe age range for the combined groups was 21 to 61 years. AGH represents the difference between GHRH stimulation testing and placebo testing at cormspc~ing sample times. AGH for 45, 60, 75, and 90 rain are estimated from a figure. *Group Amax GH and AUCs were compared on nonWansfonned data usingthe Mann-WhitneyU-test. AUC is expressedas ng x min/mL

women participated in four test sessions. Statistical comparisons of GH responsiveness between groups w e n not reported with the exception of the fasting 9 AM test condition. The peak GH response in fasting anorectic women following GHRH administration at 9 AM was not significantly different than the peak GH response of fasting normal controls at 9 AM (Table 2). Fasting obese women, however, had a peak GH response at 9 AM (8.2 + 3.7) that was significantly less than that of the anorectic women or normal controls (p < 0.01). All three groups exhibited reductions in peak GH when tested in a fasting state at I PM versus 9 AM: 55.8% in anorectic women, 64.2% in normal women, and 64.9% in obese women. Peak GH response at 9 AM following feeding was blunted in anorectic women (46.4%) and normal women (60.9%) and was increased in obese women (60%) compared to the 9 AM fasting test. Finally, changes in peak GH response at 1 PM following feeding as compared to 1 PM fasting concentrations were increased in anorexic women (50.8%) and obese women (406.9%) and reduced in normal controls (34.6%). In summary, GH responsiveness varied according to time of day in all women. Food intake inhibited GH secretion in normal women but did not have this effect in anorectic or obese women. Brambilla and co-workers (I 989) measured plasma so-

matomedin C (SIn-C) and GH response to GHRH and clonidine in 21 women with anorexia nervosa (restricted type, Feighner criteria) and in 10 normal women. The normal controls were tested in the early follicular phase of the menstrual cycle to best match the low estrogen secretion of the anorectic patients. Baseline GH concentrations were significantly higher in anorectic patients (5.6 +-. 3.7) than in normals (I .7 +- 1.2). GHRH-stimulated Amax GH, AUC, at GH concentration at each time point was a l ~ significantly higher in patients than in controls (Table 2). There were no significant differences between anorectic patients and controls in clonidine-stimulated Amax GH, AUC, or GH concentration at any of the time points. Basal Sm-C levels were observed to be lower in the 6 patients sampled versus the group of 10 controls (0.42 +- 0.35 versus 0.99 __-0.55). GH response to GHRH and clonidine were positively correlated in both anorectics and controls (r = 0.52 and r = 0.73, respectively p < 0.01). There was a significant negative correlation between patient Sm-C concentrations and GHRH-stimulated GH AUC (r = -0.84, p < 0.003); however, this relationship was not observed for clonidine. Basal estrogen concentrations were not correlated with Sm-C or with GH response to GHRH or clonidine. Coiro and colleagues (1990) evaluated GH responsive-

2~

BIOl.PSYCHIATRY !~M;36:249..2t~

heSS to GHRH, cionidine, TRH, and insulin-induced hypoglycemia in seven normal weight women with DSM-II! bulimia and seven healthy control subjects. Control subjects were matched with bulimia patients for age, weight, and BMI and all subjects began testing on the 22nd day following the menstrual cycle. Basal GH concentrations were significantly greater in bulimic patients than in controls (2.4 -+ 0.5 versus 1.6 - 0.3, p < 0.01, Kruskali Wallis' Test); however, Sm-C concentrations were similar for patients and controls (0.7 -_. 0.2 and 0.9 -+ 0.2). The results of an analysis of variance indicated that there were no significant differences between patients and controls in GH stimulated by GHRH, cionidine, or insulin-induced hypoglycemia. A sizeable GH response to TRH was observed in five of the seven bulimic women but not observed in any of the controls. Rolla and associates (1990b) examined the GH response to GHRH under normal conditions and during steady-state hyperglycemia in six adolescent girls diagnosed with anorexia nervosa (acute stage, Feighner criteria) and in five normal adolescent girls1 Normal controls were tested in the follicular phase of the menstrual cycle. Each subject was studied under the following two experimental conditions: (1) at 8:30 AM the IV was inserted, baseline samples were collected, a bolus of saline was injected and samples were collected for 2 hr, and GHRH was injected and samples were collected for an additional 2 hr; or (2) the same protocol was conducted during continuous IV infusion of glucose (8 mg/min kg) to induce steady-state h)verglycemia of 200 mg/dl. Baseline GH concentrations did not differ between groups. Fasting plasma glucose concentrations were significantly lower in anorectic subjects than in normal controls (58 -+ 3.0 mg/dl versus 70 + 2.0 mg/dl, p < 0.02). In both groups, plasma glucose reached 200 mg/dl within 90 win and remained at this level throughout the procedure. Basal GH concentrations were not altered by either saline or glucose and did not differ significantly between groups. Sm-C concentrations, however, were significantly lower in anorectic patients than in normal controls (0.6 -+ 0.1 versus 1.9 -+ 1. l, p < 0.05). Anorectic patients exhibited significantly higher GHRH-stimulated AGH AUC than normal controls for both the saline/GHRH condition and the glucose/ GHRH condition (Table i). Peak GH responses were also greater in anorectic patients than in controls (Table 1), however, statistical comparisons were not reported. In anorectic patients, significant correlations were observed between Sm-C and percentage below ideal body weight (r = not available, p < 0.05) and between Sm-C and GH response to GHRI-I under both conditions (r = not available, p < 0.05). To further examine the role of cholinergic receptors in the mediation of GH release, Tamai and colleagues (1990) tested nine women with DSM-III-R diagnoses of anorexia nervosa and six normal age-matched volunteers. GHRH

S.S. Skate et al

stimulation testing was carried out with and without pretreatment with pirenzepine (PZP), which selectively blocks muscarinic cholinergic receptors and has been observed to abolish GH release during slow wave sleep in normal males (Peters et al 1986). Each subject was studied under both of the following experimental conditions and tests were separated by I week: (1) GHRH stimulation test; and (2) GHRH stimulation test preceded by 15 rain with a PZP infusion (0.6 mg/kg IV). Baseline GH levels were not significantly different between groups; however, Sm-C levels were significantly lower in anorectic patients than in normal controls (0.59 -+ 0.12 versus 0.82 -+ 0.15). GHRH-stimulated GH did not differ significantly between the groups (Table 2). The GH response to PZP + GHRH in the anorectic patients was significantly decreased whereas the GH response in the normal controls was totally abolished. Both the max AGH and the AUC were significantly greater in anorectic patients versus normal controls following pretreatment with PZP (Table 2). As an extension of earlier work with a group of anorectic patients (Rolla et al 1990a), Rolla and colleagues (Rolla et al 1991) evaluated the effect of PZP on the GHRH stimulation test in the following groups of adolescent girls: 13 patients with DSM-HI-R anorexia nervosa (five acute phase, eight recovery phase), seven patients with DSM-HI-R atypical eating disorders (AED), and seven age-matched normal controls. Normal controls and menstruating AED patients were studies in the early follicular phase of the cycle. With the exception of the acute phase anorectic patients each subject was studied under two experimental conditions (GHRH alone, PZP + GHRH), which were randomized and separated by a 7-day interval. At 8:30 AM the IV was inserted, baseline samples were collected, a bolus of saline was injected and samples were collected for 2 hr. GHRH was then injected and samples were collected for an additional 2 hr. The second experimental condition consisted of the ~_m..eprotocol with the addition of ~ (0.6 mg~g Vv'), given 5 win before GHRH infusion. The acute phase patients received an additional test of PZP + GHRH in the recovery phase of their illness. GH concentrations were log-transformed for analysis. As compared to controls, GH in response to GHRH was significantly greater in acute phase patients at each of sample intervals (p < 0.05), in recovery phase patients at 150 win (/7 < 0.05), and in AED patients at 150 win and 180 win (p < 0.05). Grout~ comparisons of AAUC revealed that acute phase patients had significantly higher GH responses than recovery phase patients and controls, however, acute phase and AED patients did not differ significantly (Table 2). Pretreatment with PZP suppressed GHRH-stimulated GH secretion in normal controis, recovery phase, and AED patients. Acute phase patients exhibited significantly higher GH responses at sample intervals following PZP administration than did normal

GHRHTesting in Psychiatry

controls (p < 0.05); however, the peak response was lower than it had been without PZP. The AAUC in response to PZP + GHRH was significantly higher in acute phase patients than in recovery phase, AED, and controls subjects (Table 2). Baseline GH concentrations did not differ significantly between groups, although acute phase patients had

the highest levels.

Panic Disorder Rationale Two studies on the GHRH stimulation test in panic disorder patients have been carried out (Rapaport et al 1989: Tancer et al 1993) in order to further delineate the mechanism underlying the diminished GH response to clonidine reported in these patients (Charney and Heninger 1986; Nuu 1989; Uhde et al 1986).

Studies Rapaport and colleagues (1989) tested 11 outpatients (four men, seven women) with DSM III/RDC panic disorder and 11 age- and gender-matched controls subjects. Basal GH concentrations were not significantly different between panic patients and controls either before GHRH stimulation (3.7 - 4.8 versus 4.8 _ 4.6) or before placebo injections (3A +- 3.3 versus 4.7 +_ 6.6). Baseline GH concentrations were stable across the three baseline sample times for each test day. GH concentrations following placebo injections did not differ significantlyfrom baseline concentrations and were not significantlydifferent between groups at any of the time points. With GHRH stimulation, however, panic disorder patients had significantly less Amax GH than did control subjects at 15 rain and at 30 min (Table 2). Panic patients did not demonstrate significant GH response to GHRH relative to placebo values..~,1o differences in GH response were observed in patients as a function of gender or history of major depression. Tancer et al (1993) examined GH responsiveness to GHRH and clo;nidine in 13 patients (four men, nine women) with DSM-III-R panic disorder and 20 healthy volunteers (13 men, seven women) of similar age. Women were tested in the follicular stage of the menstrual cycle and each subject participated in the following three tests: 1 Ixg/kg GHRH, 2 Ixg/kg clonidine, or placebo. The tests were preceded by at least, a 72-hr low monoamine diet and an overnight fast. Only the GHRH and clonidine stimulated GH data were presented in this paper because significant responses were not observed with placebo testing. A repeated measures analysis of variance (ANOVA) using log-transformed data indicated that the GH response to GHRH was significandy lower in panic patients than controls (F = 3.0, df = 4, 124, p = 0.02), with post hoc analyses revealing

atot.~VOttA~V

257

significantlylower GH patient responses at 30 ~ 45 rain (t = -2.3, p < 0.03 and t = -2.6, p < 0.02, respectively). The Amax GH and GH AUC were also significantly lower in the patient group as compared to to the control ~ (Table 2). A "positive" GH response to GHRH, which was defined as > 5 ng/ml and at least double the basal GH concentration, was observed in three of t,~epatients (13%) versus 13 (65%) of the controls (/7 = 0.03, Fisher's exact test). Group differences of GH responsiveness to clonidine stimulmion were similar to the GHRH stimulation test findings. Panic patients had a significantly lower GH response to clonidine as evidenced by the following: ( I ) repeated measures ANOVA (log-transformed data) results with post hoc analyses indicating lower responses in panic patients at 30, 45, and 60 min: (2) significantly lower mean &max GH and mean GH AUC in the patient group: and (3) a positive GH response in only two panic patients (17%) versus 12 controls (60%) (p = 0.02, Fisher's exact test). One of the ! 2 patients (11%) had positive GH responses to both GHRH and clonidine stimulation tests whereas 10 of the 20 controls (50%) had positive responses to both. There was no significant difference in the magnitude of the GH response to GHRH as compared to clonidine and there was no difference in the positive GH response rate resulting from each of the probes. In addition, there was a significant positive relationship between clonidine-stimulated GH AUC and GHRH-stimulated GH AUC when all subjects were combined (r = 0.57, p < 0.001).

Schizophrenia Rationale Because dopamine may modulate the secretion of GH by regulation of GHRH and somatostatin activity, Mayerhoff and colleagues (Mayerhoff et al 1990) examined GH response to GHRH in schizophrenic patients. Replication studies were carried out by Nerozzi et al (1990) and Peabody et ai (1990).

Studies Mayerhoff and associates (1990) examined the GH response to GHRH stimulation in 10 DSM III schizophrenia or schizoaffective disorder patients (three first-episode, seven chronic) and five normal healthy volunteers of similar age. There were no significant differences between schizophrenic patients and normal controls in GHRH-stimulated AUC (Table 3), percentage of increase in AUC, peak GH, or time to reach peak GH. Group differences were nonsignificant for analyses of transformed data. No significant differences were observed between first-episode and chronic patients. The GH, prolactin, and cortisol responses to GHRH was measured by Nerozzi and associates (1990) in 18 male DSM III schizophrenic patients (13 acute, five chronic) and in

258

IIIOL PSYCHIATRY

S.S. S k a t e et al

19~t~36:249+265

Table 3. The GHRH Stimulation Test in Patients with Schizophrenia Study

Diagnosis

n

Meanage _ SD (range)

Gender

Mayerhoffetal SCHIZ/SCHAFF I0 1990

27.9 + _? (23-37 yrs)

7M.3W

CTRL

5

25.8 • ? (23-32 yrs)

3 M. 2 W

13 5 9 10

20.9 +- ? 28.4 ± ? 2 !. I - ? 33 = 10

13M 5M 9M 10M

6

46 __- 17

6M

Nerozziet al 1990" Peabodyet al 1990b

SCHIZ--Acute SCHIZ--Chroni¢ CTRL SCHIZ/SCHAFF CTRL

Infusiontimeand sampletimes(rain) 9:45AM:-15,0, 15, 30,45,60,90, 120

8.30 A M : - 15,0, 15, 30.45.60,90 9AM:-90.-60,-30, 0. 15, 30,45,60, 90. 120

GHRH dosage I ~g

Outcome rr~.asures

M -+SD (p value)

peakGH 15rain AUC

17.4-~ I 1.6(NS) 148.9-*-104A(NS)

% incr AUC

982.7 -*-942.3 (NS)

GH (ng/ml)

peakGH 15rain AUC % incrAUC I ttg,/kg GH--45 min

16.5 ~ 7.9 10..5~ 4.5 1761.3-* 21"/I.2 45 ~ ? (NS)

G H - - 4 5 rain peakGH adj. pe,ak GH peak G H

29 -*" ? 28.0+- 15.0(?) 20.1 ( p < 0 . 0 1 ) 37.0 ~ 30.5

adj.peak~H

44.6

I ttg/kg

? = not available "Mean GH concentrations for each group were highest at 45 rain and were estimated from a figure. The GH data from the ~hizophmnia subgroups were combined for comparison with the control group. Data from one patient was excluded because of a mean baseline GH ~eveiof 24,5 ng/ml. *The I 0 patients in the SCHIZ/SCHAFF group consisted of seven patients with schizophrenia and three patients with schizoaffeclivedisonier. Differences between groups were analyzed using an ANCOVA, on the age-adjusted means.

nine controls. No significant differences were observed in GHRH-stimulated GH AUC, peak GH, or time to peak between acute schizophrenic patients, chronic schizophrenic patients, and controls. When the two patient groups were combined, there were no significant differences in GH response between schizophrenic patients and controls (Table 3). Basal cortisol and PRL concentrations did not differ between groups; however, 90 rain following GHRH injection, cortisol levels in schizophrenic patients were significantly greater than in normal controls. In a study previously described, Peabody and colleagues (1990) examined GH responsiveness in inpatients with RDC schizophrenia (n = 7), schizoaffective disorder (n = 3), major depressive disorder (n - 7), and in normal controls (n = 6). Stimulated peak GH concentrations were compared using an ANCOVA with age as the covariate, because of the strong Spearman rank correlation between stimulated peak GH and age (r = -0.70, p < 0.01). Schizophrenic patients exhibited significantly lower GH concentrations (adjusted M = 20.1, unadjusted M _+ SD = 28.0 _+ 15.0) than normal controls (adjusted M = 44.6, unadjusted M - SD = 37.0 -+ 30.5); however, the comparison between unadjusted peak GH values was not presented. No significant differences between groups were observed for baseline GH concentrations, age, or weight; however, there was a significant negative relationship between peak GH and weight (r = -0.55, p < 0.01). Alzhehner's Disease

Rationale The GHRH stimulation test was first investigated in Alz-

heimer's disease (AD) by Cacabelos and colleagues ( 1 9 8 8 ) as a way of characterizing the effect of decreased brain somatostatin levels on its normally inhibitory role in GH release. Follow-up studies were carried out by Nemeroff et al (1989) and L e ~ h et al (1990). Thomas and associates (1989b) emphasized the importance of evaluating the pituitary response to GHRH before conclusions are drawn regarding possible suprapituitary cholinergic influences.

Studies Cacabelos and colleagues (1988) tested 20 patients who met DSM-HI criteria for primary degenerative dementia (PDD) and nine healthy elderly controls. Ten PDD patients were classified as early onset ( < 60 years) and 10 patients as late onset ( > 60 years). The GH response to GHRH was significantly higher for early onset PDD patients th~n for conwols at 45, 60, and 90 rain (Table 4). No significant difference in GH response was observed between late onset PDD patients and normal controls (Table 4) and basal GH concentrations did not differ significantly between the three groups. For patients with early onset PDD, GH responsiveness was greater for women than men at 45 rain (14.5 -+ 3.5 versus 6.7 + 2.8) and60min (19.3 _+4.8 versus 11.3 "4-2.8). There was an inverse curvilinear relationship between the Dementia Rating Scale and GH response at 60 rain (r = -0.83) in patients with early onset PDD. Nemeroff and colleagues (1989) tested eight NINCDSADRDA (McKhann et al 1984) probable AD (four men, four women) and eight age-matched controls (five men, three women). No significant differences were observed in GHRH-stimulated GH AUC or Amax GH between AD patients and controls (Table 4). Wilcoxon rank sum test

GHRH Testing in Psychiatry

I~OLPSY~qlATR¥ |9J4~=249-265

259

Table 4. The GHRH Stimulation Test in Patients with Probable AIzheimer's Disease Mean age ± SD (range)

Study

Diagnosis

-

C_~ca_beloset al

PDD Early Onset

10

65.0---3.3 (57--69 ym)

5M.SF

PDD

10

75.7-+3.8 (70-82 y~s)

9

1988-

LateOnset CTRL

Nemeroffet al

Gender

dosage

meas~s

M±SD~ vak~e)

100F.g

5M,5F

GH--30min GH--45 rain GH--~min GH--90 rain GH---30rain GH--45 rain GH--~ rain GH--90rain

70.1 ---2.8 (66-75 yrs)

4M,5F

Gl-I--30 rain

5.7 -- L9(NS) 10.6 "L'_3. [ (p<0.Q05) 15,3 z 3.8 ~<0~05) 9,1 +-4.2 ~<0+005) 3.2 z 2.1 (NS) 4,I + 3.3 (NS) 4,8 - 3+!(NS) 3.5 -+Z 7 (NS) 3.3 + 2.4 4.6 *_.3.3 3.0 _z2.2

AD

8

70.5 -+ 6.1

4M,4W

CTRL

8

72,2 -+ 5.97

5 M, 3 W

PDD

18

76.6 ± I.I

6M, 12W

1989b Thomaset al

?:0.15.30.45,60. 90. ! 20

9~:-30,0,

15,30.

I p.g,kg

45,60,90,120, 180 10AM'0,15,30,45,

! ltg/kg

60,90, 120

1989"

Leschet ai 1990a

Infusiontime and sampletimes(aria)

CTRL

20

73.4-+ !.2

7M, 13W

AD Early Onset CTRL

10

58.6-*-6.3 (49-66 yrs) 55.2±4.6 ?

3M, TW

10

3M, TW

9AM:--15,0,15, 30, 45, riO,90, ! 20

50Fg

GH--45 rain GH---~0rain GH--90 rr~n A max GH AUC A max GH AUC GH--30 rain GH---45win GH---~ rain GH--90 rr~q GH--30 rain GH---45rain GH--.60rain GH--90 rain AGH AUC A GH AUC

1.9 "4-1.6

4,9 (NS) 423 (NS)

6.2 385 13.8(NS) 9.9 (NS) 9.1 iNS) 4.7 (NS)

7.4 7.3 7.4 5.8 36! ___fi66(p<0,05) 85 ! + 734

? = not available "GH values in the table were converted from pmol/I to ngJml and were estimated by taking the mean of the sum of the GH values for the women and men for each diagnostic group. P values reported represenmd comparisons between Early Onset PDD and Late Onset PDD versus CTRLS. There were no significantdifferences in GH ~tween groups at 0 , 1 5 , a n d 120 rain. 6GH values reported in the table were estimated from figures. +Trusts were calculated on Iog-lransformed GH values. There were no significant differences between the two groups in either GH levels or in AGH levels in baseline, at any of the time points, q ' h e data were analyzed using Mann-Wlfimey U-Test.

results revealed a significantly delayed G H peak response in pafiems as compmed to controls (approx. 45 min versus approx. 15 min, p < 0.008). Thomas and colleagues (1989b) measured GH, TSH, and PRL responses to G H R H in 18 DSM III PDD and in 20 normal controls of similar age and gender. Serum GH, TSH, and PRL concentrations were log-transformed for analyses because of their highly skewed distributions. No significant differences were observed between PDD patients and controis in basal G H or in GHRl-l-stimulated G H or AGH at any of the time points (Table 4). G H R H did not result in significant stimulation of TSH or PRL in either group; however, PDD patients had significantly higher baseline PRL concentrations than controls (222.7p/L versus 114.1 p/L, logtransformed values). Lesch and co-workers (1990) measured endocrine responses to C R H and G H R H in 10 patients with early onset AD and in 10 normal controls matched for age, gender, and

BMI. Patients met DSM III-R criteria for PDD and NINCDS-ADRDA criteria for probable AD. Group differences in endocrine response were evaluated using MannWhimey's U-test and correlations were calculated with the Spearman rank order procedure. The ~ A U C of GHRH-stimulated GH was significantly less in AD patients than in normal controls (Table 4). Similarly, the AAUC of CRHstimulated ACTH was less in AD patients than controls (1431 + 825 versus 3136 +- 2798, p < 0.05); however, AAUC of cortisol did not differ between groups. No significant differences were observed between groups in basal GH, SIn-C, or cortisol. There was a negative correlation between G H response and Sm-C for the group of AD patients (r = -0.58, p < 0.05) and for the entire sample (r = -0.39, p < 0.05). Significant correlations were also observed between G H response and Brief Cognitive Rating Scale (Reisberg et al 1983) (r = --0.56, p < 0.05) and Mini-Mental State Examination (Folstein et al 1975) (r =

S.S. Skate et al

tuoc ~'YCHtATtt¥ iQQ4~:24Q~2G~

Table 5. Summary of GHRH Stimulated GH in Patients with Depression, Eating Disorders, Schizophrenia. and Probable Alzheimer's Disease, as Compared to Normal Controls Elevated GH

No difference

Blunted GH

Depression Lesch et at 1987 Eriksson et al 1988 Krishnan et at 1988 Lesch et at 1989a Thomas ¢t at 1989a Peabody et al 1990 Anorexia nervosa Baranowska et al 1986 Casanueva et at 1987 De Marinis et at 1988 Brambilla et at 1989 Rollaet at 1990b Tamai et a11990 Rolla et at 1991 Bulirnia Coiroet a11990 Panic disorder Rapaport et at 1989 Tancer et at 1993 Schizophrenia Mayeroffet al 1990 Nerozzi et at 1990 Peabedy et at 1990 Alzheimer's disease Cacabelos et at 1988 Nemeroffet al 1989 Thomas ct at 1989b Leschet at 1990

* * * * * * * * * * * * * * * * • * , * • • ,

0.5, p < 0.01). GH, ACTH, and cortisol responsiveness did not differ as a function of gender and was not significantly correlated with age or BMI.

We compared GH responsiveness to GHRH between patients and controls for each psychiatric diagnosis (Table 5) and observed that for most diagnostic categories, the overall result of studies within categories was inconclusive. The findings in depression and Alzheimer's disease, for example. were contradictory: elevated, normal, and blunted GH responses were all reported in patients compared to controis. The findings in anorexia nervosa and schizophrenia were also inconclusive. Four of the seven anorexia nervosa studies observed elevated GH responsiveness as compared to normal controls, whereas the remaining three studies found no significant difference between the two groups. One of the 3 schizophrenia studies reported that patients had a blunted response as compared to controls; however, the other two studies did not report differences between groups.

We were unable to determine a trend in G H responsiveness for bulimia because only one study had been carried out. Panic disorder was the only diagnostic category in which there was complete agreement between studies. The observed trend of a blunted GH response, however, needs to be ,-eplicated by additional studies with larger numbers of patients. One factor that may contribute substantially to the inconsistent findings within diagnostic categories is the variability of GHRH stimulated GH among control groups. Mean peak GH concentrations for controls ranged from 7.3 to 52.8 ng/ml in studies that reported peak GH response as an outc o m e measure. Similarly, Amax GH in normal control groups ranged from 6.7 to 53 ng/ml. Because of these discrepant findings, the generalizability of peak GH in normal controls is certainly questionable. The determination of a range of reliable GHRH-stimulated GH responses in normal populations is necessary to provide a more representative standard for comparison with clinical populations. Because GH responsiveness appears to be decreased in older individuals, data from Aizheimer disease study control groups were not included in the above ranges to avoid inflating the magnitude of GH response ranges obtained from studies with subjects of varying ages. Another factor that may contribute to the disparate results within diagnostic categories is the use of different measures of GH responsiveness. The outcome measures reported in the studies reviewed in this article included the GH concentration at sample time points, peak GH, Amax GH, AUC, A 15 rain AUC, and percentage of increase in AUC. It is not only difficult to compare significant findings among studies but also to quantitatively gauge the degree of similarity among studies when different outcome measures are reported. Thus, uniform reporting of one or two standard outcome measures would be an improvement in methodology. The variables peak GH and AUC are appropriate outcome measure for several reasons and each offers_ s p ~ ific advantages. One primary advantage to reporting peak GH is that most clinicians and researchers are accustomed to obtaining and interpreting GH values in familiar units ofng/ml in contrast to AUC, which is expressed in units of ng/ml/min. Also, peak GH is operationally defined as the maximum GH response during the stimulation test and can readily be compared across studies. In contrast, AUC is measured over the time period of the procedure and ranged from 60 rain to 240 rain for the studies reviewed in this article. It is also important to note that the validity of AUC may be influenced by normally occurring GH pulses that are more likely to occur during longer time intervals. Without standardization of the GHRH stimulation test length, AUC cannot be compared across studies. AUC is a variable, however, that reflects data points over the entire test versus at just one time point. Considering the variability in GH test-

GHRH Testing in Psychiau3,

mOL~SYCHtATRY

261

controlled in only one of the studies. ~ ~ colleagues ing across studies in factors such as infusion time, blood ol~,rved that naps and slow-wave sleep are assoc~ed with draws, GH assay, and GH dosage, AUC may be a more valid increased GH secretion (Othmer et al 1974). Restricting indicator of GH responsiveness. Despite the limitations of napping may be particularly ~fficult in testing Alzheimer's both measures, there is evidence to suggest that peak GH patients because of the disruption in the circadian rhythm and AUC are highly correlated and have similar reliability. that often accompanies the disease. Al*Jmugh studies reDysken et al (1993) and Peabody et al (1990) observed ported that patients and controls wine p,hysical~ ~ a l t ~ , substantial correlations of r = 0.99 and r = 0.98, respecmany studies did not specify selection criteria regarding tively, between peak GH and AUC. In addition, data from physical health, especially for normal controls. Standardthe study by Dysken et al (1993) were used to compare the ized selection criteria and screening tests, such as a thyroid reliability of peak GH and AUC for 27 subjects, each underbattery, may further reduce variability between studies. going GHRH testing tluee times at a I Itg/kg dosage. CoinThe time interval that patients were medication-free varparison of the coefficients of variation for each variable and ied considerably between studies, ranging from 24 hr to 6 comparison of the intraclass correlations both revealed simmonths, and three of the studies did not report medication ilar reliabilities for peak GH and AUC [t(26) = 0.89, p = status at all. Although no studies to date have systematically 0.38; and re, = 0.77 versus rAuc= 0.73, z = 0.58, t > 0.05, examined the effects of psychotropic medications on GH respectively). response m GHRH, Schittecaue et al assessed the effects of Another source of variability in GH response may arise tricyclic antidepressants on GH response to clonidine from the the lack of uniformity in carrying out GHRH (Schittecatte et al 1989). The authors observed significantly stimulation testing. Because GH secretion is affected by higher clonidine-stimulated GH concentrations in 14 pasuch factors as GHRH dosage, infusion time, food intake, tients with major depressive disorder who had never rephysical activity, napping, and physical health, methodceived antidepressants versus 14 patients who had received ological differences in studies may yield inconsistent retricyclic antidepressant therapy with admg-free period of at sults. GHRH dosage was relatively consistent in the studies least 15 days. It seems important to esteblish a washout reviewed with 17 of 23 studies using a dosage of I ttg/kg. period for as long as possible until more i~ understood about Evidence supporting the use of this dosage is presented the effects, and duration of effects, of different classes of Gelato et al (1984), who tested 73 healthy young men and psychotropic medications on GH response. women with dosages of GHRH, ranging from 0.01 to 10 Age is another variable that may contribute to the diveritg/kg. The authors concluded that I Itg/kg GHRH was gent results between studies. Of the 23 studies reviewed, 19 capable of producing a maximal GH response. Similarly, studies attempted to test patients and controls of similar Vance et al (1984) reported that GHRH dosages of 0. ! to I 0 ages. Thirteen of the studies reviewed did not report the age i~g/kg elicited similar peak GH responses; however, higher range of their samples and several had contiol and patient doses were associated with prolonged GH stimulation, often groups with considerably different mean ages. The literain a biphasic pattern. The time of GHRH infusion ranged ture has been relatively consistent regarding the importance from 8:30AMto 1 ! AMwith 11 of the 23 studieschonsing a9 of age on GHRH-stimulated GH, with most studies reportAM infusion time. Food intake was controlled in 18 studies ing diminished responsiveness with increasing age (Coiro et by requiring subjects to fast from some point during the al 1991; Iovino et al 1989; Lang et al 1987; Shihasaki et al evening before the protocol through test completion on the 1984). The results of Shibasaki et al (i 984) also ir~ticated a following day. The finding by De Marinis et al (1988) trend toward greater variability of the GH response in men (Table 2) of a blunted GH response in normal controls in their twenties and thirties as compared to men in their following a meal underscores the need for controlling food forties, fifties, sixties, and seventies. Thus, both age-related intake. It would be advantageous to require a fast of a differences in magnitude and variability should be considstandard length, such as 12 hr, to optimally control variabiered in the design and analysis of GHRH investigations and lity introduced by food intake. Physical activity was reshould be considered when comparing results between stricted in 19 of the 23 studies by requiring subjects to studies. remain recumbent during the procedure and by several studThe impact of gender on the GHRH stimulation test is ies that lequired a resting period of 60 to 90 min before contradictory. Investigators have observed GH responses in GHRH infusion. Because physical activity is known to afpremenopansal women that are higher (Benito et al 1991; fect GH secretion (Lal 1987), variability between studies Lang et al 1987), lower (Smals et al 1986), or not signifimay be further reduced by standardizing the length of restcantly different (Gelato et al I984) when compared to men ing time before infusion and by limiting strenuous exercise of similar ages. In addition, Lang and colleagues (1987) did for a period of time before the procedure, for example after not find a significant difference between postmenopausal 9:00 PM, as suggested by Dysken et al (1993). Napping is women older than 50 years and age-matched men. In this another potentially confounding factor and was apparently

etot. ~VCtttATRY 1~1136:249.-265

review, 21 of the 23 studies had subjects matched closely for gender, Clearly, the importance of gender on the GHRH stimulation test needs to be further characterized and until then subjects should continue to be closely matched for gender. A related issue is the effect of the menstrual cycle on GH secretion. Of the studies reviewed in this article, 16 tested premenopausal women: eight studies tested women at the follicular phase, three tested women at the midluteal phase, and five did not report the ovarian status of women subjects. Evans and colleagues (1984) tested 10 normal women (3.33 ug/kg GHRH) at the early follicular, late follicular, and midluteal phases oftbe menstrual cycle and found that GH secretion did not vary during the mens:rual cycle. Also, Benito et al (1991) did not observe a significant change in GH response between days I and 12 of the menstrual cycle (n = 10). Lang and associates, however, observed a significant positive correlation between serum estradiol and GH response to GHRH. At this point it seems prudent to control for phase of the menstrual cycle until this issue has been resolved through additional studies of larger sample size.

S.S. Skare et al

The individual reproducibility of the GHRH stimulation test is an important issue that has been relatively neglected. Until the test's stability within subjects can be systematically assessed, the validity of interpretations regarding biological markers or neuroendocrine dysfunction are in question. A preliminary study by Dysken et al (1993) is the only study to date that has systematically evaluated the individual reproducibility of the GHRH stimulation test. The data presented by the authors indicates that in some subjects the GH response to GHRH is markedly variable when subjects undergo repeated testing under tightly controlled conditions. The intrasubject variability was also greatest in younger men as compared to older women and men, although some subjects in each group had highly variable GH responses upon repeated testing. The intrasubject reliability of this test must be further investigated, in much larger samples of subjects, before the utility of the test can be established. It is possible that investigators will need to test subjects two or three times to obtain a representative sample of GH responsiveness.

References American Psychiatric Association (1980): DSM-lll--Diagnostic and Statistical Manual of Mental Disorders. Washington DC: American Psychiatric Press. Barat~owskaB, Soszynski P, Kaniewski M, Partop Singh S (1986): Exaggerated response of GH to GRF in patients with anorexia nervosa. Neuroendocrinol Lett 8:245-250. Benito P, Avila L, Corpas M, Jimenez J, Cacicedo L, Sanchez Franco F (I 991): Sex differences in growth hormone response to growth hormone-releasing hormone. J Endocrinol Invest 14:265-268. Brambilla F, Ferrari E, Cavagnini F et al (1989): Alpha2-adrenoceptor sensitivity in anorexia nervosa: GH response to clonidine or GHRH stimulation. Biol Psychiatry 25:256--264. Cacabelos R, Niigawa H, lkemura Y, et al ( ! 988): GHRH-induced GH response in patients with senile dementia of the Alzheimer t-ype.Acta Endocrinol i i7:295-301. Camanni F, Ghigo E, Tazza E, et al (! 989): Aspects of neurotransmitter control of GH secretion: basic and clinical studies. In Muller EE (eel), Advances in Growth Hormone and Growth Factor Research. Rome-Heidelberg: Springer-Verlag. Carroll B, Feinberg M, Greden J, et ai (1981): A specific laboratory test for the diagnosis of melancholia: Standardization, validation, and clinical utility. Arch Gen Psychiatry 38: ! 5-22. Casanueva F, Borras C, Burguera B, et al (1987): Growth hormone and prolactin secretion after growth hormone-releasing hormone administration in anorexia nervosa patients, normal controis, and tamexifen-pretreated volunteers. Clin Endocrinol (OxJ) 27:517-523. CeUa SG, Locatelli V, De Gennaro V, Wehrenberg WB (1987): Pharmacological manipulations of alpha-adrenoreceptors in the infant rat and effects of growth hormone secretion: Study of the underlying mechanisms of action. Endocrinology 120:i639-1643.

Chamey D, Heninger G (1986): Abnormal regulation of noradrenergic function in panic disorders: Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 43:1042-1054. Coiro V, Capretti L, Volpi R, et al (1990): Growth hormone responses to growth hormone-releasing hormone, clonidine and insulin-induced hypoglycemia in normal weight bulimic women. Neuropsychobiology 23:8-14. Coil o V, Volpi R, Cavazzini U, et al (! 99 !): Restoration of normal growth hormone responsiveness to GHRH in normal aged men by ;.nfusion of low amounts of theophylline. J Gerontol 46:155-158. Daikoku S. Tsuruo Y (1990): Neuron systems regulating growth hormone-releasing hormone containing neurons in the rat hypothalarnus. Neuroendocrinology 52 (S I): 121. r ~ Marinis L, Folli G, D'Amico C, et al (1988): Differential effects of feeding on the ultradian variation of the growth hormone (GH) response m GH-releasing hormone in normal subjects and patients with obesity and anorexia nervosa. J Clin Endocrinoi Metab 66:598--604. Durand D, Martin JB, Brazeau P (1977): Evidence for a role of alpha adrenergic mechanisms in regulation of episodic growth hormone secretion in the rat. Endocrinology 100:722-728. Dysken M, Skate S, Burke M, Mach J Jr, Galka T, Billington C (I 993): Intrasubject reproducibility of growth hormone-releasing hormone-stimulated growth hormone in" older women, older men, and younger men. Biol Psychiatry 33:6 !0-45!7. Eden S, Bolle P, Modigh K (1979): Monoaminergic control of episodic growth hormone secretion in the rat: Effects of reserpine, alpha-methyl-para-tyrosine, p-chlorophenylalanine, and haloperidol. Endocrinology 105:523-529. Epelbaum J (1992): Intrahypothalamic neurohormonal interactions in the control of growth hormone secretion. Ciba Found Syrup 168:54---64.

ato, eSYCmATey t994o,3fr.2~:~e~

GHRH Testing in Psychiatry

Epelbaum J, Tapia-Arancibia L, Kordon C (198 I): Noradrenaline stimulates somatnstatin release from incubated slices of the amygdala and the hypothalamic preoptic area. Brain Res 215:393-397. Eriksson E, Balldin J, Lindstedt G, Modigh K (1988): Growth hormone response to the alpha2-adrenoceptor agonist guanfacine and to growth hormone releasing hormone in depressed patients and controls. Psychiatry Res 26:59--67. Evans W, Borges J, Vance M, etal (1984): Effects of human pancreatic [growth hormone-releasing factor-40 on serum growth hormone, prolactin, luteinizing hormone, folliclestimulating hormone, and somatomedin-C concentrations in normal women throughout the menstrual cycle. J Ciin Endocrinol Metab 59:1006-1010. Feighner J, Robins E, Guze S, Woodruff R, Winokur G, Munoz R (1972): Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63. Folstein M, Folstein S, McHugh P (I 975): Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatry Res ! 2: ! 89- ! 98. Frohman LA, Downs TR, Chomezynski P (1992): Regulation of growth hormone secretion. Front Neuroendocrinol 13:344-405. Gelato M, Pescovitz O, Cassorla F, Lorianx D, Mernam G (1984): Dose-responso relations.hips for the effects of growth hormon~releasing factor-(l-44)-NHz in young adult men and women. J Clin Endocrinol Memb 59: ! 97-20 !. Grossman A, Lytras N, Savage MO, et al (! 984): Growth hormone releasing factor: Comparison of two analogues and demonstration of hypothalamic defect in growth hormone release after radiotherapy. Br MedJ 288: ! 785-1787. Gruen P, Sachar E, Airman N, Sassin J (1975): Growth hormone response m hypoglycemia in postmenopausa! depresseo women. Arch Gen Psychiatry 32:3 i-33. Horvath S, Palkovits M, Gorcz T, Arimura A (1989). Electron microscopic immunocytochemical evidence for the existence of bidirectional synaptic connectionsbetween growth hormone releasing hormone and somatnstatin containing neurons in the hypothalamus of the rat. Brain Res 48:8-15. Jarrett D, Greenhouse J, Coble P, Kupfer D (1986): Sleep-EEG and ne-_roendocrine secretion in depression. In Shagass C, Josiasen R, Bridger W, Weiss I(4 Stoff D, Simpson G (eds), Biological Psychiatry 1985, Proceedings of lhe 1Vth World Congress of Biological Psychiatry. New York: Elsevier. Katakami H, Arimura A, Frohman LA (1986): Growth hormone (GH)-releasing factor stimulates hypothalamic somatostatin release: An inhibitory feedback effect in GH secretion. Endocrinology I 18: ! 872-1877. Krishnan K, Manepalli A, Ritchie J, et al (1988): Growth hormone-releasing factor stimulation test in depression. Am J Psychiatry 145:90-92. Laakmann G, Schumacher G, Benkert O (1977): Stimulation of growth hormone secretion by desipramine and chlorimipramine in man. J Clin Endocrinol Metab. l.aakmann G, Treusch J, Schmanss M, Schmitt E, Treusch U 0982): Comparison of growth hormone stimulation induced by desimipramine, diazepam and metaclazepam in man. Psycboneuroendocrinology 7:14 I - 146. Laakmann G, Gugath M, Kuss H, Zygan K (! 984):Comparison of

263

growth ~ and p~.actin ~ induced by d~lorimipramine and desimipmmine in man in connemk~ chlorimipramine metabolism. Psychology 82:62-67. LaakmannG, Zygun K, SchoenH, etal (1986):Effec¢o f ~ blockers (methyseqli~, ~ , ph~nm~ ~mbine and prazosin) on d e s i m i ~ n e ~ I ~ l~rmone stimulation in hurr~qs--l. Growth hormone. Psychoneuroendocrinology I 1:447--461. Lal S (1987): Growth hormoneand schizoph~a. In Meltzer H (eds), Psychopharmacology: The Third Generatb~n of Prog. tess. New YeA: Raven Press. Lang I, Schernthaner G, Pietschmann P, Kurz R, Stephenson J. Tempi H (1987): Effects of sex and age on growth hormone response to growth hormone-releasing horrr~ne in healthy individuals. J Clin Endocrinol Metab 65:535-540. Langer G. Heinze E, Reim B, Matussek N ([976): ~ e d growth hormone response to amphetamine in "endogenous" depressive patients. Arch Gen Psychiatry 33:I471-1475. [x.sch K, Lanx G, Pfuller H, Erb A, Beckmann H ( 1987): Growth hormone (GH) response to GH-releasing hormone in depression. J Ciin Endocrinol Metab 65:1278- ! 281. Lesch K, Muller U, Rupprecht R, Krose K, Schulte H (198%): Endocrine responses to growth hormone-releasing hormone, thyrotropin-releasing hormone and corticotmpin.releasing hormone in depression. Acta Psychiatr Scand 79:597-602. Lesch IL Rupprecht R, Muller U, Pfuller H (1989b): Comparison of GH responses after human GHRH-44 am[de administration and TRH-induced TSH release in depressed patients. Biol Psychiatry 25:235-238. Lesch K, lid R, Frolich L e t al (1990): Endocrine responses to growth hormone releasing hormone and corticotropin releasing hormone in early-onset Alzheimer's disease. Psychiatry. Res 33:i07-112. Levenston SA, Cryer PE (I 980): Endogenous cholinergic modulation of growth hormone in normal and acromegalic humans. Metabolism 29:703-706. Liposits Z, Merchenthaler I, Paul WK, Flerko B (1988): Synaptic communication between somatostatinergic axons and growth hormone-releasing factor (GILt:) synthesizing neurons in the arcuate nucleusot tne rat. rttsrochemz~rfy o~,.~.-,-,-.-.. Locatelli V, Torseilo A, Redaelli M, Ghigo E, Massara F, Muller E (i 986): Cholinergic agonist and antagonist drugs modulate the growth hormone response to growth hormone-releasing hormone in the rat: Evidence for mediation by somatostatin. J Endocrinol 1 ! i :271-278. Maeda K, Kato Y, Yamaguchi K, etai ( 1976): Gro~fh hormone release following thyrotropin releasing hormone injection into patients with anorexia nervosa. Acta Endocrinol (Copenh) 81:1-8. Matussek N, Ackennheil M, Hippius H, et al (1980): Effect of clonidine on growth hormone release in psychiatric patients and controls. Psychiatry Res 2:25-36. Matussek N, Laakmann G (1981): Growth hormone response in patients with depression. Acta Psychiatr Scand (suppl) 290:122-126. Mayerhoff D, Lieberman J, Lemus C, Pollack S, Schneider B (! 990): Growth hormone response to growth hormone-releas-

-

.

rf

.

.

.

.

_'~

. ON.'2A'I

~C*~

BlOt.PSYCHIATRY

ing hormone in schizophrenic patients. Am J Psychiatry 147:1072-1074. McKhann G, Drachman D, Foistein M, Katzrnan R, Price D, Stadlan E (1984): Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease.Neurology 34:939-944. Mendlewicz J, Linkowski P, Braurnan H (! 977): Growth hormone and pmlactin response to ievndopa in affective illness. Lancet ! :652-653. Mendlewicz J, Linkowski P, Kerkhofs M, et al (1985): Diurnal hypersecretion of growth hormone in depression. J Clin Endocrinol Metab 60:505-512. Mild N, Ono M, Shizume K (1988): Withdrawal of endogenous somatostatin induces secretion of growth hormone releasing factor in rats. J Endocrinoi 117:245-252. Mitsugi N, Arita J, Kimura F ( ! 990): Effects of intracerebroventricular administration of growth hormone-releasing factor and corticotropin-releasing factor on sornatostatin secretion into rat hypophysia! portal blood. Neuroendocrinology 5 ! :93-96. Muller EE (1987): Neural control of somatotropic function. PhysioI Rev67:962-1053. Muller EE, Locatelli V, Ghigo E, et al (1991): Involvement of brain catecholamines and acetylcholine in growth hormone deficiency states. Drugs 41:16 !-177. NemeroffC, Krishnan K, Belkin B, et al (1989): Growth hormone response to growth hormone releasing factor in Alzheimer's disease. Neuroendocrinology 50:663-666, Nerozzi D. Magnani A, Sforza V, et al (1990): Prolactin and growth hormone responses to growth hormone-releasing hormone in acute schizophrenia. Neuropsychobiotogy 23: ! 5-17. Nutt D (1989): Altered central alpha2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry 46:165-169. Othmer E, Mendelson W, Levine W, Malarkey W, Danghaday W (1974): Sleep-related growth hormone secretion--and morning naps. "JteroidLipid Res 5:380-386. Peabody C, Warner M, Markoff E, Hoffman A, Wilson D, Csernansky J (1990): Growth hormone response to growth hormone releasing hormone in depression and schizophrenia Psychiatry Res 33:269-276. P e ~ J, Evans P, ~,~ge M, et al (1986): Choiinergic muscarinic receptor blockade with pirenzepine abolish slow wave sleeprelated growth hormone release in normal adult males. Clin Endocrinol (OxJ) 25:213-2 ! 7. Plotsky PM, Vale W (! 985): Pattern of growth hormone-releasing factor and sornatostatin secretion into the hypophysial-portal circulation of the rat. Science 230:46 !--463. Rapaport M, Risch S, Gillin J, Golshan S, Janowsky D (1989): Blunted growth hormone response to peripheral infusion of human growth hormone-releasing factor in patients with panic disorder. Am J Ps.vchiutry i 46:92-95. Reisberg B, London E, Ferris S, Borenstein J, Scheier L, de Leon M (1983): The Brief Cognitive Rating Scale: Language, rnotoric and mood, concomitants in primary degenerative dementia (PDD). Psychopharmacol Bull ! 9:702-708. Rolla M, Andreoni A, Belliti D, Ferdeghini M, Cristofani R, Muller E (! 990a): Effects of cholinergic muscarinic antagonist pirenzepine on GH response to GHRH 1-40 in patients with anorexia nervos,~ Endocrinol Exp 24:195-204.

S.S. Skate et al

Rolla M, Andreoni A, Iklliti D, Fedeghiui M, Fotrannini E (1990b): Failure of glucose infusion to suppress the exaggerated GH reslxmse to GHRI~, in patients with anorexia nervosa. Biol Psychiatry 27:215--222. Rolla M, Andreoni A, BelIPJ D, Cristofani R, Fordeghini M, Muller E (1991): Blocka~ of cholinergic mnscarinic ecceptors by pirenzepine and GHRH-induced GH secretion in the acute and recovery phase of anorexia nervosa and atypical eating disorders. B/o/Psych/atry 29:1079-1091. Russell C (1979): Anorexia nervosa: Its identity as an illness and its treatment. In Price J (ed), Modem Trends in Psychological Medicine. London: Buttersworth. Sato A, Shioda S, Nakai Y (1989): Catecbolaminergic innervation of GRF-containing neurons in the rat hypothalamus revealed by electron-mieroscopic cytochemistry. Cell Tissue Res 258:3 !-34. Sawchenko PE, Swanson LW, Rivier J, Vale WW (1985): The distribution of growth-hormone-releasing factor (GRF) immunoreacfivity in the central nervous system of the rat: An immunohistochemistly study using antisera directed against rat hypothalamic GRF. J Comp Neuro123?: ! 00- I ! 5. Schittecatte M, Charles G, Machowski R, Wilmotte J (1989): Tricyclic wash-out and growth hormone response to clonidine., Br J Psychiatry 154:858-863. Scholtysik G, Jerie P, Picard C (1980): Guanfacine. In Scriabine A (eds), Pharmacology of Antihypertensive Drugs. New York: Raven Press. Shibasaki T, Shizume K, Nakahara M, et al (1984): Age-related changes in plasma growth hormone response to growth hormone-releasing factor in man. J Clin Endocrinol Metab 58:212-214. Smals A, Pieters (3, Smals A, Bemaad 1", Laadtoven J, Kloppenborg P (1986): Sex difference in human growth hormone (GH) response to intravenous human pancreatic GH-releasing hormone administration in young adults. J Clin EndocrinoIMetab 62:336-341. Spitzer R, Endicott J, Robins E (1978): Research Diagnostic Criteria (RDC)for a Selected Group of Function Disorders. New York: New York State Psychiatric Institute. Tarnai H, Komaki G, Matsubayashi S, et al (1990): Effect of cboliner~c ...,.~,.~' . . . . ~. -;^,,u,. r-~-ptor blockade on human growth hormone (GH)---releasing hormone---(l-44)---induced GH serotonin in anorexia nervosa. J Clin Endocrinoi Metab 70:738-741. Tancer M, Stein M, Black B, Uhde T (1993): Blunted growth hormone responses to growth hormone-releasing factor and to clonidine in panic disorder. Am J Psychiatry ! 50:336--337. Tannenbaum GS, Ling N (I 984): The interrelationship of growth hormone (GH)-releasing factor and somatostatin in generation of the ultradian rhythm of GH secretion. Endocrinology 115:1952-1957. Thomas CR, Groot K, Arimura A (1985): Antiserum to rat growth hormone (GH)-releasing factor suppreses but does not abolish antisomatostatin-induced GH release in the rat. Endocrinology 116:2174-2178. Thomas R, Beer R, Harris B, John R, Scanlon M (1989a): GH responses to growth hormone releasing factor in depression. J Affective Disord ! 6:133-137. Thomas R, Williams P, John R, Scanlon M (1989b): Growth

GHRH Testing in Psychiatry

hormone responses to growthhormone releasing factor in primary degenerative dementia. Biol Psychiatry 26:389-396. Thorner M, Rivier J, Spiess J, et al (1983): Human pancreatic growth-hormone releasing factor selectively stimulates growth-hormone secretion in man. Lancet 1:24-28. Travaglini P, Beck-Pnccoz P, Fenmi C, et el ( ! 976): Some aspects of hypothalamic-pituitary function in patients with anorexia nervosa. Acta Endocr/nol (Kbh) 81:252-262. Uhde 1", Vittone B, Siever L, Kay W, Post R (1986): Blunted growth hormone response to clonidine in panic disorder patients. Biol Psychiatry 21:108 I-! 085. Urman S, Kaler L, Critchlow V (1985): Effects of h~ othalamic periventricular lesions on pulsatile growth hormone secretion. Heuroendocrinology 41:357-362.

mot.psYctuA'reY 1994;3¢+L249"2~

265

Vance M, Borges J, Kaiser D, et al (1984): Human tumor ggowth Itmmone-releasing factot~.O o s e ~ relationships in normal man. J Clin ~ o l Metab 58: 838-844. Vance ML, Evans WS, Kaiser DL, et al 0986): The effect of intravenous, subcutaneous, and intranasal GH-RH mmlog, [NIe27]GHRH (I-29)-NH2, on growth hormone ~ in normal men: Dose-response relationships. Cl/n Phammco/ Ther40:627-633.

Zeitler P, Chowen-Breed ]A, AxgenteJ, Tannenbaum GS, Clifton DK, Steiner RA ( 1990): Regulation of somatostatin~ g r o ~ hormone-releasing hormone gene expression in the rat brain. Metabolism 39 ($2):46-49.