Growth hormone response to growth hormone-releasing hormone and clonidine in depression

Growth Hormone Response to Growth HormoneReleasing Hormone and Clonidine in Depression Horst Gann, Dieter Riemann, Siegfried Stoll, Matthias Berger, and Walter E. Mtiller

Growth hormone ¢GH) te.~l~(~l'l.',es to lhe ~, ,-adrenocc7~lor a goni.vt clonidine and to GH-releasink, hormone (GHRH) were measureU in I2 patients)it!filling DSM-1II-R criteria f o r major depressive Ui.~order am/ m 12 a~e- aml ~ex-matehed controls. GH responses to clonidine correlated .%~nilieanlly with lhe GH resl~¢m.~es to GHRH in the depressed patients as well as in the controls. Neither the re.~ponses to chmMine nor the responses to GHRH were significantly lower in depressed patients than in controls. Similarly. somatomedin-C (SIn-C) plasma eoncentration.s and haselme GH concentrations were #tot d~[l~'renl between tile two groups. The data do not suc,~exl that blunted GH re.spon~e.s to cl
Ke.v W o r d s : Dcpression. gro,xth horlllOllC, growth hormone-releasing hormone, clonidine, {~,-adrenoceptors.

Introduction Stimulation of growth hormone (GH) release ,aith ~, adrenergic agonists such as clonidine has been widely used to assess central c~--adrenoceptor sensitivity m psychiatric patients. A large variety of experimental data has shm~n blunted GH responses to chmidine in depressive patients (Matussek et al 1980: Chcckle} et al 1981: Charne} el al 1982: Siever and Uhde 1984: Ansseau ct al 1984). The interpretation of these data as indicative of subscnsitixc central c~=-adrenoceptors in major depressixe disorder (MDD) DSM-III-R (APA 19871 has been rccentl\ challenged by findings indicating similarly blunted GH responses in depressive patients after stimulation with gro,,v th hormonc-rcleasing hormone (GHRHI (Lesch et al 1087.

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1988- Neuhauser and Laakmann 1988: Chiarini et al 1987: Peabody et al 1990). On the other hand, Krishan et al (1988) found elevated GH responses to GHRH in depression, but blriksson et al (1988) and Thomas et al (1989) reported these responses to be normal. Lesch et al (1988) studied the central control of the GHRH-GH-somatomedin axis in MDD. ('ompared to controls, depressives showed a significant attenuation of GH responses to GHRH in association with increased somatomedin (SIn-C) concentrations. The aulhors concluded that their data indicate a hyperactivity of the hypothalamic-pituitary-somatotropic (HPS) system and thai an enhanced negative feedback regulation by Sm-C might bc involved in the blunted GH response in depression. To further clarify the above-mentioned discrepancies, we investigated GH responses fl~llowing clonidine and GHRH stimulation in 12 depressive patients and 12 healthy controis. The aim of this study was to determine whether the relationship between the GH responses to both specific stimuli at different levels of the HPS system are altered in depression and to explore further the possible relevance of the Sin-C-mediated negative feedback regulation. 0006 3223/95/$0950 SSDI 0006-3223(94)00368-D

326

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Table 1. Growth Hormone {GH ) Responses, Aflcr Growth Hormone Releasing Hormone IGHRHi or Clonidine in l 2 Depressive Patients" Clonidine stimulation

( i H R H qill/tllalhni Patient

(;tt

No.

A£e.< s e x

1 ."~

~n £. / m L

50. m .

57. I .

Snr(" i

i n o~_/ n i l

ll) .

. I) ~

.

X max t

i i/g/nlk )

\t '( { n e. / m n l / n l t .

(;H i

(ne/mL)~

SM-C

A max

AUC

(nglmLI

( n £~J l l l L )

(ng/min/mL)

14')

)s

142

1.6

148

1.5

306

• :,'~

~S c

~22

n.S

233

(I.2

123

3

55, f

I).,<4

I f~2

1.5

212

I).9

180

0

59

4

41, I

() 7

2~,¢~

:,40

255~

0.6

168

17.6

1114

5

39. f

I¢~

24:

~(1

4(}f~

0.2

265

3.0

214

6

18. m

4 5

i7~

25

44,'

.~,

197

8.1

379

7

~.m

,I

:72

73

14-

(1

175

,,4

500

8

40. m

',.4

7cJ

7 7

%;¢,

1.4

131

5.3

288

9

52. t"

I /I

~,x

0 7

> .~,',

1.4

143

9.6

807

10

56, f

(~

227

2 S

c,~S

0.6

269

I).6

84

11

37, i

' i

12~

(10

15'

1.6

122

1.3

184

12

35. f

02

2~11

2 t) I

IS ~ll

40.0

205

0

181

Means

43

14-

I';' ~

_+.SD

+12

+1)4

4~

X. I ¢~ + I I.t

{~45

12

~ 77(I

+04

11'16 ?49

41" 4 5.3

353' +_317

'The data represcnl baseline (~|t at ]b \ M . ba~,t.'[/llc ~ o l / / a h l l i l c d i l I (" q SIll ('1 ~1[ I() \\1, lhC maxinlal (;H rc',pon,c o,,er baseline ,~. max i. and the area under the GH plasma concenlralloll o~er tnne curxe (.'k{ '(', llOlll I{I \M tti ] P\I I dllel Mm/ulaNoll v, ith ( ;I IRH ot c]t~nidinc "Nol significant when o,~mpaied v, dh (;ItRIt ,lirllulkllloll

Methods Sample DEPRESSIVE PATIENTS. [=our men and eight ,aomcn (Table 1) were investigated. Fixe ~omen were of premennpausal status and three women of postmenopausal status. All patients fulfilled the DSM-III-R criteria for MDD Idiagnosis was made with the Structured Clinical Interview, SCID. German Version: Wittchen et al 1988). Three depressives fulfilled the criteria for subtype melancholia. The mean 21-item Hamilton score + SEM was 25.2 +_ 1.3 (range = 18-31 ). All patients were free of any kind of psychoactive medication for a minimum of 7 days prior to the investieation and were carefully evaluated by physical examination and routine laboratory screening, including tests for endocrine status, to exclude major physical disorders. HEALTHY CONTROLS. The l~clvc healthy probands were matched with the patients in age and sex (Table 2). Six women were premenopausal, and tyro women were postmenopausal. Physical health was confirmed b \ routine blood tests, ECG, and a thorough medical in~ estigation. A personal or family history of psychiatric disorders wa~ ruled OUt b', ~i psychiatric interview. All probands had been free of an~ kind of medication (with the exception of contraceptives} for 'a minimum of 3 months prior to the stud,,. Subjects were in formed in detail about the inveqigation and gave their informed consent.

Procedure GHRH and clonidine stimulation tests v,,crc conducted on all subjects at rest at 9:00 ,XM after an mcrnight fast and in

a i-andomizcd order with a 3-day interval. One hour after lhc insertion of an intravenous (IV) catheter in an antecubital ~ein, 5() p,g of synthetic human GHRH-44-amide (Bissendorf, Hannover, FRG), dissolved in 1 mL saline 10.9¢4 ) was injected as an IV bolus within 5 sec. On the other day, 2 t.Lg/kg body weight of the selective o~2-adrenoceptor agonist clonidine diluted in 10 mL saline (0,9%) ~as iniected slo,a, ly over 10 min. Throughout the procedure, heart rate and blood pressure were recorded. For measurement of GH, blood was collected at - 6 0 , -30, 0, 30.45, 60, 75, 9(), 120, 150, and 180 rain. Sm-C concentrations were determined for the baseline samples only (at time zero). Plasma GH and Sm-C concentrations were determined with commercially available *25J-RIA kits I Serono, Freiburg). GH secretion was calculated as/3, max I maximal concentration over baseline alter stimulation) or as AUC tarea under the plasma concentration versus time curve) for time 0 - 1 8 0 min. Patients or probands with basal GH plasma level > 5 ng/mL at time zero were not included in the study. Basal GH le\ cls ,acre n o t different between the groups (Tables 1 and 2).

Sldli.vlic.s The results arc expressed as the mean + standard error of the mean (SEM) or z standard error (SD). To compare the tx~o populations, ANOVA was used with groups as independent dimension and time as repeated measures. Results t~I the correhltion analysis are given by' Pearson correlation coefficients.

Growth Hormone

Respom, c

BIOL PSYCHIATRY 1995:38:325-329

327

Table 2. Grow,th Hormone (GH) Responses After Growth Hormunc-Releasing Hormone (GHRH) or Clonidine in 12 Healthy Controls" Clonidine stimulation

G H R H stimulation Patient

Sin-(

..X m a x

AUC

GH

SM-C

A max

AUC

No.

Age. se',

~ng,'ml ~

(ill

~ng/nlI,)

IngtmL)

/ng/mintmL)

(nglmLl

(ng/mk~

(ng/mL)

(ng/min/mL)

I

58, m

I I

207

32.2

3417

1.8

193

20.6

1819

2 3 4

53. f 55. f :~7 1

5 02 q '~

112 167 :~19

2.5 75 71)

143 467 .,t(ll)

(1.6 0.4 ,..)

132 175 241

0.2 1.0 0

96 93 202

5 6 7 8 9 I0

34. f 22, m 32. m 44. m 47. f 50.1

i).~ t). ~ O2 I~ () I t l. ~

IS5 2t)(I 255 14(I 163 1'~9

4.8 "~5.S 5.7 5.4 1.8 1.4

?7o 214(~ 227 287 159 124

0.7 4.6 0.1 0 O. I 0

265 343 256 113 208 252

0 2.3 0.7 1.2 0.2 2.0

25 557 45 81 16 85

1I 12

43, f 33, t

41) I4

]gt,~ If,5

9.e 36.5

1102 354 ~

1.4 0.3

212 203

0 15.0

123 1337

tl.S ~ (la

20t) + 61

104 : 12(1

10~,1 ~ 279

1.1 ±0.4

216 ~62

2.6 + 6 . 0 ~'

374 +590;'

bleans + SD

42 z I1

' I h e dala represent ba.,eline GH at It) xxl. hase]irlc ~,t}illalomedlll-(" [Sill ('1 ill ][1 "l\l. lhc llt~l~,llllL{[(IH concentration

o,.,cr l ( m e Cl.ll vt2 I A [ T(', I rt){ll l 0 \ M ill I PM ~ d t l e l M i l l l l l J a l i o n

respo[]~,~ o ' ~ e r

baseline {_.kiI/ax), and the area under the GH plasma

~A I111 ( i l l R H ol c l i m iclirlc

'p <: .02 vdlen COlnparcd u ith GI IRt{ ~tinnllat]on

Results GHRH Test IV administration of GHRH resulted in both groups in a marked increase of GH with maxima occurring betw,een 30 and 60 min and a return to baseline between 120 and 180 min after injection (Figure l). ANOVA indicates a significant main effect Iklr time (F = 7.16, d r = 10, p = .0001 ) bul not for group i F = 0.52, df= I, / ~= .4778) and group x time interaction t F = 0.58, d/= I0. p = .8304). Additionally. thcrc was no difference of baseline GH concentrations bet,aecn the patients and the controls as well as of thc ~ max and AUC values after GHRH stimulation ITables 1 and 2~. As indicated by ANOVA, there was no significant main effect for group concerning Sm-C bascline vahies ( F = 0.10. d/= I. p = .7571 ). Similarly. w.hen the association betwccn GH responses to GHRH and SM-C concentrations was in,,estigated for both ~, no si~niticant correlations ~et-c ~ , +ups. o found.

Clonidine fe.sl The magnitude of GH rcsl)on~,c lo clonidinc was considerably lower when compared to GH output after GHRH I Figure 1, Tables I and 2). Again, ANOVA shows a significant main effect for time ( F = 3.21. ~#= 10, I~= .0007) but not for group (F = 0.03. d / ' = 1,/~ = 87321 and group × time interaction ( F = 0.39, L.(/= 10,/~ = .9495)!Figure l i. No significant main effect tk~rgroup concerning Sin-(" baseline emerged (ANOVA. F = 1.7, all= I. p = .20631 and there ~;i~ no significant corrchttion bctv~een GH responses to cloni dine and baseline SM-C concentrations. There was also n,~ difference of bascline GH concentrations between patienl~,

and controls as well as of the ~ max and AUC values alter chmidine stimulation (Tables 1 and 2). For patients as well as controls, we found significant correlations between the GH responses lk)llowing GHRH and clonidine stimulation (Figure 2). GH responses to clonidine were lower than the responses IMlowing GHRH for both groups, although the differences were significant only for the controls (Tables 1 and 2).

Discussion The results demonstrate a marked increase of GH after administration of GHRH and a lower GH response to clonidine in depressive patients and healthy controls, although the differences between GHRH and clonidine responses reached significance only in the patients group. Both responses were not different between patients and controls. We also did not observe different baseline Sm-C concentrations between depressives and controls; however, a positive correlation between GH secretion after clonidine and GHRH was flmnd for both groups. Our findings are in line with the investigation of Eriksson et a] (1988). In this study, both the ¢x~-agonist guanfacine and GHRH induced a similar GH release in depressive patients as well as in healthy controls. Similarly, no differences of the GH responses to either clonidine or GHRH x~ct-c rcccntly reported between peripubertal depressive patients and healthy controls (Brambilla et al 1994). As also reported by Eriksson et al (1988), we observed significant correlations between the GH responses to clonidine and GHRH for the patients and for the controls. Because of these cortelati~ms between the GH responses following two stim-

328

H. Gann eL al

BIOI I'S'~ C I H \ I R \ I q q 5 : I S ~25 "Q~I

o controls ] Clonidine

4, E C "1-

0

i

-60

i

1

i

i

i

-30

0

60

120

180

min

15 GHRH

E

-J

f

o controls 1 • patients

10

cO

i

i

i

i

i

i

-60

-30

0

60

120

180

rain

Figure 1. Lower: Plasma grov, th hormone { GH ) secretion al base. line and folloveing 50 ptg human growth hormone-releasing \ o f mone (GHRH) administered a~ an intravenous i lV ) bolus at 1{),\M to 12 patients with major depressive disorder IMDD) and 12 healthy controls. U F p e r : Plasma growth hormone (GH) secretion at baseline and following 2 p4/kg clonidine administered IV at 1() AM to 12 patients with MDD and 12 healthy conlruls. All data arc means + SEM.

Our results contradict findings of Lesch et al (1988) and Neuhauser and Laakmann (1988), who found significantly reduced GH responses to GHRH and to clonidine in depressive patients when compared with healthy controls. Even more surprisingly, GH responses to clonidine did not differ significantly between both groups. This finding is in obvious contras! to a number of reports, mostly obtained in male patients below age 40, indicating that the GH response to chmidine is blunted in depressive patients (see Introduction I: however, most of our healthy controls already showed a blunted GH response to clonidine (k max < 4 ng/mL). This might be explained by the slightly higher age of our patients and controls in comparison to most other studies cited above. A decline of the GH response to clonidine with age was also lbund in a recent study by Siever et al (1992). Since Shibaske cl al (1984) reported that somatotroph cells become less sensitive in the 40s, blunted GH responses in our controls and patients could be confounded by a normal aging effect. Interestingly, in a former investigation, young male healthy probands in their 20s showed a much more pronounced GH secretion to clonidine as well as to GHRH (Gann et al 1992). Based on our data, we would like to suggest that reduced GH secretion to o~,-receptor agonists might represent a biological marker for depression in young patients only. In older patients there may be an overlap between a depressionrelated and an aging effect concerning GH secretion. This agrees with the conclusions made by Gilles et al (1989). Our failure to detect differences in GH secretion to GHRH and clonidine between depressives and controls implies that no conclusions can be made from the present study concerning a specific dysfunction of the HPS system in depression. 2000

: .E E

controls patients

O

]

1500 O

C

uli acting at different levels of the HPS systent, wc agree with the conclusion of Eriksson et al (1988) that other fac tors than o~,-adrcnoceptor sensitivity should be taken into consideration for the interpretation of reduced GH response to ~3-agonists. especially if the GH response to GHRH is similarly affected. Lesch et al (1987. 1988) postulated that low GH responses in depression |night the consequence of enhanccd feedback inhibition due to clcvated Sm-C concentrations. Our data and the recent findings of Brambilla et al ( 19941 do not support this explanation, sincc SM-C levels were not different between patients and controls and \~cre within the normal range.

t.I .i tO o

1000

500 g "tO

° i

t

i

I000

2000

3000

4000

GHAuc after GHRH {ng • min/ml) Figure 2. Correlation between growth hormone releasing hor+ mone {GHRH Finduced growth hormone (GH) secretion and GH responses following clunidine in 12 depressive patients (r = .65, p = .0214 ) and 12 controls (r = .95, i ? = .001 ).

Gro~,lh Hormone Response

Research supported b,, a gram Don/lhc I)FG ISt:B 258. A I). l)t. (iann i,. presently at the Klinikum Baxmcn. I) 5600 ~,~uppcrlal. German,,. Dr Riemann and l)r. Bergcr arc pre~,cnlly at Ihc P,,ychiatric Clinic. t ni'~cr,dt5 of Freiburg. D 79104 Freiburg

BIOL PSYCHIATRY 1995:38:325-329

329

(lilies C. Ryckaert P, Del Mol J, de Maertelaere V, Mendlewicz J (1989): CIonidine-induced growth hormone secretion in elderl 5` patients with senile dementia of the Alzheimer type and major depressive disorder. Psychiato, Res 27:277-286. Krishan KR. Manepalli AN, Ritchie JC, et al (1988): Growth hormone releasing factor stimulation test in depression. Am J Ps v~hiatrv 145:90-92.

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I,csch KP, Laux G, PfiJller H, Erb A, Beckmann H ( 1987): Growth homume {GH) response to GH releasing hormone in depression. J Clin Endocrinol Metab 65:1278-1281. I+esch KP, Laux G, Erb A, Pfiiller H, Beckmann H (1988): Growth hormone responses to GH-releasing hormone in depression: Correlation with GH-release following clonidine. Psychiatry Res 25:301 310. Matussek N, Ackenheil M, Hippius H, et al (1980): Effect of chmidine on growth hormone release in psychiatric patients and controls, Psychiatry Res 2:25. Neuhauser H, Laakmann G (1988): Stimulation of growth hormone by GHRH as compared to DMI in depressed patients. Pharmacopsychiat O" 21:443-4-44. Peabod~ CA, Warner MD, Markhoff E, Hoffman AR, Wilson DM. Csernansky JG 11990): Growth hormone response to growth hormone releasing hormone in depression and schizophrenia. Psychiat O' Res 33:269 276.

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Shibasaki T, Shizume K, Nakahara M, et al (1984): Age related changes m plasma growth hormone response to growth hormone releasing factor in man. J Clin Endocrinol Metab 58:212-214.

Chiarini V. Oraziano E, Cremonini N. Slorza A. Przzoli A. Zampa GA (I987): HGH response to GHRH in d e p r e s s i o n . . / k n d ~ crinol hive,st 10:56.

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Gann H. Riemann D. Fleckcnstein P. Berger M. MLiller VVt ( 1992k Chmidinhz~. Wachstumshormon ReleasingHormon-induzierte Vcachstunlshormon-[~reisetzung an geSUlIden Probanden. In Gaebel, l_aux
Thomas R, Beer R, Harris B, John R, Scanlon M (1989): GH responses to growth hormone releasing factor in depression. J Atl?ct Disord 16:133-137. Wittchen HU, Zaudig M, Schromm E, et al ( 1988): SKID Strukturierles Klinisches lnterview {?ir DMS-III-R. Beltz: Weinheim.