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Human growth hormone releasing factor infusion effects on plasma growth hormone in affective disorder patients and normal controls
Peptides. Vol. 9, Suppl. 1, pp. 45--48.©Pergamon Journals Ltd., 1988. Printed in the U.S.A.
0196-9781/88 $3.00 + .00
Human Growth Hormone Releasing Factor Infusion Effects on Plasma Growth Hormone in Affective Disorder Patients and Normal Controls S. C R A I G R I S C H , C I N D Y E H L E R S , D A V I D S. J A N O W S K Y , L E W I S J U D D , J. C H R I S T I A N G I L L I N , R I C H A R D D A N A A N D L O U A . M c A D A M S
University o f California at San Diego, School o f Medicine, Department o f Psychiatry M-O03, La Jolla, CA 92093
RISCH, S. C., C. EHLERS, D. S. JANOWSKY, L. JUDD, J. C. GILLIN, R. DANA AND L. A. McADAMS. Human growth hormone releasing factor infusion effects on plasma growth hormone in affective disorder patients and normal contrals. PEPTIDES 9: Suppl. I, 45-48, 1988.--In a preliminary, prospective pilot study, five patients with major depressive disorder and eleven age and sex matched normal controls received intravenous human growth hormone releasing factor (hGRF) (1/.Lg/kgin 5 cc of normal saline infused over five minutes) and placebo. Thirty minutes after insertion of the catheter, blood was sampled every 15 minutes for thirty minutes prior to and for 2 hours subsequent to intravenous infusion of hGRF or placebo, hGRF but not placebo caused significant elevations of plasma growth hormone levels in all subjects. Of interest, the depressed patients had a significantly attenuated rise in plasma growth hormone concentrations when compared with the normal controls. These results must be considered preliminary awaiting replication with a larger subject population. Growth hormone
Depression
STRESS paradigms and various provocative psychopharmacological challenges of pituitary growth hormone release have been studied in an attempt to understand the pathophysiology of affective illness and in attempts to provide a laboratory basis aiding in diagnosis and predicting efficacy of psychopharmacological treatments. Unfortunately, with some notable exceptions, the literature with regard to provocative challenges of growth hormone in specific psychiatric nosological states has been both inconsistent and to date of limited clinical utility. These conflicting results presumably reflect such issues as diagnostic heterogenity, and lack of sufficient age, sex, diet, activity, menstrual cycle, menopausal status, medication status, and duration of illness controls. However, the literature suggests that future studies, using more specific hypotheses and more refined methodologies may provide significant insights into the pathogenesis of specific psychiatric disease states as well as provide a laboratory aid in nosological classification and in choosing and monitoring psychopharmacological interactions.
cretion is markedly augmented by circulating estrogen and plasma growth hormone concentrations may vary markedly with the menstrual cycle and menopausal status. Growth hormone secretion is stimulated by stress, exercise, hypoglycemia, certain hormones (insulin), and a variety of medications, such as amphetamine, l-dopa, apomorphine, and clonidine. Growth hormone secretion is stimulated by dopamine, norepinephrine, and serotonin. Growth hormone secretion increases during slow wave sleep, usually early after onset of sleep in the first non-REM phase [1]. PROVOCATIVE CHALLENGES OF GROWTH HORMONE IN THE AFFECTIVE DISORDERS AS noted above, interpretation of basal growth hormone plasma concentrations is confounded by stress, activity, diet, obesity, sex, menopausal status, state of menstrual cycle, medication status, and many other factors. In earlier studies, when these factors have been controlled for, basal plasma concentrations of growth hormone have been reported to not be significantly different between depressed patients and normal controls [9]. However, in a recent study, doing repeated plasma samples over 24 hours, depressed patients had significantly elevated plasma growth hormone levels when compared with normal controls [24]. One of the most extensively studied provocative chal-
GROWTH HORMONE PHYSIOLOGY Basal growth hormone secretion tends to have spontaneous bursts during the day averaging 6-7 bursts per 24 hours, decreasing in frequency with age [38]. Growth hormone se-
45
R I S C H El" A L.
46
lenges of growth hormone in affective disorders has been insulin-induced hypoglycemia. After controlling for the above variables, the minimally clinical adequate response is usually defined as a change in plasma growth hormone response greater than 5 ng/ml after at least a 50% drop in blood glucose level [9,31]. Although the literature is extremely inconsistent, some studies suggest that an inadequate or " b l u n t e d " growth hormone response to insulin-included hypoglycemia may occur in some hospitalized endogenously depressed patients [2, 8, 10, 14, 25, 33, 34, 39]. This abnormality appears more common in unipolar depressed patients than in bipolar depressed patients [14,34]. This growth hormone resistance to insulin challenge also occurs in prepubertal children with major depression, perhaps with a greater frequency than in adults [27, 29, 30]. These depressed children also secrete significantly more growth hormone during sleep, and there is little overlap between this abnormality and insulin resistance [30]. Both these abnormalities tend to persist for long periods after clinical recovery [26,28]. However, the abnormal growth hormone response to insulin induced hypoglycemia in depressed patients must still be considered controversial. In contrast, challenge studies of growth hormone secretion with the dopamine agonists apomorphine and l-dopa have been unrewarding in differentiating depressed patients from controls [2, 9, 13, 19, 20, 22, 23, 32]. Amphetamine challenges of growth hormone secretion differ mechanistically from l-dopa and apomorphine in that they may involve both noradrenergic and dopaminergic neurotransmission. One study [18] reported a significantly lower growth hormone secretion in response to amphetamine challenges in " e n d o g e n o u s l y " depressed patients, and significantly higher responses in " r e a c t i v e l y " depressed patients as compared with controls. Only one study [12] has attempted to replicate these findings. Unlike these unrewarding results in differentiating depressed patients from controls with growth hormone responses to apomorphine, 1-dopa and possibly amphetamine (reviewed above) a reduced growth hormone to clonidine (an s - r e c e p t o r agonist) has emerged as one of the most powerful and substantive markers for neuroendocrine dysfunction in depression [4, 6, 21, 36]. Furthermore, of both theoretical interest and clinical utility, treatment of patients with tricyclic antidepressants or monoamine oxidase inhibitors does not appear to alter the growth hormone response to clonidine [3,37]. Also of interest is a similar "blunting" or reduced growth hormone response to clonidine in patients with obsessive-compulsive illness, which together with an increased frequency of abnormal Dexamethasone Suppression Test and shortened rapid eye movement (REM) sleep latency suggests that they may share similar biological abnormalities with depressed patients [35]. Desmethylimipramine (DMI) stimulates growth hormone secretion. A reduced growth hormone response to DMI has also been observed in depressed patients as compared with controls [7, 15, 16]. These observations, like those with clonidine, support that this abnormality may be selectively noradrenergically, rather than dopaminergically, mediated. From the above review, it would appear that reduced growth hormone secretion responsivity to insulin, and more specifically and substantively to clonidine and DMI occur in depressed patients as compared with controls. These observations suggest that noradrenergic systems, at least in part, may mediate the pathogenesis of this neuroendocrine abnormality, and that further studies appear warranted.
From the above mini-review, it appears manifest that abnormalities in growth hormone secretion occur in affective illness, and may be elicited and studied by a variety of provocative challenge tests. Since the above reviewed literature in many places is inconsistent and since hGRF does not cross the blood-brain barrier, we decided to bypass the supra-hypothalamic systems involved in the pharmacological testing of growth hormone release described above and test pituitary sensitivity directly. In this study we report the effects of intravenous Human Growth Hormone Releasing Factor (hGRF) on pituitary growth hormone response in affective disorder patients and in age and sex matched normal controls. METHOD
Subjects ranged in age from 21 years to 30 years, were male, were drug free for at least 14 days prior to participation in the study, were voluntary and able to give informed consent and were medically healthy as determined by medical history, physical examination, and laboratory tests including: EKG, CBC with differential, urinalysis, SMA 12, serum electrolytes, BUN, CPK, T4, and fasting glucose. Subjects also received a DSM-III and SADS-RDC Diagnosis. Subjects were 11 normal controls and 5 Major Depressive Disorder inpatients, endogenous subtype. All patients were within 20% of ideal body weight. Around 0730 a.m. an indwelling heparin lock catheter (19 gauge "butterfly") was inserted in the subject's forearm, after 30 minutes of accommodation (0800) baseline blood samples (8 cc) were drawn from the catheter at 15 minute intervals for 30 minutes, hGRF was provided by Dr. Guillemin, Director of the Laboratories for Neuroendocrinology of the Salk Institute, La Jolla, CA. The peptide h G R F was synthesized and characterized by Dr. Nicholas Ling of these laboratories [18]. At 0830, synthetic hGRF or placebo was infused into the heparin lock at a dosage of 1 /zg/kg in 5 cc of normal saline solution over 5 minutes. Blood samples (8 cc) were then drawn every 15 minutes for two hours subsequent to the hGRF or placebo infusion (i.e., at 0850, 0905, 0920, 0935, 0950, 1005, 1020, and 1035). Vital signs (blood pressure and pulse) were monitored and recorded at each blood draw. Blood samples were collected in polypropylene tubes with EDTA on ice, immediately centrifuged in a refrigerated centrifuge at 15,000 RPM × 20 minutes, then stored in a -80°C freezer for subsequent hGH measurements, hGRF and placebo administration was separated by at least one week and were performed in a doubleblind randomized, counterbalanced paradigm, hGH plasma concentrations were determined using a double antibody ~25I commercially available RIA kit manufactured by Bio RIA Corporation. It has a sensitivity of 0.03 /zlU. Antibody cross-reactivities to hFSH, hLH, hTSH, hCG, and hPRL are all 0.03% at 50% B/Bo binding. Between assay variation is 4.9-+0.6 at 50% B/Bo binding in our laboratory. RESULTS
There were no significant changes in pulse or blood pressure or behavioral effects of h G R F or placebo administered in this paradigm. Placebo administration had no significant effects on plasma levels of growth hormone while h G R F administration significantly increased plasma levels of growth hormone in all subjects. Growth hormone levels peaked 15 minutes after h G R F infusions and were still elevated at about 50% of maximal increase (i.e., level at 15
hGRF
47
TABLE 1 MEAN CHANGE IN LOG (hGH) FROM BASELINE TO + 15 MINUTES POST-INJECTION OF hGRF FOR ll NORMAL CONTROLS AND 5 DEPRESSED PATIENTS Placebo Condition Group
hGRF
Control
Depressed
Control
Depressed
0.289 0.296 0.007
0.345 0.328 -0.017
0.308 1.474 1.166
0.341 1.007 0.665
Baseline + 15 Minutes Change
Diagnostic Group × Drug × Time, p<0.0322.
minutes post h G R F infusions) at 120 minutes post h G R F infusion, the last plasma sampling timepoint. O f interest, as noted in Table 1, the depressed patient group had significantly diminished or " b l u n t e d " plasma growth h o r m o n e increases in response to h G R F administration than did the age and sex matched normal control group. DISCUSSION These results
parallel the a b o v e
r e v i e w e d literature
suggesting that m a n y d e p r e s s e d patients m a y d e m o n s t r a t e a reduced or " b l u n t e d " pituitary growth h o r m o n e response to p r o v o c a t i v e challenges. T o our knowledge, h o w e v e r , this is the first d e m o n s t r a t i o n o f a diminished pituitary growth h o r m o n e response to the hypothalamic releasing factor h G R F in depressed patients. Although we can only speculate about the m e c h a n i s m i n v o l v e d in the pathophysiology of this diminished response o f the pituitary to administered h G R F in depressed patients, it is known that intravenously administered h G R F does not appear to cross the blood-brain barrier and therefore does not act centrally in this paradigm. T h e r e f o r e , the loci o f the action of h G R F must be at the pituitary somatotroph. As noted above, an elegant study of M e n d l e w i c z and colleagues [24] has d e m o n s t r a t e d an elevation in 24 hour growth hormone secretion in both bipolar and major depressive disorder patients. It is possible that chronically elevated plasma growth h o r m o n e concentrations could " d o w n - r e g u l a t e " or diminish the pituitary somatotroph G R F receptors and/or provide increased negative feedback w h e n h G R F is intravenously administered. The results of this pilot study must be considered preliminary and further studies will be needed to d e m o n s t r a t e what percentage o f d e p r e s s e d patients have this abnormality, if there are differences in patients with major depressive disorder and bipolar disorder and " s t a t e trait" distinctions.
REFERENCES 1. Brown, G. M., J. A. Seggie, J. W. Chambers and P. G. Ettigi. 13. Insel, T. R. and L. J. Siever. The dopamine system challenge in affective disorders: A review of behavioral and neuroendocrine Psychoendocrinoiogy and growth hormone: A review. responses. J Clin Psychopharmacol 1: 207-213, 1981. Psychoneuroendocrinology 2: 131-153, 1978. 14. Kathol, R. G., B. M. Sherman, G. Winokur, D. Lewis and M. 2. Casper, R. C., J. M. Davis, G. N. Pandey, D. L. Garver and H. Schlesser. Dexamethasone suppression, protirelin stimulation, Dekirmenjian. Neuroendocrine and amine studies in affective and insulin infusion in subtypes of recovered depressive paillness. Psychoneuroendocrinology 2: 105-113, 1977. tients. Psychiatry Res 9: 9%106, 1983. 3. Charney, D. S., G. R. Heninger and D. E. Sternberg. Failure of 15. Laakman von, G. and O. Benkert. Neuroendokrinologie und chronic antidepressants, desmethylimipramine and amitripPsychopharmaka. Arzneimittelforsch 28: 1277-1280, 1980. tyline on the growth hormone response to clonidine. Psychiatry 16. Laakman von, G., O. Benkert, E. Neurlinger, K. V. Werder Res 7: 135-138, 1982. and F. Erhardt. Beeinflussing der Hypophysen-Vorderlappen4. Charney, D. S., G. R. Heninger, D. E. Sternberg, K. M. Hormon-Secretion nach akuter und chronischer Gabe on DesipHafstad, S. Gillings and D. H. Landis. Adrenergic receptor ramin. Arzneimittelforsch 18: 1292-1294, 1978. sensitivity in depression. Effects on clonidine in depressed pa17. Langer, G., G. Heinze, B. Reim and N. Matussek. Reduced tients and healthy subjects. Arch Gen Psychiatry 39: 290-294, growth hormone response to amphetamine in "endogenous" 1982. 5. Checkley, S. A. Corticosteroid and growth hormone responses depressive patients: Studies in normal, "reactive" and "endogenous" depressive, schizophrenic, and chronic alcoholic subto methylamphetamine in depressive illness. Psychol Med 9: 107-115, 1979. jects. Arch Gen Psychiatry 33: 1471-1475, 1976. 18. Ling, N., F. Esch, P. Bohlen, P. Brazou, W. Weherenberg and 6. Checkley, S. A., A. P. Slade and E. Shur. Growth hormone and R. Guillemin. Isolation, primary structure and synthesis of other responses to clonidine in patients with endogenous dehuman hypothalamic somatocrinin: Growth hormone-releasing pression. Br J Psychiatry 138: 51-55, 1981. factor. Proc Natl Acad Sci USA 81: 4302-4306, 1984. 7. Glass, I. B., S. A. Checkley, E. Shur and S. Dawling. The effect of desipramine upon central adrenergic function in depressed 19. Linkowski, P., H. Brauman and J. Mendlewicz. Prolactin and patients. Br J Psychiatry 141: 372-376, 1982. growth hormone response to levodopa in affective illness. 8. Grof, E., G. M. Brown and P. Grof. Neuroendocrine responses Neuropsychobiology 9: 108-112, 1983. as an indicator of recurrence liability in primary affective ill20. Maany, I., J. Mendels, A. Frazer and D. Brunswick. A study of ness. Br J Psychiatry 140: 320--322, 1982. growth hormone release in depression. Neuropsychobiology 5: 9. Gruen, P. H. Endocrine changes in psychiatric diseases. Med 181-189, 1979. Clin North Am 62: 285-296, 1978. 21. Matussek, N., M. Ackenheil, H. Hippius, F. Muller, H. T. 10. Gruen, P. H., E. Sachar, N. Altman and S. Sassin. Growth Schroder, H. Schultes and B. Wasilewski. Effects of clonidine hormone responses to hypoglycemia in post-menopausal deon growth hormone release in psychiatric patients and controls. pressed women. Arch Gen Psychiatry 32: 31-33, 1975. Psychiatry. Res 2: 25-36, 1980. 11. Gruen, P. H., E. J. Sachar, G. Langer, N. Altman, M. Leifer, 22. Meltzer, H. Y., T. Kolakowska, V. S. Fang, L. Fogg, A. A. Frantz and F. S. Halpern. Prolactin responses to neurolepRobertson, R. Lewine, M. Strahilevits and D. Busch. Growth tics in normal and schizophrenic subjects. Arch Gen Psychiatry hormone and prolactin response to apomorphine in schizo35: t08-116, 1978. phrenia and the major affective disorders. Relation to duration 12. Halbreich, U., E. J. Sachar, G. M. Asnis, F. Quitkin, R. S. of illness and depressive symptoms. Arch Gen Psychiatry 41: Nathan, F. S. Halpern and D. F. Klein. Growth hormone re512-519, 1984. sponse to dextroamphetamine in depressed patients and normal subjects. Arch Gen Psychiatry 39: 18%192, 1982.
48 23. Mendlewicz, J., P. Linkowski and E. Van Cauter. Some neuroendocrine parameters in bipolar and unipolar depression. J Affective Disord 1: 25-32, 1979. 24. Mendlewicz, J., P. Linkowski, M. Kerkhofs, D. Desmedt, J. Goldstein, G. Copinschi and C. Van Cuter. Diurnal hypersecretion of growth hormone in depression. J Clin Endocrinol Metab 60: 505-511, 1985. 25. Mueller, P. S., G. R. Heninger and R. K. McDonald. Insulin tolerance test in depression. Arch Gen Psychiatry 21: 587-594, 1969. 26. Puig-Antich, J., R. Goetz, M. Davies, M. A. Tabrizi, H. Novacenko, C. Hanlon, E. J. Sachar and E. C. Weitzman. Growth hormone secretion in prepubertal children with major depression. IV. Sleep related plasma concentrations in a drugfree, fully recovered clinical state. Arch Gen Psychiatry 41: 47%483, 1984. 27. Puig-Antich, J., H. Novacenko, M. Davies, W. J. Chambers, M. A. Tabrizi, V. Krawiec, P. J. Ambrosini and E. J. Sachar. Growth hormone secretion in prepubertal children with major depression. I. Final report on response to insulin-induced hypoglycemia during a depressive episode. Arch Gen Psychiatry 41: 455-460, 1984. 28. Puig-Antich, J., H. Novacenko, M. Davies, M. A. Tabrizi, P. Ambrosini, R. Goetz, J. Bianca, D. Goetz and E. J. Sachar. Growth hormone secretion in prepubertal children with major depression. III. Response to insulin-induced hypoglycemia after recovery from a depressive episode and in a drug-free state. Arch Gen Psychiatry 41: 471-475, 1984. 29. Puig-Antich, J., M. A. Tabrizi, M. Davies, R. Goetz, W. J. Chambers, F. Halpern and E. J. Sachar. Prepubertal endogenous major depressives hyposecrete growth hormone in response to insulin-induced hypoglycemia. Biol Psychiatry 16: 801-818, 1981.
RISCH ET AL. 30. Puig-Antich, J. and B. Weston. The diagnosis and treatment of major depressive disorder in childhood. Atom Rev Med 34: 231-245, 1983. 31. Sachar, E. Neuroendocrine dysfunction in depressive illness. Annu Rev Med 27: 38%396, 1976. 32. Sachar, E. J., N. Altman, P. Gruen, A. Glassman, F. S. Halpern and J. Sassin. Human growth hormone response to levodopa. Relevation to menopause, depression and plasma dopamine concentration. Arch Gen Psychiatt3, 32: 502-503, 1975. 33. Sachar, E. J., J. Finkelstein and L. Hellman. Growth hormone responses in depressive illness. Arch Gen Psychiato" 25: 263269, 1971. 34. Sachar, E. J., A. G. Frantz, N. Altman and J. Sassin. Growth hormone and prolactin in unipolar and bipolar patients: Responses to hypoglycemia and I-dopa. Am ,I Psychiatry 130: 1362-1367, 1973. 35. Siever, L. J., T. R. Insel, D. C. Jimerson, C. R. Lake, T. W. Uhde, J. Aloi and D. L. Murphy. Growth hormone response to clonidine in obsessive-compulsive patients. Brd Psychiato" 142: 184-187, 1983. 36. Siever, L., T. Insel and T. Uhde. Noradrenergic challenges in the affective disorders. J Clin Psychopharmaeol 1: 193-206, 1981. 37. Siever, L., T. W. Uhde, T. R. Insel, B. F. Roy and D. L. Murphy. Growth hormone response to clonidine unchanged chronic clorgyline treatment. Psychiatry Res 7: 13%144, 1982. 38. Van Pragg, H. M. The significance of biological factors in the diagnosis of depressions: II. Hormonal variables. Cotnp Psychiatry 23: 216-226, 1982. 39. Winokur, A., J. Amsterdam, S. Caroff, P. J. Snyder and D. Brunswick. Variability of hormonal responses to a series of neuroendocrine challenges in depressed patients. Am J Psychiato' 139: 3%44, 1982.
0196-9781/88 $3.00 + .00
Human Growth Hormone Releasing Factor Infusion Effects on Plasma Growth Hormone in Affective Disorder Patients and Normal Controls S. C R A I G R I S C H , C I N D Y E H L E R S , D A V I D S. J A N O W S K Y , L E W I S J U D D , J. C H R I S T I A N G I L L I N , R I C H A R D D A N A A N D L O U A . M c A D A M S
University o f California at San Diego, School o f Medicine, Department o f Psychiatry M-O03, La Jolla, CA 92093
RISCH, S. C., C. EHLERS, D. S. JANOWSKY, L. JUDD, J. C. GILLIN, R. DANA AND L. A. McADAMS. Human growth hormone releasing factor infusion effects on plasma growth hormone in affective disorder patients and normal contrals. PEPTIDES 9: Suppl. I, 45-48, 1988.--In a preliminary, prospective pilot study, five patients with major depressive disorder and eleven age and sex matched normal controls received intravenous human growth hormone releasing factor (hGRF) (1/.Lg/kgin 5 cc of normal saline infused over five minutes) and placebo. Thirty minutes after insertion of the catheter, blood was sampled every 15 minutes for thirty minutes prior to and for 2 hours subsequent to intravenous infusion of hGRF or placebo, hGRF but not placebo caused significant elevations of plasma growth hormone levels in all subjects. Of interest, the depressed patients had a significantly attenuated rise in plasma growth hormone concentrations when compared with the normal controls. These results must be considered preliminary awaiting replication with a larger subject population. Growth hormone
Depression
STRESS paradigms and various provocative psychopharmacological challenges of pituitary growth hormone release have been studied in an attempt to understand the pathophysiology of affective illness and in attempts to provide a laboratory basis aiding in diagnosis and predicting efficacy of psychopharmacological treatments. Unfortunately, with some notable exceptions, the literature with regard to provocative challenges of growth hormone in specific psychiatric nosological states has been both inconsistent and to date of limited clinical utility. These conflicting results presumably reflect such issues as diagnostic heterogenity, and lack of sufficient age, sex, diet, activity, menstrual cycle, menopausal status, medication status, and duration of illness controls. However, the literature suggests that future studies, using more specific hypotheses and more refined methodologies may provide significant insights into the pathogenesis of specific psychiatric disease states as well as provide a laboratory aid in nosological classification and in choosing and monitoring psychopharmacological interactions.
cretion is markedly augmented by circulating estrogen and plasma growth hormone concentrations may vary markedly with the menstrual cycle and menopausal status. Growth hormone secretion is stimulated by stress, exercise, hypoglycemia, certain hormones (insulin), and a variety of medications, such as amphetamine, l-dopa, apomorphine, and clonidine. Growth hormone secretion is stimulated by dopamine, norepinephrine, and serotonin. Growth hormone secretion increases during slow wave sleep, usually early after onset of sleep in the first non-REM phase [1]. PROVOCATIVE CHALLENGES OF GROWTH HORMONE IN THE AFFECTIVE DISORDERS AS noted above, interpretation of basal growth hormone plasma concentrations is confounded by stress, activity, diet, obesity, sex, menopausal status, state of menstrual cycle, medication status, and many other factors. In earlier studies, when these factors have been controlled for, basal plasma concentrations of growth hormone have been reported to not be significantly different between depressed patients and normal controls [9]. However, in a recent study, doing repeated plasma samples over 24 hours, depressed patients had significantly elevated plasma growth hormone levels when compared with normal controls [24]. One of the most extensively studied provocative chal-
GROWTH HORMONE PHYSIOLOGY Basal growth hormone secretion tends to have spontaneous bursts during the day averaging 6-7 bursts per 24 hours, decreasing in frequency with age [38]. Growth hormone se-
45
R I S C H El" A L.
46
lenges of growth hormone in affective disorders has been insulin-induced hypoglycemia. After controlling for the above variables, the minimally clinical adequate response is usually defined as a change in plasma growth hormone response greater than 5 ng/ml after at least a 50% drop in blood glucose level [9,31]. Although the literature is extremely inconsistent, some studies suggest that an inadequate or " b l u n t e d " growth hormone response to insulin-included hypoglycemia may occur in some hospitalized endogenously depressed patients [2, 8, 10, 14, 25, 33, 34, 39]. This abnormality appears more common in unipolar depressed patients than in bipolar depressed patients [14,34]. This growth hormone resistance to insulin challenge also occurs in prepubertal children with major depression, perhaps with a greater frequency than in adults [27, 29, 30]. These depressed children also secrete significantly more growth hormone during sleep, and there is little overlap between this abnormality and insulin resistance [30]. Both these abnormalities tend to persist for long periods after clinical recovery [26,28]. However, the abnormal growth hormone response to insulin induced hypoglycemia in depressed patients must still be considered controversial. In contrast, challenge studies of growth hormone secretion with the dopamine agonists apomorphine and l-dopa have been unrewarding in differentiating depressed patients from controls [2, 9, 13, 19, 20, 22, 23, 32]. Amphetamine challenges of growth hormone secretion differ mechanistically from l-dopa and apomorphine in that they may involve both noradrenergic and dopaminergic neurotransmission. One study [18] reported a significantly lower growth hormone secretion in response to amphetamine challenges in " e n d o g e n o u s l y " depressed patients, and significantly higher responses in " r e a c t i v e l y " depressed patients as compared with controls. Only one study [12] has attempted to replicate these findings. Unlike these unrewarding results in differentiating depressed patients from controls with growth hormone responses to apomorphine, 1-dopa and possibly amphetamine (reviewed above) a reduced growth hormone to clonidine (an s - r e c e p t o r agonist) has emerged as one of the most powerful and substantive markers for neuroendocrine dysfunction in depression [4, 6, 21, 36]. Furthermore, of both theoretical interest and clinical utility, treatment of patients with tricyclic antidepressants or monoamine oxidase inhibitors does not appear to alter the growth hormone response to clonidine [3,37]. Also of interest is a similar "blunting" or reduced growth hormone response to clonidine in patients with obsessive-compulsive illness, which together with an increased frequency of abnormal Dexamethasone Suppression Test and shortened rapid eye movement (REM) sleep latency suggests that they may share similar biological abnormalities with depressed patients [35]. Desmethylimipramine (DMI) stimulates growth hormone secretion. A reduced growth hormone response to DMI has also been observed in depressed patients as compared with controls [7, 15, 16]. These observations, like those with clonidine, support that this abnormality may be selectively noradrenergically, rather than dopaminergically, mediated. From the above review, it would appear that reduced growth hormone secretion responsivity to insulin, and more specifically and substantively to clonidine and DMI occur in depressed patients as compared with controls. These observations suggest that noradrenergic systems, at least in part, may mediate the pathogenesis of this neuroendocrine abnormality, and that further studies appear warranted.
From the above mini-review, it appears manifest that abnormalities in growth hormone secretion occur in affective illness, and may be elicited and studied by a variety of provocative challenge tests. Since the above reviewed literature in many places is inconsistent and since hGRF does not cross the blood-brain barrier, we decided to bypass the supra-hypothalamic systems involved in the pharmacological testing of growth hormone release described above and test pituitary sensitivity directly. In this study we report the effects of intravenous Human Growth Hormone Releasing Factor (hGRF) on pituitary growth hormone response in affective disorder patients and in age and sex matched normal controls. METHOD
Subjects ranged in age from 21 years to 30 years, were male, were drug free for at least 14 days prior to participation in the study, were voluntary and able to give informed consent and were medically healthy as determined by medical history, physical examination, and laboratory tests including: EKG, CBC with differential, urinalysis, SMA 12, serum electrolytes, BUN, CPK, T4, and fasting glucose. Subjects also received a DSM-III and SADS-RDC Diagnosis. Subjects were 11 normal controls and 5 Major Depressive Disorder inpatients, endogenous subtype. All patients were within 20% of ideal body weight. Around 0730 a.m. an indwelling heparin lock catheter (19 gauge "butterfly") was inserted in the subject's forearm, after 30 minutes of accommodation (0800) baseline blood samples (8 cc) were drawn from the catheter at 15 minute intervals for 30 minutes, hGRF was provided by Dr. Guillemin, Director of the Laboratories for Neuroendocrinology of the Salk Institute, La Jolla, CA. The peptide h G R F was synthesized and characterized by Dr. Nicholas Ling of these laboratories [18]. At 0830, synthetic hGRF or placebo was infused into the heparin lock at a dosage of 1 /zg/kg in 5 cc of normal saline solution over 5 minutes. Blood samples (8 cc) were then drawn every 15 minutes for two hours subsequent to the hGRF or placebo infusion (i.e., at 0850, 0905, 0920, 0935, 0950, 1005, 1020, and 1035). Vital signs (blood pressure and pulse) were monitored and recorded at each blood draw. Blood samples were collected in polypropylene tubes with EDTA on ice, immediately centrifuged in a refrigerated centrifuge at 15,000 RPM × 20 minutes, then stored in a -80°C freezer for subsequent hGH measurements, hGRF and placebo administration was separated by at least one week and were performed in a doubleblind randomized, counterbalanced paradigm, hGH plasma concentrations were determined using a double antibody ~25I commercially available RIA kit manufactured by Bio RIA Corporation. It has a sensitivity of 0.03 /zlU. Antibody cross-reactivities to hFSH, hLH, hTSH, hCG, and hPRL are all 0.03% at 50% B/Bo binding. Between assay variation is 4.9-+0.6 at 50% B/Bo binding in our laboratory. RESULTS
There were no significant changes in pulse or blood pressure or behavioral effects of h G R F or placebo administered in this paradigm. Placebo administration had no significant effects on plasma levels of growth hormone while h G R F administration significantly increased plasma levels of growth hormone in all subjects. Growth hormone levels peaked 15 minutes after h G R F infusions and were still elevated at about 50% of maximal increase (i.e., level at 15
hGRF
47
TABLE 1 MEAN CHANGE IN LOG (hGH) FROM BASELINE TO + 15 MINUTES POST-INJECTION OF hGRF FOR ll NORMAL CONTROLS AND 5 DEPRESSED PATIENTS Placebo Condition Group
hGRF
Control
Depressed
Control
Depressed
0.289 0.296 0.007
0.345 0.328 -0.017
0.308 1.474 1.166
0.341 1.007 0.665
Baseline + 15 Minutes Change
Diagnostic Group × Drug × Time, p<0.0322.
minutes post h G R F infusions) at 120 minutes post h G R F infusion, the last plasma sampling timepoint. O f interest, as noted in Table 1, the depressed patient group had significantly diminished or " b l u n t e d " plasma growth h o r m o n e increases in response to h G R F administration than did the age and sex matched normal control group. DISCUSSION These results
parallel the a b o v e
r e v i e w e d literature
suggesting that m a n y d e p r e s s e d patients m a y d e m o n s t r a t e a reduced or " b l u n t e d " pituitary growth h o r m o n e response to p r o v o c a t i v e challenges. T o our knowledge, h o w e v e r , this is the first d e m o n s t r a t i o n o f a diminished pituitary growth h o r m o n e response to the hypothalamic releasing factor h G R F in depressed patients. Although we can only speculate about the m e c h a n i s m i n v o l v e d in the pathophysiology of this diminished response o f the pituitary to administered h G R F in depressed patients, it is known that intravenously administered h G R F does not appear to cross the blood-brain barrier and therefore does not act centrally in this paradigm. T h e r e f o r e , the loci o f the action of h G R F must be at the pituitary somatotroph. As noted above, an elegant study of M e n d l e w i c z and colleagues [24] has d e m o n s t r a t e d an elevation in 24 hour growth hormone secretion in both bipolar and major depressive disorder patients. It is possible that chronically elevated plasma growth h o r m o n e concentrations could " d o w n - r e g u l a t e " or diminish the pituitary somatotroph G R F receptors and/or provide increased negative feedback w h e n h G R F is intravenously administered. The results of this pilot study must be considered preliminary and further studies will be needed to d e m o n s t r a t e what percentage o f d e p r e s s e d patients have this abnormality, if there are differences in patients with major depressive disorder and bipolar disorder and " s t a t e trait" distinctions.
REFERENCES 1. Brown, G. M., J. A. Seggie, J. W. Chambers and P. G. Ettigi. 13. Insel, T. R. and L. J. Siever. The dopamine system challenge in affective disorders: A review of behavioral and neuroendocrine Psychoendocrinoiogy and growth hormone: A review. responses. J Clin Psychopharmacol 1: 207-213, 1981. Psychoneuroendocrinology 2: 131-153, 1978. 14. Kathol, R. G., B. M. Sherman, G. Winokur, D. Lewis and M. 2. Casper, R. C., J. M. Davis, G. N. Pandey, D. L. Garver and H. Schlesser. Dexamethasone suppression, protirelin stimulation, Dekirmenjian. Neuroendocrine and amine studies in affective and insulin infusion in subtypes of recovered depressive paillness. Psychoneuroendocrinology 2: 105-113, 1977. tients. Psychiatry Res 9: 9%106, 1983. 3. Charney, D. S., G. R. Heninger and D. E. Sternberg. Failure of 15. Laakman von, G. and O. Benkert. Neuroendokrinologie und chronic antidepressants, desmethylimipramine and amitripPsychopharmaka. Arzneimittelforsch 28: 1277-1280, 1980. tyline on the growth hormone response to clonidine. Psychiatry 16. Laakman von, G., O. Benkert, E. Neurlinger, K. V. Werder Res 7: 135-138, 1982. and F. Erhardt. Beeinflussing der Hypophysen-Vorderlappen4. Charney, D. S., G. R. Heninger, D. E. Sternberg, K. M. Hormon-Secretion nach akuter und chronischer Gabe on DesipHafstad, S. Gillings and D. H. Landis. Adrenergic receptor ramin. Arzneimittelforsch 18: 1292-1294, 1978. sensitivity in depression. Effects on clonidine in depressed pa17. Langer, G., G. Heinze, B. Reim and N. Matussek. Reduced tients and healthy subjects. Arch Gen Psychiatry 39: 290-294, growth hormone response to amphetamine in "endogenous" 1982. 5. Checkley, S. A. Corticosteroid and growth hormone responses depressive patients: Studies in normal, "reactive" and "endogenous" depressive, schizophrenic, and chronic alcoholic subto methylamphetamine in depressive illness. Psychol Med 9: 107-115, 1979. jects. Arch Gen Psychiatry 33: 1471-1475, 1976. 18. Ling, N., F. Esch, P. Bohlen, P. Brazou, W. Weherenberg and 6. Checkley, S. A., A. P. Slade and E. Shur. Growth hormone and R. Guillemin. Isolation, primary structure and synthesis of other responses to clonidine in patients with endogenous dehuman hypothalamic somatocrinin: Growth hormone-releasing pression. Br J Psychiatry 138: 51-55, 1981. factor. Proc Natl Acad Sci USA 81: 4302-4306, 1984. 7. Glass, I. B., S. A. Checkley, E. Shur and S. Dawling. The effect of desipramine upon central adrenergic function in depressed 19. Linkowski, P., H. Brauman and J. Mendlewicz. Prolactin and patients. Br J Psychiatry 141: 372-376, 1982. growth hormone response to levodopa in affective illness. 8. Grof, E., G. M. Brown and P. Grof. Neuroendocrine responses Neuropsychobiology 9: 108-112, 1983. as an indicator of recurrence liability in primary affective ill20. Maany, I., J. Mendels, A. Frazer and D. Brunswick. A study of ness. Br J Psychiatry 140: 320--322, 1982. growth hormone release in depression. Neuropsychobiology 5: 9. Gruen, P. H. Endocrine changes in psychiatric diseases. Med 181-189, 1979. Clin North Am 62: 285-296, 1978. 21. Matussek, N., M. Ackenheil, H. Hippius, F. Muller, H. T. 10. Gruen, P. H., E. Sachar, N. Altman and S. Sassin. Growth Schroder, H. Schultes and B. Wasilewski. Effects of clonidine hormone responses to hypoglycemia in post-menopausal deon growth hormone release in psychiatric patients and controls. pressed women. Arch Gen Psychiatry 32: 31-33, 1975. Psychiatry. Res 2: 25-36, 1980. 11. Gruen, P. H., E. J. Sachar, G. Langer, N. Altman, M. Leifer, 22. Meltzer, H. Y., T. Kolakowska, V. S. Fang, L. Fogg, A. A. Frantz and F. S. Halpern. Prolactin responses to neurolepRobertson, R. Lewine, M. Strahilevits and D. Busch. Growth tics in normal and schizophrenic subjects. Arch Gen Psychiatry hormone and prolactin response to apomorphine in schizo35: t08-116, 1978. phrenia and the major affective disorders. Relation to duration 12. Halbreich, U., E. J. Sachar, G. M. Asnis, F. Quitkin, R. S. of illness and depressive symptoms. Arch Gen Psychiatry 41: Nathan, F. S. Halpern and D. F. Klein. Growth hormone re512-519, 1984. sponse to dextroamphetamine in depressed patients and normal subjects. Arch Gen Psychiatry 39: 18%192, 1982.
48 23. Mendlewicz, J., P. Linkowski and E. Van Cauter. Some neuroendocrine parameters in bipolar and unipolar depression. J Affective Disord 1: 25-32, 1979. 24. Mendlewicz, J., P. Linkowski, M. Kerkhofs, D. Desmedt, J. Goldstein, G. Copinschi and C. Van Cuter. Diurnal hypersecretion of growth hormone in depression. J Clin Endocrinol Metab 60: 505-511, 1985. 25. Mueller, P. S., G. R. Heninger and R. K. McDonald. Insulin tolerance test in depression. Arch Gen Psychiatry 21: 587-594, 1969. 26. Puig-Antich, J., R. Goetz, M. Davies, M. A. Tabrizi, H. Novacenko, C. Hanlon, E. J. Sachar and E. C. Weitzman. Growth hormone secretion in prepubertal children with major depression. IV. Sleep related plasma concentrations in a drugfree, fully recovered clinical state. Arch Gen Psychiatry 41: 47%483, 1984. 27. Puig-Antich, J., H. Novacenko, M. Davies, W. J. Chambers, M. A. Tabrizi, V. Krawiec, P. J. Ambrosini and E. J. Sachar. Growth hormone secretion in prepubertal children with major depression. I. Final report on response to insulin-induced hypoglycemia during a depressive episode. Arch Gen Psychiatry 41: 455-460, 1984. 28. Puig-Antich, J., H. Novacenko, M. Davies, M. A. Tabrizi, P. Ambrosini, R. Goetz, J. Bianca, D. Goetz and E. J. Sachar. Growth hormone secretion in prepubertal children with major depression. III. Response to insulin-induced hypoglycemia after recovery from a depressive episode and in a drug-free state. Arch Gen Psychiatry 41: 471-475, 1984. 29. Puig-Antich, J., M. A. Tabrizi, M. Davies, R. Goetz, W. J. Chambers, F. Halpern and E. J. Sachar. Prepubertal endogenous major depressives hyposecrete growth hormone in response to insulin-induced hypoglycemia. Biol Psychiatry 16: 801-818, 1981.
RISCH ET AL. 30. Puig-Antich, J. and B. Weston. The diagnosis and treatment of major depressive disorder in childhood. Atom Rev Med 34: 231-245, 1983. 31. Sachar, E. Neuroendocrine dysfunction in depressive illness. Annu Rev Med 27: 38%396, 1976. 32. Sachar, E. J., N. Altman, P. Gruen, A. Glassman, F. S. Halpern and J. Sassin. Human growth hormone response to levodopa. Relevation to menopause, depression and plasma dopamine concentration. Arch Gen Psychiatt3, 32: 502-503, 1975. 33. Sachar, E. J., J. Finkelstein and L. Hellman. Growth hormone responses in depressive illness. Arch Gen Psychiato" 25: 263269, 1971. 34. Sachar, E. J., A. G. Frantz, N. Altman and J. Sassin. Growth hormone and prolactin in unipolar and bipolar patients: Responses to hypoglycemia and I-dopa. Am ,I Psychiatry 130: 1362-1367, 1973. 35. Siever, L. J., T. R. Insel, D. C. Jimerson, C. R. Lake, T. W. Uhde, J. Aloi and D. L. Murphy. Growth hormone response to clonidine in obsessive-compulsive patients. Brd Psychiato" 142: 184-187, 1983. 36. Siever, L., T. Insel and T. Uhde. Noradrenergic challenges in the affective disorders. J Clin Psychopharmaeol 1: 193-206, 1981. 37. Siever, L., T. W. Uhde, T. R. Insel, B. F. Roy and D. L. Murphy. Growth hormone response to clonidine unchanged chronic clorgyline treatment. Psychiatry Res 7: 13%144, 1982. 38. Van Pragg, H. M. The significance of biological factors in the diagnosis of depressions: II. Hormonal variables. Cotnp Psychiatry 23: 216-226, 1982. 39. Winokur, A., J. Amsterdam, S. Caroff, P. J. Snyder and D. Brunswick. Variability of hormonal responses to a series of neuroendocrine challenges in depressed patients. Am J Psychiato' 139: 3%44, 1982.