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Nocturnal growth hormone secretion in schizophrenic patients and healthy subjects
Psvchiarry Research, 41: 155-161 Elsevier
Nocturnal Patients
155
Growth Hormone Secretion and Healthy Subjects
in Schizophrenic
Rem5 S. Kahn, Michael Davidson, Jack Hirschowitz, Robert G. Stern, Bonnie M. Davis, Steve Gabriel, Clare Moore, and Kenneth L. Davis Received September January 19, 1992.
30, 1991; revised
version
received
December
30, 1991; accepted
Abstract. Plasma growth hormone concentrations were measured at hourly intervals between 10 p.m. and 8 a.m. the next morning in 15 drug-free chronic schizophrenic male inpatients and 14 healthy males. Growth hormone secretion was significantly lower in the patients as compared with the controls. Growth hormone release peaked around I a.m. in the controls, but a growth hormone peak was absent in the patient group. Increased dopamine activity, increased serotonin activity, or both could explain the absence of a nocturnal growth hormone surge in the schizophrenic patients.
Key Words. Psychoendocrinology,
hormones,
dopamine,
serotonin.
Growth hormone (GH) release is under the control of various monoaminergic neurotransmitters, most notably dopamine (DA), noradrenalin, and serotonin (5 hydroxytryptamine; 5HT) (Lal, 1987) all of which have been implicated in the pathophysiology of schizophrenia. Therefore, GH secretion, at baseline and after stimulation, has been measured to investigate neurotransmitter abnormalities in schizophrenia (for a review, see Tuomisto and Mtinnistb, 1985). Under physiological conditions, GH is secreted in several bursts during a 24-hour period (Thorner et al., 1990). The maximal peak occurs during sleep, and is most likely related to Slow Wave Sleep (SWS) (Mendelson, 1982; Costin et al., 1989). Other factors, not related to monoaminergic control, also affect GH secretion. For example, obesity (Williams et al., 1984) and advanced age (Vermeulen, 1987; Costin et al., 1989) reduce the magnitude and frequency of GH peaks. In contrast, fasting
Rene S. Kahn, M.D., is Acting
Chief of the Clinical Research Unit, Bronx Veterans Administration Hospital, Department of Psychiatry, Mount Sinai School of Medicine. Michael Davidson, M.D., is Director of Research and Associate Professor, Department of Psychiatry, Mount Sinai School of Medicine. Jack Hirschowitz. M.D.. is Chief of Service for Psvchiatrv. Bronx Veterans Administration Hospital and Professor of Psychiatry, Department of Psychiatry, Mount Sinai School of Medicine. Robert G. Stern, M.D., is Chief Resident, Department of Psychiatry, Mount Sinai School of Medicine. Bonnie M. Davis, M.D., was Medical Director, Clinical Research Unit, Bronx Veterans Administration Hospital and Associate Professor, Department of Psychiatry, Mount Sinai School of Medicine at the time the study was conceived. Steve Gabriel, Ph.D., is Chief of the Neuroendocrinology Laboratory and Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine. Clare Moore, M.S., is Research Assistant, Department of Psychiatry, Mount Sinai School of Medicine. Kenneth L. Davis, M.D., is Professor and Chairman, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY. (Reprint requests to Dr. R.S. Kahn, Dept. of Psychiatry, Bronx Veterans Administration Hospital, 140 W. Kingsbridge Rd., Bronx, NY 10468, USA.) 01651781/92/SO5.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd
156 enhances GH release (Ho et al., 1988). Gender and phase of the menstrual cycle affect GH release as well, probably because estradiol augments GH secretion (Ho et al., 1987). Measurement of baseline plasma GH concentrations in schizophrenia (without prior challenge) has produced inconsistent findings. Studies that measured daytime GH secretion found no differences between schizophrenic patients and normal controls (Tuomisto and Mannistii, 1985). Since under physiologic conditions the largest GH secretion occurs during SWS periods (Mendelson, 1982; Costin et al., 1989) the failure to find group differences may partly reflect the lack of nocturnal GH measurement. In fact, three small studies that examined GH release during sleep in schizophrenic patients reported group differences, suggesting that nocturnal GH secretion is diminished in schizophrenic patients (Vigneri et al., 1974; Isidori et al., 1976; Syvalahti and Pekkarinen, 1977). One study, which measured nocturnal GH release in 10 medicated schizophrenic patients (but not in normal controls), found that the GH peak was absent in two of the patients (Syvalahti and Pekkarinen, 1977). The other two studies compared drug-free patients with normal controls (Vigneri et al., 1974; Isidori et al., 1976). In the latter study, the patients were significantly older than the controls, which may account for the lower GH release found in the patient group (Isidori et al., 1976). The former study included only four patients (Vigneri et al., 1974). Moreover, diagnostic criteria for schizophrenia were not specified in two of the studies (Isidori et al., 1976; Syvllahti and Pekkarinen, 1977). Because of small sample size and methodological problems, these three studies examining (nocturnal) GH release in schizophrenia should be viewed as inconclusive. In contrast to these studies, a recently published report found 24-hour GH secretion to be normal in nine schizophrenic males when compared with that in nine healthy males (Van Cauter et al., 1991). This study examined nocturnal GH release in 15 drug-free male schizophrenic patients and 14 male controls with special consideration given to methodological issues related to psychiatric diagnosis and factors that could affect or interfere with measurements of GH secretion. Methods Subjects. Fourteen normal male controls (mean age = 37.9 years, SD = 11.6) and IS male schizophrenic inpatients (mean age = 41.3 years, SD = 9.4; mean age of onset of illness = 23. I years, SD = 3. I) participated in this study. All subjects were within 25% of their ideal body weight, had normal laboratory (including thyroid indices) and physical examinations, and had been free of drug and alcohol use for at least 2 weeks. All patients were given the Schedule for Affective Disorders and Schizophrenia (SADS) interview (Endicott and Spitzer, 1978) and received diagnoses based on Research Diagnostic Criteria (RDC; Spitzer et al., 1978) and 1987). Patients were interviewed by two DSM-III- R (American Psychiatric Association, raters, who, present during the same interview, independently assigned DSM-III-R and RDC diagnoses. The ratings and diagnoses were presented at a consensus meeting with a supervising diagnostician who obtained a consensus on the final diagnosis. Interrater reliability for the initial independent diagnoses was high (K = 0.86). All patients were diagnosed as having schizophrenia. Procedures.
Control
subjects
arrived
on the research
unit around
5 p.m. and stayed on the
157 unit for about 40 hours. Patients had been on the unit at least 6 weeks and were drug-free for at least 2 weeks (mean time drug-free = 22.5, SD = 8.2 days) and free of depot neuroleptic for at least 3 months. Patients were allowed chloral hydrate (up to 1000 mg/day) for insomnia or agitation (except for the two study days). Patients and controls were maintained on a low monoamine diet from admission until discharge. At 10 p.m. of the first study day, an armboard was attached to adapt the subject to the procedure. This was removed the next morning at 10 a.m. On the second night, an intravenous catheter was inserted at 10 p.m. and remained in place until 10 a.m. the next morning. Blood samples were obtained once every hour from 11 p.m. until 10 a.m. the next morning. Sleep was recorded in a logbook once every hour. Assay Method. GH was measured using a room temperature modification of the reagents purchased from ICN/Micromedic (Carson, CA). Samples, standards, and controls were assayed in lOO+.d aliquots and run under equilibrium conditions with 100 ~1 of each primary antibody and radio-iodinated tracer. Phase separation was achieved by the addition of 0.5 ml of a goat anti-rabbit gamma globulin/ polyethylene glycol solution followed by centrifugation, decanting, and gamma counting of the precipitate. This assay had an ED,, of 4.08 ng/ml and a sensitivity (ED,,) of 0.5 ng/ ml. The interassay and intra-assay coefficients of variation were 8% and 3%, respectively. Data Analysis. GH levels were compared for the two groups using repeated measures analysis of variance with one between-subjects variable, group (patients and controls) and one repeated measure, time (23, 24, 1, 2, 3, 4, 5, 6, 7, and 8 hours; due to missing values, results
from the 9 a.m. and 10 a.m. time were not used for analysis). For post hoc analysis, the Scheffe method was used. To compare the total amount of GH released during the period of study, the two groups were compared by Student’s t test on GH area under the curve (AUC). The AUC was calculated using the 1I p.m. GH value as a baseline. To examine the relationship between GH release and weight, height and age, Pearson product-moment correlations were conducted between GH AUC and these variables. Data are presented as mean f SD, unless otherwise indicated.
Results GH plasma concentrations over time were significantly lower in the patients as compared with the controls (F = 9.95; df = 1,27;p < 0.005)(Fig. 1). Total GH release, as expressed as AUC, in patients (2.7f 1110.1 ng/ml/ 11 hours) was also significantly lower than that of the normal controls (1160.4 I!Z858.4 ng/ ml/ 1 I hours; t = 3.13, df = 27,p < 0.005) (Fig. 2). There was also a significant group X time interaction (F= 2.29; df = 9,243;p < 0.02) (Fig. 1). A post hoc analysis using the Scheffe method showed that this interaction was due to a GH peak among the normal subjects at I and 2 a.m. that was absent in the patients. When data were analyzed after logarithmic conversion, the results did not change. Patients and controls did not differ significantly in age, weight (controls: 74.2 + 10.3 kg; patients: 76.8 + 13.5 kg), height (controls: 174.8 f 7.3 cm; patients: 173.5 f 8.4 cm), and time slept (controls: 5.5 + 2.5 hours; patients: 5.6 f 3.6 hours). Weight (r = -0.35) and age (r = -0.29) showed negative, but nonsignificant, correlations with total nocturnal GH secretion. Age of onset of illness in the patients was positively, but not significantly, correlated (r = 0.36) with total nocturnal GH release. Time drugfree was not correlated with total nocturnal GH secretion in the patients (r = 0.005).
158
Fig. 1. Mean and standard error of the mean plasma growth hormone concentrations in schizophrenic patients and controls 8 - n NC (N=14)
(W
6-
2-
24
2
6 CLOCK
Schizophrenic
8
H:“RS
patbents (PT; open squares, n = 15). Normal controls (NC; solid squares, n = 14)
Fig. 2. Individual, mean, and standard error of the mean total nocturnal GH secretion for normal controls and schizophrenic patients 3000
n nn
2000
-
0
l .=
0 0 NC
PT
Growth hormone (GH) secretion (from 11 p.m. until 8 a.m.1 is expressed as area under the curve (AUC) for normal controls (NC; solid squares) and schizophrenic patients (PT: open squares).
Discussion This study found decreased nocturnal GH release in male schizophrenic patients as compared with healthy male controls, a finding that is in agreement with three prior studies (Vigneri et al., 1974; lsidori et al., 1976; Syvalahti and Pekkarinen, 1977). In contrast to these earlier studies, the present study examined a well-defined group of schizophrenic patients and controlled for confounding factors, such as age, weight, and diet. However, a more recent study, also controlling for age, weight, and diet,
159 found nocturnal GH release to be normal in nine schizophrenic males (Van Cauter et al., 1991). The different results may be due to differences in patient population studied. The mean duration of illness in the present study was 18 years, while Van Cauter et al. (1991) studied patients with a more recent onset of illness (duration of illness = 8.7 years). Thus, we studied an older, more chronically ill patient population. It may be that blunted nocturnal GH secretion is primarily found in chronic schizophrenic patients. Finally, the study by Van Cauter et al. (1991) did find higher nocturnal peak GH release in the controls than in the patients, an effect that might have proved significant had more subjects been studied. Since the release of GH that is normally induced by GH releasing factor is inhibited by DA in vitro (Lindstrom and Ohlsson, 1987) it may be hypothesized that the blunting of GH release found in the schizophrenic patients in this study is due to increased DA activity. However, the one study examining the effect of DA on nocturnal GH release in man found that increasing DA activity (through administration of L-dopa) did not alter nocturnal GH release (Chihara et al., 1976). Moreover, in another nocturnal study comparing plasma homovanillic acid (pHVA, the metabolite of DA) concentrations in schizophrenic patients and healthy controls, pHVA was actually lower in patients than in controls (Davidson and Davis, 1988). Since the 5HT antagonist, methysergide, augments nocturnal GH release in man (Mendelson, 1982), the diminished GH release in the patients could also be due to increased 5HT activity. Moreover, the 5HTtc,2 antagonist, ritanserin, increases SWS in normal human subjects (Idzikowski et al., 1986; Sharpley et al., 1990) suggesting that increasing 5HT function decreases SWS. Indeed, the 5HT agonist, meta-chlorophenylpiperazine, decreases SWS in healthy human subjects (Lawlor et al., 1991). Thus, increased 5HT function may explain the blunted nocturnal GH secretion in the schizophrenic patients, either as a direct inhibition of GH release, or as a result of decreasing SWS (as indicated, SWS probably leads to the nocturnal GH surge). Increased 5HT function has been suggested as a pathogenetic mechanism in some schizophrenic patients-in particular, chronic treatment-refractory patients (see Bleich et al., 1988). It is important to note that the patient sample from this study consisted of chronic patients with an average duration of illness of 18 years, and that 13 out of the 15 patients had proved refractory to treatment with conventional neuroleptics. Indeed, the fact that this study examined a cohort of chronic schizophrenic patients, who were predominantly treatment refractory, may explain the disparity between our results and those of Van Cauter et al., 1991, who found normal nocturnal GH release in a much younger group of schizophrenic patients. It would be overly simplistic, however, to attribute the control of GH secretion or the neurotransmitter defect in schizophrenia exclusively to either a dopaminergic or a serotonergic mechanism. A more plausible hypothesis is that the blunted nocturnal GH secretion reported in schizophrenic patients reflects the dysregulation of both (or more) neurotransmitter systems or an abnormal interrelationship between them, as has been suggested by others (Meltzer, 1989). Results from this study could not be attributed to differences in age, weight, height, or time asleep. However, no electroencephalographic sleep monitoring was available, and therefore it is not possible to assess whether the GH blunting observed
160
was due to a decrease in the amount of SWS in the patient group. Decreased SWS time has been reported in schizophrenia in most studies (see Keshavan et al., 1990), suggesting that the diminished GH secretion found in the schizophrenic patients in this study may be secondary to decreased SWS time. Since it has been suggested that GH inhibits its own release (e.g., Faria et al., 1989), it cannot be ruled out that the decreased nocturnal GH secretion in the schizophrenic patients is a consequence of increased daytime release of GH. However, two studies showed that daytime GH release was normal in schizophrenic patients (Gil-Ad et al., 1986; Van Cauter et al., 1991). Finally, although no effect of a drug-free period on GH release was found, it cannot be ruled out that lingering effects of medication influenced the results of the study. Future studies need to examine whether the diminished nocturnal GH release in schizophrenia is related to decreased SWS. Second, it needs to be studied in normal subjects whether dopaminergic and serotonergic agents affect SWS and nocturnal GH release. Since it has been hypothesized that 5HT mechanisms, or the interaction between 5HT and DA systems, are involved in the efficacy of atypical neuroleptics (Meltzer, 1989), nocturnal GH release in schizophrenic patients should be studied in relationship to chronicity of illness, and treatment response to conventional and atypical neuroleptics. Finally, nocturnal GH release in schizoid and schizotypal personality disorders, first-degree family members of schizophrenic probands, and patients with schizophreniform disorder would be of real interest. The authors are grateful to D. Weston, R.N., and the nursing staff from 3B2 at the Bronx VA Hospital for their work, Dr. J. Schmeidler for his help with the data
Acknowledgments.
analysis, and Ms. Nancy Ruiz for technical assistance. This work was supported by the VA Schizophrenia Biological Research Center grant 4125-020 (Dr. Davis) and by National Institute of Mental Health grant ROI MH-37922-07 (Dr. Davidson).
References American Psychiatric Association. DSM-III-R:
Diagnostic and Statistical Manual ofMental Disorders. 3rd ed., revised. Washington, DC: APA, 1987. Bleich, A.; Brown, S.; Kahn, R.S.; and van Praag, H.M. The role of serotonin in schizophrenia. Schizophrenia Bulletin, 14:297-315, 1988. Chihara, K.; Kato, Y.: Maeda, K.; Ohgo, S.; and Imura, H. Suppressive effect of I-DOPA on human prolactin release during sleep. Acta Endocrinologica, 8 I : 19-27, 1976. Costin, G.; Kaufman, F.R.; and Brasel, J.A. Growth hormone secretory dynamics in subjects with normal stature. Journal of Pediatrics, 115:537-544, 1989. Davidson, M., and Davis, K.L. A comparison of plasma homovanillic acid concentrations in schizophrenics and normal controls. Archives of General Psychiatry, 45:561-563, 1988. Endicott, J., and Spitzer, R.L. A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Archives of General Psychiatry, 35:837-844, 1978. Faria, A.C.S.; Veldhuis, J.D.; Thorner, M.O.; and Vance, M.L. Half-time of endogenous growth hormone (GH) disappearance in normal man after stimulation of GH secretion by GH-releasing hormone and suppression with somatostatin. Journalof Clinical Endocrinology and Metabolism, 68:535-541, 1989. Gil-Ad, 1.; Dickerman, Z.; Amdursky, S.; and Laron, Z. Diurnal rhythm of plasma betaendorphin, cortisol and growth hormone in schizophrenics as compared to control subjects. Psychopharmacology, 88:496-499, 1986.
161 Ho, K.Y.; Evans, W.S.; Blizzard, R.M.; Veldhuis, J.D.; Merriam, G.R.; Samojlik, E.; Furlanetto, R.; Rogol, A.D.; Kaiser, D.L.; and Thorner, M.O. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: Importance of endogenous estradiol concentrations. Journal of Clinical Endocrinology and Metabolism, 6451-58, 1987. Ho, K.Y.; Veldhuis, J.D.; Johnson, M.L.; Furlanetto, R.; Evans, W.S.; Alberti, K.G.M.M.; and Thorner, M.O. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. Journal of Clinical Investigation, 81:968-975, 1988. Idzikowski, C.; Mills, F.J.; and Glennard, R. 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. Brain Research, 378:164-168, 1986. Isidori, A.; Fraioli, F.; Rotolo, A.; Piro, C.; Conte, D.; Muratorio, A.; Murri, L.; and Cerone, G. Poly-hormonal evaluation of pulsatile adenohypophysis incretory activity during sleep in normal experimental and pathological conditions. Chronobiologia, 3:39-50, 1976. Keshavan, MS.; Reynolds, C.F.; and Kupfer, D.J. Electroencephalographic sleep in schizophrenia: A critical review. Comprehensive Psychiatry, 30:34-47, 1990. Lal, S. Growth hormone and schizophrenia. In: Meltzer, H.Y., ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987. pp. 809-818. Lawlor, B.; Newhouse, P.A.; Ba1kinT.U.J.; Molchan, S.E.; Mellow, A.M.; Murphy, D.L.; and Sunderland, T. A preliminary study of the effects of nighttime administration of the serotonin agonist, m-chlorophenylpiperazine on sleep architecture and behavior in healthy volunteers. Biological Psychiatry, 29:28 l-286, 199 I. Lindstrom, P., and Ohlsson, L. Effects of 5_hydroxytryptamine, dopamine and aromatic amino acids on growth hormone (GH) releasing factor-stimulated GH release in rat anterior pituitaries. Endocrinology, 120:780-784, 1987. Meltzer, H.Y. Clinical studies on the mechanisms of action of clozapine: The dopamine serotonin hypothesis of schizophrenia. Psychopharmacology, 99:S18-S27, 1989. Mendelson, W.B. Studies of human growth hormone secretion in sleep and waking. Reviews in Neurobiology, 23:367-389, 1982. Sharpley, A.L.; Solomon, R.A.; Fernando, A.I.; da Roza Davis, D.M.; and Cowen, P.J. Dose-related effects of selective 5HT2 receptor antagonists on slow wave sleep in humans. Psychopharmacology, 101:568-569, 1990. Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 35:773-782, 1978. Syvalahti, E., and Pekkarinen, A. Serum growth hormone levels in schizophrenic patients during sleep. Journal of Neural Transmission, 40:221-226, 1977. Thorner, M.O.; Vance, M.L.; Hartman, R.W.; Evans, W.S.; Veldhuis, J.D.; Van Cauter, E.; Copinschi, G.; and Bowers, C.Y. Physiological role of somatostatin on growth hormone regulation in humans. Metabolism, 39:40-42, 1990. Tuomisto, J., and Mannistii, P. Neurotransmittor regulation of anterior pituitary hormones. Pharmacological Reviews, 371249-332, 1985. Van Cauter, E.; Linkowski, P.; Kerkhofs, M.; Hubain, Ph.; L’Hermitte-Baleriaux, M.; Leclerq, R.; Brasseur, M.; Copinschi, G.; and Mendlewicz, J. Circadian and sleep-related endocrine rhythms in schizophrenia. Archives of General Psychiatry, 48:348-356, 1991. Vermeulen, A. Nyctohemeral growth hormone profiles in young and aged men: Correlation with somatomedin-C levels. Journal of Clinical Endocrinology and Metabolism, 64:884-888, 1987. Vigneri, R.; Pezzino, V.; Squatrito, S.; Calandra, A.; and Marcchiolo, M. Sleep-associated growth hormone (GH) release in schizophrenia. Neuroendocrinology, 14:356-361, 1974. Williams, T.; Berelowitz, M.; Joffe, S.N.; Thorner, M.O.; Rivier, J.; Vale, W.; and Frohman, L.A. Impaired growth hormone responses to growth hormone releasing factor in obesity: A pituitary defect reversed with weight reduction. New England Journal of Medicine, 311:1403-1407. 1984.
Nocturnal Patients
155
Growth Hormone Secretion and Healthy Subjects
in Schizophrenic
Rem5 S. Kahn, Michael Davidson, Jack Hirschowitz, Robert G. Stern, Bonnie M. Davis, Steve Gabriel, Clare Moore, and Kenneth L. Davis Received September January 19, 1992.
30, 1991; revised
version
received
December
30, 1991; accepted
Abstract. Plasma growth hormone concentrations were measured at hourly intervals between 10 p.m. and 8 a.m. the next morning in 15 drug-free chronic schizophrenic male inpatients and 14 healthy males. Growth hormone secretion was significantly lower in the patients as compared with the controls. Growth hormone release peaked around I a.m. in the controls, but a growth hormone peak was absent in the patient group. Increased dopamine activity, increased serotonin activity, or both could explain the absence of a nocturnal growth hormone surge in the schizophrenic patients.
Key Words. Psychoendocrinology,
hormones,
dopamine,
serotonin.
Growth hormone (GH) release is under the control of various monoaminergic neurotransmitters, most notably dopamine (DA), noradrenalin, and serotonin (5 hydroxytryptamine; 5HT) (Lal, 1987) all of which have been implicated in the pathophysiology of schizophrenia. Therefore, GH secretion, at baseline and after stimulation, has been measured to investigate neurotransmitter abnormalities in schizophrenia (for a review, see Tuomisto and Mtinnistb, 1985). Under physiological conditions, GH is secreted in several bursts during a 24-hour period (Thorner et al., 1990). The maximal peak occurs during sleep, and is most likely related to Slow Wave Sleep (SWS) (Mendelson, 1982; Costin et al., 1989). Other factors, not related to monoaminergic control, also affect GH secretion. For example, obesity (Williams et al., 1984) and advanced age (Vermeulen, 1987; Costin et al., 1989) reduce the magnitude and frequency of GH peaks. In contrast, fasting
Rene S. Kahn, M.D., is Acting
Chief of the Clinical Research Unit, Bronx Veterans Administration Hospital, Department of Psychiatry, Mount Sinai School of Medicine. Michael Davidson, M.D., is Director of Research and Associate Professor, Department of Psychiatry, Mount Sinai School of Medicine. Jack Hirschowitz. M.D.. is Chief of Service for Psvchiatrv. Bronx Veterans Administration Hospital and Professor of Psychiatry, Department of Psychiatry, Mount Sinai School of Medicine. Robert G. Stern, M.D., is Chief Resident, Department of Psychiatry, Mount Sinai School of Medicine. Bonnie M. Davis, M.D., was Medical Director, Clinical Research Unit, Bronx Veterans Administration Hospital and Associate Professor, Department of Psychiatry, Mount Sinai School of Medicine at the time the study was conceived. Steve Gabriel, Ph.D., is Chief of the Neuroendocrinology Laboratory and Assistant Professor, Department of Psychiatry, Mount Sinai School of Medicine. Clare Moore, M.S., is Research Assistant, Department of Psychiatry, Mount Sinai School of Medicine. Kenneth L. Davis, M.D., is Professor and Chairman, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY. (Reprint requests to Dr. R.S. Kahn, Dept. of Psychiatry, Bronx Veterans Administration Hospital, 140 W. Kingsbridge Rd., Bronx, NY 10468, USA.) 01651781/92/SO5.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd
156 enhances GH release (Ho et al., 1988). Gender and phase of the menstrual cycle affect GH release as well, probably because estradiol augments GH secretion (Ho et al., 1987). Measurement of baseline plasma GH concentrations in schizophrenia (without prior challenge) has produced inconsistent findings. Studies that measured daytime GH secretion found no differences between schizophrenic patients and normal controls (Tuomisto and Mannistii, 1985). Since under physiologic conditions the largest GH secretion occurs during SWS periods (Mendelson, 1982; Costin et al., 1989) the failure to find group differences may partly reflect the lack of nocturnal GH measurement. In fact, three small studies that examined GH release during sleep in schizophrenic patients reported group differences, suggesting that nocturnal GH secretion is diminished in schizophrenic patients (Vigneri et al., 1974; Isidori et al., 1976; Syvalahti and Pekkarinen, 1977). One study, which measured nocturnal GH release in 10 medicated schizophrenic patients (but not in normal controls), found that the GH peak was absent in two of the patients (Syvalahti and Pekkarinen, 1977). The other two studies compared drug-free patients with normal controls (Vigneri et al., 1974; Isidori et al., 1976). In the latter study, the patients were significantly older than the controls, which may account for the lower GH release found in the patient group (Isidori et al., 1976). The former study included only four patients (Vigneri et al., 1974). Moreover, diagnostic criteria for schizophrenia were not specified in two of the studies (Isidori et al., 1976; Syvllahti and Pekkarinen, 1977). Because of small sample size and methodological problems, these three studies examining (nocturnal) GH release in schizophrenia should be viewed as inconclusive. In contrast to these studies, a recently published report found 24-hour GH secretion to be normal in nine schizophrenic males when compared with that in nine healthy males (Van Cauter et al., 1991). This study examined nocturnal GH release in 15 drug-free male schizophrenic patients and 14 male controls with special consideration given to methodological issues related to psychiatric diagnosis and factors that could affect or interfere with measurements of GH secretion. Methods Subjects. Fourteen normal male controls (mean age = 37.9 years, SD = 11.6) and IS male schizophrenic inpatients (mean age = 41.3 years, SD = 9.4; mean age of onset of illness = 23. I years, SD = 3. I) participated in this study. All subjects were within 25% of their ideal body weight, had normal laboratory (including thyroid indices) and physical examinations, and had been free of drug and alcohol use for at least 2 weeks. All patients were given the Schedule for Affective Disorders and Schizophrenia (SADS) interview (Endicott and Spitzer, 1978) and received diagnoses based on Research Diagnostic Criteria (RDC; Spitzer et al., 1978) and 1987). Patients were interviewed by two DSM-III- R (American Psychiatric Association, raters, who, present during the same interview, independently assigned DSM-III-R and RDC diagnoses. The ratings and diagnoses were presented at a consensus meeting with a supervising diagnostician who obtained a consensus on the final diagnosis. Interrater reliability for the initial independent diagnoses was high (K = 0.86). All patients were diagnosed as having schizophrenia. Procedures.
Control
subjects
arrived
on the research
unit around
5 p.m. and stayed on the
157 unit for about 40 hours. Patients had been on the unit at least 6 weeks and were drug-free for at least 2 weeks (mean time drug-free = 22.5, SD = 8.2 days) and free of depot neuroleptic for at least 3 months. Patients were allowed chloral hydrate (up to 1000 mg/day) for insomnia or agitation (except for the two study days). Patients and controls were maintained on a low monoamine diet from admission until discharge. At 10 p.m. of the first study day, an armboard was attached to adapt the subject to the procedure. This was removed the next morning at 10 a.m. On the second night, an intravenous catheter was inserted at 10 p.m. and remained in place until 10 a.m. the next morning. Blood samples were obtained once every hour from 11 p.m. until 10 a.m. the next morning. Sleep was recorded in a logbook once every hour. Assay Method. GH was measured using a room temperature modification of the reagents purchased from ICN/Micromedic (Carson, CA). Samples, standards, and controls were assayed in lOO+.d aliquots and run under equilibrium conditions with 100 ~1 of each primary antibody and radio-iodinated tracer. Phase separation was achieved by the addition of 0.5 ml of a goat anti-rabbit gamma globulin/ polyethylene glycol solution followed by centrifugation, decanting, and gamma counting of the precipitate. This assay had an ED,, of 4.08 ng/ml and a sensitivity (ED,,) of 0.5 ng/ ml. The interassay and intra-assay coefficients of variation were 8% and 3%, respectively. Data Analysis. GH levels were compared for the two groups using repeated measures analysis of variance with one between-subjects variable, group (patients and controls) and one repeated measure, time (23, 24, 1, 2, 3, 4, 5, 6, 7, and 8 hours; due to missing values, results
from the 9 a.m. and 10 a.m. time were not used for analysis). For post hoc analysis, the Scheffe method was used. To compare the total amount of GH released during the period of study, the two groups were compared by Student’s t test on GH area under the curve (AUC). The AUC was calculated using the 1I p.m. GH value as a baseline. To examine the relationship between GH release and weight, height and age, Pearson product-moment correlations were conducted between GH AUC and these variables. Data are presented as mean f SD, unless otherwise indicated.
Results GH plasma concentrations over time were significantly lower in the patients as compared with the controls (F = 9.95; df = 1,27;p < 0.005)(Fig. 1). Total GH release, as expressed as AUC, in patients (2.7f 1110.1 ng/ml/ 11 hours) was also significantly lower than that of the normal controls (1160.4 I!Z858.4 ng/ ml/ 1 I hours; t = 3.13, df = 27,p < 0.005) (Fig. 2). There was also a significant group X time interaction (F= 2.29; df = 9,243;p < 0.02) (Fig. 1). A post hoc analysis using the Scheffe method showed that this interaction was due to a GH peak among the normal subjects at I and 2 a.m. that was absent in the patients. When data were analyzed after logarithmic conversion, the results did not change. Patients and controls did not differ significantly in age, weight (controls: 74.2 + 10.3 kg; patients: 76.8 + 13.5 kg), height (controls: 174.8 f 7.3 cm; patients: 173.5 f 8.4 cm), and time slept (controls: 5.5 + 2.5 hours; patients: 5.6 f 3.6 hours). Weight (r = -0.35) and age (r = -0.29) showed negative, but nonsignificant, correlations with total nocturnal GH secretion. Age of onset of illness in the patients was positively, but not significantly, correlated (r = 0.36) with total nocturnal GH release. Time drugfree was not correlated with total nocturnal GH secretion in the patients (r = 0.005).
158
Fig. 1. Mean and standard error of the mean plasma growth hormone concentrations in schizophrenic patients and controls 8 - n NC (N=14)
(W
6-
2-
24
2
6 CLOCK
Schizophrenic
8
H:“RS
patbents (PT; open squares, n = 15). Normal controls (NC; solid squares, n = 14)
Fig. 2. Individual, mean, and standard error of the mean total nocturnal GH secretion for normal controls and schizophrenic patients 3000
n nn
2000
-
0
l .=
0 0 NC
PT
Growth hormone (GH) secretion (from 11 p.m. until 8 a.m.1 is expressed as area under the curve (AUC) for normal controls (NC; solid squares) and schizophrenic patients (PT: open squares).
Discussion This study found decreased nocturnal GH release in male schizophrenic patients as compared with healthy male controls, a finding that is in agreement with three prior studies (Vigneri et al., 1974; lsidori et al., 1976; Syvalahti and Pekkarinen, 1977). In contrast to these earlier studies, the present study examined a well-defined group of schizophrenic patients and controlled for confounding factors, such as age, weight, and diet. However, a more recent study, also controlling for age, weight, and diet,
159 found nocturnal GH release to be normal in nine schizophrenic males (Van Cauter et al., 1991). The different results may be due to differences in patient population studied. The mean duration of illness in the present study was 18 years, while Van Cauter et al. (1991) studied patients with a more recent onset of illness (duration of illness = 8.7 years). Thus, we studied an older, more chronically ill patient population. It may be that blunted nocturnal GH secretion is primarily found in chronic schizophrenic patients. Finally, the study by Van Cauter et al. (1991) did find higher nocturnal peak GH release in the controls than in the patients, an effect that might have proved significant had more subjects been studied. Since the release of GH that is normally induced by GH releasing factor is inhibited by DA in vitro (Lindstrom and Ohlsson, 1987) it may be hypothesized that the blunting of GH release found in the schizophrenic patients in this study is due to increased DA activity. However, the one study examining the effect of DA on nocturnal GH release in man found that increasing DA activity (through administration of L-dopa) did not alter nocturnal GH release (Chihara et al., 1976). Moreover, in another nocturnal study comparing plasma homovanillic acid (pHVA, the metabolite of DA) concentrations in schizophrenic patients and healthy controls, pHVA was actually lower in patients than in controls (Davidson and Davis, 1988). Since the 5HT antagonist, methysergide, augments nocturnal GH release in man (Mendelson, 1982), the diminished GH release in the patients could also be due to increased 5HT activity. Moreover, the 5HTtc,2 antagonist, ritanserin, increases SWS in normal human subjects (Idzikowski et al., 1986; Sharpley et al., 1990) suggesting that increasing 5HT function decreases SWS. Indeed, the 5HT agonist, meta-chlorophenylpiperazine, decreases SWS in healthy human subjects (Lawlor et al., 1991). Thus, increased 5HT function may explain the blunted nocturnal GH secretion in the schizophrenic patients, either as a direct inhibition of GH release, or as a result of decreasing SWS (as indicated, SWS probably leads to the nocturnal GH surge). Increased 5HT function has been suggested as a pathogenetic mechanism in some schizophrenic patients-in particular, chronic treatment-refractory patients (see Bleich et al., 1988). It is important to note that the patient sample from this study consisted of chronic patients with an average duration of illness of 18 years, and that 13 out of the 15 patients had proved refractory to treatment with conventional neuroleptics. Indeed, the fact that this study examined a cohort of chronic schizophrenic patients, who were predominantly treatment refractory, may explain the disparity between our results and those of Van Cauter et al., 1991, who found normal nocturnal GH release in a much younger group of schizophrenic patients. It would be overly simplistic, however, to attribute the control of GH secretion or the neurotransmitter defect in schizophrenia exclusively to either a dopaminergic or a serotonergic mechanism. A more plausible hypothesis is that the blunted nocturnal GH secretion reported in schizophrenic patients reflects the dysregulation of both (or more) neurotransmitter systems or an abnormal interrelationship between them, as has been suggested by others (Meltzer, 1989). Results from this study could not be attributed to differences in age, weight, height, or time asleep. However, no electroencephalographic sleep monitoring was available, and therefore it is not possible to assess whether the GH blunting observed
160
was due to a decrease in the amount of SWS in the patient group. Decreased SWS time has been reported in schizophrenia in most studies (see Keshavan et al., 1990), suggesting that the diminished GH secretion found in the schizophrenic patients in this study may be secondary to decreased SWS time. Since it has been suggested that GH inhibits its own release (e.g., Faria et al., 1989), it cannot be ruled out that the decreased nocturnal GH secretion in the schizophrenic patients is a consequence of increased daytime release of GH. However, two studies showed that daytime GH release was normal in schizophrenic patients (Gil-Ad et al., 1986; Van Cauter et al., 1991). Finally, although no effect of a drug-free period on GH release was found, it cannot be ruled out that lingering effects of medication influenced the results of the study. Future studies need to examine whether the diminished nocturnal GH release in schizophrenia is related to decreased SWS. Second, it needs to be studied in normal subjects whether dopaminergic and serotonergic agents affect SWS and nocturnal GH release. Since it has been hypothesized that 5HT mechanisms, or the interaction between 5HT and DA systems, are involved in the efficacy of atypical neuroleptics (Meltzer, 1989), nocturnal GH release in schizophrenic patients should be studied in relationship to chronicity of illness, and treatment response to conventional and atypical neuroleptics. Finally, nocturnal GH release in schizoid and schizotypal personality disorders, first-degree family members of schizophrenic probands, and patients with schizophreniform disorder would be of real interest. The authors are grateful to D. Weston, R.N., and the nursing staff from 3B2 at the Bronx VA Hospital for their work, Dr. J. Schmeidler for his help with the data
Acknowledgments.
analysis, and Ms. Nancy Ruiz for technical assistance. This work was supported by the VA Schizophrenia Biological Research Center grant 4125-020 (Dr. Davis) and by National Institute of Mental Health grant ROI MH-37922-07 (Dr. Davidson).
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