25
Journal ofAffective Disorders, 1 (1979) 25-32 0 Elsevier/North-Holland Biomedical Press
SOME NEUROENDOCRINE UNIPOLAR DEPRESSION
J. MENDLEWICZ, Department
P. LINKOWSKI
of Psychiatry,
~__
PARAMETERS
IN BIPOLAR
AND
and E. VAN CAUTER
Erasme Hospital,
IJniuersity
of Brussels,
Brussels
(Belgium)
_.._
SUMMARY There is mounting evidence showing that some pituitary and hypothalamic hormones play an important role in the affective disorders and may directly affect brain function and behavior. This report briefly reviews some recent endocrinological studies in affective illness with special reference to bipolar and unipolar form of illness. Data on prolactin and growth hormone response to levodopa in bipolar and unipolar illness are presented. Preliminary data on plasma dopamine beta hydroxylase activity measured over a 24-h period are illustrated in patients suffering from bipolar and unipolar illnesses as compared to controls. The significance of these results is discussed in relation to biogenic amine dysfunction in the major affective disorders.
INTRODUCTION
Alterations in neurotransmitter activity as has been postulated in the major affective illnesses may result in neuroendocrine disturbances in these mood disorders. A relationship between hormones and behavior has been recognized for many years, although the concrete interaction between the endocrine system and brain function remains to be clarified. The recent development of reliable radioimmunoassay methods for measuring pituitary hormones such as growth hormone (HGH), prolactin and thyrotropin (TSH) has led to studies indicating that some of these hormones may respond rapidly and markedly to psychological influence in both humans and animals (Noel et al. 1972; Brown 1974). Carol1 (1972) has made extensive reviews of adrenocortical activity in relation to the hypothalamopituitary-adrenal axis in depression. According to this author, most studies demonstrate hypercorticosteroid secretion in depression. Much literature has also been devoted to the relationship between the thyroid axis and depression. Several controlled studies have reported that triiodothyronine potentiates the effect of tricyclic antidepressants by increasing the responsiveness of some receptor sites in the brain (Prange et al. 1969; Wilson et al. 1970). This is based, however, on the assumption that receptors involved in the action of antidepres-
26
sant drugs are also implicated in the etiology of depressive illness, a fact which remains to be proven. Secondly, it has been observed that the administration of thyrotropin-releasing hormone (TRH) causes a rapid but transient, elevation of mood in some depressed patients (Prange et al. 1972; Coppen et al. 1974). TRH indeed possesses brain actions in animals, which do not seem to be mediated by the anterior pituitary. TRH has been shown to potentiate in hypophysectomized mice the behavioral activation caused by the administration of pargyline (a monoamine oxydase inhibitor) and levodopa (Breese et al. 1974). Furthermore, there is biochemical evidence (although controversial) showing that TRH increases brain catecholamine turnover (Keller et al. 1974). These animal findings have led a number of investigators to test the antidepressive effect of TRH in depressed patients. The results are conflicting (Kastin et al. 1972; Prange et al. 1972; Coppen et al. 1974), but it is now clear that TRH is not an effective and lasting treatment for depression. TRH rapid and brief physiologic action remains puzzling and is of great interest for research. The TRH studies have also contributed to our knowledge of depressive disorders by showing that after the administration of TRH, the thyrotropin (TSH) output of the pituitary is flat in some depressed patients (Kastin et al. 1972; Prange et al. 1972). This observation has now been widely confirmed and suggests that pituitary reaction to TRH is reduced in depression through thyroid function revealed to be normal (Kastin et al. 1972; Takahashi et al. 1973). After recovery from antidepressant drug treatment or electro-convulsive treatment, a significant increase of TSH response to TRH was observed (Kirkegaard et al. 1975). Recently, Gold et al. (1978) have shown differences in TSH response to TRH in major affective disorders. Unipolar (depressive) patients had a lower TSH secretion than did bipolar patients, as compared to normal controls. Furthermore, there was a difference in TSH output in bipolar (manic-depressive) patients according to clinical state. TSH response was lower in mania than in depression. Growt,h hormone (HGH), another pituitary hormone has been extensively studied in affective disorders and its regulation has been shown to be abnormal in depression. Studies have been conducted by Sachar’s group indicating a lack of GH response to insulin hypoglycemia in postmenopausal depressed women when compared with proprer controls (Sachar et al. 1972). Levodopa, an amino acid precursor of dopamine and norepinephrine has been shown to cause an elevation in plasma GH in normal subjects (Martin 1970). The levodopa test is an interesting research tool in the neuroendocrinological assessment of the affective disorders, because it allows to monitor HGH and prolactin response (two important pituitary hormones) in various affective states. Sachar et al. have reported diminished GH levels in response to levodopa in unipolar depressed patients, but this reduction in GH response has been partly related to age and sex (Sachar et al. 1972, 1973, 1975). There are indeed a number of factors affecting GH secretion. Among them
27
are sleep, diet, oestrogen levels and phase of menstrual cycle (Brown and Reichlin 1972). Frazer (1975) has also shown that GH response to levodopa was abnormal in two out of three hypomanic bipolar patients. More recently, Gold et al. (1976) reported an elevated GH response and greater prolactin suppression of levodopa in bipolar depressed patients than in unipolar patients and controls. Among the bipolar patients the depressive phase was associated with a significantly better GH response to levodopa than the manic phase. Furthermore, these authors failed to observe a relationship between neuroendocrine response to levodopa and age in their group of affectively ill patients. Because of apparent discrepancies between the above studies, we have conducted levodopa tests in a large and homogenous group of patients diagnosed as having primary affective disorders. Preliminary results on the levodopa tests in affective illness were reported elsewhere (Mendlewicz et al. 1977). Studies on 24-h plasma DBH activity in some unipolar and bipolar depressed patients were also performed (Van Cauter and Mendlewicz 1978). METHOD
AND RESULTS
All patients consecutively admitted to a female inpatient unit with a diagnosis of primary affective disorder according to Feighner’s criteria (1972) and who were willing to participate in our endocrinological investigations were included in the present study. There were 43 such women subdiagnosed in 18 bipolar and 25 unipolar female patients, using a modified version of a semi-structured interview: the Current and Past Psychopathology Scales (CAPPS). GH and prolactin secretion to levodopa were studied in these 43 patients. All subjects were on a controlled monoamine-free diet and had been off drugs for at least a week before the levodopa test. After an overnight fast, patients were given 500 mg of levodopa by mouth and blood was drawn every 30 min for 120 min through a plastic indwelling catheter for radioimmunoassay of GH and prolactin (Aubert et al. 1974; Virasoro et al. 1971). Unipolar patients, as a group, had a peak GH increment not different from that in bipolar patients (Fig. 1). However, when menopausal status was taken into account, a difference in GH response to levodopa emerged between bipolar premenopausal women compared to bipolar postmenopausal women. Premenopausal bipolar women had a higher peak GH than did unipolar premenopausal women, but the difference was not significant. The apparent discrepancy between our findings and those of Gold et al. (1976) might be due to the fact that they studied bipolar menopausal females and bipolar males only, while we investigated both premenopausal (N = 3) and postmenopausal (N = 15) bipolar women. In our unipolar group, there were 15 unipolar premenopausal women as compared to 10 unipolar postmenopausal women. We were unable to find any significant difference in GH response and prolactin response to levodopa between pre- and postmenopausal unipolar depressed women, an
28
Unipolar
(25)
Bipolar
Prolactin
(18)
response
O/o Of base line 160
GH response “g/ml
+&zbb--
!?3kbk-
120
Min
Fig. 1. pausal;.
Prolactin
120
Min
and
GH
response
to levodopa
in affective
illness.
-
-
-
= premeno.
. . . . . = postmenopausal.
observation indicating that in our unipolar subgroup, endocrine responses to levodopa are not significantly influenced by the menopausal status. Furthermore, we failed to confirm Gold’s observation of a greater prolactin suppression after levodopa in the bipolar patients. In fact, the opposite seems to be true in our sample. There is a paradoxical rise in prolactin secretion 30--90 min after levodopa administration followed by a subsequent suppression in the bipolar patients. This peak is not present in the unipolar group. This paradoxical response to levodopa is more pronounced in bipolar premenopausal women than in bipolar postmenopausal women. Baseline prolactin levels were not significantly different in bipolar and unipolar patients. Our results on GH response in affective illness accord with the work of Gruen et al. (1975), who found a reduction in GH response to levodopa in postmenopausal women, an observation consistent with the fact that GH stimulation is related to circulating oestrogens (Brown and Reichlin 1972), although this relationship is not apparent in our unipolar population. Nevertheless, bipolar and unipolar premenopausal women cannot be differentiated on the basis of their GH response to levodopa, although there is a trend toward a bigger GH response and less prolactin suppression in the bipolar group. The results on prolactin response to levodopa in affective illness are conflicting and more
difficult to interpret. On our data, the influence of stress-related factors and oestrogen levels on prolactin response to levodopa cannot be excluded. Catecholamine control of GH secretion is mediated through adrenergic receptors in the hypophysiotropic area of the hypothalamus. Dopamine, norepinephrine and serotonin seem to have a positive effect on GH release. Dopamine beta hydroxylase (DBH) is the enzyme which catalyses the terminal step in the biosynthesis of norepinephrine from dopamine. The activity of this enzyme is also used as a monitor of sympathetic activity in man (Viveros et al. 1968). Because of the importance of dopamine and noradrenaline in the control of GH secretion in man and in light of the possible involvement of noradrenaline turnover anomalies in affective disorders, we have measured plasma DBH activities in some bipolar and unipolar patients. Although prior studies including our own have demonstrated that resting levels of plasma DBH activity do not seem to be altered in patients with affective disorders (Shopsin et al. 1972; Levitt et al. 1976), we were able to show in preliminary studies that DBH activity raises significantly along with heart rate after exercise in the cold in some manic-depressive patients as compared to normal controls (Levitt et al. 1976). This observation and the potential (although controversial) value of plasma DBH activity as a possible monitor of sympathetic activity stimulated our interest in measuring plasma DBH activity over 24-h period in depressed patients subdiagnosed as bipolar and unipolar. Blood samples were drawn for 24-h through a plastic indwelling catheter. They were collected every hour during day time and every 30 min during the night. All patients were confined to bed, had normal breakfast, lunch and supper except for a controlled amine diet and their nocturnal sleep was rarely interrupted. DBH activity in plasma was assayed by a modification of the spectrophotometric method described by Nagatsu and Udenfriend (1972). The statistical analysis of the data, including the objective detection of the possible periodicities was performed using the periodogram method (Van Cauter and Huyberechts 1973; Van Cauter 1974). This method applies to each individual series and gives an estimation of the amplitude and the phases of each significant periodicity. Estimated amplitudes and phases of plasma DBH patterns observed in depressed patients (N = 17) were compared to those of normal controls (N = 8). The 17 affectively ill patients were subdiagnosed in bipolar subjects (7 females, one male, aged 37-766) and unipolar subjects (8 females, one male, aged 18--53), all hospitalized at the Psychiatric Institute of the University of Brussels. Figure 2 shows, as an example, the almost identical daily patterns for plasma DBH activity in a pair of monozygotic twins. Theoretical curves are illustrated by the dotted lines. Very similar profiles, all characterized by the occurrence in the mid afternoon hours (3 p.m. to 5 p.m.) of a peak of magnitude between 13 and 39% of the mean, were observed in all normal subjects. A circadian rhythm with no other significant episodic variations is present. When compared to the patterns of normal subjects, the 24-h profiles
301. 8am
Fig.
1
2pm
2. Plasma
I
tipnl
2am
CLock
time
DBH
activity
I
_iOl!
8om
1
3 0 111 2pn-n
Ciock
in normal
,
8pm
2om
1
8ar
time
tissues
for plasma DBH activity present more episodic variations in depressed patients although the afternoon elevation is present in all patterns. Figure 3 shows typical 24-h DBH profiles recorded in the affective patients, one unipolar with a mild depression (SE) and two bipolars with high Hamilton depression scores (TR and ME). Episodic variations are more frequent and their magnitude may be of the same order than of the mid afternoon elevation which no longer appeared as the sole major event in the 24-h variation. In the most severely affected patients, the afternoon elevation completely disappears and no circadian rhythm could be detected. The periodogram analysis allowed to discriminate between bipolar and unipolar patients. Deviations from normal of the 24-h DBH pattern are significantly more important in bipolar than unipolar patients, although they do not correlate with the severity of the mood alterations as assessed by the Hamilton scores. Alterations in 24-h DBH activity in depressed patients may relate to abnormal noradrenergic turnover in the affective psychoses. The studies described above combining neuropharmacological and endocrine methods may enable us to investigate disturbances in hypothalamic functions in various subgroups of
Fig.
3. Plasma
DBH
activity
in affective
illness.
31
affective patients. Caution should be kept neuroendocrine abnormalities in relation neurotransmitter disturbances in the major
however, in the interpretation of to the nature of the underlying affective disorders.
REFERENCES Aubcrt, M.L., Becker, R.L., Saxena, B.B. and Raiti, S., Report of the National Pituitary Agency collaborative study of the radioimmunoassay of human prolactin, J. chn. Endocrinol. Metab., 38 (1974) 1115-l 120. Breese, G.R. Cooper, B.R. and Prange, Jr. A.J., Interactions of thyrotropin-releasing hormone with centrally acting drugs. In: A.J. Prange, Jr. (Ed.), The Thyroid Axis, Drugs and Behavior, Raven Press, New York, NY, 1974, pp. 115--127. Brown, G. and Reichlin, S., Psychological and neural regulations of growth hormone secretion, Psyrhosom. Med., 34 (1972) 45-61. Brown, G.M., Corticosterone, prolactin and growth hormone responses to handling and new environment in the rat, Psychosom. Med., 36 (1974) 241. Carroll, B.J. The hypothalamic-pituitary axis -- Functions, control mechanisms and method of study. In: B. Davies, B.J. Carol1 and R.M. Mowbray (Eds.), Depressive Illness -~ Some Research Studies, Charles C. Thomas, Springfield, IL, pp. 23-68. Coppen, A., Montgomery, S. and Peet, M. Thyrotropin-releasing hormone in the treatment of depression, Lancet, 2 (1974) 433-440. Endicott, J. and Spitzer, R.L., Current and past psychopathology scales - Rationale, reliability and validity, Arch. gen. Psychiat., 27 (1972) 678-687. Feighner, J.P., Robins, E., Guze, S.B., Woodruff, Jr., R.A., Winokur, G. and Munoz, R., Diagnostic criteria for use in psychiatric research, Arch. gen. Psychiat., 26 (1972) 5763. Frazer, A., Adrenergic responses in depression - Implications for a receptor defect. In: J. Mendels (Ed.), The Psychobiology of Depression, Spectrum Publications, New York, NY, 1975, pp. 7-26. Gold, P.W., Goodwin, F.K., Wehr, T., Rebar, R. and Sack, R., Growth hormone and prolactin response to levodopa in affective illness, Lancet, 2 (1976) 1308-1309. Gold, P.W., Goodwin, F.K., Wehr, T. and Rehar, R., Pituitary thyrotropin response to thyrotropin releasing hormone in affective illness - Relationship to spinal fluid mrtaholites, Amer. J. Psychiat., 133 (1978) 1028-1031. Gruen, P.H., Sachar, E.J., Altman, N. and Sassin, Growth hormone responses to hypoglycemia in post-menopausal depressed women, Arch. gen. Psychiat., 32 (1975) 3133. Imura, H., Nakai, Y. and Yoshimi, T., Effect of 5-hydroxytryptophan on GH and ACTH release in man, J. clin. Endocrinol. Metab., 36 (1973) 204-206. Kastin, A.J., Ehrensing, R.H. and Schalch, D.S., Improvement in mental depression with decreased thyrotropin response after administration of thyrotropin-releasing hormone, Lancet, 2 (1972) 740-742. Keller, H.H., Bartholini, G. and Pletscher, A., Enhancement of cerebral noradrenaline turnover by thyrotropin-releasing hormone, Nature (Lond.), 248 (1974) 528-529. Kirkegaard, C., Norlem, N., Lavridsen, U.B. and Bjorum, N., Prognostic value of thyrotropin-releasing hormone stimulation test in endogenous depression, Acta psychiat. stand., 52 (1975) 170-177. Levitt, M., Dunner, D.L., Mendlewicz, J., Frewin, D.B., Lawlor, W., Fleiss, J.L., Stallone, F. and Fieve, R.R. Plasma dopamine beta-hydroxylase activity in affective disorders, Psychopharmacologia, 146 (1976) 205-210. McClure, D.J. and Cleghorn, R.A., Hormone deficiency in depression. In: J.H. Masserman (Ed.), Science and Psychoanalysis, Vol. 17, Grune and Stratton, New York, NY, pp. 12-19.
32 Martin, J., Neural regulation of growth hormone secretion, New Engl. J. Med., 288 (1970) 1384-1393. Mendlewicz, J., Linkowski, P. and Brauman, II., Growth hormone and prolactin response to levodopa in affective illness, Lancet, 2 (1977) 652-653. Nagatsu, T. and Udenfriend, S., Photometric assay of dopamine beta-hydroxylase activity in human blood, Clin. Chem., 18 (1972) 980-983. Noel, G.L., Suh, H.K. and Stone, J.C., Human prolactin and growth hormone release during surgery and other conditions of stress, J. clin. Endocrinol., 35 (1972) 840-851. Prange, Jr., A.J., Wilson, J.C., Rabon, A.M. and Lipton, M.A., Enhancement of imipramine antidepressant activity by thyroid hormone, Amer. J. Psychiat., 126 (1969) 457-469. Prange Jr., A.J., Wilson, I.C., Lara, P.P., Alltop, L.B. and Breese, G.R., Effects of thyrotropin-releasing hormone in depression, Lancet, 2 (1972) 99991002. Sachar, E.J., Hellman, L. and Fukushima, D.K., Cortisol production in depressive illness, Arch. gen. Psychiat., 122 (1970b) 289-298. Sachar, E.J., Frantz, A.G., Altman, N. and Sassin, J., Growth hormone and prolactin in unipolar and bipolar depressed patients - Responses to hypoglycemia and L-dopa, Amer. J. Psychiat., 130 (1973) 1362-1367. Sachar, E.J., Kanter, S., Buie, D., Engel, R. and Mehlman, R., Psychoendocrinology of ego disintegration, Amer. J. Psychiat., 122 (1970a) 72-80. Sachar, E.J., Mushrush, G., Perlow, M., Weitzman, E.D. and Sassin, J., Growth hormone responses to L-dopa in depressed patients, Science, 178 (1972) 1304-1305. Sachar, E.J., Altman, N., Gruen, P.H., Glassman, A., Halpern, F. and Sassin, J., Human growth hormone response to levodopa - Relation to menopause, depression and plasma dopa concentration, Arch. gen. Psychiat., 32 (1975) 502-503. Shopsin, B., Freedman, L.S., Goldstein, M. and Gershon, S., Serum dopamine betahydroxylase (DBH) activity in affective states, Psychopharmacologia, 27 (1972) 11-16. Takahashi, S., Kondon, H., Yoshimura, M. and Ochi, Y., Antidepressant effect of thyroand the plasma thyrotropin levels in depression, Fol. tropin releasing hormone (TRH) psychiat. neurol. Jap., 27 (1973) 305-314. Van Cauter, E., Methods for the analysis of multifrequential biological time series, J. interdisc. Res., 5 (1974) 131-148. Van Cauter, E. and Huyberechts, S., Problems in the statistical analysis of biological time series - The Cosinor test and the periodogram, J. interdisc. Res., 4 (1973) 41-57. Van Cauter, E. and Mendlewicz, J., 24-h dopamine-beta-hydroxylase pattern - A possible biological index of manic-depression, Life Sci., 22 (1978) 147-155. Virasoro, E., Copinschi, G., Bruno, O.D. and Leclercq, R., Radioimmunoassay of human growth hormone using a charcoal dextran separation procedure, Clin. Chim. Acta, 31 (1971) 294-297. Viveros, O.H., Arquers, L. and Kishner, N., Release of catecholamines and dopamine betahydroxylase from the adrenal medulla, Life Sci., 7 (1968) 609-618. Wilson, I.C., Prange, Jr., A.J., McClane, T.K., Rabon, A.M. and Lipton, M.A., Thyroid hormone enhancement of imipramine in non retarded depression, New Engl. J. Med., 282 (1970) 1063-1067.
Journal ofAffective Disorders, 1 (1979) 25-32 0 Elsevier/North-Holland Biomedical Press
SOME NEUROENDOCRINE UNIPOLAR DEPRESSION
J. MENDLEWICZ, Department
P. LINKOWSKI
of Psychiatry,
~__
PARAMETERS
IN BIPOLAR
AND
and E. VAN CAUTER
Erasme Hospital,
IJniuersity
of Brussels,
Brussels
(Belgium)
_.._
SUMMARY There is mounting evidence showing that some pituitary and hypothalamic hormones play an important role in the affective disorders and may directly affect brain function and behavior. This report briefly reviews some recent endocrinological studies in affective illness with special reference to bipolar and unipolar form of illness. Data on prolactin and growth hormone response to levodopa in bipolar and unipolar illness are presented. Preliminary data on plasma dopamine beta hydroxylase activity measured over a 24-h period are illustrated in patients suffering from bipolar and unipolar illnesses as compared to controls. The significance of these results is discussed in relation to biogenic amine dysfunction in the major affective disorders.
INTRODUCTION
Alterations in neurotransmitter activity as has been postulated in the major affective illnesses may result in neuroendocrine disturbances in these mood disorders. A relationship between hormones and behavior has been recognized for many years, although the concrete interaction between the endocrine system and brain function remains to be clarified. The recent development of reliable radioimmunoassay methods for measuring pituitary hormones such as growth hormone (HGH), prolactin and thyrotropin (TSH) has led to studies indicating that some of these hormones may respond rapidly and markedly to psychological influence in both humans and animals (Noel et al. 1972; Brown 1974). Carol1 (1972) has made extensive reviews of adrenocortical activity in relation to the hypothalamopituitary-adrenal axis in depression. According to this author, most studies demonstrate hypercorticosteroid secretion in depression. Much literature has also been devoted to the relationship between the thyroid axis and depression. Several controlled studies have reported that triiodothyronine potentiates the effect of tricyclic antidepressants by increasing the responsiveness of some receptor sites in the brain (Prange et al. 1969; Wilson et al. 1970). This is based, however, on the assumption that receptors involved in the action of antidepres-
26
sant drugs are also implicated in the etiology of depressive illness, a fact which remains to be proven. Secondly, it has been observed that the administration of thyrotropin-releasing hormone (TRH) causes a rapid but transient, elevation of mood in some depressed patients (Prange et al. 1972; Coppen et al. 1974). TRH indeed possesses brain actions in animals, which do not seem to be mediated by the anterior pituitary. TRH has been shown to potentiate in hypophysectomized mice the behavioral activation caused by the administration of pargyline (a monoamine oxydase inhibitor) and levodopa (Breese et al. 1974). Furthermore, there is biochemical evidence (although controversial) showing that TRH increases brain catecholamine turnover (Keller et al. 1974). These animal findings have led a number of investigators to test the antidepressive effect of TRH in depressed patients. The results are conflicting (Kastin et al. 1972; Prange et al. 1972; Coppen et al. 1974), but it is now clear that TRH is not an effective and lasting treatment for depression. TRH rapid and brief physiologic action remains puzzling and is of great interest for research. The TRH studies have also contributed to our knowledge of depressive disorders by showing that after the administration of TRH, the thyrotropin (TSH) output of the pituitary is flat in some depressed patients (Kastin et al. 1972; Prange et al. 1972). This observation has now been widely confirmed and suggests that pituitary reaction to TRH is reduced in depression through thyroid function revealed to be normal (Kastin et al. 1972; Takahashi et al. 1973). After recovery from antidepressant drug treatment or electro-convulsive treatment, a significant increase of TSH response to TRH was observed (Kirkegaard et al. 1975). Recently, Gold et al. (1978) have shown differences in TSH response to TRH in major affective disorders. Unipolar (depressive) patients had a lower TSH secretion than did bipolar patients, as compared to normal controls. Furthermore, there was a difference in TSH output in bipolar (manic-depressive) patients according to clinical state. TSH response was lower in mania than in depression. Growt,h hormone (HGH), another pituitary hormone has been extensively studied in affective disorders and its regulation has been shown to be abnormal in depression. Studies have been conducted by Sachar’s group indicating a lack of GH response to insulin hypoglycemia in postmenopausal depressed women when compared with proprer controls (Sachar et al. 1972). Levodopa, an amino acid precursor of dopamine and norepinephrine has been shown to cause an elevation in plasma GH in normal subjects (Martin 1970). The levodopa test is an interesting research tool in the neuroendocrinological assessment of the affective disorders, because it allows to monitor HGH and prolactin response (two important pituitary hormones) in various affective states. Sachar et al. have reported diminished GH levels in response to levodopa in unipolar depressed patients, but this reduction in GH response has been partly related to age and sex (Sachar et al. 1972, 1973, 1975). There are indeed a number of factors affecting GH secretion. Among them
27
are sleep, diet, oestrogen levels and phase of menstrual cycle (Brown and Reichlin 1972). Frazer (1975) has also shown that GH response to levodopa was abnormal in two out of three hypomanic bipolar patients. More recently, Gold et al. (1976) reported an elevated GH response and greater prolactin suppression of levodopa in bipolar depressed patients than in unipolar patients and controls. Among the bipolar patients the depressive phase was associated with a significantly better GH response to levodopa than the manic phase. Furthermore, these authors failed to observe a relationship between neuroendocrine response to levodopa and age in their group of affectively ill patients. Because of apparent discrepancies between the above studies, we have conducted levodopa tests in a large and homogenous group of patients diagnosed as having primary affective disorders. Preliminary results on the levodopa tests in affective illness were reported elsewhere (Mendlewicz et al. 1977). Studies on 24-h plasma DBH activity in some unipolar and bipolar depressed patients were also performed (Van Cauter and Mendlewicz 1978). METHOD
AND RESULTS
All patients consecutively admitted to a female inpatient unit with a diagnosis of primary affective disorder according to Feighner’s criteria (1972) and who were willing to participate in our endocrinological investigations were included in the present study. There were 43 such women subdiagnosed in 18 bipolar and 25 unipolar female patients, using a modified version of a semi-structured interview: the Current and Past Psychopathology Scales (CAPPS). GH and prolactin secretion to levodopa were studied in these 43 patients. All subjects were on a controlled monoamine-free diet and had been off drugs for at least a week before the levodopa test. After an overnight fast, patients were given 500 mg of levodopa by mouth and blood was drawn every 30 min for 120 min through a plastic indwelling catheter for radioimmunoassay of GH and prolactin (Aubert et al. 1974; Virasoro et al. 1971). Unipolar patients, as a group, had a peak GH increment not different from that in bipolar patients (Fig. 1). However, when menopausal status was taken into account, a difference in GH response to levodopa emerged between bipolar premenopausal women compared to bipolar postmenopausal women. Premenopausal bipolar women had a higher peak GH than did unipolar premenopausal women, but the difference was not significant. The apparent discrepancy between our findings and those of Gold et al. (1976) might be due to the fact that they studied bipolar menopausal females and bipolar males only, while we investigated both premenopausal (N = 3) and postmenopausal (N = 15) bipolar women. In our unipolar group, there were 15 unipolar premenopausal women as compared to 10 unipolar postmenopausal women. We were unable to find any significant difference in GH response and prolactin response to levodopa between pre- and postmenopausal unipolar depressed women, an
28
Unipolar
(25)
Bipolar
Prolactin
(18)
response
O/o Of base line 160
GH response “g/ml
+&zbb--
!?3kbk-
120
Min
Fig. 1. pausal;.
Prolactin
120
Min
and
GH
response
to levodopa
in affective
illness.
-
-
-
= premeno.
. . . . . = postmenopausal.
observation indicating that in our unipolar subgroup, endocrine responses to levodopa are not significantly influenced by the menopausal status. Furthermore, we failed to confirm Gold’s observation of a greater prolactin suppression after levodopa in the bipolar patients. In fact, the opposite seems to be true in our sample. There is a paradoxical rise in prolactin secretion 30--90 min after levodopa administration followed by a subsequent suppression in the bipolar patients. This peak is not present in the unipolar group. This paradoxical response to levodopa is more pronounced in bipolar premenopausal women than in bipolar postmenopausal women. Baseline prolactin levels were not significantly different in bipolar and unipolar patients. Our results on GH response in affective illness accord with the work of Gruen et al. (1975), who found a reduction in GH response to levodopa in postmenopausal women, an observation consistent with the fact that GH stimulation is related to circulating oestrogens (Brown and Reichlin 1972), although this relationship is not apparent in our unipolar population. Nevertheless, bipolar and unipolar premenopausal women cannot be differentiated on the basis of their GH response to levodopa, although there is a trend toward a bigger GH response and less prolactin suppression in the bipolar group. The results on prolactin response to levodopa in affective illness are conflicting and more
difficult to interpret. On our data, the influence of stress-related factors and oestrogen levels on prolactin response to levodopa cannot be excluded. Catecholamine control of GH secretion is mediated through adrenergic receptors in the hypophysiotropic area of the hypothalamus. Dopamine, norepinephrine and serotonin seem to have a positive effect on GH release. Dopamine beta hydroxylase (DBH) is the enzyme which catalyses the terminal step in the biosynthesis of norepinephrine from dopamine. The activity of this enzyme is also used as a monitor of sympathetic activity in man (Viveros et al. 1968). Because of the importance of dopamine and noradrenaline in the control of GH secretion in man and in light of the possible involvement of noradrenaline turnover anomalies in affective disorders, we have measured plasma DBH activities in some bipolar and unipolar patients. Although prior studies including our own have demonstrated that resting levels of plasma DBH activity do not seem to be altered in patients with affective disorders (Shopsin et al. 1972; Levitt et al. 1976), we were able to show in preliminary studies that DBH activity raises significantly along with heart rate after exercise in the cold in some manic-depressive patients as compared to normal controls (Levitt et al. 1976). This observation and the potential (although controversial) value of plasma DBH activity as a possible monitor of sympathetic activity stimulated our interest in measuring plasma DBH activity over 24-h period in depressed patients subdiagnosed as bipolar and unipolar. Blood samples were drawn for 24-h through a plastic indwelling catheter. They were collected every hour during day time and every 30 min during the night. All patients were confined to bed, had normal breakfast, lunch and supper except for a controlled amine diet and their nocturnal sleep was rarely interrupted. DBH activity in plasma was assayed by a modification of the spectrophotometric method described by Nagatsu and Udenfriend (1972). The statistical analysis of the data, including the objective detection of the possible periodicities was performed using the periodogram method (Van Cauter and Huyberechts 1973; Van Cauter 1974). This method applies to each individual series and gives an estimation of the amplitude and the phases of each significant periodicity. Estimated amplitudes and phases of plasma DBH patterns observed in depressed patients (N = 17) were compared to those of normal controls (N = 8). The 17 affectively ill patients were subdiagnosed in bipolar subjects (7 females, one male, aged 37-766) and unipolar subjects (8 females, one male, aged 18--53), all hospitalized at the Psychiatric Institute of the University of Brussels. Figure 2 shows, as an example, the almost identical daily patterns for plasma DBH activity in a pair of monozygotic twins. Theoretical curves are illustrated by the dotted lines. Very similar profiles, all characterized by the occurrence in the mid afternoon hours (3 p.m. to 5 p.m.) of a peak of magnitude between 13 and 39% of the mean, were observed in all normal subjects. A circadian rhythm with no other significant episodic variations is present. When compared to the patterns of normal subjects, the 24-h profiles
301. 8am
Fig.
1
2pm
2. Plasma
I
tipnl
2am
CLock
time
DBH
activity
I
_iOl!
8om
1
3 0 111 2pn-n
Ciock
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,
8pm
2om
1
8ar
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for plasma DBH activity present more episodic variations in depressed patients although the afternoon elevation is present in all patterns. Figure 3 shows typical 24-h DBH profiles recorded in the affective patients, one unipolar with a mild depression (SE) and two bipolars with high Hamilton depression scores (TR and ME). Episodic variations are more frequent and their magnitude may be of the same order than of the mid afternoon elevation which no longer appeared as the sole major event in the 24-h variation. In the most severely affected patients, the afternoon elevation completely disappears and no circadian rhythm could be detected. The periodogram analysis allowed to discriminate between bipolar and unipolar patients. Deviations from normal of the 24-h DBH pattern are significantly more important in bipolar than unipolar patients, although they do not correlate with the severity of the mood alterations as assessed by the Hamilton scores. Alterations in 24-h DBH activity in depressed patients may relate to abnormal noradrenergic turnover in the affective psychoses. The studies described above combining neuropharmacological and endocrine methods may enable us to investigate disturbances in hypothalamic functions in various subgroups of
Fig.
3. Plasma
DBH
activity
in affective
illness.
31
affective patients. Caution should be kept neuroendocrine abnormalities in relation neurotransmitter disturbances in the major
however, in the interpretation of to the nature of the underlying affective disorders.
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