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Neurotransmitter metabolites and endocrine responses in depression
Pmg. Printed
Neum-Psychophormocol. in Great
Britain.
C+Biol All rights
Psychiot
1985, Vol
9, pp. 613-617 Copyright
reserved.
NE~ROT~NSMI~R
GARY M. HASEYls*,
SCOLDS AND E~~~~ IN DEP~SSION
HARVEY C. STANCER132, IAffective
JERRY
Disorders
J. WARSHI,
0
0276-5646165 $0.00 + 50 1965 Pergamon Press Ltd.
RESPONSES
and EMMANUEL
PERSADl
Unit
2Section of Bio~~~i~al Psychiatry Clarke Institute of Psychiatry University of Toronto Toronto, Ontario, Canada
(Final form, July 1985) Abstract Neurotransmitter Hasey, Gary M., Harvey C. Stancer, Jerry J. Warsh, Emmanual Persad: metabolites and endocrine responses in depression. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1985, 2 (5/6): 613-617. 1.
2.
3.
Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3-4-dihydroxyphenylethyleneglycol (DHPG), +hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 < p < .lO) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH. In all subjects the TSH response correlated positively with pre- and post-TRH The PRL response correlated negatively with pre-TRH urinary 5-HIAA. urinary MHPG. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.
depression, growth hormone, MHPG, noradrenaline, * stlmu sting hormone, thyrotropin releasing hormone
prolactin,
serotonin,
thyroid
Abbreviations: 3-methoxy-4-hydroxyphenylethylene glycol (MHPG); 3-4 dihydroxyphenylethylene glYCo1 (DHPG); 5-hydroxyindoleacetic acid (5-HIAA); growth hormone (GH); noradrenaline (NE); prolactin (PRL); serotonin (5-HT); thyroid stimulating hormone (TSH); thyrotropin releasing hormone (TRH)
Introduction Altered TSH, PRL and GH responses to TRH have been reported in depressed patients (Loosen et al 1976). Release of these hormones from the anterior pituitary appears to be influenced by NE and/or 5-HT (Annunziato et al 1981, Charney et al 1982). This pilot project was designed to test the hypothesis that a disorder of NE and/or 5-HT may be related to both depressive illness and altered hormonal responses to TRH.
Methods Subjects. Nine depressed subjects (3 unipolar females, 2 bipolar and 4 unipolar males; mean age 40.2 * 12.9 yr) were studied. All satisfied modified Feighner's criteria for primary affective disorder using the standardized Renard Diagnostic Interview. All had Beck depression scores of 18 or more. A control group consisted of eight healthy
613
614
G. M. Hasey et al.
subjects (2 female, 6 male; mean age 25.5 f 2.3 yr) with no personal or family history of psychiatric illness. No subject had endocrine disease or used lithium in the past. Except for oxazepam used as a sedative by depressed patients, subjects Protocol. drug free for at least one week prior to study entry. Subjects were provided with specially prepared low-amine diets. Vigorous physical exercise was prohibited.
were
After 24 hours of exercise and dietary control, 12 hour urine collections i.e. 0900-2100 hr ("Day" collection) and 2100-8100 hr ("Night" collection) were started. Urine collections were regarded as complete if the 24 hr volume was greater than 1 1 or if the urinary creatinine was at least 1.0 g for males or 0.8 g for females. After 24 hr of urine collection an intravenous line running 0.9% saline was started at 0800 hr. At 0830 hr and 0845 hr blood samples were drawn for baseline plasma TSH, PRL and GH levels. Immediately after the 0845 hr sampling, 500 micrograms of synthetic TRH (Relefact-Hoechst) was injected over 30 sec. Blood samples were drawn 20, 40, 60 and 120 min after TRH injection. State-anxiety rating tests were administered prior to each blood sample. Metabolite assay. The NE metabolites MHPG and DHPG were measured simultaneously in urine by gas chromatography-mass spectrometry as described by Warsh et al (1981). The 5-HT metabolite 5-HIAA was measured in urine fluorometrically as described by Garfinkel et al (1977). TSH, PRL and GH were measured using double antibody immunoassays. The ower lmits of detection and interassay coefficient of variation for TSH, PRL and Y=-F= GH respectively were 0.4 mcIU/ml - 8%, 0.8 ng/ml - 10% and 0.6 ng/ml - 8%.
Results The TRH induced hormonal response was the highest post-TRH value Response to TRH. No hormonal baseline or response to TRH differed minus the mean of the baseline values. in depressed compared with control subjects. Post-TRH responses (mean f s.d.) for TSH, PRL and GH were, for depressed (n=8) and control (n=5) respectively: TSH: 9.0 f 4.9 vs 12.6 f 1.4 mcIU/ml; PRL: 40.2 f 29.2 vs 73.3 f 42.3 ng/ml; GH: 2.0 f 3.9 vs 3.2 f 3.5 There was a trend among males for the PRL response to be lower in depressed ng/ml. (30.6 f 21.4 ng/ml, n=6) compared with control (56.6 f 23 ng/ml, n=4) subjects (t=1.84, df=8, pc.10 E-tailed). Clear GH increases after TRH (>5 ng/ml and at least twice baseline) were seen in one depressed subject 20 min post-TRH and in two control subjects at 40 and 120 min post-TRH. Neither subject age nor state anxiety score correlated significantly with any hormonal response to TRH. Creatinine adjusted urinary 5-HIAA was significantly Monoamine Metabolite Levels. (t=3.42 df=ll, p<.OO2 2-tailed) higher in depressed (n=8) compared with control (n=5) subject; during the 12'hr "Day" period prior to TRH injection (2629 f 400 vs 1925 f 281 Urinary MHPG and DHPG levels did not differ significantly mcg/12hr/g creatinine). between the depressed and control groups.
In depressed and control subjects combined (n=lO), Metabolites and Hormonal Responses. the TSH responses correlated significantly with urinary "Day" creatinine adjusted MHPG collected both pre-TRH and post-TRH (see fig 1, 2). The PRL response to TRH correlated negatively with pre-TRH urinary "Day" 5-HIAA, but only when not creatinine adjusted (see fig. 3). Discussion Hormonal res onses Like Gold et al (1977), we were unable to demonstrate a significant .__.. _ + t e TSH response to TRH of unipolar and bipolar depressed patients with difference in primary affective disorder compared to healthy control subjects. When male subjects
Monoamine
metabolites
and TRH in depression
615
were analyzed separately, a trend (.05
l200
1400
1600
1800
2ooo
UR. MHPG [M&/l2WG Fig. 1. Correlation between the TSH response and urinary MHPG collected during the 12 hr "Day" period starting the morning before TRH injection (Pre-TRH). r=.84, df=8, pc.002
CR]
616
G.
M. Hasey et al.
A A
00
12001400 1800 1800 2000 2200 UR. MHPG [McG/lZ IIR/G CR]
Fig. 2. Correlation between the TSH response and urinary MHPG collected during the 12 hr "Day" period starting the morning of TRH injection (Post-TRH). r=.85, df=8, pc.005
A 60-
DERtESEDA CONTROL
t&l NJ-
A
d B EM
20-
0
I
I
r
1
1000 1400 18bO 2200 2800 3000
uR 5-43~~ [MCC~/IZ HR] Fig. 3. Correlation between the PRL response and urinary 5-HIAA (not creatinine adjusted) collected during the 12 hr "Day" period starting the morning before TRH injection r=-.74, df=8, p<.O2 (Pre-TRH).
Monamine
metabolites
617
and TRH in depression
Conclusion The findings of this pilot study must be replicated using larger numbers of age, sex and menopausally matched depressed and control subjects before being accepted with We have, however, found evidence for the involvement of NE and possibly confidence. 5-HT in the regulation of TSH and PRL responses to TRH and evidence for a disturbance of The hypothesis of a disturbance of NE or 5-HT functioning in our depressed subjects. 5-HT systems underlying both affective and endocrine changes is only partially supported.
Acknowledgement We gratefully acknowledge synthetic TRH (Relefact).
the generosity
of Hoechst
Pharmaceuticals
in providing
References ANNUNZIATO, L., DiRENZO, G., QUATTRONE, A., SCHETTINI, G., PREZIOSI, P. (1981) Brain neurotransmitters regulating TRH producing neurons. Pharmacol. Res. Comm. 13: l-10. CHARNEY, D., HENINGER, G., REINHARD, J., STERNBERG, D., HAFSTEAD, K. (1982) TG effect of intravenous 1-tryptophan on prolactin and growth hormone and mood in healthy subjects. Psychopharmacol. 77: 217-222. Neuroendocrine and neurochemical measurements DAVIS, K., HOLLISTEK L., MATHE,A. (1981) in depression. Am. J. Psychiat. 138: 1555-1562. DeLEON, A., GARON, M., KELLY, P. (1977) Changes of pituitary thyrotropin releasing hormone receptor level and prolactin response to TRH during the rat estrous cycle. Endocrinology 100: 1505-1510. GARFINKEL, P., WARSH, J., STANCER, C. (1977) CNS monoamine metabolism in bipolar affective disorder: evaluation using a peripheral decarboxylase inhibitor. Arch. Gen. Psychiat. 5: 735-739. GOrD, P., GOODWIN, F., WEHR, T., REBAR, R. (1977) Pituitary thyrotropin response to thyrotropin-releasing-hormone in affective illness: relationship to spinal fluid amine metabolites. Am. J. Psychiat. 134: 1028-1031. HALBREICH, V., GRUNHAUS, L., BEN-DAVID,x (1979) Twenty-four hour rhythm of prolactin in depressive patients. Arch. Gen. Psychiat. 36: 1183. LINNOILA, M., MILLER, T., BARTKO, J., POTTER, W.71984) Five antidepressant treatments in depressed patients effects on urinary serotonin and 5-hydroxyindoleacetic acid output. Arch. Gen. Psychiat. 41: 688-692. LOOSEN, P., PRANGE, A., WILSON, r;, LARA, P. (1976) Pituitary responses to thyrotropin releasing hormone in depressed patients: a review. Pharmacol. Bioch. Behav. Lsuppl. 1: 95-101. MARTIN, J.B. (1980) Functions of central nervous system neurotransmitters in regulation of growth hormone secretion. Fed. Proc. 39: 2902-2906. WARSH, J., GOOSE, D., CHEUNG, S. (1981) Ratbrain and plasma norepinephrine glycol metabolites determined by gas chromatography-mass fragmentography. J. Neurochem. -36: 893-901.
Inquiries
and reprint
requests
Dr. Gary M. Hasey Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada, M5T-lR8
should be addressed
to:
Neum-Psychophormocol. in Great
Britain.
C+Biol All rights
Psychiot
1985, Vol
9, pp. 613-617 Copyright
reserved.
NE~ROT~NSMI~R
GARY M. HASEYls*,
SCOLDS AND E~~~~ IN DEP~SSION
HARVEY C. STANCER132, IAffective
JERRY
Disorders
J. WARSHI,
0
0276-5646165 $0.00 + 50 1965 Pergamon Press Ltd.
RESPONSES
and EMMANUEL
PERSADl
Unit
2Section of Bio~~~i~al Psychiatry Clarke Institute of Psychiatry University of Toronto Toronto, Ontario, Canada
(Final form, July 1985) Abstract Neurotransmitter Hasey, Gary M., Harvey C. Stancer, Jerry J. Warsh, Emmanual Persad: metabolites and endocrine responses in depression. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1985, 2 (5/6): 613-617. 1.
2.
3.
Urinary 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3-4-dihydroxyphenylethyleneglycol (DHPG), +hydroxyindoleacetic acid (5-HIAA), plasma thyroid stimulating hormone (TSH), prolactin (PRL) and growth hormone (GH) were measured before and after the injection of thyrotropin releasing hormone (TRH) in healthy subjects and depressed patients with primary affective disorder. The TSH response to TRH did not differ in depressed compared with control subjects. A trend (.05 < p < .lO) toward a lower PRL response appeared in male depressed compared with male control subjects. GH levels did not consistently change after TRH. In all subjects the TSH response correlated positively with pre- and post-TRH The PRL response correlated negatively with pre-TRH urinary 5-HIAA. urinary MHPG. Pre-TRH daytime urinary 5-HIAA levels were elevated in depressed subjects.
depression, growth hormone, MHPG, noradrenaline, * stlmu sting hormone, thyrotropin releasing hormone
prolactin,
serotonin,
thyroid
Abbreviations: 3-methoxy-4-hydroxyphenylethylene glycol (MHPG); 3-4 dihydroxyphenylethylene glYCo1 (DHPG); 5-hydroxyindoleacetic acid (5-HIAA); growth hormone (GH); noradrenaline (NE); prolactin (PRL); serotonin (5-HT); thyroid stimulating hormone (TSH); thyrotropin releasing hormone (TRH)
Introduction Altered TSH, PRL and GH responses to TRH have been reported in depressed patients (Loosen et al 1976). Release of these hormones from the anterior pituitary appears to be influenced by NE and/or 5-HT (Annunziato et al 1981, Charney et al 1982). This pilot project was designed to test the hypothesis that a disorder of NE and/or 5-HT may be related to both depressive illness and altered hormonal responses to TRH.
Methods Subjects. Nine depressed subjects (3 unipolar females, 2 bipolar and 4 unipolar males; mean age 40.2 * 12.9 yr) were studied. All satisfied modified Feighner's criteria for primary affective disorder using the standardized Renard Diagnostic Interview. All had Beck depression scores of 18 or more. A control group consisted of eight healthy
613
614
G. M. Hasey et al.
subjects (2 female, 6 male; mean age 25.5 f 2.3 yr) with no personal or family history of psychiatric illness. No subject had endocrine disease or used lithium in the past. Except for oxazepam used as a sedative by depressed patients, subjects Protocol. drug free for at least one week prior to study entry. Subjects were provided with specially prepared low-amine diets. Vigorous physical exercise was prohibited.
were
After 24 hours of exercise and dietary control, 12 hour urine collections i.e. 0900-2100 hr ("Day" collection) and 2100-8100 hr ("Night" collection) were started. Urine collections were regarded as complete if the 24 hr volume was greater than 1 1 or if the urinary creatinine was at least 1.0 g for males or 0.8 g for females. After 24 hr of urine collection an intravenous line running 0.9% saline was started at 0800 hr. At 0830 hr and 0845 hr blood samples were drawn for baseline plasma TSH, PRL and GH levels. Immediately after the 0845 hr sampling, 500 micrograms of synthetic TRH (Relefact-Hoechst) was injected over 30 sec. Blood samples were drawn 20, 40, 60 and 120 min after TRH injection. State-anxiety rating tests were administered prior to each blood sample. Metabolite assay. The NE metabolites MHPG and DHPG were measured simultaneously in urine by gas chromatography-mass spectrometry as described by Warsh et al (1981). The 5-HT metabolite 5-HIAA was measured in urine fluorometrically as described by Garfinkel et al (1977). TSH, PRL and GH were measured using double antibody immunoassays. The ower lmits of detection and interassay coefficient of variation for TSH, PRL and Y=-F= GH respectively were 0.4 mcIU/ml - 8%, 0.8 ng/ml - 10% and 0.6 ng/ml - 8%.
Results The TRH induced hormonal response was the highest post-TRH value Response to TRH. No hormonal baseline or response to TRH differed minus the mean of the baseline values. in depressed compared with control subjects. Post-TRH responses (mean f s.d.) for TSH, PRL and GH were, for depressed (n=8) and control (n=5) respectively: TSH: 9.0 f 4.9 vs 12.6 f 1.4 mcIU/ml; PRL: 40.2 f 29.2 vs 73.3 f 42.3 ng/ml; GH: 2.0 f 3.9 vs 3.2 f 3.5 There was a trend among males for the PRL response to be lower in depressed ng/ml. (30.6 f 21.4 ng/ml, n=6) compared with control (56.6 f 23 ng/ml, n=4) subjects (t=1.84, df=8, pc.10 E-tailed). Clear GH increases after TRH (>5 ng/ml and at least twice baseline) were seen in one depressed subject 20 min post-TRH and in two control subjects at 40 and 120 min post-TRH. Neither subject age nor state anxiety score correlated significantly with any hormonal response to TRH. Creatinine adjusted urinary 5-HIAA was significantly Monoamine Metabolite Levels. (t=3.42 df=ll, p<.OO2 2-tailed) higher in depressed (n=8) compared with control (n=5) subject; during the 12'hr "Day" period prior to TRH injection (2629 f 400 vs 1925 f 281 Urinary MHPG and DHPG levels did not differ significantly mcg/12hr/g creatinine). between the depressed and control groups.
In depressed and control subjects combined (n=lO), Metabolites and Hormonal Responses. the TSH responses correlated significantly with urinary "Day" creatinine adjusted MHPG collected both pre-TRH and post-TRH (see fig 1, 2). The PRL response to TRH correlated negatively with pre-TRH urinary "Day" 5-HIAA, but only when not creatinine adjusted (see fig. 3). Discussion Hormonal res onses Like Gold et al (1977), we were unable to demonstrate a significant .__.. _ + t e TSH response to TRH of unipolar and bipolar depressed patients with difference in primary affective disorder compared to healthy control subjects. When male subjects
Monoamine
metabolites
and TRH in depression
615
were analyzed separately, a trend (.05
l200
1400
1600
1800
2ooo
UR. MHPG [M&/l2WG Fig. 1. Correlation between the TSH response and urinary MHPG collected during the 12 hr "Day" period starting the morning before TRH injection (Pre-TRH). r=.84, df=8, pc.002
CR]
616
G.
M. Hasey et al.
A A
00
12001400 1800 1800 2000 2200 UR. MHPG [McG/lZ IIR/G CR]
Fig. 2. Correlation between the TSH response and urinary MHPG collected during the 12 hr "Day" period starting the morning of TRH injection (Post-TRH). r=.85, df=8, pc.005
A 60-
DERtESEDA CONTROL
t&l NJ-
A
d B EM
20-
0
I
I
r
1
1000 1400 18bO 2200 2800 3000
uR 5-43~~ [MCC~/IZ HR] Fig. 3. Correlation between the PRL response and urinary 5-HIAA (not creatinine adjusted) collected during the 12 hr "Day" period starting the morning before TRH injection r=-.74, df=8, p<.O2 (Pre-TRH).
Monamine
metabolites
617
and TRH in depression
Conclusion The findings of this pilot study must be replicated using larger numbers of age, sex and menopausally matched depressed and control subjects before being accepted with We have, however, found evidence for the involvement of NE and possibly confidence. 5-HT in the regulation of TSH and PRL responses to TRH and evidence for a disturbance of The hypothesis of a disturbance of NE or 5-HT functioning in our depressed subjects. 5-HT systems underlying both affective and endocrine changes is only partially supported.
Acknowledgement We gratefully acknowledge synthetic TRH (Relefact).
the generosity
of Hoechst
Pharmaceuticals
in providing
References ANNUNZIATO, L., DiRENZO, G., QUATTRONE, A., SCHETTINI, G., PREZIOSI, P. (1981) Brain neurotransmitters regulating TRH producing neurons. Pharmacol. Res. Comm. 13: l-10. CHARNEY, D., HENINGER, G., REINHARD, J., STERNBERG, D., HAFSTEAD, K. (1982) TG effect of intravenous 1-tryptophan on prolactin and growth hormone and mood in healthy subjects. Psychopharmacol. 77: 217-222. Neuroendocrine and neurochemical measurements DAVIS, K., HOLLISTEK L., MATHE,A. (1981) in depression. Am. J. Psychiat. 138: 1555-1562. DeLEON, A., GARON, M., KELLY, P. (1977) Changes of pituitary thyrotropin releasing hormone receptor level and prolactin response to TRH during the rat estrous cycle. Endocrinology 100: 1505-1510. GARFINKEL, P., WARSH, J., STANCER, C. (1977) CNS monoamine metabolism in bipolar affective disorder: evaluation using a peripheral decarboxylase inhibitor. Arch. Gen. Psychiat. 5: 735-739. GOrD, P., GOODWIN, F., WEHR, T., REBAR, R. (1977) Pituitary thyrotropin response to thyrotropin-releasing-hormone in affective illness: relationship to spinal fluid amine metabolites. Am. J. Psychiat. 134: 1028-1031. HALBREICH, V., GRUNHAUS, L., BEN-DAVID,x (1979) Twenty-four hour rhythm of prolactin in depressive patients. Arch. Gen. Psychiat. 36: 1183. LINNOILA, M., MILLER, T., BARTKO, J., POTTER, W.71984) Five antidepressant treatments in depressed patients effects on urinary serotonin and 5-hydroxyindoleacetic acid output. Arch. Gen. Psychiat. 41: 688-692. LOOSEN, P., PRANGE, A., WILSON, r;, LARA, P. (1976) Pituitary responses to thyrotropin releasing hormone in depressed patients: a review. Pharmacol. Bioch. Behav. Lsuppl. 1: 95-101. MARTIN, J.B. (1980) Functions of central nervous system neurotransmitters in regulation of growth hormone secretion. Fed. Proc. 39: 2902-2906. WARSH, J., GOOSE, D., CHEUNG, S. (1981) Ratbrain and plasma norepinephrine glycol metabolites determined by gas chromatography-mass fragmentography. J. Neurochem. -36: 893-901.
Inquiries
and reprint
requests
Dr. Gary M. Hasey Clarke Institute of Psychiatry 250 College Street Toronto, Ontario, Canada, M5T-lR8
should be addressed
to: