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The patterns of prolactin release by ECT and TRH compared
Life Sciences, Vol. 41, pp. 1273-1276 Printed in the U.S.A.
Pergamon Journals
TIlE PATTErnS OF PROLACTIN RELEASE BY ECT AND TRH CO~,~ARED
Manolis Harkianos, Yiannis Papakostas and Costas Stefanis Athens University Medical School, Psychiatric Clinic, Eginition Hospital, Vass. Sophias 74, Athens 11528, Greece (Received in final form July 6, 1987)
_~i~m~_ The patterns of prolactin release after bilateral ECT and after 0.4 mg TRH i.v. were studied in 11 female melancholic patients in a 5-min sampling protocol. Mean prolactin peaking times were 10.2 min after ECT and 20.5 min after TRH. The elimination rate coefficients were significantly lower - and the corresponding half-lives longer for prolactin released by TRH than by ECT. A significant positive correlation of the maximal prolactin responses by the two stimuli was also found. Among the long list of physiological substances, drugs and conditions that are known to increase plasma prolactin (PRL) levels (I), the responses caused by neuroleptic drugs, thyrotropin-releasing hormone (TRH), and electroconvulsive therapy (ECT) are most studied in psychiatric patients. These three stimuli give different patterns of PRL release regarding a number of parameters, like the time of the occurence and magnitude of the PRL peak, the duration of PRL release, and the total amount released. The patterns of PP~ levels represent the sum total of the underlying mechanisms of the PRL release, binding, and clearance, and their closer study may reveal similarities and differences about those mechanisms activated by these stimuli. The action of neuroleptics on PRL secretion is due to their ability to block dopamine (DA) receptors mainly at the pituitary level (2,3), that of TRH to its action on the lactotrophs of the pituitary (4), while the mechanism by which ECT releases PRL is still hypothetical; it has been suggested that ECT increases the postsynaptic dopamine receptor sensitivity (5). In a recent study of PRL responses by ECT and TRH in 10 melancholic patients, our group found a significant correlation between the maximal PRL responses caused by the two stimuli (6). This correlation may indicate a functional similarity and a common underlying mechanism of ECT and TRH regarding PRL release. We further investigated the two PRL response patterns in a new group of 11 melancholic patients in a more detailed protocol, and compared the peaking times, the elimination rate coefficients, and the half-lives of PRL released, to study in a direct comparative way the similarities and differences between the two stimuli regarding PRL release. _S~bjects and Hethods Eleven female patients suffering from major affective disorder, melancholia type, according to D~I-III criteria, were studied. They were hospitalized in the Athens University Psychiatric Clinic in the Eginition Hospital. The diagnosis was made on the basis of standard clinical interviews and patients' records. The age range was from 26 to 74 years (mean 57.3). Uith the 0024-3025/87 $3.00 + .00 Copyright (c) 1987 Pergamon Journals Ltd.
1274
ECT, TRH and Prolactin Release
Vol. 41, No. i0, 1987
exception of small doses of flunitrazepam given at bed time, patients were free of drugs for at least one week. The TRH test (0.4 mg TRH i.v.) and the ECT were performed between 0800 and 0900, with a 2 to 7 days interval. In 6 patients the T ~ was given before, and in 5 patients after the ECT. Conventional bilateral ECT was given. The procedure is described in detail elsewhere (7). Shortly, the peak current intensity was 400-450 mA and the current flow time 2.5-3 sec. Five minutes before ECT, 0.5 mg atropine was given i.v., followed by pentothal anaesthesia (250-300 mg), succinylcholine (30-40 mg), and oxygenation. The seizure duration was 35 sec in the mean. Blood samples were taken every 5 minutes, beginning 5 min before, and ending 60 min after the TRH or the ECT. Plasma was separated by centrifugation and kept at -30 C. PRL levels were assessed by a double antivody radioimmunoassay supplied by Biodata, and the results expressed in ng/ml plasma. One ng PRL corresponds to 0.023 mlU of the ~ 0 75/504 International Reference Preparation. The disappearance of PRL in humans follows a multiexponential curve, with a break at 40-50 min, which separates the early from the late phase, as it has been sho~m by infusion of labelled PRL (8). Our samples are thus all within the early phase of PRL disappearance, since the last sample, dra~n~ at +60 min, is taken 35 to 50 min after the occurence of the PRL peak. The assumptions as formulated by Swartz for the calculations of PRL r@lease parameters after ECT were used for the calculations below. They are: I) there is a steady concentration of PRL at pre-stimulus baseline; 2) after the peak PRL level, the amount of PRL released by stimulus related procedures is negligible; 3) PRL is removed from blood at a rate proportional to its concentration, and 4) the volume of the compartment through which PRL is distributed in the body does not change substantially during the post-stimulus period. We calculated the elimination rate coefficients by inserting the difference from baseline (zero-time value) into the exponential regression equation Pt = a'e-b't, where Pt is the difference in PRL from baseline at time t, ~ i c h is taken zero when the peak PRL occurs; the factor a, represents ~he calculated from the best fit curve PRL value at time zero (peaking time), and b is the elimination rate coefficient for the subject and stimulus. The half -lives are calculated from the equation ti/2 : in2 / b. Results The mean baseline PRL values of the 11 patients were 7.5 ng/ml (SD=3.7) on TRH administration and 6.9 ng/ml (SD=2.2) on ECT administration. The maximal PRL responses (maximal post-stimulus value minus baseline value) were 53.8 (mean, SD=27.7) for TRH and 51.0 (SD=42.7) for ECT. There were no significant differences (paired t-test) between the baseline PRL values or the PRL responses between TRH and ECT. The maximal responses of the 11 patients to the two stimuli correlated significantly (linear regression, r : 0.6467, 2a 0.05), while no significant correlation existed between the baseline PRL values and the responses to T~{ or to ECT. The time of the occurence of the PRL peak in our 5-min sampling was 10.2 min in the mean (SD=2.0) after ECT, and 20.5 min (SD=4.7) after TRH. The difference is significant at the O.001 level (paired t-test). The results of the calculations of the elimination rate coefficients and the half-lives of PRL for each subject and stimulus are presented in the Table.
Vol. 41, No.
i0, 1987
ECT, TRH and Prolactin Release
1275
Table: Parameters of the PRL elimination after ECT and after TRH in 11 subjects, calculated from the exponential regression model Pt = a . e-b't Half-lives tl/2 = in2/b, r = correlation coefficients of the regression line.
Subject Nr.
a
-b.I03
F,CT
TRH
I 2 3 4 5 6 7 8 9 10 11
19.6 41.4 69.9 40.4 40.2 87.7 154.3 121.6 24.5 7.3 6.5
mean S.D.
55.8 48.0
t 2p
r
ti/2
ECT
TRH
ECT
TRH
ECT
19.8 67.0 45.1 34.1 80.4 102.2 61.2 80.8 53.6 8.8 27.0
31.0 36.2 gl .8 37.5 34.8 26.6 39.5 17.5 41.4 34.8 28.3
10.7 25.1 24.2 13.4 23.9 15.3 29. I 27.1 9.2 20.9 12.1
0.963 0.937 0.977 0.992 0.978 0.987 0.969 0.952 0.964 0.928 0.944
0.985 0.985 0.989 0.927 O. 987 0.983 0.979 0.978 0.989 0.911 0.986
22.4 19.1 16.6 18.5 19.9 26.1 17.5 39.6 16.7 19.9 24.5
64.8 27.1 28.6 51.7 29.0 45.3 23.8 25.6 75.3 33.2 57.3
54.5 29.0
33.6 7.3
19.2 7.2
21.9 6.6
42.0 17.9
4. 5867 O. 001
TRH
-3.3237 O. 005
The coefficients varied from 0.0175 to 0.0418 for ECT, and from 0.0092 to 0.0291 for TRH. The corresponding half-lives varied from 16.6 to 39.6 min for ECT and from 23.8 to 75.3 min for TRH. Statistical evaluation (paired t-test) revealed significantly higher PRL elimination rate coefficients after ECT than after TRH (2p < 0.005). Consequently, the half-lives of PRL elimination were significantly lower after ECT (2p < 0.01). These results are not easily understood if the assumptions we made for the calculations are all valid, and we discuss the discrepancy below. Discussion One difference in the patterns of PRL release by ECT and by TRH is in the time of occurence of the maximal value, the peaking time, which has been reported to be 10.6 min in the mean after ECT (9), and 20-30 min after TRH (4). These results are confirmed in the present study with data from the same subjects for both stimuli, i.e. in a direct comparative way: the peaking time after ECT was 10.2 min in the mean (SD=-2.0), and after TRH 20.5 min in the mean (SD=4.7). A similarity of the two stimuli was found by our group in the magnitude of the maximal PRL responses, which correlated significantly (6). This correlation is present also in the new sample of 11 patients of this study (r=0.6467, 2a 0.05). A third point of interest is the duration of PRL release by the two stimuli, which may not be in relation to the stimulus duration, but to the nature of the mechanism which they initiate. Both ECT and T~I are short lasting stimuli, and it is of interest that the elimination rate coefficients of PRL released by ECT are much lower than these for TRII. Indeed, if the assumptions we made for their calculation were all valid, there should not be significant differences in this parameter, since the rate of elimination of a substance is expected to be the same for the same subject, independent of the stimulus that elicited the release. Since this is not the case, some assumptions we made in order to apply the exponential regression model may not
1276
ECT, TRH and Prolactin Release
be valid. The most suspicious after the peak PRL value, the procedures is negligible. The after the peak level has been
Vol. 41, No. i0, 1987
one seems to be assumption Nr. 2, i.e. that amount of PRL released by stimulus related release of PRL by TRH seems thus to continue reached.
The mechanism by which ECT releases PRL is not well understood. A modulation of neurotransmitter function has been hypothesized (5), while non-specific factors like stress or anaesthesia do not seem to be related to the secretion (10,11,12). Neither does this effect seem to be mediated through internal opioid activity, released by ECT, since naloxone fails to block the PRL response to ECT (12,13). It seems equally implausible that TRH mediates ECT-induced PRL release, since no plasma T ~ or TSH changes occur during ECT (14), although this fact does not, by itself, rule out the possibility that TRH may be involved in that response. Indeed, TRH levels in the hypophyseal portal blood can be greatly changed without seeing changes in peripheral plasma levels of T ~ . At any case, the findings of the present study offer additional evidence arguing against the notion of an exclusive TRH mediation of PRL release during ECT.References I.
D.A.LEONG, L.S.FRAELEY, and J.D.NEILL, Ann. Rev. Physiol. 45
2. 3. 4. 5. 6.
G.M.BRO~'~, P.SEEMAN, and T.LEE, Endocrinology 99 1407-1410 (1976). R.T.RUBIN, and S.E.HAYS, Psychoneuroendocrinol~-gy 5 121-137 (1980). I.M.D.JACKSON, New Engl. J. Med. 206 145-155 (19827. R.ABRAHS, and C.M.SWARTZ, Convul. Ther. 1 38-42 (1985). Y.PAPAKOSTAS, M.MARKIANOS, G.PAPADIHITRI~U, and C.STEFANIS, Brit.J. Psychiat. 148 721-723 (1986). Y.PAPAKOSTAS, C.STF2ANIS, M.~,t~RKIANOS, and G.PAPADIMITRIOU, Convul. Ther. 2 99-107 (1986). G.D.SIEVERTSEN, V.S.LIM, C.NAKAWATASE, and L.A.FROI~IAN, J. Clin. Endocrinol. Metab. 50 846-852 (1980). C.M.SWARTZ, Convul. Ther. 1 81-86 (1985). ~,I.ARATO, and G.BAGDY, Neur~psychobiology 8_ 162-168 (1982). J.F.W.DEAKIN, I.N.FERRIER, T.J.CROW, E.C.JOHNSTONE, and P.LA~gLER, Brit. J. Psychiat. 1.42 618-624 (1983). Y.G.PAPAKOSTAS, C.N.STEFANIS, H°NAPd(IANOS, and G.N.PAPADIMITRIOU, Biol. Psychiatry 20 1326-1327 (1985). R.F.HASKETT, A.P.ZI---S, and A.A.ALBALA, Biol. Psychiatry 20 623-633
109-127 (1983).
7. 8. 9. 10. 11. 12. 13.
(1985). 14. L.J.WHALLEY, If.DICK, A.G.WATTS, L.E.CHRISTIE, R.ROSIE, G.LEVY, W.J.SHE~VARD, and G.FINK, Lancet ii 1064-1068 (1982).
Pergamon Journals
TIlE PATTErnS OF PROLACTIN RELEASE BY ECT AND TRH CO~,~ARED
Manolis Harkianos, Yiannis Papakostas and Costas Stefanis Athens University Medical School, Psychiatric Clinic, Eginition Hospital, Vass. Sophias 74, Athens 11528, Greece (Received in final form July 6, 1987)
_~i~m~_ The patterns of prolactin release after bilateral ECT and after 0.4 mg TRH i.v. were studied in 11 female melancholic patients in a 5-min sampling protocol. Mean prolactin peaking times were 10.2 min after ECT and 20.5 min after TRH. The elimination rate coefficients were significantly lower - and the corresponding half-lives longer for prolactin released by TRH than by ECT. A significant positive correlation of the maximal prolactin responses by the two stimuli was also found. Among the long list of physiological substances, drugs and conditions that are known to increase plasma prolactin (PRL) levels (I), the responses caused by neuroleptic drugs, thyrotropin-releasing hormone (TRH), and electroconvulsive therapy (ECT) are most studied in psychiatric patients. These three stimuli give different patterns of PRL release regarding a number of parameters, like the time of the occurence and magnitude of the PRL peak, the duration of PRL release, and the total amount released. The patterns of PP~ levels represent the sum total of the underlying mechanisms of the PRL release, binding, and clearance, and their closer study may reveal similarities and differences about those mechanisms activated by these stimuli. The action of neuroleptics on PRL secretion is due to their ability to block dopamine (DA) receptors mainly at the pituitary level (2,3), that of TRH to its action on the lactotrophs of the pituitary (4), while the mechanism by which ECT releases PRL is still hypothetical; it has been suggested that ECT increases the postsynaptic dopamine receptor sensitivity (5). In a recent study of PRL responses by ECT and TRH in 10 melancholic patients, our group found a significant correlation between the maximal PRL responses caused by the two stimuli (6). This correlation may indicate a functional similarity and a common underlying mechanism of ECT and TRH regarding PRL release. We further investigated the two PRL response patterns in a new group of 11 melancholic patients in a more detailed protocol, and compared the peaking times, the elimination rate coefficients, and the half-lives of PRL released, to study in a direct comparative way the similarities and differences between the two stimuli regarding PRL release. _S~bjects and Hethods Eleven female patients suffering from major affective disorder, melancholia type, according to D~I-III criteria, were studied. They were hospitalized in the Athens University Psychiatric Clinic in the Eginition Hospital. The diagnosis was made on the basis of standard clinical interviews and patients' records. The age range was from 26 to 74 years (mean 57.3). Uith the 0024-3025/87 $3.00 + .00 Copyright (c) 1987 Pergamon Journals Ltd.
1274
ECT, TRH and Prolactin Release
Vol. 41, No. i0, 1987
exception of small doses of flunitrazepam given at bed time, patients were free of drugs for at least one week. The TRH test (0.4 mg TRH i.v.) and the ECT were performed between 0800 and 0900, with a 2 to 7 days interval. In 6 patients the T ~ was given before, and in 5 patients after the ECT. Conventional bilateral ECT was given. The procedure is described in detail elsewhere (7). Shortly, the peak current intensity was 400-450 mA and the current flow time 2.5-3 sec. Five minutes before ECT, 0.5 mg atropine was given i.v., followed by pentothal anaesthesia (250-300 mg), succinylcholine (30-40 mg), and oxygenation. The seizure duration was 35 sec in the mean. Blood samples were taken every 5 minutes, beginning 5 min before, and ending 60 min after the TRH or the ECT. Plasma was separated by centrifugation and kept at -30 C. PRL levels were assessed by a double antivody radioimmunoassay supplied by Biodata, and the results expressed in ng/ml plasma. One ng PRL corresponds to 0.023 mlU of the ~ 0 75/504 International Reference Preparation. The disappearance of PRL in humans follows a multiexponential curve, with a break at 40-50 min, which separates the early from the late phase, as it has been sho~m by infusion of labelled PRL (8). Our samples are thus all within the early phase of PRL disappearance, since the last sample, dra~n~ at +60 min, is taken 35 to 50 min after the occurence of the PRL peak. The assumptions as formulated by Swartz for the calculations of PRL r@lease parameters after ECT were used for the calculations below. They are: I) there is a steady concentration of PRL at pre-stimulus baseline; 2) after the peak PRL level, the amount of PRL released by stimulus related procedures is negligible; 3) PRL is removed from blood at a rate proportional to its concentration, and 4) the volume of the compartment through which PRL is distributed in the body does not change substantially during the post-stimulus period. We calculated the elimination rate coefficients by inserting the difference from baseline (zero-time value) into the exponential regression equation Pt = a'e-b't, where Pt is the difference in PRL from baseline at time t, ~ i c h is taken zero when the peak PRL occurs; the factor a, represents ~he calculated from the best fit curve PRL value at time zero (peaking time), and b is the elimination rate coefficient for the subject and stimulus. The half -lives are calculated from the equation ti/2 : in2 / b. Results The mean baseline PRL values of the 11 patients were 7.5 ng/ml (SD=3.7) on TRH administration and 6.9 ng/ml (SD=2.2) on ECT administration. The maximal PRL responses (maximal post-stimulus value minus baseline value) were 53.8 (mean, SD=27.7) for TRH and 51.0 (SD=42.7) for ECT. There were no significant differences (paired t-test) between the baseline PRL values or the PRL responses between TRH and ECT. The maximal responses of the 11 patients to the two stimuli correlated significantly (linear regression, r : 0.6467, 2a 0.05), while no significant correlation existed between the baseline PRL values and the responses to T~{ or to ECT. The time of the occurence of the PRL peak in our 5-min sampling was 10.2 min in the mean (SD=2.0) after ECT, and 20.5 min (SD=4.7) after TRH. The difference is significant at the O.001 level (paired t-test). The results of the calculations of the elimination rate coefficients and the half-lives of PRL for each subject and stimulus are presented in the Table.
Vol. 41, No.
i0, 1987
ECT, TRH and Prolactin Release
1275
Table: Parameters of the PRL elimination after ECT and after TRH in 11 subjects, calculated from the exponential regression model Pt = a . e-b't Half-lives tl/2 = in2/b, r = correlation coefficients of the regression line.
Subject Nr.
a
-b.I03
F,CT
TRH
I 2 3 4 5 6 7 8 9 10 11
19.6 41.4 69.9 40.4 40.2 87.7 154.3 121.6 24.5 7.3 6.5
mean S.D.
55.8 48.0
t 2p
r
ti/2
ECT
TRH
ECT
TRH
ECT
19.8 67.0 45.1 34.1 80.4 102.2 61.2 80.8 53.6 8.8 27.0
31.0 36.2 gl .8 37.5 34.8 26.6 39.5 17.5 41.4 34.8 28.3
10.7 25.1 24.2 13.4 23.9 15.3 29. I 27.1 9.2 20.9 12.1
0.963 0.937 0.977 0.992 0.978 0.987 0.969 0.952 0.964 0.928 0.944
0.985 0.985 0.989 0.927 O. 987 0.983 0.979 0.978 0.989 0.911 0.986
22.4 19.1 16.6 18.5 19.9 26.1 17.5 39.6 16.7 19.9 24.5
64.8 27.1 28.6 51.7 29.0 45.3 23.8 25.6 75.3 33.2 57.3
54.5 29.0
33.6 7.3
19.2 7.2
21.9 6.6
42.0 17.9
4. 5867 O. 001
TRH
-3.3237 O. 005
The coefficients varied from 0.0175 to 0.0418 for ECT, and from 0.0092 to 0.0291 for TRH. The corresponding half-lives varied from 16.6 to 39.6 min for ECT and from 23.8 to 75.3 min for TRH. Statistical evaluation (paired t-test) revealed significantly higher PRL elimination rate coefficients after ECT than after TRH (2p < 0.005). Consequently, the half-lives of PRL elimination were significantly lower after ECT (2p < 0.01). These results are not easily understood if the assumptions we made for the calculations are all valid, and we discuss the discrepancy below. Discussion One difference in the patterns of PRL release by ECT and by TRH is in the time of occurence of the maximal value, the peaking time, which has been reported to be 10.6 min in the mean after ECT (9), and 20-30 min after TRH (4). These results are confirmed in the present study with data from the same subjects for both stimuli, i.e. in a direct comparative way: the peaking time after ECT was 10.2 min in the mean (SD=-2.0), and after TRH 20.5 min in the mean (SD=4.7). A similarity of the two stimuli was found by our group in the magnitude of the maximal PRL responses, which correlated significantly (6). This correlation is present also in the new sample of 11 patients of this study (r=0.6467, 2a 0.05). A third point of interest is the duration of PRL release by the two stimuli, which may not be in relation to the stimulus duration, but to the nature of the mechanism which they initiate. Both ECT and T~I are short lasting stimuli, and it is of interest that the elimination rate coefficients of PRL released by ECT are much lower than these for TRII. Indeed, if the assumptions we made for their calculation were all valid, there should not be significant differences in this parameter, since the rate of elimination of a substance is expected to be the same for the same subject, independent of the stimulus that elicited the release. Since this is not the case, some assumptions we made in order to apply the exponential regression model may not
1276
ECT, TRH and Prolactin Release
be valid. The most suspicious after the peak PRL value, the procedures is negligible. The after the peak level has been
Vol. 41, No. i0, 1987
one seems to be assumption Nr. 2, i.e. that amount of PRL released by stimulus related release of PRL by TRH seems thus to continue reached.
The mechanism by which ECT releases PRL is not well understood. A modulation of neurotransmitter function has been hypothesized (5), while non-specific factors like stress or anaesthesia do not seem to be related to the secretion (10,11,12). Neither does this effect seem to be mediated through internal opioid activity, released by ECT, since naloxone fails to block the PRL response to ECT (12,13). It seems equally implausible that TRH mediates ECT-induced PRL release, since no plasma T ~ or TSH changes occur during ECT (14), although this fact does not, by itself, rule out the possibility that TRH may be involved in that response. Indeed, TRH levels in the hypophyseal portal blood can be greatly changed without seeing changes in peripheral plasma levels of T ~ . At any case, the findings of the present study offer additional evidence arguing against the notion of an exclusive TRH mediation of PRL release during ECT.References I.
D.A.LEONG, L.S.FRAELEY, and J.D.NEILL, Ann. Rev. Physiol. 45
2. 3. 4. 5. 6.
G.M.BRO~'~, P.SEEMAN, and T.LEE, Endocrinology 99 1407-1410 (1976). R.T.RUBIN, and S.E.HAYS, Psychoneuroendocrinol~-gy 5 121-137 (1980). I.M.D.JACKSON, New Engl. J. Med. 206 145-155 (19827. R.ABRAHS, and C.M.SWARTZ, Convul. Ther. 1 38-42 (1985). Y.PAPAKOSTAS, M.MARKIANOS, G.PAPADIHITRI~U, and C.STEFANIS, Brit.J. Psychiat. 148 721-723 (1986). Y.PAPAKOSTAS, C.STF2ANIS, M.~,t~RKIANOS, and G.PAPADIMITRIOU, Convul. Ther. 2 99-107 (1986). G.D.SIEVERTSEN, V.S.LIM, C.NAKAWATASE, and L.A.FROI~IAN, J. Clin. Endocrinol. Metab. 50 846-852 (1980). C.M.SWARTZ, Convul. Ther. 1 81-86 (1985). ~,I.ARATO, and G.BAGDY, Neur~psychobiology 8_ 162-168 (1982). J.F.W.DEAKIN, I.N.FERRIER, T.J.CROW, E.C.JOHNSTONE, and P.LA~gLER, Brit. J. Psychiat. 1.42 618-624 (1983). Y.G.PAPAKOSTAS, C.N.STEFANIS, H°NAPd(IANOS, and G.N.PAPADIMITRIOU, Biol. Psychiatry 20 1326-1327 (1985). R.F.HASKETT, A.P.ZI---S, and A.A.ALBALA, Biol. Psychiatry 20 623-633
109-127 (1983).
7. 8. 9. 10. 11. 12. 13.
(1985). 14. L.J.WHALLEY, If.DICK, A.G.WATTS, L.E.CHRISTIE, R.ROSIE, G.LEVY, W.J.SHE~VARD, and G.FINK, Lancet ii 1064-1068 (1982).