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Effects of methysergide and ritanserin on the prolactin and thyrotropin responses to TRH in depressed patients
EUROPEANNEURO. PSYCHOPHARMACOLOGY ELSEVIER
European Neuropsychopharmacology5 (1995) 15-18
Effects of methysergide and ritanserin on the prolactin and thyrotropin responses to TRH in depressed patients Yiannis G. Papakostas*, Manolis Markianos, George N. Papadimitriou, Iannis M. Zervas, Costas N. Stefanis Department of Psychiatry. Athens University Medical School and the University Research Institute for Mental Health. Eginition Hospital, Psychiatric Clinic, 72-74 Vas. Sophias Ave., 115 28 Athens, Greece
Received 27 January 1994; accepted 9 August 1994
Abstract Despite extensive study of the effects of various pharmacological agents on the thyrotropin (TSH) and prolactin (PRL) responses to TRH challenge, the effect of serotoninergic agents remains inconclusive. We studied the effect of the serotonin antagonists methysergide (non-selective 5-HT1/5-HT: blocker with dopaminergic properties) and ritanserin (selective 5-HT 2 blocker) on the TSH and PRL responses to TRH stimulation in two groups of medication-free female depressed patients in a double-blind, within-subject design. Methysergide was found to decrease significantly the PRL response to TRH, while ritanserin had no effect. Neither compound influenced the TSH response. Results suggest that 5-HT 2 mechanisms do not mediate the PRL and TSH responses to TRH challenge in depression. The reduction in PRL observed after methysergide is probably due to either 5-HT 1 or dopaminergic mechanisms. Keywords: Methysergide; Ritanserin; Prolactin; Thyrotropin releasing hormone; Depression
1. Introduction The relevance of thyrotropin releasing hormone ( T R H ) as a psychoneuroendocrine tool has been investigated intensely (Loosen, 1988) and multiple sources of variance have been identified. Among these, a significant factor is the co-administration of various compounds, including the use of medications (Loosen, 1988). Thus, dopamine agonists and antagonists (i.e. L-dopa, lergotrile mesylate, neuroleptics) alter the hormonal response to the T R H test (Besses et al., 1975; Burrow et al., 1977; Thorner et al., 1978). On the other hand, atropine, as well as/3 and a adrenergic agonists and antagonists (such as epinephrine, propranolol, phentolamine, dexmetodine, atipamezol, etc.) appear to have no effect (Lauridsen et al., 1978; Rogol et al., 1979; Nathan et al., 1984; Karhuvaara et al., 1990). Where serotoninergic agents are concerned, the issue assumes particular importance for clinical research in view of the recent sharp increase in the * Corresponding author. Fax: (301) 72 43 905. 0924-977X/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0924-977X(94)00126-X
interest in, and use of, such compounds in psychiatric research and clinical practice (Meltzer and Lowy, 1987). Data on the effect of such agents on the prolactin (PRL) and thyrotropin ( T S H ) responses to T R H are scarce and inconclusive. Methysergide (a mixed serotonin antagonist with dopaminergic properties) has been reported to reduce the P R L and T S H responses (Egge et al., 1977); cyproheptadine, a related compound, increases the P R L and reduces the TSH response to T R H in healthy volunteers (Collu, 1979). We are aware of no studies investigating the effect of selective serotonin agents (i.e. ritanserin or ketanserin, both 5-HT 2 selective antagonists, in the absence of selective 5-HT I agents) on the hormonal responses to T R H in depressed patients. In this paper we report the effects of two serotoninergic agents, methysergide and ritanserin, on the PRL and TSH responses to T R H .
2. Subjects and methods Subjects were two groups of female depressed
16
Y.G. Papakostas et al. / European Neuropsychopharmacology 5 (1995) 15-18
inpatients, medication free for a mean of 5 days (range 3-7 days), scheduled for electroconvulsive therapy. Diagnosis was established by DSM-IIIR criteria following semi-structured interview and treatment team consensus. Informed consent was signed by all patients. 400 ttg of T R H was injected intravenously as a bolus twice (with a 3-5-day interval between administrations), once after pretreatment with the investigational compound (methysergide or ritanserin) and once with placebo, in random order. Patients and investigators were blind to whether active drug or placebo was given. Blood samples were collected at - 5 , 0, + 10, +20, +40, and +60 min. Plasma was separated by centrifugation and PRL and TSH were measured with commercial radioimmunoassay kits (intra-interassay coefficients of variation below 5%, sensitivity: 0.025 /xIU/ml).
2.1. Study 1: methysergide The sample consisted of 10 female patients ranging in age from 49 to 72 years except for two patients aged 24 and 29 years (mean age: 51.2 years, SD: 15.3). Of them, seven (70%) had previous depressive episodes and eight (80%) were post-menopausal. The two premenopausal patients were in the pre-ovulatory phase of the cycle (LH plasma levels below 12 mlU/ml). Hamilton scale score range was 20-38 (mean: 28.2, SD: 5.6). Methysergide (Sansert) 2 mg or placebo was given orally 2.5 h prior to T R H administration.
2.2. Study 2: ritanserin Subjects were eight depressed female patients with a mean age of 58.9 years (SD: 7.0, range: 47-70), seven (87.5%) of whom were post-menopausal. The premenopausal patient was in the pre-ovulatory phase of the cycle. All had previous depressive episodes. Hamilton scale scores ranged from 18 to 35 (mean: 25.9, SD: 5.8). Ritanserin 10 mg (in topo-tablets) or placebo was given orally, 1.5 h prior to T R H administration, a time when peak plasma concentration is attained (Leysen et al., 1985). The 10 mg dose was chosen based on reports that it is sufficient to reduce PRL in healthy females (Falashi et al., 1985) and has been used in challenge studies (Idzikowski et al., 1987).
3. Results
The area under the response curve (AUC) for the PRL and TSH responses (with subtraction of the baseline values) was calculated at times 0, 20, 40, and 60 min for drug (methysergide or ritanserin) and placebo conditions. Similar analysis has been employed by other investigators (Anderson et al., 1992).
Table 1 Mean AUC values for PRL and TSH responses to TRH for drug (methysergide or ritanserin) and placebo conditions Methysergide (n = 10)
Ritanserin (n = 8)
Mean (SD)
Range
Mean (SD)
Range
PRL Placebo Drug
1839 (945) 1222 (911)
719-3073 64-3112
1968 (1001) 1890 ((867)
792-3489 564-3147
TSH Placebo Drug
345 (257) 287 (265)
51-755 25-935
369 (258) 351 (213)
94-916 72-683
Standard deviations in parentheses and range values. Numbers represent total area units using the trapezoid method after subtraction of the baseline value.
Mean A U C standard deviations and range values are presented in Table 1. As parametric statistics were not suitable, due to the large intra-and inter-subject variability in hormonal values, the Wilcoxon matched pairs test was used for statistical evaluation. For methysergide a significant reduction was found in PRL secretion as compared to placebo (Z = 2.56, P =0.009). We failed to find a significant effect on TSH secretion (Z = 1.24, P = 0.21). For ritanserin, no significant reduction was found for either PRL or TSH.
4. Discussion
We examined the effect of the serotonin antagonists methysergide and ritanserin on the PRL and TSH responses to T R H stimulation in depressed patients. Only methysergide was shown to reduce the PRL response, while neither compound had an effect on the TSH response.
4.1. Prolactin response Methysergide has been reported to decrease the PRL response to T R H in healthy volunteers (Collu, 1979). This finding was replicated for depressed patients in this study. If this effect is serotoninergically mediated, it would seem to be a 5-HT 1 rather than a 5-HT 2 related event as ritanserin (a specific 5-HT 2 antagonist) failed to produce an effect. However, existing data do not support 5-HT1 mediation either. For example, some /3 adrenergic blockers, such as propranolol, display potent 5-HT 1 receptor antagonist properties in animal studies (Hoyer et al., 1988), yet they have no effect on the PRL response to TRH (Lauridsen et al., 1978). Moreover, methysergide can indiscriminately reduce the PRL response to such diverse PRL reducing stimuli as L-tryptophan (Maclndoe and Turkington, 1974), clomipramine (Laackman et al., 1986) and ECT (Papakostas et al., 1988),
Y.G. Papakostas et al. / European Neuropsychopharmacology 5 (1995) 15-18
irrespective of the site of action of these stimuli, be it the pituitary (TRH), suprahypophyseal (e-tryptophan), or unknown (ECT). This consistent effect may point toward a rather direct action of methysergide on the pituitary possibly via its dopaminergic properties, since the involvement of the serotoninergic system at pituitary level is still controversial (Anderson et al., 1992). On the other hand, the effect of ritanserin and related compounds, such as ketanserin, on basal PRL levels, as well as after stimulation with various agents, has not been adequately defined. Ritanserin and ketanserin have failed to modify the PRL response to ECS and ECT (Swartz et al., 1988; Zis et al., 1989; Papakostas et al., 1990). Ritanserin had no effect on the PRL response to L-tryptophan in one study (Idzikowski et al., 1987) but enchanced it in another (Charig et al., 1986). Ketanserin increased the PRL response to T R H in rats (Pan and Tai, 1992), an effect attributed by the authors to the dopamine antagonistic properties of the drug. On the other hand, ketanserin reduced the PRL response to insulin induced hypoglycemia possibly through serotoninergic mechanisms (Prescott et al., 1984). Our findings are consistent with recent evidence suggesting that the PRL response to 5-HT administration and the PRL response to T R H are independent of each other at least in psychiatric disorders (Golden et al., 1990).
17
preted. On the other hand, tryptophan had no effect on the TSH response to TRH (Woolf and Lee, 1977), as did ritanserin in our study. In conclusion, our results suggest that 5-HT 2 mechanisms do not seem to be involved in the regulation of PRL and TSH secretion after TRH stimulation in depressed patients. TRH releases PRL and TSH at the hypophyseal level via plasma membrane TRH receptors on the anterior pituitary lactotrophs and thyrotrophs (Hershman and Pekary, 1985). Ritanserin, supposedly acting through serotoninergic mechanisms, i.e. at the suprahypophyseal level, did not affect this response. Methysergide may act both at the hypophyseal level directly (as a dopamine agonist) and suprahypophyseally (as a serotonin antagonist). If serotonin is involved at all this must be 5-HT1 rather than 5-HT 2 mediated. This, however, is unlikely since /J-blockers with 5-HT~ properties, as mentioned, do not affect the PRL response (Hoyer et al., 1988). Consequently, the observed action of methysergide on the PRL response to TRH may be attributed mainly to its dopaminergic action at the hypophyseai level. There are certain limitations in our study, such as the small sample size, lack of a healthy comparison sample and the short drug free interval. However, our findings are consistent with the prevailing notion that the hormonal responses induced by TRH are mediated by direct action on pituitary lactotrophs and thyrotrophs.
4.2. Thyrotropin response Collu (1979) reported that 2 mg of oral methysergide given every 6 h for 48 h attenuated the TSH response to T R H in healthy volunteers. This is in contrast to our results and various explanations can be offered for this discrepancy. First, different schedules of administration (repeated dosing in Collu's sample versus single dosing in ours) may account for the different response. In addition, sample differences may also explain the discrepancy. Collu used healthy subjects unlike our depressed sample. This may or may not be relevant, but comparison on this matter is difficult given the lack of studies investigating the effect of serotonin agents on the hormonal responses to T R H stimulation. Further, the age difference (younger subjects in Collu's sample) may offer an additional explanation for the discrepancy since the TSH response to TRH has been shown to diminish with advancing age (Snyder and Utiger, 1972). Similarly, cyproheptadine, another serotonin antagonist, has been shown to attenuate the TSH response to T R H in some studies (Ferrari et al., 1976; Egge et al., 1977), but not in others (Goldstein et al., 1979). Since both drugs are ergot compounds with dopaminergic properties, their observed effect on the T R H induced TSH secretion cannot be easily inter-
Acknowledgement This work was supported in part by Grant No. 250 of the STRIDE project of the European Economic Community.
References Anderson, I.M., Ware, C.J., DaRosa Davis, J.M. and Cowen, P.J. (1992) Decreased 5-HT mediated prolactin release in major depression. Br. J. Psychiatry 160, 372-378. Besses, G.S., Burrow, G.N. and Spaulding, S.W. (1975) Dopamine infusion acutely inhibits the TSH and prolactin responses to TRH. J. Clin. Endocrinol. Metab. 41, 985-988. Burrow, G.M., May, P.B., Spaulding, S.W. and Donabedian, R.K. (1977) TRH and dopamine interactions affecting pituitary hormone secretions. J. Clin. Endocrinol. Metab. 45, 76-82. Charig, E.M., Anderson, I.M., Robinson, J.M., Nutt, D.J. and Cowen, P.J. (1986) L-Tryptophan and prolactin release: evidence for interaction between 5-HT~ and 5-HT 2 receptors. Hum. Psychopharmacol. 1, 93-97. Collu, R. (1979) Abnormal pituitary hormone response to TRH: An index of central nervous system dysfunction. In: Tolis, G. et al. (Eds.), Clinical Neuroendocrinology: A Pathophysiological Approach. Raven Press, New York, pp. 129-137. Egge, A.C., Rogol, A.O., Varina, M.M. and Blizzard, R.M. (1977) Effect of cyproheptadine on the TRH-stimulated PRL and TSH release in man. J. Clin. Endocrinol. Metab. 44, 210-213.
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Falashi, P., Rocco, A., Marini, S., Delitala, G. and Melis, G.B. (1985) The implication of serotoninergic system in the control of prolactin secretion. 4th Capo Boi Conference on Neuroscience, Villasimius, Sardinia. Ferrari, C., Paracchi, A., Rondena, M., Beck-Peccoz, P. and Faglia, G. (1976) Effect of two serotonin antagonists on prolactin and thyrotropin secretion in man. Clin. Endocrinol. (Oxford) 5, 575-578. Golden, R.N., Ruegg, R., Brown, T.M., Haggerty, J. Jr., Garbutt, J.C., Pendersen, C.A. and Evans, D. (1990) Abnormal neuroendocrine responsivity to clomipramine in depression. Psychopharmacol. Bull. 26, 317-320. Goldstein, J., Vanhaelst, L., Bruno, O.D. and L'Hermite, M. (1979) Effect of cyproheptadine on thyrotropin and prolactin secretion in normal man. Acta Endocrinol. (Copenhagen) 92, 205-213. Hershman, J.M. and Pehary, A.E. (1985) Regulation of thyrotropin secretion. In: Imura, H. (Ed.), The Pituitary Gland. Raven Press, New York, pp. 149-188. Hoyer, D. (1988) Functional correlates of serotonin 5-HT~ recognition sites. J. Receptor Res. 8, 59-81. Idzikowski, C., Cowen, EJ., Nutt, D. and Mills, F.J. (1987) The effects of chronic ritanserin treatment on sleep and the neuroendocrine response to L-tryptophan. Psychopharmacology 93,416420. Karhuvaara, S., Kallio, A., Kouly, M., Scheinin, H. and Scheinin, M. (1990) No involvement of a2-adrenoreceptors in the regulation of basal prolactin secretion in healthy men. Psychoneuroendocrinology 15, 125-129. Laackman, G., Schoen, H.W., Zygan, K., Weiss, A., Mittman, M. and Meissner, R. (1986) Effects of receptor blockers (methysergide, propranolol, phentolamine, yohimbine and prazosin) on desipramine-induced pituitary hormone stimulation in humans. II. Prolactin. Psychoneuroendocrinology 11, 463-474. Lauridsen, U.B., Eskildsen, P.C., Kirgegaard, C. and Lund, B. (1978) Prolactin release after TRH during altered adrenergic a and/3 receptor influence. Hormone Metab. Res. 10, 452-454. Leysen, J.E., Gommeren, W., VanGompel, P., Wynants, J., Jansen P.F.M. and Laduron, P.M. (1985) Receptor-binding properties in vitro and in vivo of ritanserin, a very potent and long-acting serotonin-S2 antagonist. Mol. Pharmacol. 27, 600-611 Loosen, P.T. (1988) TRH: Behavioral and endocrine effects in man. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 12, $87-$117.
MacIndoe, J.H. and Turkington, R.W. (1974) Stimulation of human prolactin secretion by intravenous infusion of L-tryptophan. J. Clin. Invest. 52, 1972-1978. Meltzer, H.Y. and Lowy, M.T. (1987) The serotonin hypothesis of depression. In: Meltzer, H.Y. (Ed.), Psychopharmaeology: The Third Generation of Progress. Raven Press, New York. Nathan, R.S., McCarthy, T. and Jarrett, D.B. (1984) Effect of atropine on the diurnal prolactin responses to TRH in normal subjects. Psychoneuroendocrinology 9, 301-304. Pan, J.T. and Tai, M.H. (1992) Effect of ketanserin on DOI-, mCPP-, and TRH-induced prolactin secretion in estrogen-treated rats. Life Sci. 51, 839-845. Papakostas, Y., Markianos, M. and Stefanis, C. (1988) Methysergide reduces the prolactin response to ECT. Biol. Psychiatry 24, 465-468. Papakostas, Y., Markianos, M., Papadimitriou, G. and Stefanis, C. (1990) Ritanserin, a 5-HT, receptor antagonist does not modify ECT-induced prolactin release. Psychopharmacology 100, 206208. Prescott, R.W.G., Kendall-Taylor, P., Weightman, D.R., Watson, M.J. and Ratcliffe, W.A. (1984) The effect of ketanserin, a specific serotonin antagonist, on the PRL, GH, ACTH and cortisol responses to hypoglycaemia in normal subjects. Clin. Endocrinol. 20, 137-142. Rogol, A.D., Reeves, G.D., Varma, M.M. and Blizzard, R.M. (1979) TSH and PRL responses to TRH during infusion of epinephrine and propranolol in man. Neuroendocrinology 29, 413-417. Snyder, P.J. and Utiger, R.D. (1972) Response to TRH in normal man. J. Clin. Endocrinol. Metab. 34, 380-385. Swartz, C.M., Abrams, R. and Drews, U.C. (1988) Serotonin and ECS induced prolactin release. Convuls. Ther. 4, 141-145. Thorner, M.O., Ryan, S.M., Wass, J.A.H., Jones, A., Bouloux, P., Williams, S. and Besser, G.M. (1978) Effect of the dopamine agonist lergotrile mesylate on circulating anterior pituitary hormones in man. J. Clin. Endocrinol. Metab. 47, 372-378. Woolf, P.O. and Lee, L. (1977) Effect of the serotonin precursor tryptophan on pituitary hormone secretion. J. Clin. Endocrinol. Metab 45, 123-133. Zis, A.P., Manji, H.K., Remick, R.A., Grant, B.E.K. and Clark, C.M. (1989) Effect of the 5-HT2 antagonist ketanserin on the ECT-induced prolactin release. Biol. Psychiatry 26, 102-106.
European Neuropsychopharmacology5 (1995) 15-18
Effects of methysergide and ritanserin on the prolactin and thyrotropin responses to TRH in depressed patients Yiannis G. Papakostas*, Manolis Markianos, George N. Papadimitriou, Iannis M. Zervas, Costas N. Stefanis Department of Psychiatry. Athens University Medical School and the University Research Institute for Mental Health. Eginition Hospital, Psychiatric Clinic, 72-74 Vas. Sophias Ave., 115 28 Athens, Greece
Received 27 January 1994; accepted 9 August 1994
Abstract Despite extensive study of the effects of various pharmacological agents on the thyrotropin (TSH) and prolactin (PRL) responses to TRH challenge, the effect of serotoninergic agents remains inconclusive. We studied the effect of the serotonin antagonists methysergide (non-selective 5-HT1/5-HT: blocker with dopaminergic properties) and ritanserin (selective 5-HT 2 blocker) on the TSH and PRL responses to TRH stimulation in two groups of medication-free female depressed patients in a double-blind, within-subject design. Methysergide was found to decrease significantly the PRL response to TRH, while ritanserin had no effect. Neither compound influenced the TSH response. Results suggest that 5-HT 2 mechanisms do not mediate the PRL and TSH responses to TRH challenge in depression. The reduction in PRL observed after methysergide is probably due to either 5-HT 1 or dopaminergic mechanisms. Keywords: Methysergide; Ritanserin; Prolactin; Thyrotropin releasing hormone; Depression
1. Introduction The relevance of thyrotropin releasing hormone ( T R H ) as a psychoneuroendocrine tool has been investigated intensely (Loosen, 1988) and multiple sources of variance have been identified. Among these, a significant factor is the co-administration of various compounds, including the use of medications (Loosen, 1988). Thus, dopamine agonists and antagonists (i.e. L-dopa, lergotrile mesylate, neuroleptics) alter the hormonal response to the T R H test (Besses et al., 1975; Burrow et al., 1977; Thorner et al., 1978). On the other hand, atropine, as well as/3 and a adrenergic agonists and antagonists (such as epinephrine, propranolol, phentolamine, dexmetodine, atipamezol, etc.) appear to have no effect (Lauridsen et al., 1978; Rogol et al., 1979; Nathan et al., 1984; Karhuvaara et al., 1990). Where serotoninergic agents are concerned, the issue assumes particular importance for clinical research in view of the recent sharp increase in the * Corresponding author. Fax: (301) 72 43 905. 0924-977X/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0924-977X(94)00126-X
interest in, and use of, such compounds in psychiatric research and clinical practice (Meltzer and Lowy, 1987). Data on the effect of such agents on the prolactin (PRL) and thyrotropin ( T S H ) responses to T R H are scarce and inconclusive. Methysergide (a mixed serotonin antagonist with dopaminergic properties) has been reported to reduce the P R L and T S H responses (Egge et al., 1977); cyproheptadine, a related compound, increases the P R L and reduces the TSH response to T R H in healthy volunteers (Collu, 1979). We are aware of no studies investigating the effect of selective serotonin agents (i.e. ritanserin or ketanserin, both 5-HT 2 selective antagonists, in the absence of selective 5-HT I agents) on the hormonal responses to T R H in depressed patients. In this paper we report the effects of two serotoninergic agents, methysergide and ritanserin, on the PRL and TSH responses to T R H .
2. Subjects and methods Subjects were two groups of female depressed
16
Y.G. Papakostas et al. / European Neuropsychopharmacology 5 (1995) 15-18
inpatients, medication free for a mean of 5 days (range 3-7 days), scheduled for electroconvulsive therapy. Diagnosis was established by DSM-IIIR criteria following semi-structured interview and treatment team consensus. Informed consent was signed by all patients. 400 ttg of T R H was injected intravenously as a bolus twice (with a 3-5-day interval between administrations), once after pretreatment with the investigational compound (methysergide or ritanserin) and once with placebo, in random order. Patients and investigators were blind to whether active drug or placebo was given. Blood samples were collected at - 5 , 0, + 10, +20, +40, and +60 min. Plasma was separated by centrifugation and PRL and TSH were measured with commercial radioimmunoassay kits (intra-interassay coefficients of variation below 5%, sensitivity: 0.025 /xIU/ml).
2.1. Study 1: methysergide The sample consisted of 10 female patients ranging in age from 49 to 72 years except for two patients aged 24 and 29 years (mean age: 51.2 years, SD: 15.3). Of them, seven (70%) had previous depressive episodes and eight (80%) were post-menopausal. The two premenopausal patients were in the pre-ovulatory phase of the cycle (LH plasma levels below 12 mlU/ml). Hamilton scale score range was 20-38 (mean: 28.2, SD: 5.6). Methysergide (Sansert) 2 mg or placebo was given orally 2.5 h prior to T R H administration.
2.2. Study 2: ritanserin Subjects were eight depressed female patients with a mean age of 58.9 years (SD: 7.0, range: 47-70), seven (87.5%) of whom were post-menopausal. The premenopausal patient was in the pre-ovulatory phase of the cycle. All had previous depressive episodes. Hamilton scale scores ranged from 18 to 35 (mean: 25.9, SD: 5.8). Ritanserin 10 mg (in topo-tablets) or placebo was given orally, 1.5 h prior to T R H administration, a time when peak plasma concentration is attained (Leysen et al., 1985). The 10 mg dose was chosen based on reports that it is sufficient to reduce PRL in healthy females (Falashi et al., 1985) and has been used in challenge studies (Idzikowski et al., 1987).
3. Results
The area under the response curve (AUC) for the PRL and TSH responses (with subtraction of the baseline values) was calculated at times 0, 20, 40, and 60 min for drug (methysergide or ritanserin) and placebo conditions. Similar analysis has been employed by other investigators (Anderson et al., 1992).
Table 1 Mean AUC values for PRL and TSH responses to TRH for drug (methysergide or ritanserin) and placebo conditions Methysergide (n = 10)
Ritanserin (n = 8)
Mean (SD)
Range
Mean (SD)
Range
PRL Placebo Drug
1839 (945) 1222 (911)
719-3073 64-3112
1968 (1001) 1890 ((867)
792-3489 564-3147
TSH Placebo Drug
345 (257) 287 (265)
51-755 25-935
369 (258) 351 (213)
94-916 72-683
Standard deviations in parentheses and range values. Numbers represent total area units using the trapezoid method after subtraction of the baseline value.
Mean A U C standard deviations and range values are presented in Table 1. As parametric statistics were not suitable, due to the large intra-and inter-subject variability in hormonal values, the Wilcoxon matched pairs test was used for statistical evaluation. For methysergide a significant reduction was found in PRL secretion as compared to placebo (Z = 2.56, P =0.009). We failed to find a significant effect on TSH secretion (Z = 1.24, P = 0.21). For ritanserin, no significant reduction was found for either PRL or TSH.
4. Discussion
We examined the effect of the serotonin antagonists methysergide and ritanserin on the PRL and TSH responses to T R H stimulation in depressed patients. Only methysergide was shown to reduce the PRL response, while neither compound had an effect on the TSH response.
4.1. Prolactin response Methysergide has been reported to decrease the PRL response to T R H in healthy volunteers (Collu, 1979). This finding was replicated for depressed patients in this study. If this effect is serotoninergically mediated, it would seem to be a 5-HT 1 rather than a 5-HT 2 related event as ritanserin (a specific 5-HT 2 antagonist) failed to produce an effect. However, existing data do not support 5-HT1 mediation either. For example, some /3 adrenergic blockers, such as propranolol, display potent 5-HT 1 receptor antagonist properties in animal studies (Hoyer et al., 1988), yet they have no effect on the PRL response to TRH (Lauridsen et al., 1978). Moreover, methysergide can indiscriminately reduce the PRL response to such diverse PRL reducing stimuli as L-tryptophan (Maclndoe and Turkington, 1974), clomipramine (Laackman et al., 1986) and ECT (Papakostas et al., 1988),
Y.G. Papakostas et al. / European Neuropsychopharmacology 5 (1995) 15-18
irrespective of the site of action of these stimuli, be it the pituitary (TRH), suprahypophyseal (e-tryptophan), or unknown (ECT). This consistent effect may point toward a rather direct action of methysergide on the pituitary possibly via its dopaminergic properties, since the involvement of the serotoninergic system at pituitary level is still controversial (Anderson et al., 1992). On the other hand, the effect of ritanserin and related compounds, such as ketanserin, on basal PRL levels, as well as after stimulation with various agents, has not been adequately defined. Ritanserin and ketanserin have failed to modify the PRL response to ECS and ECT (Swartz et al., 1988; Zis et al., 1989; Papakostas et al., 1990). Ritanserin had no effect on the PRL response to L-tryptophan in one study (Idzikowski et al., 1987) but enchanced it in another (Charig et al., 1986). Ketanserin increased the PRL response to T R H in rats (Pan and Tai, 1992), an effect attributed by the authors to the dopamine antagonistic properties of the drug. On the other hand, ketanserin reduced the PRL response to insulin induced hypoglycemia possibly through serotoninergic mechanisms (Prescott et al., 1984). Our findings are consistent with recent evidence suggesting that the PRL response to 5-HT administration and the PRL response to T R H are independent of each other at least in psychiatric disorders (Golden et al., 1990).
17
preted. On the other hand, tryptophan had no effect on the TSH response to TRH (Woolf and Lee, 1977), as did ritanserin in our study. In conclusion, our results suggest that 5-HT 2 mechanisms do not seem to be involved in the regulation of PRL and TSH secretion after TRH stimulation in depressed patients. TRH releases PRL and TSH at the hypophyseal level via plasma membrane TRH receptors on the anterior pituitary lactotrophs and thyrotrophs (Hershman and Pekary, 1985). Ritanserin, supposedly acting through serotoninergic mechanisms, i.e. at the suprahypophyseal level, did not affect this response. Methysergide may act both at the hypophyseal level directly (as a dopamine agonist) and suprahypophyseally (as a serotonin antagonist). If serotonin is involved at all this must be 5-HT1 rather than 5-HT 2 mediated. This, however, is unlikely since /J-blockers with 5-HT~ properties, as mentioned, do not affect the PRL response (Hoyer et al., 1988). Consequently, the observed action of methysergide on the PRL response to TRH may be attributed mainly to its dopaminergic action at the hypophyseai level. There are certain limitations in our study, such as the small sample size, lack of a healthy comparison sample and the short drug free interval. However, our findings are consistent with the prevailing notion that the hormonal responses induced by TRH are mediated by direct action on pituitary lactotrophs and thyrotrophs.
4.2. Thyrotropin response Collu (1979) reported that 2 mg of oral methysergide given every 6 h for 48 h attenuated the TSH response to T R H in healthy volunteers. This is in contrast to our results and various explanations can be offered for this discrepancy. First, different schedules of administration (repeated dosing in Collu's sample versus single dosing in ours) may account for the different response. In addition, sample differences may also explain the discrepancy. Collu used healthy subjects unlike our depressed sample. This may or may not be relevant, but comparison on this matter is difficult given the lack of studies investigating the effect of serotonin agents on the hormonal responses to T R H stimulation. Further, the age difference (younger subjects in Collu's sample) may offer an additional explanation for the discrepancy since the TSH response to TRH has been shown to diminish with advancing age (Snyder and Utiger, 1972). Similarly, cyproheptadine, another serotonin antagonist, has been shown to attenuate the TSH response to T R H in some studies (Ferrari et al., 1976; Egge et al., 1977), but not in others (Goldstein et al., 1979). Since both drugs are ergot compounds with dopaminergic properties, their observed effect on the T R H induced TSH secretion cannot be easily inter-
Acknowledgement This work was supported in part by Grant No. 250 of the STRIDE project of the European Economic Community.
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