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Fabrice Duval - One of the best experts on this subject based on the ideXlab platform.
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Are the thyroid and adrenal system alterations linked in depression
Psychoneuroendocrinology, 2020Co-Authors: Marie-claude Mokrani, Fabrice Duval, Alexis Erb, Felix Gonzalez Lopera, Vlad DanilaAbstract:Abstract Background Disturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently found in major depression. Given that glucocorticoids may inhibit thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) secretion, it has been hypothesized that hypercortisolemia could lead to HPT axis abnormalities. So far, data on interactions between the HPA and HPT axes in depression remain inconclusive. Methods In order to investigate this issue, we examined circadian rhythms of serum TSH and cortisol (sampled at 4 -hly intervals throughout a 24 -h span), TSH responses to 0800 h and 2300 h Protirelin (TRH) tests and cortisol response to dexamethasone suppression test (DST) in 145 unmedicated inpatients meeting DSM-IV criteria for major depressive disorder (MDDs) and 25 healthy hospitalized control subjects (HCs). Results The secretion of TSH and cortisol exhibited a significant circadian rhythm both in HCs and MDDs. However, compared to HCs, MDDs showed: 1) reduced TSH mesor and amplitude values; 2) blunted 2300 h-ΔTSH and ΔΔTSH values (i.e. differences between 2300 h and 0800 h TRH-TSH responses); and 3) increased cortisol mesor and post-DST cortisol values. DST nonsuppresssors (n = 40, 27 %) showed higher cortisol mesor than DST suppressors (n = 105, 73 %). There was no difference between DST suppressors and nonsuppressors in their TSH circadian parameters and TRH-TSH responses. In addition, cortisol values (circadian and post-DST) were not related to TRH test responses. Conclusion Our results do not confirm a key role for hypercortisolemia in the HPT axis dysregulation in depression.
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Thyroid Hormone Treatment of Mood Disorders
Current Treatment Options in Psychiatry, 2018Co-Authors: Fabrice DuvalAbstract:Purpose of review Both excess and insufficient thyroid hormones can lead to depression that is generally reversible with adequate thyroid treatment. On the other hand, major depression is associated with subtle chronobiological hypothalamic-pituitary-thyroid (HPT) axis dysregulation and thyroid hormones can be an effective adjunct to antidepressant treatment. However, the links between HPT axis status and efficacy of thyroid hormone supplementation in depression remain to be further clarified. Recent findings While generally, depressed patients are chemically euthyroid, most exhibit a chronobiological HPT axis dysregulation (i.e., loss of the nocturnal thyrotropin [TSH] rise, blunted evening TSH response to Protirelin [TRH], reduced difference in TSH response between 11 PM and 8 AM TRH tests [ΔΔTSH]), possibly associated with blunted 8 AM-TSH response to TRH and/or altered levels of circulating thyroxine (FT4) and triiodothyronine (T3). Usually, chronobiological HPT axis abnormalities are unrelated to increased cortisol levels. Normalization of thyroid function tests by antidepressants, especially the ΔΔTSH test, may occur before the clinical response. In patients who are resistant to antidepressants, there is good evidence for adjuvant therapy with thyroid hormones. Summary While there is a limited evidence base to guide long-term adjunctive use, thyroid hormone augmentation can be a safe and effective alternative treatment for euthyroid-depressed patients who receive appropriate baseline and follow-up safety monitoring. However, it remains to be established which bio-clinical subtypes of depression respond preferentially to thyroid hormone supplementation. In the next future, metabolically stable TRH analogs could be used in order to maintain or restore homeostasis, which is frequently disrupted in depressive states.
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Thyroid Hormone Treatment of Mood Disorders
Current Treatment Options in Psychiatry, 2018Co-Authors: Fabrice DuvalAbstract:Both excess and insufficient thyroid hormones can lead to depression that is generally reversible with adequate thyroid treatment. On the other hand, major depression is associated with subtle chronobiological hypothalamic-pituitary-thyroid (HPT) axis dysregulation and thyroid hormones can be an effective adjunct to antidepressant treatment. However, the links between HPT axis status and efficacy of thyroid hormone supplementation in depression remain to be further clarified. While generally, depressed patients are chemically euthyroid, most exhibit a chronobiological HPT axis dysregulation (i.e., loss of the nocturnal thyrotropin [TSH] rise, blunted evening TSH response to Protirelin [TRH], reduced difference in TSH response between 11 PM and 8 AM TRH tests [ΔΔTSH]), possibly associated with blunted 8 AM-TSH response to TRH and/or altered levels of circulating thyroxine (FT4) and triiodothyronine (T3). Usually, chronobiological HPT axis abnormalities are unrelated to increased cortisol levels. Normalization of thyroid function tests by antidepressants, especially the ΔΔTSH test, may occur before the clinical response. In patients who are resistant to antidepressants, there is good evidence for adjuvant therapy with thyroid hormones. While there is a limited evidence base to guide long-term adjunctive use, thyroid hormone augmentation can be a safe and effective alternative treatment for euthyroid-depressed patients who receive appropriate baseline and follow-up safety monitoring. However, it remains to be established which bio-clinical subtypes of depression respond preferentially to thyroid hormone supplementation. In the next future, metabolically stable TRH analogs could be used in order to maintain or restore homeostasis, which is frequently disrupted in depressive states.
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Relationship between chronobiological thyrotropin and prolactin responses to Protirelin (TRH) and suicidal behavior in depressed patients.
Psychoneuroendocrinology, 2017Co-Authors: Fabrice Duval, Marie-claude Mokrani, Alexis Erb, Felix Gonzalez Opera, Cécile Calleja, Veronique ParisAbstract:Abstract Background So far, investigations of the relationships between suicidality and the activity of the thyrotropic and lactotropic axes are scarce and have yielded conflicting results. Methods We studied the thyrotropin (TSH) and prolactin (PRL) responses to 0800 h and 2300 h Protirelin (TRH) stimulation tests, carried out on the same day, in 122 euthyroid DSM-5 major depressed inpatients with suicidal behavior disorder (SBD) (either current [n = 71], or in early remission [n = 51]); and 50 healthy hospitalized controls. Results Baseline TSH and PRL measurements did not differ across the 3 groups. In SBDs in early remission, the TSH and PRL responses to TRH tests (expressed as the maximum increment above baseline value after TRH [Δ]) were indistinguishable from controls. Current SBDs showed (1) lower 2300 h-ΔTSH and lower ΔΔTSH values (differences between 2300 h-ΔTSH and 0800 h-ΔTSH) than controls and SBDs in early remission; and (2) lower baseline free thyroxine (FT 4B ) levels than controls. In the current SBD group, ΔΔPRL values (differences between 2300 h-ΔPRL and 0800 h-ΔPRL) were correlated negatively with lethality. Moreover, in current SBDs (1) violent suicide attempters (n = 15) showed lower FT 4B levels, lower TSH-TRH responses (both at 0800 h and 2300 h), and lower ΔΔTSH and ΔΔPRL values than controls, while (2) non-violent suicide attempters (n = 56) showed lower ΔΔTSH values than controls and higher TSH-TRH responses (both at 0800 h and 2300 h) than violent suicide attempters. Conclusions Our results suggest that central TRH secretion is not altered in depressed patients with SBD in early remission. The findings that current SBDs exhibit both decreased FT 4B levels and decreased evening TSH responses (and consequently, decreased ΔΔTSH values) support the hypothesis that hypothalamic TRH drive is reduced—leading to an impaired TSH resynthesis in the pituitary during the day after the morning TRH challenge. In violent suicide attempters, the marked abnormalities of TRH test responses might indicate a greatest reduction in hypothalamic TRH drive. These results further strengthen the possibility that a deficit in central TRH function may play a key role in the pathogenesis of suicidal behavior.
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Chronobiological hypothalamic–pituitary–thyroid axis status and antidepressant outcome in major depression
Psychoneuroendocrinology, 2015Co-Authors: Fabrice Duval, Marie-claude Mokrani, Alexis Erb, Felix Gonzalez Lopera, Claudia Alexa, Xenia Proudnikova, Iuliana ButucaruAbstract:Summary Background We previously demonstrated that the difference between 2300 h and 0800 h TSH response to Protirelin (TRH) tests on the same day (ΔΔTSH test) is an improved measure in detecting hypothalamic–pituitary–thyroid (HPT) axis dysregulation in depression. This chronobiological index (1) is reduced in about three quarters of major depressed inpatients, and (2) is normalized after successful antidepressant treatment. In the present study, we examined whether early changes in HPT axis activity during the first 2 weeks of antidepressant treatment could be associated with subsequent outcome. Methods The ΔΔTSH test was performed in 50 drug-free DSM-IV euthyroid major depressed inpatients and 50 hospitalized controls. After 2 weeks of antidepressant treatment the ΔΔTSH test was repeated in all inpatients. Antidepressant response was evaluated after 6 weeks of treatment. Results At baseline, ΔΔTSH values were significantly lower in patients compared to controls and 38 patients (76%) showed reduced ΔΔTSH values (i.e., Conclusions Our results suggest that after 2 weeks of antidepressant treatment: (1) chronobiological restoration of the HPT axis activity precedes clinical remission, and (2) alteration of the HPT axis is associated with treatment resistance.
Yoshihiro Takeuchi - One of the best experts on this subject based on the ideXlab platform.
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A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report.
American journal of physical medicine & rehabilitation, 2000Co-Authors: Alice C. Tzeng, Yoshihiro Takeuchi, Jenfu Cheng, Hillary Fryczynski, Vis Niranjan, Todd P. Stitik, Ashu Sial, Patrick M. Foye, Melissa Deprince, John R. BachAbstract:Objective: To determine whether thyrotropin-releasing hormone (TRH) can increase muscle strength in children with spinal muscular atrophy types 2 and 3. Design: A randomized, double-blinded, controlled, 5-wk drug trial of six subjects and three controls. Subjects and controls ranged from 4 to 8 yr of age and were randomly assigned to treatment and placebo groups in a ratio of 2:1. TRH (Protirelin) or placebo was delivered intravenously through percutaneous intravenous catheters at a dose of 0.1 mg/kg (in 50 ml of normal saline) for a total of 29 days. Patients were evaluated using electromyography and handheld dynamometry of the deltoids, biceps, triceps, wrist extensors, hip flexors, quadriceps, hamstrings, and grip strength before and immediately after 5 wk of treatment. A unidirectional t test was used to compare mean values. Results: Dynamometry improved significantly only for the six treated subjects (P < 0.02). Peroneal nerve conduction velocities were significantly faster in the treatment group (paired t test, P = 0.036). The parents of the treated children also provided anecdotal evidence of improvements in function. Improvements lasted 6-12 mo. Conclusions: TRH may be a useful treatment for spinal muscular atrophy. A larger, crossover design group comparison study is warranted.
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Thyrotropin-Releasing Hormone (Protirelin)
CNS Drugs, 1996Co-Authors: Yoshihiro TakeuchiAbstract:Thyrotropin-releasing hormone (TRH; Protirelin) is the smallest known peptide hormone. It has central effects, unrelated to its endocrine effects, via an action at the pituitary-thyroid axis. TRH has been used successfully to treat children with neurological disorders including intractable epilepsy. The effectiveness of TRH, and an analogue of the peptide (DN-1417), has been reported as both add-on and monotherapy in the treatment of progressive myoclonic epilepsy, West syndrome, Lennox-Gastaut syndrome, complex partial seizures, severe myoclonic epilepsy in infancy, and early infantile epileptic encephalopathy. No serious adverse effects have been reported. TRH may, thus, be considered to be a possible treatment for intractable epilepsy, especially for children with West syndrome and Lennox-Gastaut syndrome. However, it should be noted that the studies were not placebo-controlled or double-blind in design, and most were performed in Japan (the peptide has not been widely studied as a treatment for epilepsy in other countries). The relatively prolonged duration of action of TRH may indicate that the mechanism of its anticonvulsant action differs from that of other anticonvulsant drugs. It is likely that TRH contributes to the plasticity of the seizure network, in analogy to its known trophic effect on spinal motoneurons. Additional research is required to further elucidate the mechanism of action of TRH in children who have epilepsy that is refractory to conventional treatment, and further efforts should be made to develop more potent and selective TRH analogues for neurological disorders.
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Thyrotropin-Releasing Hormone (Protirelin)
CNS Drugs, 1996Co-Authors: Yoshihiro TakeuchiAbstract:Thyrotropin-releasing hormone (TRH; Protirelin) is the smallest known peptide hormone. It has central effects, unrelated to its endocrine effects, via an action at the pituitary-thyroid axis.
Marie-claude Mokrani - One of the best experts on this subject based on the ideXlab platform.
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Are the thyroid and adrenal system alterations linked in depression
Psychoneuroendocrinology, 2020Co-Authors: Marie-claude Mokrani, Fabrice Duval, Alexis Erb, Felix Gonzalez Lopera, Vlad DanilaAbstract:Abstract Background Disturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently found in major depression. Given that glucocorticoids may inhibit thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) secretion, it has been hypothesized that hypercortisolemia could lead to HPT axis abnormalities. So far, data on interactions between the HPA and HPT axes in depression remain inconclusive. Methods In order to investigate this issue, we examined circadian rhythms of serum TSH and cortisol (sampled at 4 -hly intervals throughout a 24 -h span), TSH responses to 0800 h and 2300 h Protirelin (TRH) tests and cortisol response to dexamethasone suppression test (DST) in 145 unmedicated inpatients meeting DSM-IV criteria for major depressive disorder (MDDs) and 25 healthy hospitalized control subjects (HCs). Results The secretion of TSH and cortisol exhibited a significant circadian rhythm both in HCs and MDDs. However, compared to HCs, MDDs showed: 1) reduced TSH mesor and amplitude values; 2) blunted 2300 h-ΔTSH and ΔΔTSH values (i.e. differences between 2300 h and 0800 h TRH-TSH responses); and 3) increased cortisol mesor and post-DST cortisol values. DST nonsuppresssors (n = 40, 27 %) showed higher cortisol mesor than DST suppressors (n = 105, 73 %). There was no difference between DST suppressors and nonsuppressors in their TSH circadian parameters and TRH-TSH responses. In addition, cortisol values (circadian and post-DST) were not related to TRH test responses. Conclusion Our results do not confirm a key role for hypercortisolemia in the HPT axis dysregulation in depression.
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Relationship between chronobiological thyrotropin and prolactin responses to Protirelin (TRH) and suicidal behavior in depressed patients.
Psychoneuroendocrinology, 2017Co-Authors: Fabrice Duval, Marie-claude Mokrani, Alexis Erb, Felix Gonzalez Opera, Cécile Calleja, Veronique ParisAbstract:Abstract Background So far, investigations of the relationships between suicidality and the activity of the thyrotropic and lactotropic axes are scarce and have yielded conflicting results. Methods We studied the thyrotropin (TSH) and prolactin (PRL) responses to 0800 h and 2300 h Protirelin (TRH) stimulation tests, carried out on the same day, in 122 euthyroid DSM-5 major depressed inpatients with suicidal behavior disorder (SBD) (either current [n = 71], or in early remission [n = 51]); and 50 healthy hospitalized controls. Results Baseline TSH and PRL measurements did not differ across the 3 groups. In SBDs in early remission, the TSH and PRL responses to TRH tests (expressed as the maximum increment above baseline value after TRH [Δ]) were indistinguishable from controls. Current SBDs showed (1) lower 2300 h-ΔTSH and lower ΔΔTSH values (differences between 2300 h-ΔTSH and 0800 h-ΔTSH) than controls and SBDs in early remission; and (2) lower baseline free thyroxine (FT 4B ) levels than controls. In the current SBD group, ΔΔPRL values (differences between 2300 h-ΔPRL and 0800 h-ΔPRL) were correlated negatively with lethality. Moreover, in current SBDs (1) violent suicide attempters (n = 15) showed lower FT 4B levels, lower TSH-TRH responses (both at 0800 h and 2300 h), and lower ΔΔTSH and ΔΔPRL values than controls, while (2) non-violent suicide attempters (n = 56) showed lower ΔΔTSH values than controls and higher TSH-TRH responses (both at 0800 h and 2300 h) than violent suicide attempters. Conclusions Our results suggest that central TRH secretion is not altered in depressed patients with SBD in early remission. The findings that current SBDs exhibit both decreased FT 4B levels and decreased evening TSH responses (and consequently, decreased ΔΔTSH values) support the hypothesis that hypothalamic TRH drive is reduced—leading to an impaired TSH resynthesis in the pituitary during the day after the morning TRH challenge. In violent suicide attempters, the marked abnormalities of TRH test responses might indicate a greatest reduction in hypothalamic TRH drive. These results further strengthen the possibility that a deficit in central TRH function may play a key role in the pathogenesis of suicidal behavior.
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Chronobiological hypothalamic–pituitary–thyroid axis status and antidepressant outcome in major depression
Psychoneuroendocrinology, 2015Co-Authors: Fabrice Duval, Marie-claude Mokrani, Alexis Erb, Felix Gonzalez Lopera, Claudia Alexa, Xenia Proudnikova, Iuliana ButucaruAbstract:Summary Background We previously demonstrated that the difference between 2300 h and 0800 h TSH response to Protirelin (TRH) tests on the same day (ΔΔTSH test) is an improved measure in detecting hypothalamic–pituitary–thyroid (HPT) axis dysregulation in depression. This chronobiological index (1) is reduced in about three quarters of major depressed inpatients, and (2) is normalized after successful antidepressant treatment. In the present study, we examined whether early changes in HPT axis activity during the first 2 weeks of antidepressant treatment could be associated with subsequent outcome. Methods The ΔΔTSH test was performed in 50 drug-free DSM-IV euthyroid major depressed inpatients and 50 hospitalized controls. After 2 weeks of antidepressant treatment the ΔΔTSH test was repeated in all inpatients. Antidepressant response was evaluated after 6 weeks of treatment. Results At baseline, ΔΔTSH values were significantly lower in patients compared to controls and 38 patients (76%) showed reduced ΔΔTSH values (i.e., Conclusions Our results suggest that after 2 weeks of antidepressant treatment: (1) chronobiological restoration of the HPT axis activity precedes clinical remission, and (2) alteration of the HPT axis is associated with treatment resistance.
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Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates.
Psychoneuroendocrinology, 2006Co-Authors: Fabrice Duval, Marie-claude Mokrani, José A. Monreal-ortiz, Said Fattah, C. Champeval, Pierre Schulz, J.p. MacherAbstract:Evidence supports that hyperactivity of the hypothalamic-pituitary-adrenal axis has a pivotal role in the psychobiology of severe depression. The present study aimed at assessing hypothalamic-pituitary dopaminergic, noradrenergic, and thyroid activity in unipolar depressed patients with melancholic and psychotic features and with concomitant hypercortisolemia. Hormonal responses to dexamethasone, apomorphine (a dopamine receptor agonist), clonidine (an alpha 2-adrenoreceptor agonist) and 0800 and 2300 h Protirelin (TRH) were measured in 18 drug-free inpatients with a DSM-IV diagnosis of severe major depressive disorder with melancholic and psychotic features showing cortisol nonsuppression following dexamethasone and 23 matched hospitalized healthy controls. Compared with controls, patients showed (1) lower adrenocorticotropin and cortisol response to apomorphine (p
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Circadian variations in response to Protirelin test in major depressive episode
European Psychiatry, 1991Co-Authors: Fabrice Duval, Marie-claude Mokrani, Marc-antoine Crocq, S Rosenberg, J. Oliveira Castro, S. Valdivieso, J.p. MacherAbstract:SummaryWe studied circadian thyrotropin (TSH) and prolactin (PRL) response to synthetic thyrotropin-releasing-hormone (Protirelin) infusion (200μg IV) at 8 am and 11 pm in 35 drug-free inpatients with DSM III-R Major Depressive Episode and in 22 hospitalized controls. In each group, maximum TSH and PRL responses were lower at 8 am than at 11 pm. The difference between 11 pm-ΔTSH and 8 am-ΔJTSH (ΔΔTSH) was significantly lower in depressed patients compared to controls. No such blunting was observed in PRL responses to Protirelin in depressed patients. In the overall population, TSH response to Protirelin (ie8 am-ΔTSH, 11 pm-ΔTSH,ΔΔTSH) correlated significantly with TSH circadian parameters (iemesor and amplitude). These correlations were also observed with PRL (except forΔΔPRL). TSH mesor and amplitude were lower in depressives than in controls. In contrast, PRL mesor and amplitude were not significantly different between diagnostic groups.ΔΔTSH is thus a chronobiological refinement to the measure of thyroid axis dysfunction in major depression. The blunted TSH response to Protirelin suggests that the TRH receptors of the pituitary thyrotrophs are hyposensitive in major depression.
J.p. Macher - One of the best experts on this subject based on the ideXlab platform.
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Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates.
Psychoneuroendocrinology, 2006Co-Authors: Fabrice Duval, Marie-claude Mokrani, José A. Monreal-ortiz, Said Fattah, C. Champeval, Pierre Schulz, J.p. MacherAbstract:Evidence supports that hyperactivity of the hypothalamic-pituitary-adrenal axis has a pivotal role in the psychobiology of severe depression. The present study aimed at assessing hypothalamic-pituitary dopaminergic, noradrenergic, and thyroid activity in unipolar depressed patients with melancholic and psychotic features and with concomitant hypercortisolemia. Hormonal responses to dexamethasone, apomorphine (a dopamine receptor agonist), clonidine (an alpha 2-adrenoreceptor agonist) and 0800 and 2300 h Protirelin (TRH) were measured in 18 drug-free inpatients with a DSM-IV diagnosis of severe major depressive disorder with melancholic and psychotic features showing cortisol nonsuppression following dexamethasone and 23 matched hospitalized healthy controls. Compared with controls, patients showed (1) lower adrenocorticotropin and cortisol response to apomorphine (p
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Circadian variations in response to Protirelin test in major depressive episode
European Psychiatry, 1991Co-Authors: Fabrice Duval, Marie-claude Mokrani, Marc-antoine Crocq, S Rosenberg, J. Oliveira Castro, S. Valdivieso, J.p. MacherAbstract:SummaryWe studied circadian thyrotropin (TSH) and prolactin (PRL) response to synthetic thyrotropin-releasing-hormone (Protirelin) infusion (200μg IV) at 8 am and 11 pm in 35 drug-free inpatients with DSM III-R Major Depressive Episode and in 22 hospitalized controls. In each group, maximum TSH and PRL responses were lower at 8 am than at 11 pm. The difference between 11 pm-ΔTSH and 8 am-ΔJTSH (ΔΔTSH) was significantly lower in depressed patients compared to controls. No such blunting was observed in PRL responses to Protirelin in depressed patients. In the overall population, TSH response to Protirelin (ie8 am-ΔTSH, 11 pm-ΔTSH,ΔΔTSH) correlated significantly with TSH circadian parameters (iemesor and amplitude). These correlations were also observed with PRL (except forΔΔPRL). TSH mesor and amplitude were lower in depressives than in controls. In contrast, PRL mesor and amplitude were not significantly different between diagnostic groups.ΔΔTSH is thus a chronobiological refinement to the measure of thyroid axis dysfunction in major depression. The blunted TSH response to Protirelin suggests that the TRH receptors of the pituitary thyrotrophs are hyposensitive in major depression.
Michael J. Kubek - One of the best experts on this subject based on the ideXlab platform.
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Thyrotropin-releasing hormone (Protirelin) inhibits potassium-stimulated glutamate and aspartate release from hippocampal slices in vitro.
Brain research, 2005Co-Authors: Y. Nie, Darryle D. Schoepp, J.e. Klaunig, Michael Yard, Debomoy K. Lahiri, Michael J. KubekAbstract:Abstract Excess excitatory amino acid release is involved in pathways associated with seizures and neurodegeneration. Thyrotropin-releasing hormone (TRH; Protirelin), a brain-derived tripeptide, has shown efficacy in the treatment of such disorders, yet its mechanism of neuroprotection is poorly understood. Using superfused hippocampal slices, we tested the hypothesis that TRH could inhibit evoked glutamate/aspartate release in vitro. Rat hippocampal slices were first equilibrated in oxygenated Krebs buffer (KRB) (120 min) then superfused for 10 min with KRB (control), or KRB containing 0.1, 1, or 10 μM TRH respectively, prior to and during 5 min depolarization with high potassium KRB (50 mM [K+] ± TRH). Fractions (1 min) were collected during the 5 min stimulation and for an additional 10 min thereafter and analyzed for glutamate and aspartate by HPLC. TRH had no effect on baseline glutamate/aspartate release, while all three TRH doses significantly (P
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Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation
Brain research, 1998Co-Authors: Michael J. Kubek, Dong Liang, Kenneth E. Byrd, Abraham J. DombAbstract:Abstract Thyrotropin-releasing hormone (TRH; Protirelin) is an endogenous neuropeptide known to have anticonvulsant effects in several seizure models and in intractable epileptic patients. Like most neuropeptides, its duration of action may be limited by a lack of sustained site-specific bioavailability. To attempt to provide long-term delivery, we attached TRH to a biodegradable polyanhydride copolymer as a sustained-release carrier. Utilizing the rat kindling model of temporal lobe epilepsy, a single TRH microdisk implanted stereotaxically into the seizure focus (amygdala) significantly suppressed kindling expression when assessed by the number of stimulations required to reach each behavioral stage and to become fully kindled (8.63±0.92 vs. 16.17±1.37; Mean±S.E.M.). Two indices of seizure severity, afterdischarge duration (Mean±S.E.M., sec.) (stimulated amygdala [87.40±5.47 vs. 51.80±15.65] and unstimulated amygdala [89.60±5.55 vs. 48.67±15.8] and clonus duration (71.2±5.94 vs. 29.40±8.87; Mean±S.E.M., sec.), were also significantly reduced by a single polymeric-TRH implant. Fifty days after initiation of the study a significant reduction in clonus duration (53.90±3.27 vs. 40.09±4.14) still remained in the TRH-implanted groups. This report is the first to provide evidence in support of in situ microdisk pharmacotherapy for potential neuropeptide delivery in intractable epilepsy and possibly other neurological disorders.
