Carbamazepine increases cerebrospinal fluid thyrotropin-releasing hormone levels in affectively ill patients.

BACKGROUND: Thyrotropin-releasing hormone is an endogenous tripeptide with endocrine-independent neurophysiologic properties that may be relevant to affective or seizure disorders. We studied the effect of carbamazepine, which has both mood-stabilizing and anticonvulsant properties, on cerebrospinal fluid thyrotropin-releasing hormone levels in affectively ill patients. METHOD: Paired cerebrospinal fluid samples were collected from nine inpatients with mood disorders, both while medication free and while taking carbamazepine for an average of longer than 1 month at 950 mg/d, achieving blood levels of 8.8 mg/L. RESULTS: Carbamazepine treatment was consistently and significantly associated with increased cerebrospinal fluid thyrotropin-releasing hormone levels (P < .0001). CONCLUSION: As carbamazepine-induced increases in thyrotropin-releasing hormone levels could be relevant to either its psychotropic or anticonvulsant properties, further clinical and preclinical investigation of this finding appears indicated.

Transport of thyrotropin-releasing hormone from cerebrospinal fluid to hypophysial portal blood and the release of thyrotropin.

The capacity of the medium eminence to transport thyrotropin-releasing hormone (TRH) from cerebrospinal fluid (CSF) to hypophysial portal blood, and the ability of TRH when introduced into a lateral ventricle to stimulate TSH release from the pituitary gland were investigated. Male rats were injected either intraventricularly or intravenously with 0, 1, 10, or 100 ng of TRH, and plasma TSH concentrations were determined at various times thereafter. TRH administration via both routes resulted in substantial release of TSH. Following intraventricular injection of TRH, there was a delay in reached maximal TSH concentration when compared with the faster elevation and faster decline in TSH concentrations which followed intravenous injection of the same dose of TRH. In a second experiment, 7 muCi of [3H]TRH were introduced intraventricularly or intravenously, and hypophysial portal and arterial blood were simultaneously collected and examined for the presence of radioactivity. The intraventricular injection of [3H]TRH resulted in a peak of radioactivity in portal blood within minutes, which was maintained for 20--30 min and then declined. The concentration of radioactivity in arterial blood from the same animals was considerably lower than that in portal blood. The intravenous administration of [3H]TRH resulted in radioactive peaks in both portal and arterial blood with a higher concentration of radioactive substances in arterial blood. However, the level of radioactivity in portal blood following intravenous injection of [3H]TRH comprised no more than 5--10% of that found following intraventricular administration of the saem dose. The data support the view that TRH is able to cross the medium eminence from CSF into hypophysial portal blood and that it is capable of stimulating the pituitary gland to release TSH.

Thyrotropin-releasing hormone (TRH): Measurements in human spinal fluid.

Levels of thyrotropin-releasing hormone (TRH) were quantitated in human lumbar spinal fluid (CSF) utilizing a sensitive and specific TRH radioimmunoassay. Endogenous TRH was sufficiently stable in CSF to permit 85% recovery of intact TRH after 48 h storage at 4 C. TRH levels in AM or PM samples obtained from 15 women and 12 men were easily detected in all CSF specimens. No significant difference between the TRH concentration in CSF of men and women was observed (44.2+/-6.8 and 38.1+/-6.5 pg/ml (mean+/-SE) respectively). TRH concentrations were 40.2+/-6.9 pg/ml (mean+/-SEM) in AM and 41.4+/-8.0 pg/ml in PM samples. By contrast, CSF cortisol levels obtained concurrently were twofold higher in AM than PM (0.68+/-0.08 vs 0.38+/-0.02 mug/100 ml (mean+/-SEM) respectively, P less than 0.001). These data are consistent with the possibility that a portion of the TRH in CSF can be derived from the central nervous system (CNS) and unrelated to the hypo-physiotropic control of thyrotropin (TSH) synthesis and secretion.

Thyrotropin-releasing hormone hyperactivity in the preoptic area of spontaneously hypertensive rats.

Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation through the activation of different neurotransmitter systems at distinct extrahypothalamic sites. To study possible alterations in the TRH system in the hypertensive state, we measured TRH concentration in cerebrospinal fluid and TRH content of the preoptic area in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) by radioimmunoassay. In addition, we also measured the density of the TRH receptor in this area by a rapid filtration technique using [3H]methyl-TRH. We found a significant increase in both the TRH content (634 +/- 61 versus 350 +/- 26 pg/mg protein, SHR versus WKY; P < .01, n = 5) and density of TRH receptors without changes in affinity (Bmax, 5.0 +/- 0.1 versus 3.3 +/- 0.1 fmol/mg protein, P < .01, n = 4). An increase in TRH concentration was also found in the cerebrospinal fluid of SHR (30 +/- 3 versus 21 +/- 2 pg/mL, P < .01, n = 5), suggesting increased TRH release in the central nervous system. Northern blot analysis indicated a threefold augmented abundance of TRH precursor mRNA in the preoptic area of SHR. A polyclonal antibody raised against TRH injected peripherally or intracerebroventricularly lowered arterial blood pressure in SHR but not in WKY. In addition, long-term treatment with enalapril (5 mg/kg twice daily), which was effective in inhibiting serum angiotensin-converting enzyme activity by more than 50%, decreased arterial blood pressure and preoptic area TRH content of SHR, whereas another vasodilator, diltiazem (10 mg/kg every 8 hours), failed to produce a similar change.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid TRH immunoreactivity in anorexia nervosa.

Central nervous system (CNS) thyrotropin-releasing hormone (TRH) activity is of interest in patients with anorexia nervosa. First, anorexics have peripheral thyroid abnormalities that appear to be related to weight and nutritional status. Second, CNS TRH activity may effect many other physiologic systems that are known to be disturbed in patients with anorexia nervosa. We found that anorexic patients, when both underweight and studied after attaining goal weight, had significantly reduced CSF TRH concentrations in comparison to controls. These data suggest that weight gain or increased caloric intake, in contrast to its large effect on peripheral thyroid function, has relatively little effect on CNS TRH activity. The reason for reduced CSF TRH in goal weight anorexics is not known but could be trait related, a persistent defect slow to normalize after weight gain, or related to these patients still being at a weight lower than controls. Finally, in terms of CSF TRH concentrations, this study suggests that anorexia nervosa has a different pathophysiology than major depressive disorder.

Cerebrospinal fluid thyrotropin-releasing hormone concentrations in alcoholics and normal controls.

Alterations in hypothalamic-pituitary-thyroid axis function have been reported in alcoholism. Blunting of the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) occurs in approximately 25% of alcoholic patients. Using a sensitive radioimmunoassay that allows TRH itself to be measured in cerebrospinal fluid (CSF), CSF concentrations of TRH were measured in alcoholics and normal controls. There was no significant difference in TRH concentrations between the groups. However, among the controls there was a significant correlation between CSF concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and CSF concentrations of TRH. This correlation was lacking in the alcoholics. These findings are of interest because basic neurobiological studies have reported that TRH and serotonin are co-localized in certain neurons in the rat central nervous system.

Lack of correlation between cerebrospinal fluid thyrotropin-releasing hormone (TRH) and TRH-stimulated thyroid-stimulating hormone in patients with depression.

BACKGROUND: It has been proposed that elevated central thyrotropin-releasing hormone (TRH) is associated with the blunted thyroid-stimulating hormone (TSH) response to TRH in patients with depression. Few studies have directly evaluated this relationship between central nervous system and peripheral endocrine systems in the same patient population. METHODS: 15 depressed patients (4 male, 11 female, 12 bipolar, and 3 unipolar) during a double-blind, medication-free period of at least 2 weeks duration, underwent a baseline lumbar puncture followed by a TRH stimulation test. Cerebrospinal fluid (CSF) TRH and serial serum TSH, free thyroxine, triiodothyronine, prolactin, and cortisol were measured. A blunted response to TRH was defined as a delta TSH less than 7 microU/mL. RESULTS: There was no significant difference in mean CSF TRH between "blunters" (2.82 +/- 1.36 pg/mL) and "non-blunters" (3.97 +/- 0.62 pg/mL, p = .40). There was no evidence of an inverse relationship between CSF TRH and baseline or delta TSH. There was no correlation between CSF TRH and the severity of depression or any other endocrine measure. CONCLUSIONS: These data are not consistent with the prediction of hypothalamic TRH hypersecretion and subsequent pituitary down-regulation in depression; however, CSF TRH may be from a nonparaventricular nucleus-hypothalamic source (i.e., limbic area, suprachiasmatic nucleus, brain stem-dorsal raphe) and thus, not necessarily related to peripheral neuroendocrine indices.

Ziskind-Somerfeld Research Award 1992. Endogenous biochemical abnormalities in affective illness: therapeutic versus pathogenic.

Examination of the neurobiology of psychiatric illness in general, and of affective disorders in particular, reveals a variety of associated biochemical abnormalities. These have generally been assumed to be part of the pathological process or secondary to it, and thus deserving of therapeutic efforts aimed at reversal. However, recent clinical and preclinical data suggest that some alterations occurring in the affective disorders may be compensatory and adaptive; that is, part of an endogenous therapeutic mechanism rather than part of the evolving disease process. For example, the symptom of sleep loss in depression seems to fall under this rubric inasmuch as sleep deprivation induces mood improvement in depressed patients. Preclinical data are presented that another primary pathological process--the occurrence of kindled seizures--can evoke endogenous compensatory processes that are either anticonvulsant in their own right, or enable the anticonvulsant effects of a drug such as carbamazepine. It may be that some biochemical abnormalities occurring in affective illness are similarly adaptive. As one example, increased thyrotropin-releasing hormone (TRH) has been reported in the cerebrospinal fluid (CSF) of depressed patients. This elevation of TRH and the resulting neuroendocrine profile may be part of an endogenous counter-regulatory process aimed at mood improvement. Again, preclinical seizure models are supportive in that TRH not only is induced following repeated seizures, but also exerts anticonvulsant effects on these same seizures. In an analogous fashion, TRH elevations in depressed patients may also exert ameliorating effects on depressive symptomatology. This formulation presents directly testable hypotheses that could importantly impact on our understanding of the pathophysiology of affective disorders, and suggests novel therapeutic strategies through the enhancement of endogenous compensatory mechanisms.

Differences in CSF concentrations of thyrotropin-releasing hormone in depressed patients and normal subjects: negative findings.

Since there have been reports of elevated CSF concentrations of thyrotropin-releasing hormone (TRH) in depression, the authors compared the TRH levels of 17 depressed patients and 19 normal subjects. All subjects underwent lumbar punctures after fasting overnight, and CSF concentrations of TRH were determined by radioimmunoassay. CSF concentrations of norepinephrine and monoamine metabolites were also measured. There was no significant difference between the two groups on any measure, and in the depressed patients there was no significant relation between CSF concentrations of TRH and thyrotropin-stimulating hormone responses to TRH infusion.

Elevation of immunoreactive CSF TRH in depressed patients.

The concentration of thyrotropin-releasing hormone (TRH), a tripeptide (pyroglutamylhistidylprolin-amide), in the CSF of drug-free patients with DSM-III major depression, somatization disorder, and peripheral neurological disorders was measured with a sensitive and specific radioimmunoassay. The depressed patients had markedly higher CSF TRH concentrations than the other patient groups, and this finding could not be attributed to any demographic variables. The elevation of TRH in CSF provides further evidence of hypothalamic-pituitary-thyroid dysfunction in depression.

Inverse relationship between CSF TRH concentrations and the TSH response to TRH in abstinent alcohol-dependent patients.

The authors performed the thyrotropin-releasing hormone (TRH) stimulation test and measured CSF concentrations of TRH in 13 abstinent alcohol-dependent subjects. They found an inverse correlation between the thyrotropin (TSH) response to TRH and endogenous CSF TRH concentrations. This finding supports the hypothesis that as the concentration of CSF TRH increases, anterior pituitary TRH receptor density decreases, resulting in a blunted TSH response to TRH stimulation.

Pharmacokinetics of intrathecal thyrotropin-releasing hormone.

An investigation of the efficacy of thyrotropin-releasing hormone in amyotrophic lateral sclerosis included study of the intrathecal pharmacokinetics of this neuropeptide. Its mean elimination half-life in CSF was 0.90 hours and was monoexponential. During a 2-hour infusion, 2.75% crossed the CSF/blood-brain barrier. Infusion for 12 months with an implanted pump in three patients at a rate of 3 mg/24 hr resulted in a mean CSF steady state of 2.88, 2.42, and 2.74 micrograms/ml, respectively. Pharmacokinetic data were similar at 6 and 12 months. This is an effective system with potential uses in the treatment of other degenerative diseases.

Amyotrophic lateral sclerosis: thyrotropin-releasing hormone and histidyl proline diketopiperazine in the spinal cord and cerebrospinal fluid.

In spinal cords from seven amyotrophic lateral sclerosis (ALS) patients and four controls, we found no difference in thyrotropin-releasing hormone (TRH) concentration relative to protein content, but there was a reduction per tissue wet weight in ALS. Immunohistochemical localization of TRH in ALS cord was unaltered. Histidyl proline diketopiperazine (HisPro-DKP), a possible metabolite of TRH, was significantly elevated per protein content in ALS. CSF levels of TRH and HisPro-DKP were unchanged. These findings suggest that TRH neurons are not primarily affected in ALS, but TRH and tissue protein are lost together as the disease progresses.

Amyotrophic lateral sclerosis: effects of acute intravenous and chronic subcutaneous administration of thyrotropin-releasing hormone in controlled trials.

We performed double-blind crossover trials to assess the effects of thyrotropin-releasing hormone (TRH) on amyotrophic lateral sclerosis patients. For acute intravenous trials, 500 mg TRH or placebo with norepinephrine was given at 1-week intervals (16 patients). CSF TRH concentration increased, and clinical side effects appeared with TRH. For chronic studies, 25 mg TRH and a saline placebo were given subcutaneously every day for 3 months (25 patients). CSF TRH level increased 29-fold after a single TRH injection, and mild transient side effects occurred. Vital signs, respiratory function, semiquantitative and quantitative neurologic function, muscle strength by manual and dynamometer testing, and EMG were studied. With daily TRH, 10 patients noted subjective improvement without objective evidence, and 10 patients complained of worsening of the disease with objective decline after TRH was stopped. Statistical analysis, however, showed no beneficial effects from either acute or chronic TRH trials.

Interaction between thyrotrophin-releasing hormone and the muscarinic cholinergic system in rat brain.

TRH increases the pressor response to acetylcholine through an increment in muscarinic receptors. As chronic atropinization produces a similar effect, we hypothesized that both phenomena may be related. The effect of chronic atropine treatment on the TRH content of several brain areas in Wistar rats was studied. Atropine produced significant increases in TRH content in the preoptic and septal areas, while decreases were observed in the hypothalamus and hypophysis. The concentration of TRH in cerebrospinal fluid rose significantly in atropine-treated rats compared with controls. A similar effect was observed with eserine, an acetylcholinesterase inhibitor. Finally, perfusion of brain preoptic area slices from normal rats with Krebs-Ringer solution in the presence of pilocarpine increased basal TRH release significantly and this effect was blocked by atropine. These results are compatible with a muscarinic control on the activity of the central TRH system.

CSF thyrotropin-releasing hormone concentrations differ in patients with schizoaffective disorder from patients with schizophrenia or mood disorders.

OBJECTIVE: To determine if there were differences in CSF-TRH concentrations among several acute major psychiatric disorders and to investigate the effects of antipsychotic treatment on CSF-TRH levels. METHOD: CSF-TRH concentrations were measured in 62 psychiatric inpatients during an acute phase of illness after a drug-free period. CSF-TRH measurements were repeated in 14 of these patients after 4 weeks of antipsychotic treatment. RESULTS: Post-hoc tests (Tukey HSD) revealed significant differences among patients with schizoaffective disorder and both schizophrenia (P<0.03) and major depression (P<0.01). There were no significant differences between pre and posttreatment levels of CSF-TRH in the 14 patients treated with conventional agents for 4 weeks (1.54 pg/ml vs. 1.47 pg/ml). However, patients with a reduction in CSF-TRH concentration had a significantly better symptom response measured by the Brief Psychiatric Rating Scale (BPRS) positive factor (61% in six subjects) vs. those who had an increase in posttreatment CSF-TRH (29% in eight subjects; t=2.2; d.f.=12; P<0.04). CONCLUSIONS: These results provide further evidence for a neuromodulatory role for TRH and suggest a re-examination of its behavioral effects and interactions with brain neurotransmitter systems relevant to major psychotic and mood disorders.

Intracisternal injection of TRH precursor, TRH-glycine, stimulates gastric acid secretion in rats.

Intracisternal injection of thyrotropin-releasing hormone (TRH)-Gly (pGlu-His-Pro-Gly) produced a dose-dependent (1-100 micrograms) stimulation of gastric acid secretion in urethane-anesthetized rats implanted acutely with a gastric fistula. The peak response occurred 20-30 min after intracisternal injection and lasted for more than 2 h. Intravenous injection of TRH-Gly (100 micrograms) did not modify gastric acid secretion. Following intracisternal injection of TRH-Gly, a peak elevation of both TRH-Gly and TRH levels is observed in the cerebrospinal fluid (CSF) within 15 min. Thereafter, TRH values are returned to basal levels at 75 min after the injection, whereas TRH-Gly concentrations remain significantly elevated throughout the 2-h period of measurement. Compartmental analysis revealed that CSF conversion of TRH-Gly to TRH was only 0.0072%/min. Medullary coronal sections containing the dorsal vagal complex and the raphé nucleus revealed increased content of TRH-Gly, but not TRH, 40 min after administration of TRH-Gly at an intracisternal dose effective in stimulating gastric acid secretion (100 micrograms). In addition, TRH but not TRH-Gly (10(-7)-10(-5) M) displaced [3H]MeTRH binding from rat medullary blocks containing the dorsal vagal complex. These data suggest that the intracisternal TRH-Gly-induced stimulation of gastric acid secretion is not related to its conversion to TRH in the CSF, or direct activation of TRH receptors in the medulla. The acid secretory response of TRH-Gly may be due to the formation of TRH at the active brain sites, or alternatively to activation of its own specific receptors.

Thyrotropin-releasing hormone metabolism is attenuated in the cerebrospinal fluid of the human neonate.

The present study was designed to investigate the ontogeny of thyrotropin-releasing hormone (TRH) metabolism in human cerebrospinal fluid (CFS). The activity of pyroglutamate aminopeptidase (EC 3.4.11.8), the major enzyme catalyzing TRH metabolism in human CSF, was measured in CSF of 11 premature infants (gestational age, 29-39 weeks; birth weight, 1774 +/- 274 g), 8 newborn infants (term delivery; birth weight, 3648 +/- 240 g), and 11 adults (mean age, 29.6 +/- 1.5 years). Pyroglutamate aminopeptidase activity in CSF of premature and newborn infants was significantly lower (p less than 0.05) than that of adult CSF. These observed differences in the enzymatic activities were not due to changes in the affinity of the enzyme for its substrate TRH or the presence of enzyme inhibitor(s)/stimulator(s).

Metabolism of thyrotropin-releasing hormone in human cerebrospinal fluid. Isolation and characterization of pyroglutamate aminopeptidase activity.

Pyroglutamate aminopeptidase, which catalyzes metabolism of thyrotropin-releasing hormone (TRH) to cyclo(His-Pro), is the major enzyme of TRH metabolism in human CSF. The partially purified CSF pyroglutamate aminopeptidase has a pH optimum between 6.0 and 7.4, and a Km of 15.9 +/- 3.1 microM. A number of potential competitive inhibitors of the enzymatic activity were examined, of which luteinizing hormone-releasing hormone and bombesin were the most effective. An examination of the structure of various peptides that inhibit pyroglutamate aminopeptidase activity indicated that the enzyme generally prefers a substrate having amino-terminal pyroglutamic acid (pGlu) and a COOH-terminal that is either blocked or distant from amino-terminal pGlu. Heavy metals, EDTA and reducing agents inactivated the enyzme, whereas benzamidine, phenylmethylsulfonylfluoride, trypsin inhibitor and alkylating agents had little or no effect on the enzymatic activity. Thiol-oxidizing agent 5,5'-dithiobis(2-nitrobenzoic acid), however, considerally inhibited the enzymatic activity. We hypothesize that CSF pyroglutamate aminopeptidase may play a role in the biologic actions of TRH.

The cholinergic system participates in thyrotropin-releasing hormone (TRH) regulation.

The effect of chronic atropine treatment was studied on thyrotropin releasing hormone (TRH) content of several brain areas in Wistar rats. Atropine produced TRH increases in the septal area, preoptic area and the hypophysis; this was observed when rats were killed immediately after the last dose, while a decrease was observed only in the hypophysis 48 h after the last atropine dose. TRH concentration in cerebrospinal fluid rose significantly after atropine withdrawal with respect to controls. Treatment with eserine, an acetylcholinesterase inhibitor, produced the same effect. These results indicate cholinergic participation in central TRH regulation.