Thyroid function during carbamazepine.
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Carbamazepine↗
Biomedical subjects
R M Post
Publications and source records attributed to R M Post.
Programmed cell death: implications for neuropsychiatric disorders.
Programmed cell death, sometimes referred to as apoptosis, occurs through an active process requiring new gene transcription, in contrast to the passive cell death produced by metabolic toxins. Programmed cell death is an essential part of normal development, particularly in the nervous system. Spatial, temporal, or quantitative errors in the stimuli that initiate programmed cell death, or errors within the programmed cell death pathway itself, can result in an abnormal number of neurons and pathological neural development. Excesses and deficits in neuronal numbers have now been observed not only in typical neurodegenerative disorders such as Alzheimer's and Huntington's diseases, but also in several neurodevelopmental disorders, including schizophrenia and autism. Recent investigations into the mechanisms of cell death during C. elegans neurodevelopment thymocyte negative selection, and withdrawal of sympathetic ganglion cells trophic support provides intriguing clues to the etiology and pathophysiology of these neuropsychiatric disorders.
Apoptosis↗
CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI.
Recently several steroid compounds have been discovered to act as neuromodulators in diverse central nervous system (CNS) functions. We wondered if neuroactive steroids might be involved in affective illness or in the mode of action of mood-regulating medications such as carbamazepine. Levels of the neuroactive steroids pregnenolone and progesterone, as well as the neuropeptide diazepam binding inhibitor (DBI) (known to promote steroidogenesis), were analyzed from cerebrospinal fluid (CSF) obtained by lumbar puncture (LP) from 27 medication-free subjects with affective illness and 10 healthy volunteers. Mood-disordered subjects who were clinically depressed at the time of the LP had lower CSF pregnenolone (n = 9, 0.16 ng/ml) compared with euthymic volunteers (n = 10, 0.35 ng/ml; p < 0.01). In addition, pregnenolone was lower in all affectively ill subjects (n = 26, 0.21 ng/ml), regardless of mood state on the LP day, than healthy volunteers (p < 0.05). No differences were found for progesterone or DBI levels by mood state or diagnosis. Progesterone, pregnenolone, and DBI did not change significantly or consistently in affectively ill subjects after treatment with carbamazepine. CSF pregnenolone is decreased in subjects with affective illness, particularly during episodes of active depression. Further research into the role of neuroactive steroids in mood regulation is warranted.
Adult↗
Focal and systemic cocaine differentially affect extracellular norepinephrine in the locus coeruleus, frontal cortex and hippocampus of the anaesthetized rat.
The purpose of this study was to characterize and compare the effects of cocaine on norepinephrine (NE) overflow in the forebrain and somatodendritic regions of anaesthetized rats with microdialysis. Intraperitoneal injections of cocaine (20 mg/kg) failed to increase NE overflow in the hippocampus and the frontal cortex but did elevate NE in the region of the locus coeruleus. Focal application of cocaine (1-100 microM) via the dialysis probe into the region of the locus coeruleus also produced a concentration dependent elevation of extracellular NE. In the terminal regions the application of focal cocaine (1-100 microM) showed a differential effect, with a concentration dependent increase in extracellular NE in the hippocampus, whilst in the frontal cortex only the highest concentration of cocaine (100 microM) elevated extracellular NE. The regional differences seen following focal applications in this study may be related to differences in transporter function in the three brain areas or to differences in the affinity for cocaine. The inability of systematically administered cocaine to increase hippocampal and cortical NE is probably related to its predominant actions in the somatodendritic region.
Analysis of Variance↗
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.
Adult↗
CSF magnesium in affective disorder: lack of correlation with clinical course of treatment.
There has been recent renewed interest in the role of magnesium in affective disorder, particularly in the bipolar subtype. However, determinations of serum magnesium concentrations have not yielded consistent findings and little is known about cerebrospinal fluid (CSF) magnesium in these patients. We analyzed CSF magnesium levels from 173 medication-free patients with affective disorder (76 bipolar I, 54 bipolar II, and 43 unipolar) and 59 healthy volunteers. In addition, we examined CSF magnesium from 32 patients before and during carbamazepine treatment and 13 patients before and during lithium treatment. CSF magnesium levels varied significantly according to gender (with lower concentrations in women) but not with respect to age, diagnosis, mood state, or treatment with carbamazepine or lithium. An abnormality of magnesium in affective disorders, if it exists, is not readily detectable in CSF.
Adult↗
Analysis of the hippocampal GABAA receptor system in kindled rats by autoradiographic and in situ hybridization techniques: contingent tolerance to carbamazepine.
Tolerance to the anticonvulsant effects of carbamazepine (CBZ) in the amygdala kindling paradigm is a contingent process, since it only develops in rats treated with CBZ before the kindling stimulation and not in those animals treated after the stimulation. The present study was designed to investigate the GABAA receptor system in CBZ contingent tolerance. Receptor autoradiography utilizing various radioligands that bind to different components of the GABAA receptor system and in situ hybridization with oligonucleotides that recognize different subunits of the GABAA receptor were performed. Kindling increased binding to benzodiazepine, picrotoxin, and GABA recognition sites selectively in the dentate gyrus of the hippocampus. Kindling also increased levels of mRNA for the alpha 4, beta 1, and beta 3 subunits but did not change alpha 1, alpha 2, or gamma 2 subunit levels. Rats tolerant to CBZ showed decreased [3H]muscimol binding, diazepam-insensitive [3H]Ro 15-4513 binding, and decreased alpha 4 subunit mRNA content compared to non-tolerant rats, whereas [3H]flunitrazepam binding, [35S]TBPS binding, and the levels of beta 1, and beta 3 subunit mRNAs remained elevated. The data suggest an indirect interaction of CBZ with the GABAA receptor system, since CBZ reportedly does not bind to this receptor system.
Affinity Labels↗
Differential regional and time course increases in thyrotropin-releasing hormone, neuropeptide Y and enkephalin mRNAs following an amygdala kindled seizure.
Previous studies have shown that neuropeptide mRNA expression is altered in the dentate gyrus, and pyriform, entorhinal and perirhinal cortices following amygdala kindling. However, because rats were kindled every day and some mRNA alterations last longer than 24 h, a true measure of the alterations induced by a single seizure was confounded by the previous day's seizure. To circumvent this problem, rats were fully kindled, had six days without stimulation, and then were given one more seizure. Rats were sacrificed either 4 h, 24 h or 4 days after this last seizure. The levels of mRNAs for TRH, NPY and ENK were measured in the dentate gyrus and limbic cortices. Four hours after a seizure, TRH and NPY mRNAs were maximally increased in the dentate gyrus granule layer, but returned to baseline levels by 24 h. In contrast, 4 h after a seizure, TRH and NPY mRNAs were not, or only slightly, increased in the pyriform, entorhinal and perirhinal cortices, but significantly elevated 24 h after a seizure. ENK mRNA was increased both 4 and 24 h after a seizure in the pyriform, entorhinal and perirhinal cortices but showed no increases in the dentate gyrus at any time. By 4 days, peptide mRNA levels returned to baseline, except for ENK mRNA in the pyriform cortex. These results demonstrate a non-uniform and complex pattern of peptide mRNA expression following an amygdala kindled seizure. They further suggest that regional and time course differences in gene transcription and expression may be important factors in understanding both the transient, adaptive anticonvulsant and longer lasting proconvulsant effects of these neuropeptides.
Amygdala↗
Modulation of hippocampal glucocorticoid and mineralocorticoid receptor mRNA expression by amygdaloid kindling.
In situ hybridization was used to examine the effects of amygdala kindling on the expression of mRNAs for mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the rat hippocampus. Kindling increased MR mRNA levels in the dentate gyrus of the hippocampus 4 h after the last seizure, and these levels remained elevated 24 h later, but returned to baseline at 4 days. The only other hippocampal region that showed changes was the ipsilateral CA2 subfield where MR mRNA was significantly increased only at the 4-hour time point. Kindling also increased the levels of GR mRNA in the dentate gyrus at 4 h; however, GR mRNA levels significantly decreased below control values at 24 h before returning to normal at 4 days. These data indicate differential transient alterations in hippocampal MR and GR receptor mRNA expression following amygdala-kindled seizures.
Amygdala↗
Anticonvulsant withdrawal-emergent psychopathology.
We prospectively investigated psychopathology in 32 epilepsy inpatients openly withdrawn from all antiepileptic drugs (AEDs) prior to entering a controlled trial of an investigational AED. Psychiatric ratings and seizures increased significantly with AED discontinuation. Anxiety and depression were the most prominent symptoms. Thirty-eight percent of patients developed moderate-to-severe psychopathology, and 28% dropped out of the study at various stages due to psychiatric symptoms. In 22 patients openly restarted on AEDs, psychiatric ratings returned to baseline within 2 weeks. Increases in partial seizures were weakly related to emergent anxiety and depression. Increases in generalized seizures were related to increases in global impairment but not to increases in specific psychopathology. AED withdrawal-emergent psychopathology was not fully explained by increases in seizures, demographic factors, or psychiatric history and may be partially due to pharmacodynamic effects following drug discontinuation.
Anticonvulsants↗
Rash complicating carbamazepine treatment.
Carbamazepine--widely used in the treatment of trigeminal neuralgia, seizure disorders, and more recently, manic-depressive illness--is generally safe and well tolerated. Although serious adverse reactions, such as hematologic toxicity, may occur rarely, we have found that carbamazepine-induced rash is common, occurring in 13 (12%) of 113 patients. We describe our experience with carbamazepine-induced rash, including clinical characteristics, demographic features, and associated laboratory findings. Integrating our findings with the literature, we also discuss incidence, possible mechanisms, and implications for treatment because these benign rashes can occasionally progress to more fulminant and life-threatening eruptions.
Adult↗
Shared mechanisms in affective illness, epilepsy, and migraine.
For a specific subgroup of patients with migraine or affective illness who experience illness progression and drug tolerance, the amygdala kindling paradigm can be a useful, but nonhomologous, model. Although these patients do not have a seizure or seizure-like disorder, kindling has been used to examine the types of memory-like mechanisms that could underlie syndrome evolution in both migraine and affective illness. While the precipitants, symptomatology, duration of attack, and aura symptoms differ among epilepsy, migraine, and the affective disorders, all are paroxysmal dysregulations that partially share effective drug treatment. The principles of seizure progression presented here may apply to affective and migraine patients whose episodes progress from isolated and intermittent to more chronic or daily. These patients may also develop tolerance to long-term prophylactic treatments.
Animals↗
Efficacy of carbamazepine compared with other agents: a clinical practice survey.
BACKGROUND: To gain an impression of the experience with and efficacy of carbamazepine relative to other agents and relative to its use in treating psychiatric and neurologic disorders in general clinical practice, a survey was distributed in 1988 to psychiatrists practicing in the United States. METHOD: The survey was mailed to 9030 members of the American Psychiatric Association (APA) who had expressed an interest in the study and treatment of affective disorders in a 1982 APA survey. The survey sampled clinicians' experience of the efficacy and side effects of carbamazepine in a number of psychiatric and neurologic conditions. Each clinician also provided global impression ratings of the efficacy of a variety of traditional and novel treatments. RESULTS: Completed surveys were returned by 2543 (28%) physicians. Carbamazepine was reported to be moderately to markedly effective in the following percentage of patients: partial complex seizures, 85.2%; generalized seizures, 82.9%; trigeminal neuralgia, 81.5%; mania prophylaxis, 72.9%; acute bipolar depression, 67.5%; intermittent explosive disorder, 65.2%; acute mania, 62.2%; schizoaffective disorder, 58.8%; other pain syndromes, 51.2%; posttraumatic stress disorder, 48.1%; borderline personality disorder, 43.0%; unipolar depression, 32.2%; schizophrenia, 25.7%; and alcohol withdrawal, 15.9%. About 4.4% of the patients reported were withdrawn from carbamazepine because of side effects. CONCLUSION: Carbamazepine was widely used to treat a variety of psychiatric conditions in 1988 and found to be of use in the acute and long-term treatment of bipolar illness. It was rated slightly less effective than lithium, electroconvulsive therapy, or neuroleptics, but more effective than several other agents. The results of the survey highlight many areas in need of further systematic investigation.
Attitude of Health Personnel↗
Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.
Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.
Adrenocorticotropic Hormone↗
Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine.
Stimuli associated with cocaine come to acquire incentive-motivational as well as secondary reinforcing properties which can energize and maintain behavior in laboratory animals as well as precipitate craving in addicts. Environmental stimuli paired with a large dose of cocaine for one training session elicited significant increases in locomotor activity and in extracellular dopamine in the nucleus accumbens of rats during a second test session with a low dose of cocaine. The increases in extracellular dopamine are not likely a secondary consequence of this increase in locomotor output of rats conditioned to cocaine, since doses of MK-801 which produced similar increases in locomotor behavior had no effect on mesolimbic dopamine. These findings provide a neurochemical mechanism for understanding the incentive motivational properties of stimuli associated with cocaine and may help to explain recidivism of cocaine addicts when they return to an environment in which the drug was used.
3,4-Dihydroxyphenylacetic Acid↗
Autoradiographic analysis of serotonin receptors and transporter in kindled rat brain.
While serotonin (5-HT) has been shown to be anticonvulsant in several types of experimentally induced seizures, 5-HT receptor binding has not been investigated in the kindling model of epilepsy. The present study examined the effects of amygdala kindling on two 5-HT receptor subtypes and on the 5-HT transporter in rat brain. Kindling induced a persistent bilateral increase in 5-HT1A binding in the dentate gyrus, while 5-HT1B receptors increased only in a delayed fashion. Binding to the 5-HT transporter was transiently decreased in dentate gyrus. In cerebral cortex, binding of the three ligands was unchanged. Alterations in 5-HT receptors and the 5-HT transporter may endogenously modulate kindled seizures. Additionally, autoradiography of adenosine A1 receptors revealed no change for these receptors in any brain region.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Effect of cocaine, lidocaine kindling and carbamazepine on batrachotoxin-induced phosphoinositide hydrolysis in rat brain slices.
Repeated administration of a subconvulsant dose of a local anesthetic will eventually induce seizures, a phenomenon similar to electrical kindling. We have investigated the effect of repeated lidocaine and cocaine administration on the phosphoinositide (PI) hydrolysis induced by batrachotoxin (BTX), a specific Na channel activator. Rats were injected with cocaine or saline daily for 6 days and PI hydrolysis was assayed in sliced frontal cortex. Cocaine treatment had no effect on BTX-induced PI hydrolysis while in vitro cocaine blocked the BTX effect. In a second experiment, rats received daily injections of lidocaine or saline. After a rat developed at least two seizures, it was sacrificed together with a rat receiving lidocaine injections which had never seized and a rat receiving saline injections. Basal, BTX and ibotenic acid (IBO; a glutamate receptor agonist)-stimulated PI hydrolysis did not differ among the three groups in slices of either hippocampus (HC) or piriform cortex (PC) though IBO-stimulated PI hydrolysis was much greater in the HC than in the PC. Neither in vitro nor in vivo carbamazepine altered the effect of cocaine on BTX-induced PI hydrolysis. These results demonstrate that local anesthetic kindling does not alter PI hydrolysis coupled to Na channel or IBO activation.
Animals↗
Carbamazepine attenuates cocaine-induced increases in dopamine in the nucleus accumbens: an in vivo dialysis study.
Carbamazepine's effects on cocaine-induced increases in dopamine overflow in the nucleus accumbens were studied using in vivo microdialysis in anesthetized rats. Rats were chronically treated with a diet containing carbamazepine or no drug for one week prior to microdialysis procedures. The basal levels of dopamine in the nucleus accumbens did not differ between groups; however, the increases in dopamine following cocaine administration (4 mg/kg i.v.) were significantly reduced by carbamazepine. In addition, basal levels of dihydroxyphenyl acetic acid (DOPAC) were significantly diminished in the carbamazepine group and a trend in the same direction was observed for homovanilic acid (HVA). These results are consistent with reports that carbamazepine might decrease dopamine synthesis. Further studies are required to determine the mechanism of carbamazepine's inhibition of cocaine-induced dopamine overflow and its potential clinical implications.
3,4-Dihydroxyphenylacetic Acid↗