Carbamazepine and lithium carbonate synergism in mania.
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Biomedical subjects
Publications and source records attributed to R M Post.
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We attempted to investigate the relationship between hypothalamic-pituitary-adrenal axis activity and cognitive function by measuring mean urinary free cortisol (MUFC) excretion and performance on the Halstead Category Test in depressed patients and normal controls. We observed a significant relationship between category test errors and MUFC in the depressed patients, but not in the controls. While an even more robust correlation was observed between age and category test errors in the patients, it appeared that age and depression interacted to produce severe cognitive impairment. Depression-related cortisol hypersecretion or its underlying determinants may contribute to depression-related cognitive dysfunction.
Thyroid function was examined in 50 affectively ill patients before and four weeks after carbamazepine treatment. Carbamazepine significantly and substantially decreased peripheral thyroid hormone levels while increases in thyrotropin levels, although significant, were of much smaller magnitude. Furthermore, the decreases in levels of thyroxine (T4) and free T4 were significantly greater in carbamazepine responders than in nonresponders. These findings are discussed in light of current theories of the role of the thyroid axis in affective illness.
Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.
Treatment with carbamazepine is associated with decreases in the serum levels of thyroxine, free thyroxine and triiodothyronine without alteration in the thyrotropin. Therefore, the mechanism of action of carbamazepine on the hypothalamo-pituitary thyroid axis may involve interference in the feedback regulation of secretion of thyroid hormone by interacting with the pituitary thyroid hormone receptors. The present authors investigated the ability of carbamazepine to compete with the nuclear uptake of [125I]triiodothyronine in dispersed intact cultured fibroblasts of human skin. Carbamazepine did not inhibit the specific binding of [125I]triiodothyronine into the nuclei of intact fibroblasts, suggesting that it does not interact with thyroid hormone receptors in this system and is unlikely to do so in vivo.
A thyrotropin (thyroid-stimulating hormone; TSH) stimulation test with thyroid-releasing hormone (TRH) was performed on six patients with a DSM-III diagnosis of major depressive disorder, both before and during a trial of carbamazepine. Carbamazepine, an anticonvulsant effective in the treatment of affective illness, caused a reduction in the TSH response to TRH. This finding suggests that carbamazepine may decrease thyroid function primarily at the level of the pituitary in affectively ill patients.
Electroencephalographic sleep recordings were compared in patients with panic disorder and normal controls. Correlation coefficients of standard sleep parameters versus ratings of anxiety, depression, and panic attack frequency were calculated in the panic-anxious patients. Overall findings are discussed in the context of previous sleep studies in patients with depressive, anxiety, and obsessive-compulsive disorders.
Increasing evidence implicates altered dopamine function in major affective illness. In the present study, growth hormone responses to the dopamine agonist apomorphine were not different for 14 male depressed patients and 16 healthy male volunteers. Baseline and post-apomorphine prolactin levels were lower for the depressed patients than the control subjects, but the percent decrease following apomorphine was not different for the two groups. Neuroendocrine responses were not significantly altered during chronic treatment with the dopamine agonist piribedil. These neuroendocrine results suggest that decreased baseline prolactin levels in depressed patients do not reflect altered postsynaptic receptor sensitivity in the tuberoinfundibular dopamine system.
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The phosphorylation of both particulate and soluble proteins in the amygdala was examined in electrically kindled rats. In animals receiving electrical stimulation in the left amygdala for 5-6 days that displayed electrical after-discharges but no motor seizures, no changes were observed in the phosphorylation of either particulate or soluble proteins. In animals stimulated for 20-21 days where major motor seizures were produced, the phosphorylation of a protein having a molecular weight of 45,000 ( 45K ) was markedly increased. The phosphorylation of this protein was increased in both the right (unstimulated) and left (stimulated) amygdala. Major motor seizures induced by electroconvulsive shocks, however, did not alter phosphorylation of this protein. Phosphorylation of the 45K protein was stimulated by calcium and calmodulin. The 45K protein is a major phosphoprotein of amygdala, representing 3.2% of the total particulate phosphoproteins in control animals and 7.4% in the kindled animals. In the presence of calcium-calmodulin, 16.2% of net protein phosphorylation was accounted for by the 45K protein.
Amygdala kindling, the progressive development of seizures following repeated electrical stimulation, has been used as a model of epileptogenesis, neural memory, and the development of behavioral alterations. In an attempt to interfere with the kindling process, electroconvulsive seizures (ECS) were administered 6 h prior to or immediately after once-daily amygdala stimulation. ECS compared with sham ECS 6 h prior to kindling profoundly inhibited the development of amygdala-kindled seizures, while ECS immediately after the afterdischarge (AD) were not effective. In a second study, seven daily ECS, but not a single ECS followed by a 6-day delay, markedly suppressed established amygdala-kindled seizures compared with sham ECS controls. The generalized seizures of ECS thus appear to be paradoxically anticonvulsant to limbic seizures. Carbamazepine, a potent anticonvulsant for temporal lobe and limbic seizures in animals and man, inhibits amygdala-kindled seizures and is effective in the treatment of manic-depressive illness. The current findings suggest the possibility that the efficacy of ECS in affective illness may be, in part, related to its limbic antikindling and anticonvulsant effects.
The responses of 16 patients with major depressive disorder to one night's sleep deprivation and a subsequent double-blind, placebo-controlled trial of carbamazepine were compared. There was a significant association between the presence or absence of an antidepressant response to each of these treatments. Further studies are required to assess the clinical utility of this relationship and whether it is based on antidepressant response to any agent or is more specific to carbamazepine.
The experiences of human fear and anxiety are discussed within the context of locus ceruleus function in animals. The rationale for studying correlates of noradrenergic function, such as 3-methoxy-4-hydroxyphenethylene glycol (MHPG), is reviewed, and data demonstrating a positive correlation between plasma free MHPG and state anxiety in normal volunteers is presented. The behavioral effects of oral caffeine (240-720 mg), intravenous clonidine (2 micrograms/kg), and oral yohimbine (20 mg) were studied in various psychiatric patients and normal volunteers. Caffeine and yohimbine had anxiogenic properties; conversely, clonidine reduced self-rated measures of anxiety across a wide spectrum of psychiatric conditions. These findings expand previous research indicating that noradrenergic hyperactivity may be associated with many types of human fear and anxiety.
The authors describe two patients with rapidly cycling bipolar disorder who were found to have multiple sclerosis. They suggest that multiple sclerosis be considered in the differential diagnosis of patients who have affective disorders and minor neurological complaints.
Seven of nine patients with panic disorder given a standard glucose tolerance test developed symptomatic hypoglycemia but not panic attacks. These findings suggest that hypoglycemia is an unlikely cause of "spontaneous" panic attacks in this population.
For prospective longitudinal confirmation of menstrually related mood changes, the authors selected a 100-mm visual analogue scale for twice-daily self-rating of mood. The advantages of this method are simplicity; increased compliance; ease of graphic presentation, allowing evaluation of severity and relationship to menstruation; and greater uniformity among studies of menstrually related syndromes. In a preliminary application of this measure to 20 women with self-diagnosed premenstrual syndrome, eight (40%) had a mean depression rating during the week before menstruation that was 30% higher than during the week after cessation of menstruation.
The authors measured plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine, blood pressure, and heart rate responses to the alpha 2-adrenergic agonist clonidine in 25 depressed patients and 25 normal control subjects. In the control subjects clonidine reduced plasma norepinephrine, blood pressure, and heart rate significantly more than placebo. In the depressed patients clonidine reduced blood pressure and the percent fall in plasma norepinephrine but not plasma MHPG or heart rate significantly more than placebo. The absolute and percent reductions in plasma MHPG and heart rate following clonidine were significantly less than in control subjects. These results raise the possibility that the sensitivity of the alpha 2-adrenergic receptors inhibitory to noradrenergic output may be reduced in depression.
The definition and clinical aspects of rapid cycling affective illness are reviewed and various factors associated with the onset and maintenance of rapid cycling enumerated. On the basis of this information and of reports of the response of rapid cycling patients to various treatment interventions, an approach is suggested to the evaluation and treatment of rapid cycling affective illness.