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Biomedical subjects

R M Post

Publications and source records attributed to R M Post.

At least 19 recordsLinked to original sources
PubMed1995

Cerebrospinal fluid total protein in patients with affective disorders.

Cerebrospinal fluid (CSF) total protein was evaluated in 240 patients with affective disorders and compared with findings in 55 normal comparison subjects. Subtype diagnoses were as follows: bipolar I (n = 108, 47 men, 61 women); bipolar type II (n = 67, 26 men, 41 women); and unipolar (n = 65, 22 men, 43 women). Men had significantly elevated values compared with women. In men with bipolar I disorder, mean CSF protein levels were found to be significantly elevated over those in normal subjects, with 31.9% above the traditional normal range cutoff of 45 mg/dl. Moreover, CSF protein levels in male bipolar I patients were found to be positively correlated with severity of depression at the time of the lumbar puncture and with duration of illness. It thus appears that increased protein levels may be associated with illness severity or progression in male patients with bipolar I disorder. Although elevated CSF protein is a nonspecific marker of cerebral pathology, further search for the potential underlying pathophysiological mechanisms related to this finding would now appear to be warranted.

Adult↗
PubMed1995

Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms.

Contingent tolerance to the anticonvulsant effects of carbamazepine on amygdala kindled seizures develops when the drug is repeatedly given prior to but not after the electrical stimulation. Such tolerance can be reversed by kindling the rats for several days without drug or even by continuing to give the drug but after each seizure has occurred. Contingent tolerance can be slowed by reducing the electrical stimulus intensity and by chronic continuous (as opposed to repeated paired) drug administration. Contingent cross-tolerance has been demonstrated from carbamazepine to PK11195 (a drug active at peripheral-type benzodiazepine receptors) and valproate, but not to clonazepam and diazepam (two drugs active at central-type benzodiazepine receptors) or phenytoin. Endogenous physiological changes occur in conjunction with contingent tolerance, exemplified by the decrease in seizure threshold that returns to normal upon reversal of tolerance. We suggest that contingent tolerance is associated with a loss of seizure-induced adaptations, since many biochemical changes that occur following seizures (or in non-tolerant animals given drug after seizures) are not observed in tolerant animals. These include a loss of seizure-induced up-regulation of GABAA receptors and a loss of increases in mRNA expression for corticotropin-releasing-factor (CRF), thyrotropin-releasing-hormone (TRH), neuropeptide Y (NPY), glucocorticoid receptors and brain-derived neurotrophic factor (BDNF). Thus, several putative seizure-induced anticonvulsant adaptations, such as increases in GABAA receptors and TRH and NPY mRNA fail to occur in tolerant animals. These findings are consistent with the novel observations that, paradoxically, seizures themselves appear to facilitate the anticonvulsant effects of carbamazepine or diazepam on amygdala kindled seizures. That is, animals given a 'vacation' from seizures show a decreased response to these agents, a phenomenon we have called the 'time-off seizure' effect. Thus, seizures are postulated to induce adaptive changes that influence seizure thresholds and potentiate the anticonvulsant effects of exogenously administered drugs such as carbamazepine and diazepam. Taken together, these data suggest that seizures are associated with endogenous adaptations lasting days to weeks and that a selective failure of some of these to occur during contingent drug administration may underlie the development of contingent tolerance. These observations suggest tht endogenous illness-related mechanisms may participate both in the therapeutic responses of some agents and that their failure to occur could relate to loss of drug efficacy via tolerance; these processes may reveal new potential targets for therapeutic intervention.

Adaptation, Physiological↗
PubMed1995

Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression.

BACKGROUND: Depression is often resistant to treatment with mood stabilizers. The antidepressant effects of carbamazepine can be potentiated by lithium supplementation, but some patients fail to respond to the combination. Although monoamine oxidase inhibitors (MAOIs) appear useful in atypical and bipolar depressions, concerns have been raised regarding safety and pharmacokinetic interactions when they are combined with carbamazepine. METHOD: Ten inpatients (7 bipolar, 3 unipolar) with refractory DSM-III-R major depression, also resistant to double-blind treatment with carbamazepine, plus lithium augmentation in 8, received double-blind MAOI augmentation (phenelzine in 4, tranylcypromine in 6). RESULTS: All 10 patients tolerated the addition of an MAOI well, and mean self-rated side effect scores did not change significantly. Four of 10 patients improved substantially and became euthymic, allowing discharge from hospital on the carbamazepine +/- lithium plus MAOI combination. These 4 patients improved in spite of prior inadequate responses to the same MAOI without carbamazepine and carbamazepine without an MAOI. CONCLUSION: This preliminary evidence suggests that the addition of MAOIs to carbamazepine +/- lithium may be well tolerated, may not affect carbamazepine and lithium pharmacokinetics, and may provide relief of refractory depressive symptoms in some patients. Further studies are needed to establish the safety and efficacy of combining carbamazepine with MAOIs.

Adult↗
PubMed1992

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.

Amygdala↗
PubMed1992

Expression of c-fos mRNA in acute and kindled cocaine seizures in rats.

In situ hybridization for c-fos mRNA was performed on brain sections (a) from rats after an acute cocaine-induced seizure or from saline-injected controls and (b) from rats after their first cocaine-kindled seizure, as well as from rats that had not yet developed cocaine-kindled seizures (but were exposed to the same amount of cocaine as those that did exhibit convulsions) and from saline-injected controls. Increased expression of c-fos mRNA was observed in animals demonstrating cocaine-induced seizures acutely or following pharmacological kindling. Rats that experienced acute seizures after cocaine (65 mg/kg) showed pronounced increase in expression of c-fos mRNA in the dentate gyrus of the hippocampus and olfactory bulb. Increases were also observed in several other limbic cortical regions, as well as the striatum and ventromedial hypothalamic nucleus (VMH). In rats that were injected daily with an initially subconvulsive dose of cocaine-HCl (40 mg/kg), the cocaine-kindled seizures induced elevations in c-fos mRNA in the same brain regions as with an acute cocaine-induced seizure with the single exception of the VMH. These findings not only suggest the involvement of limbic, cortical and striatal structures in the cocaine-induced seizure, but also raise the possibility that alterations in the proto-oncogene c-fos and its subsequent impact on gene expression could play a role in the changes in neural excitability associated with cocaine-induced kindling.

Animals↗
PubMed1992

Impaired recognition of affect in facial expression in depressed patients.

Measures of recognition of seven affects in facial and verbal expressions to 17 depressed patients and 31 controls were administered. Depressed patients were significantly impaired in the recognition of affect in the facial, but not verbal, expressions. Among the seven affects examined, depressed patients made significantly or near significantly fewer correct matches for sad, happy, and interested face items. The performance of the depressed patients was similar to that observed by Kolb and Taylor in patients with right, but not left, hemisphere cortical excisions. The neurobiology of facial recognition is reviewed, and the relevance of the observed perceptual deficit in depressed patients to the pathophysiology and symptomatology of depression is discussed.

Adult↗
PubMed1992

Cerebral metabolism and depression in patients with complex partial seizures.

Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.

Adolescent↗
PubMed1992

Induction of constitutive heat shock protein 73 mRNA in the dentate gyrus by seizures.

We examined the effects of generalized seizures on heat shock protein (hsp) mRNA induction in the rat brain using in situ hybridization. Seizures induced by electroconvulsive shock, electrical or cocaine kindling caused a selective induction of the constitutive hsp 73 gene in the dentate gyrus. In these seizure paradigms, not thought to induce widespread tissue damage, neither the heat-inducible hsp 72 gene nor a member of the hsp 90 family (hsp 84) were induced. Hsp 73 may play a role in the adaptation and/or in the maintenance of dentate granule cell integrity following seizures.

Amygdala↗
PubMed1992

Alterations in mRNA of enkephalin, dynorphin and thyrotropin releasing hormone during amygdala kindling: an in situ hybridization study.

The present study examined changes in mRNA expression of various neuropeptides at several stages of amygdala kindled seizures. 35S-labelled oligonucleotide probes for mRNA of enkephalin (ENK), dynorphin (DYN) and thyrotropin releasing hormone (TRH) were hybridized to brain sections of rats sacrificed 24 h after a stage 1 or stage 5 seizure, or 2 weeks after a stage 5 seizure. Changes in expression developed as kindling progressed, with long-lasting changes in ENK and transient changes in DYN and TRH. ENK mRNA levels increased in pyriform and entorhinal cortices at stage 1 and 5 and remained elevated in the pyriform two weeks after a stage 5 seizure. In contrast, DYN mRNA was decreased bilaterally in the dentate gyrus 24 h after a stage 5 seizure, but returned to control levels two weeks after a stage 5 seizure. TRH mRNA was dramatically increased 24 h after a stage 1 or stage 5 seizure. After a stage 1 seizure two patterns developed. One showed increases in the pyriform, entorhinal and perirhinal cortices ipsilateral to the stimulation. The other pattern displayed bilateral increases in the dentate gyrus with or without the unilateral increases the limbic cortices. Twenty-four hours after a stage 5 seizure, large bilateral increases were found in these areas, but these returned to baseline levels by two weeks after a stage 5 seizure. The data demonstrate a constellation of alterations in several peptide systems with distinct spatiotemporal patterns, particularly in regions known to be important in kindling and epilepsy, such as the dentate gyrus and pyriform and entorhinal cortices. The relationship of these neuropeptide mRNA changes to those previously found in c-fos mRNA expression during the development of kindling is discussed.

Amygdala↗
PubMed1992

Mechanisms of action of anticonvulsants in affective disorders: comparisons with lithium.

Until recently it appeared that lithium carbonate possessed a unique spectrum of clinical action in the acute and prophylactic treatment of manic and depressive episodes. It is now increasingly apparent that the anticonvulsants carbamazepine and valproate also share components of this spectrum of efficacy in the affective disorders but, in addition, are clinically effective in some lithium nonresponders. This clinical convergence can now drive a reexamination of the potential mechanisms of action of these compounds in the affective disorders. In spite of intensive study over several decades, the mechanism of action of lithium has remained elusive. A basic conundrum in the consideration of the actions of lithium has also been to explain how a simple ion could have such complex effects on multiple neurotransmitter systems and, in particular, have bimodal actions in the treatment of both manic and depressive phases of the illness. We suggest that a fundamental reconceptualization of both mania and depression as overactivated neural systems (either excitatory or inhibitory) could facilitate this conceptualization. Given the recent evidence linking lithium's effects to uncoupling receptor-mediated activity at the level of G-proteins or attenuating it at the level of second messenger systems mediated by adenylate cyclase or phosphoinositide turnover, these mechanisms become ideal candidates for considering how the drug could dampen overactivated systems potentially relevant to either depression or mania. The lag in onset of maximum therapeutic action of lithium, carbamazepine, and valproate further suggests that biologic effects associated with chronic compared with acute administration are the prime candidates for psychotropic effects. Comparison of the acute and chronic effects of carbamazepine with those of valproate is also offered to focus on the most likely receptor, second-messenger, and ion channel mechanisms involved in their anticonvulsant and psychotropic actions. It is hoped that better understanding of the comparative actions of lithium, carbamazepine, and valproate will allow better targeting of individual drugs for individual patients as well as, ultimately, the development of new and more selective treatments for the recurrent affective disorders.

Anticonvulsants↗
PubMed1992

Lithium-discontinuation-induced refractoriness: preliminary observations.

The authors used a systematic life-chart methodology to observe four patients with bipolar disorder in whom long periods (6-15 years) of effective lithium prophylaxis were followed by relapses on lithium discontinuation. Once the drug was reinstituted, it was no longer effective. The incidence, predictors, and mechanisms underlying this phenomenon all require further systematic study. The current preliminary observations suggest an additional reason for caution when lithium discontinuation in the well-maintained patient is considered.

Bipolar Disorder↗
PubMed1992

Transduction of psychosocial stress into the neurobiology of recurrent affective disorder.

Early clinical observations and recent systematic studies overwhelmingly document a greater role for psychosocial stressors in association with the first episode of major affective disorder than with subsequent episodes. The author postulates that both sensitization to stressors and episode sensitization occur and become encoded at the level of gene expression. In particular, stressors and the biochemical concomitants of the episodes themselves can induce the protooncogene c-fos and related transcription factors, which then affect the expression of transmitters, receptors, and neuropeptides that alter responsivity in a long-lasting fashion. Thus, both stressors and episodes may leave residual traces and vulnerabilities to further occurrences of affective illness. These data and concepts suggest that the biochemical and anatomical substrates underlying the affective disorders evolve over time as a function of recurrences, as does pharmacological responsivity. This formulation highlights the critical importance of early intervention in the illness in order to prevent malignant transformation to rapid cycling, spontaneous episodes, and refractoriness to drug treatment.

Animals↗
PubMed1992

Contingent tolerance and reresponse to carbamazepine: a case study in a patient with trigeminal neuralgia and bipolar disorder.

This retrospective single-case study demonstrates the development of tolerance and reresponse to carbamazepine in a patient with coexisting trigeminal neuralgia and manic-depressive illness. After an initial positive response, tolerance to the antinociceptive and psychotropic effects of carbamazepine appeared during treatment, despite increasing doses. As in preclinical studies of contingent tolerance, periods of carbamazepine discontinuation were associated with reresponse following reinstitution. These are the first clinical data interpreted in a contingent tolerance formulation with reresponse following a medication-free interval. Controlled and prospective studies are needed of the reliability and the pathophysiological and therapeutic implications of this phenomenon.

Aged↗