Manic-depressive Subjects Research Articles

Beta-adrenoceptor function in human adult skin fibroblasts: a study of manic-depressive illness.

Catecholamine theories of affective illness provide a rationale for the study of beta-adrenoceptor function in these disorders. Skin fibroblasts were grown in tissue culture from skin biopsies of normal volunteers and manic-depressive subjects for measurement of isoprenaline-stimulated production of cyclic AMP. Monolayers of fibroblasts in wells were incubated for 3 min with or without 0.5 microM-isoprenaline. The cyclic AMP was isolated by ion-exchange chromatography and quantitated by radioimmunoassay. The isoprenaline-stimulated levels of cyclic AMP in manic-depressive subjects (n = 12) were no different from those in normal volunteers (n = 13). Thus, no evidence was found for abnormal beta-adrenoceptor function in manic-depressive illness.

Glutamate decarboxylase 65-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain

Recent postmortem studies have been suggesting that a defect of GABAergic neurotransmission might occur in the corticolimbic system of subjects with schizophrenia and bipolar disorder. To explore this possibility, a method for immunolocalizing the 65 kdalton isoform of glutamate decarboxylase (GAD 65) has been developed and applied to the anterior cingulate (ACCx) and prefrontal (PFCx) cortices of 12 normal controls (CONs), 12 schizophrenics (SZs) and 5 manic depressive (MDs) subjects. A computer-assisted technique was employed under strictly blind conditions to determine the density of GAD 65-IR terminals in apposition with pyramidal (PNs) and nonpyramidal (NPs) neurons and in neuropil (NPL) of layers II, III, V and VI of each cortical region. For SZs, no difference in the numerical density of GAD 65-IR terminals in contact with either PNs or NPs or in NPL of layers II–VI in ACCx or PFCx was detected. There were also no differences in the size of either PNs and NPs that could have influenced the nature of these findings. Using a pixel count analysis, the size of IR terminals was, however, found to be increased in layers II (10.3%) and III (15.8%) of SZs, but only in subjects treated with neuroleptic drugs. For MDs, the density of GAD 65-IR terminals was significantly reduced in all four layers of ACCx, but these differences were most significant in layers II (27.8%) and III (37.2%), whether or not the subjected were treated with neuroleptics. In PFCx, the MDs showed similar differences in terminal density for PNs and NPs but not neuropil in the four laminae examined. The MD group showed no differences in either the size of cell bodies or IR terminals. Age and PMI did not account for any of the differences between the CONs vs SZs and MDs. Overall, the results of this study, though preliminary, suggest that there may be complex changes in GABAergic terminals in SZ and MD, ones that may vary with respect to primary diagnosis and neuroleptic exposure.

A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives

Background: Recent studies have suggested that there may be a preferential decrease of “nonpyramidal” neurons (NPs) in several corticolimbic regions of schizophrenic (SZ) brain. The current study was undertaken to determine whether a change in the density of pyramidal neurons (PNs) and NPs might be present in the hippocampal formation (HIPP) of SZ brain. Methods: A spatial counting approach in which the location of each and every PN and NP in the stratum pyramidale of sectors CA1–4 was applied to 11 normal control (CONs) and 10 SZs matched for age and postmortem interval, as well as 4 manic depressive (MD) subjects matched for age. Results: The data indicate that the CONs had approximately 10–20 times as many PNs than NPs in the various HIPP subfields. When the CON data were compared to those for the SZs, both the total number and density of PNs were found to be similar in all four sectors, while NPs were found to be selectively reduced by approximately 40% in CA2 of the SZ group. When the data were broken down according to patients with and without neuroleptic exposure, drug-free SZs showed a significant reduction in the density of NPs in CA2. The 4 MD cases both with and without neuroleptic exposure also showed a similar reduction of NPs in sector CA2. Conclusions: Taken together, the results of this study suggest that there may be a highly selective decrease in the number of NPs in sector CA2 that could play a contributory role in the pathophysiology of the major psychoses.

A comparison of clinical and linguistic indices of deviance in the verbal discourse of schizophrenics

AbstractThe goal of this study was to compare clinical and psycholinguistic approaches to the measurement of verbal behavior according to their ability to discriminate schizophrenic (n = 11) from manic-depressive (n = 11) and normal control (n = 11) subjects. Language samples were obtained during Rorschach testing and analyzed using a clinical measure, the Thought Disorder Index (TDI), and a battery of linguistic measures. Five linguistic categories were examined: productivity, repetition, dysfluency, cohesiveness, and syntactic complexity. On the clinical measure, schizophrenic subjects had high thought disorder scores. On the linguistic measures, the speech of schizophrenics differed significantly from the other two groups in productivity and in the number of clearly referenced elements, a measure of cohesion. This measure of cohesion was positively correlated with TDI scores. The findings are discussed in terms of the benefits of using more objective and quantitative measurements in research on thought disorganization in schizophrenia.

A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manicdepressive psychosis

A 2-year prophylactic trial was carried out in 31 bipolar manic-depressive subjects, comparing 300 mg/day methylene blue on a double-blind crossover basis with 15 mg/day. All patients were also maintained on lithium. Seventeen patients completed the 2-year trial. During the year the patients were treated with methylene blue at 300 mg/day, they were significantly less depressed than during the year on 15 mg/day. No significant difference in the severity of manic symptoms was shown. The trial had obvious limitations, e.g., a small number of subjects, a relatively large number of dropouts, relatively simple rating scales, doubts about blindness, and uncertainty as to whether or not 15 mg methylene blue per day could be considered a placebo. However, the results suggest that methylene blue may be a useful addition to lithium in the long-term treatment of manicdepressive psychosis and warrants further investigation.

Fenfluramine stimulation of serum cortisol in patients with major affective disorders and healthy controls: further evidence for a central serotonergic action of lithium in man.

In order to investigate the influence of lithium long-term medication on serotonergic neurotransmission, fenfluramine stimulation (FFS) was used for the assessment of hormonal effects under serotonergic control. The cortisol plasma concentration following FFS was examined between 8 a.m. and 1 p.m. in 11 manic-depressive subjects under lithium prophylaxis and in 8 untreated euthymic patients. In addition, 11 healthy subjects with FFS, and 12 other subjects without FFS were investigated. The basal cortisol concentrations show considerable variation. Those of the lithium patients were in general found lower than those of the control groups. In both, the controls and the manic-depressive patients without lithium medication, no gross deviation from the expected physiological decline of morning cortisol values was found. A subtle effect of FFS in healthy subjects could be observed. In the lithium patients, however, a significant inversion of the cortisol secretion pattern with a steep increase between 10 and 12 a.m. could be demonstrated. It is concluded that FFS and lithium long-term medication exert an agonistic influence onto central serotonergic neurotransmission. Pharmacological challenge with fenfluramine may prove to be a useful tool for the investigation of serotonergic mechanisms in biological psychiatry.

Reversal of vanadate-induced inhibition of Na-K ATPase: A possible explanation of the therapeutic effect of carbamazepine in affective illness

There is evidence that carbamazepine is of therapeutic benefit in manic depressive illness. There is also evidence that raised vanadium levels may be of aetiological importance in manic depressive illness. The present study examined the effect, in vitro, of therapeutic concentrations of carbamazepine on the inhibition by ammonium metavanadate of the Na-K ATPase of erythrocytes from normal and from manic depressive subjects. The inhibition by vanadate was largely reversed by carbamazepine. This effect may be related to the therapeutic action of carbamazepine in manic depressive illness.

Clinical correlates of lateral ventricular enlargement in bipolar affective disorder.

The presence of lateral ventricular enlargement in some manic-depressive subjects, as assessed by ventricular-brain ratios (VBRs), has been reported. A study of 27 bipolar patients and 27 individually matched normal controls confirmed that finding. Bipolar patients had significantly larger VBRs than did controls. Clinical measures associated with the presence of ventricular enlargement in the bipolar patients included more frequent hospitalizations and histories of persistent unemployment. Other measures of illness severity or social deterioration were not significantly associated with large VBR.

Some Biochemical Findings during Pregnancy and after Delivery in Relation to Mood Change

BALLINGER, C. BARBARA; KAY, DAVID S. G.; NAYLOR, GRAHAM J.; SMITH, ANNE H. W. Author Information

Plasma vanadium concentration in manic-depressive illness

133 samples of plasma taken from 9 normal control and 8 manic-depressive subjects were analysed for vanadium by atomic absorption spectrometry. Mean plasma vanadium concentrations were 0 . 15 microM in normal control, 0 . 34 microM in manic and 0 . 28 microM in depressed subjects, and 0 . 23 microM in manic-depressive subjects after recovery. The differences between normal subjects and manic and recovered subjects were statistically significant. Significant negative correlations were found between plasma vanadium concentration and the ratio of Na-K-Mg ATPase to Mg-ATPase in 2 manic-depressive subjects, but not in normal subjects. The results suggest that vanadium may be a cause of the variations in Na-K-Mg ATPase and sodium pump activity which are associated with manic-depressive illness.

Some biochemical findings during pregnancy and after delivery in relation to mood change.

Thirty-four women who had vaginal deliveries of live infants completed behavioural ratings and supplied blood and 24-hour urine samples on three occasions during pregnancy and on three occasions after delivery. Approximately one third of the women indicated a distinct upswing in mood between Days 2 and 4 following delivery. These "positive mood change' subjects showed changes in urinary cyclic AMP (adenosine 3'5' cyclic monophosphate), plasma cyclic AMP, whole blood cell cyclic AMP, whole blood cell ATP (adenosine triphosphate), haematocrit and urinary 11 OHCS (11-hydroxycortisol steroids) following delivery which were different from those observed in the rest of the subjects and comparable with the biochemical changes described during upswings in mood in short-cycle manic-depressive subjects. There was also an indication that the women showing this upswing in mood following delivery were distinct in some respects on both behavioural ratings and biochemical findings during pregnancy.

Abnormal calmodulin-activated CaATPase in manic-depressive subjects

CaATPase of human erythrocyte membranes exists in both a basal and a calmodulin-activated form, each of which can be further activated by monovalent ions such as sodium, potassium or lithium. We have measured the extent of such activation in erythrocyte membranes obtained from 14 manic-depressive outpatients under treatment with lithium carbonate, nine such patients not treated with lithium carbonate, and eight normal controls. The principal findings were as follows: (1) when further activation of the calmodulin-dependent enzyme was measured in the presence of a sub-optimal concentration of lithium ions, greater activation was observed for all manic-depressive subjects, whether or not treated with lithium carbonate, than for controls. We interpret this observation to mean that a biochemical abnormality exists in this patient population with respect to controls; (2) when activation was measured in the presence of optimal concentrations of sodium and potassium ions, the control and the untreated patient groups each showed lesser activity than the lithium carbonate treated groups, indicating that this treatment sensitized the membrane enzyme to monovalent cations. Overall, both of these results indicate that calmodulin-activated CaATPase is abnormal in manic-depressive patients.

Intellectual efficiency in manic-depressive patients treated with lithium. A control study.

A longitudinal study of 21 non-hospitalized manic-depressive subjects treated with lithium was carried out over a 3-year period: year 1 (Y1), year 2 (Y2), year 3 (Y3). A control group C of 21 subjects matched for age, sex and educational level was compared to Y1, Y2 and Y3 using the Cattell Intelligence Scale, the immediate memory recall test of numbers, the Code Test (WAIS), the 15-Word Test and the Benton Visual Retention Test. The vocabulary test of Binois and Pichot was first applied to C and Y1 to test the homogeneity of intellectual level between these two groups. A strategy of variance analysis followed by non-parametric Mann-Whitney and Wilcoxon tests was applied for statistical analysis of the results. Generally, except for the Cattell test, the patients presented lower scores than the control group. This decrease was not accentuated as time elapsed; the non-verbal were not affected more than the verbal tests. A clinical analysis was carried out relating the importance of the criteria "deterioration" to four other criteria: "age", "gravity and duration of illness ", "history of E.C.T." and "insufficient mood stabilization". The factor "gravity of the illness" was slightly more frequently associated with factor deterioration.

Prediction of clinical course of bipolar manic depressive illness treated with lithium.

A group of bipolar manic depressive patients attending a routine lithium clinic were investigated. The results suggest that, when on treatment with lithium, manic depressive patients with a good prognosis tend to have a higher erythrocyte Na-K ATPase and higher plasma and erythrocyte lithium concentrations than those with a poor prognosis. There was no evidence to suggest that the erythrocyte: plasma lithium ratio was useful in predicting clinical response to lithium therapy. There was also a positive correlation between plasma lithium concentration and Na-K ATPase activity, confirming that in manic depressive subjects lithium produces a rise in erythrocyte Na-K ATPase activity.

The effect of ruthenium red and NEM on lithium efflux from human erythrocytes.

The lithium pump in intact human erythrocytes which has previously been shown to be repressed following lithium carbonate ingestion by manic-depressive subjects is now shown to be inhibited selectively by N-ethylmaleimide and ruthenium red, both of which are known to inhibit the erythrocyte Ca pump. It is proposed that active lithium efflux is linked to the concurrent operation of the calcium pump.

Effect of lithium on the physostigmine-induced behavioral syndrome and plasma cyclic GMP

Physostigmine has been reported to induce a syndrome of psychomotor retardation and in some cases a depressive syndrome. We attempted to investigate a possible mode of action of lithium's proven prophylactic value in depression by assessing the effect of pre-treatment with lithium on this physostigmine-induced behavioral response. A marked physostigmine response was observed in 5 lithium-treated, euthymic manic-depressive subjects as well as in 5 lithium-free, normal controls, with no diminution in the lithium-treated subjects. Plasma cyclic GMP, a possible product of cholinergic receptor activity, also showed no differential response in lithium-treated and lithium-free subjects.

Plasma cyclic AMP in manic‐depressive illness

The postulated disturbance of cyclic AMP (cAMP) in manic-depressive illness was investigated by using plasma as the biological material. Cyclic AMP was measured by a protein-binding assay, which was found very satisfactory for the purpose of this study. In the drug-free state, depressed patients (n = 28) had significantly lower and manic patients (n = 9) significantly higher plasma concentrations of cAMP than controls. Unmedicated manic-depressive subjects had normal cAMP levels during normothymic phases (n = 7). Cyclic AMP was reduced by neuroleptics in mania and elevated by tricyclics in depression. Lithium exerted a normalizing effect on cAMP in both phases of the illness. It is concluded that manic-depressive illness is associated with a disturbance in the cAMP system. The use of plasma rather than urine for the investigation of the state of cAMP in psychiatric disorders is advocated.

Lithium and erythrocyte membrane cation carrier studies in normal and manic depressive subjects.

Changes in the erythrocyte membrane cation carrier following lithium ingestion in normal human subjects were studied; ouabain sensitive potassium influx fell significantly during the lithium treated phase. Lithium was fed to rats and no change in erythrocyte Na-K ATPase was shown. These findings contrast with studies of lithium in manic depressive psychosis. The fluctuations in the erythrocyte membrane cation carrier were studied in 5 normal subjects over 12 weeks and the correlations between the parameters calculated. The erythrocyte sodium concentration correlated positively with the ouabain sensitive potassium influx. This too contrasts with findings in manic depressive psychosis.

Repression of a lithium pump as a consequence of lithium ingestion by manic-depressive subjects

The lithium pump in human erythrocyte membranes, which is responsible for extrusion of lithium against a concentration gradient, has been found to be reversibly repressed during periods of lithium carbonate administration. The pump activity of patients prior to lithium therapy is not different from controls. The onset of repression may require several days to several weeks and occurs at specific individual threshold levels of lithium carbonate dosage. Reactivation of the lithium pump occurs sometime after the dosage is discontinued. We postulate that repression of the lithium pump results from systemically available factors which alter membrane structure, and suggest that is such changes also occur in the central nervous system, they may provide insight into one means by which lithium produces its psychotropic affects.

Active efflux of lithium from erythrocytes of manic-depressive subjects

Lithium transport kinetics, studied under physiological conditions in erythrocytes obtained from manic-depressive patients, are characterized by asymmetric rate constants of efflux and influx. The efflux constants, which are more than twice as large as the influx constants, correlate well with the in vivo distribution of lithium between erythrocytes and plasma. The efflux process, which is not inhibited by ouabain and is therefore distinct from the sodium-potassium pump, is characterized by Michaelis - Menten kinetics and a large energy of activation. There appears to be a normal endogenous inhibitor which regulates the activity of the postulated lithium pump.