Platelet activation in depression and effects of sertraline treatment: An open-label study.

OBJECTIVE: The authors' goal was to determine whether sertraline attenuates the increased platelet activation seen among depressed patients. METHOD: They tested 21 otherwise healthy patients with untreated major depressive episode who were 25-52 years old and 21 age- and sex-matched comparison subjects. Patients received 6 weeks of sertraline treatment, and 17 returned for retesting. RESULTS: At baseline, the depressed patients had greater platelet secretion than the comparison subjects in response to collagen. Depressed patients with a family history of coronary disease had nonsignificantly greater wound-induced fibrinogen receptor binding than the other subjects. Platelet secretion in response to collagen was significantly reduced after treatment with sertraline. CONCLUSIONS: Sertraline diminished the increased platelet secretion found among depressed patients, although the findings are limited by a lack of a placebo control group.

Functional deficits in autistic disorder: characterization by technetium-99m-HMPAO and SPECT.

UNLABELLED: Autistic disorder is an early and severe developmental disorder characterized by deficits in verbal and nonverbal language, social skills, cognitive functioning and an abnormal repertoire of behaviors. Current research, however, has failed to identify the neurobiological mechanisms that underlie autism or those cortical brain regions, if any, that are abnormal. METHODS: We examined regional cerebral blood flow (rCBF) in six young, severely autistic patients. High-resolution brain SPECT with 99mTc-HMPAO was performed while five of the six patients were under general anesthesia. The scans reflected the subjects' rCBF in their usual alert behavioral state, since the tracer was injected at least 15 min prior to anesthesia and is rapidly extracted and fixed in the brain. A computer-automated cortical region of interest (ROI) generator was used to define 12 annular cortical regions (region 1 = left frontal, clockwise to region 12 = right frontal) for count data acquisition. The ratio of average counts in each ROI to whole-slice counts for the autistic patients was compared to age-matched controls using repeated measures (splt-plot) ANOVA statistical analysis for three representative brain levels. RESULTS: In the autistic patients, cortical regions 3, 4, and 10 were abnormally low at the cortical level canthomeatal (CM) + 3.5 cm. At level CM + 5.5 cm, regions 3, 4, 5 and 10 were abnormally low, and at level CM + 7.5 cm, regions 7 and 9 were also abnormally low. These regions correspond to abnormally low rCBF values located predominately in the temporal and parietal lobes, with the left cerebral hemisphere showing greater rCBF abnormalities than the right. CONCLUSION: Our findings suggest that the temporal and parietal lobes have abnormal rCBF in autism. HMPAO brain SPECT in combination with general anesthesia is particularly useful for imaging severely noncompliant patients.

Stereospecific effects of ascorbic acid and analogues on D1 and D2 agonist binding.

Ascorbic acid inhibited the specific binding of both the D1 agonist, [3H] SKF 38393, and the D2 agonist, [3H] N-0437 at physiologically relevant concentrations. This inhibition was both stereospecific and receptor selective. Using ligand concentrations approximating their KD's, the IC50's for ascorbate and two structural analogues, isoascorbate and D-glucoascorbate, were determined. The rank order of IC50's at both D1 and D2 were D-glucoascorbate greater than isoascorbate greater than ascorbate. However, the IC50 for each compound was greater at D1 than D2. Evaluation of the relationship between the IC50 for ascorbate and the ligand concentration using both the D1 and the D2 ligand yielded data inconsistent with competitive inhibition models. Preliminary experiments were conducted to evaluate the site and type of inhibition with results consistent with an allostearic effect at the level of the receptor.

Clinical correlations of one-carbon metabolism abnormalities.

1. Ninety psychiatric inpatients with a DSM III diagnosis of schizophrenia, mania, or major depression were studied. 2. Upon admission/transfer to the Clinical Studies Unit, and prior to discharge, measurements of symptom severity (BPRS, Ham-D, Young's Mania Scale) and blood samples were obtained. 3. Erythrocytes from these paired (admission and discharge) blood samples were assayed for methionine adenosyltransferase (MAT) activity and phosphatidylcholine (PC) content. 4. Comparisons were made between the changes in MAT Vmax, or % PC, and changes in symptom severity. 5. For the majority of the patients (79.3% of the schizophrenics; 84.6% of the depressives; and 93.8% of the manics), clinical improvement was associated with a "normalization" of enzyme activity. The association between changes in % PC and clinical response did not achieve significant correlation.

Abnormalities of one-carbon metabolism in psychiatric disorders: study of methionine adenosyltransferase kinetics and lipid composition of erythrocyte membranes.

Two independent lines of inquiry have implicated some disturbance of one-carbon cycle metabolism in affective disorders. Folic acid deficiency commonly leads to depression, and S-adenosylmethionine has been reported to have antidepressant properties. Methionine adenosyltransferase has been reported to be underactive in depression and schizophrenia and overactive in mania. This study reports the effects on erythrocyte methionine adenosyltransferase (MAT) kinetics (Vmax) of a 2-week treatment in a population of patients housed on a psychiatric research ward. The drug-free schizophrenic patients and depressives had, upon admission, low Vmax values, and the drug-free manic patients had high Vmax values on admission. After 2 weeks of appropriate treatment, the values for all three patient samples showed significant normalization (i.e., the levels rose in schizophrenics and depressives and fell in manics). We have further shown that pretreatment low levels of erythrocyte membrane phosphatidylcholine in depressives and high levels in manics show statistically significant normalization following 2 weeks of pharmacotherapy. The significance of these results is discussed.

Medication effects on one-carbon metabolism in schizophrenia, mania, and major depression.

Erythrocyte methionine adenosyltransferase (MAT) activity (Vmax) and phosphatidylcholine (PC) levels previously have been found increased in manic patients and decreased in depressive and schizophrenic patients. To evaluate whether these abnormalities were the result of medication effects, erythrocyte MAT activity (Vmax) was assayed for paired samples from 29 schizophrenic, 16 manic, and 12 depressive patients, an erythrocyte PC levels were obtained for paired samples from 13 schizophrenic, seven manic, and seven depressive patients. Patients were medication free for at least 3 weeks. Vmax was significantly increased in schizophrenic and depressive patients (p less than 0.01; p less than 0.01) and significantly decreased (p less than 0.01) in manic patients after 2 weeks of psychotropic medication. Similar trends were found in PC levels. The findings of those one-carbon metabolism tests following medication are generally opposite to those reported to be related to specific disorders and tend toward normalization. Moreover, in vitro preincubation of erythrocytes of three normal subjects with the most commonly used neuroleptics had no consistent effects of MAT Vmax. These findings confirm previous studies that showed similarities in one-carbon metabolism of schizophrenic and depressed patients as opposed to manic patients and suggest that medications tend to correct or minimize rather than induce such abnormalities.

One-carbon metabolism disturbances in affective disorders. A preliminary report.

Methionine adenosyltransferase (MAT) activity (Vmax) and the relative amount of phosphatidylcholine (% PC) were measured in erythrocytes of up to 30 DSM-III diagnosed manic, 17 unipolar depressed patients, and 28 normal controls. Manic subjects had significantly higher and depressed subjects significantly lower MAT Vmax than normals. The relative amount of PC was in the low range for the depressives, and in the high range for the manics. Depressive patients present, in these tests, similar abnormalities to those seen previously in schizophrenic patients. Clinical and diagnostic implications of these findings are discussed.

Biochemical RBC abnormalities in drug-free and lithium-treated manic patients.

RBCs from two lithium-free manic patients displayed lower choline transport and higher choline concentrations and methionine S-adenosyltransferase activity than those of controls. Lithium therapy decreased RBC methionine S-adenosyltransferase activity to normal, decreased choline transport further, and increased choline concentrations further.

The effect of toxin from Leiurus quinquestriatus scorpion venom on the polymerization and stability of microtubules.

The venom of the scorpion Leiurus quinquestriatus, well-known for its actions on voltage-sensitive sodium channels, has now been shown to have pronounced effects on the in vitro polymerization and stability of neuronal microtubules purified by temperature-dependent cycles of assembly and disassembly. The crude venom, at concentrations as low as 100 micrograms/ml, alters both the extent of tubulin polymerization, as monitored by turbidity, and the appearance of polymerized material under electron microscopic examination. Structures formed in the presence of the venom retain the temperature sensitivity characteristic of normal microtubules, but respond to calcium ions abnormally with a dispersal of ordered structures, as reflected by both increased light scattering and electron microscopic analysis. Fractionation of the crude venom suggested that the active component was the same as the polypeptide neurotoxin which interacts with voltage-sensitive sodium channels and this identity was subsequently verified. Thus, the effect on microtubules of highly purified L. quinquestriatus sodium channel toxin obtained from an independent source was indistinguishable from that of the crude venom. These results indicate that the sodium channel toxin from L. quinquestriatus is also a potent cytoskeletal agent in vitro. This finding may be related to the growing body of evidence suggesting that the neuronal cytoskeleton plays a functional role in the maintenance of membrane excitability.

Kinetic evidence for decreased methionine adenosyltransferase activity in erythrocytes from schizophrenics.

We have observed significantly lower kinetic parameters (KM and Vmax) for methionine adenosyltransferase activity in erythrocytes obtained from early onset schizophrenics when compared to samples from normal subjects. These differences are apparently not due to differences in S-adenosylmethionine (SAM) utilization. These results offer an explanation for the conflicting reports of previous investigators and support the concept that undermethylation may characterize some forms of schizophrenia. Methylation is involved in multiple aspects of metabolism and although similar differences in the MAT enzyme in the brain have not been reported, such a deficit could have profound effects on the nervous system. Decreased availability of SAM could decrease catecholamine metabolism or rates of phospholipid methylation.

Gas chromatographic/mass spectrometric evidence for the identification of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline as a normal constituent of rat brain. Its quantification and comparison to rat whole brain levels of dopamine.

Gas chromatographic/mass spectrometric data are presented which demonstrate the presence of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (DHTIQ) as a normal constituent of rat brain. The level of DHTIQ was calculated to be 10.0 +/- 3.0 ng/g wet weight (+/- S.D., N = 9) of brain tissue while the level of dopamine (DA) was measured as 1.22 +/- 0.22 microg/g (N = 14). The ratio of DHTIQ:DA was thus observed to be approximately 1:100. The possible formation of DHTIQ in alcoholism and schizophrenia is discussed.

Ascorbate blocks amphetamine-induced turning behavior in rats with unilateral nigro-striatal lesions.

Unilateral nigro-striatal lesions were produced in rats using 6-hydroxydopamine. Intraperitoneal injections of amphetamine induced circling behavior in these rats due to release of striatal dopamine contralateral to the lesion. Intraperitoneal injections of 1 g/kg of ascorbic acid elevated brain ascorbate. Ascorbate, like other drugs blocking dopamine receptors, attenuated the amphetamine-induced turning behavior. Thus, ascorbic acid might have a role in regulating dopaminergic transmission and could be of therapeutic value in disorders involving functional dopamine excess.