The effect of long-term physostigmine administration in Alzheimer's disease.

We assessed the effect of chronic long-term physostigmine in 20 patients with probable Alzheimer's disease. Initially, all patients went through a dose-finding phase and a double-blind crossover period, and were subsequently classified as physostigmine responders or nonresponders based on an a priori classification system. We then offered all patients long-term treatment with physostigmine regardless of their initial classification. Results revealed that responders spent significantly (p less than 0.0005) longer time periods on drug (36.1 +/- 4.6 months) than nonresponders (10.8 +/- 3.2). During a 2nd crossover period, 18 months into treatment, responders still demonstrated behavioral improvement, as assessed with the Sandoz Clinical Assessment-Geriatric Scale, whereas there were no behavioral changes observed in nonresponders. There were no effects on formal neuropsychological assessment. The results suggest that a subgroup of Alzheimer's patients benefits from long-term physostigmine therapy.

Speech lateralization in deaf populations: evidence for a developmental critical period.

Cerebral lateralization for speech in right-handed normal hearing and deaf adolescents was assessed using the dual-task paradigm. Subjects with normal hearing and deafness acquired after 3 years of age displayed left hemispheric dominance for speech production, whereas both congenitally deaf and those with an early acquired deafness (onset 6-36 months) showed atypical, anomalous cerebral representation. These results suggest the presence of a developmental critical period for cerebral lateralization during which exposure to adequate environmental stimulation may be needed to activate left hemispheric dominance for speech.

Biological and neuropsychological characterization of physostigmine responders and nonresponders in Alzheimer's disease.

To assess the efficacy of oral physostigmine for the treatment of Alzheimer's disease, 20 patients were entered into a clinical trial. All patients underwent a dose-finding phase (two weeks), followed by an open trial (two weeks), and a double-blind crossover phase (two weeks drug, two weeks placebo). Extensive neuropsychological testing (Buschke Selective Reminding procedure, category generation, picture recognition, finger tapping) and measurement of systemic cholinergic parameters were measured during each of these phases. Patients were classified as physostigmine responders and nonresponders based on a priori established criteria. Using these, nine patients were found to respond to physostigmine, while 11 were classified as nonresponders. During baseline conditions, responders when compared to nonresponders were found to have higher concentrations of red blood cell (RBC) choline (Ch) and higher ratios of RBC Ch to plasma Ch. Neuropsychological tests were found to fall into one of three categories. The first group of tests were sensitive to drug effects and differentiated physostigmine responders from nonresponders; the second group was found to predict responsiveness; and the third group was neither predictive nor sensitive to drug effects.

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.