Dexamethasone suppression testing of alcoholics.

Fourteen (33%) of 43 men hospitalized for alcohol abuse showed abnormal cortisol levels at 4 pm, 17 hours after administration of 1 mg of dexamethasone (median, five days after admission). Most (but not all) of these nonsuppressors showed multiple signs of alcoholic physical deterioration; there may be more than one mechanism by which alcohol abuse can lead to an abnormal result of this test. Suppressors and nonsuppressors reported similar alcohol consumption, symptoms of depression, and occurrence of depression among close relatives. Only two patients (5%) showed abnormal cortisol levels at 8 am, nine hours after administration of dexamethasone. These results suggest that, as a screen for primary depressive illness among recently abstinent alcohol abusers, the 4 pm cortisol level is not specific enough, but the 8 am level might be useful in patients who have no alcoholic relatives.

Characterization and prediction of lithium blood levels and clearances.

Mathematical simulations and nonlinear numerical methods for characterizing the serum elimination half-life, volume of distribution, and renal clearance of lithium after multiple oral doses of lithium carbonate and two or more blood level determinations were constructed and adapted for clinical use. These characteristics were measured for 24 inpatients; predictions were made with the simulation and compared with actual succeeding blood levels. The average elimination half-life of 25.9 hours was compared with half-lives reported after single oral doses. Average and median errors of prediction were negligible; the root mean square error was 0.12 mEq/L, near the coefficient of variation of 0.082 mEq/L. The correlation between predicted and observed levels (r) was .82; a small systematic effect of weight was found.

Decreased epinephrine in familial alcoholism. Initial findings.

Stress-induced epinephrine release, measured in urine, was less in a group of 17 nonalcoholic adoptee probands, aged 18 to 36 years, with alcoholic biologic relatives than in 12 similar controls with no alcoholic relatives. This result is similar to previous observations of small stress-induced epinephrine release in humans with aggressive or hyperactive character traits. Resting epinephrine levels and epinephrine released by alcohol in soft drink were also lower in our probands than in controls. Familial alcoholism might be associated with a trait of globally decreased epinephrine responsiveness.

Antidepressant effects of high-dose right unilateral electroconvulsive therapy.

In a random-assignment, double-blind, controlled comparison in 38 melancholic men, overall antidepressant potency of high-dose electroconvulsive therapy (378-mC charge) given with right unilateral electrode placement was not significantly different from that with bilateral placement, although there was a trend for faster improvement with bilateral ECT. The suprathreshold character of the stimulus, about 2.5 times the expected seizure threshold, may have contributed to the high efficacy of brief-pulse right unilateral electroconvulsive therapy found in this study.

Generalization, duration, and low-frequency electroencephalographic persistence of bilateral electroconvulsive therapy seizure.

Measurements were made at the beginning and end of a course of bifrontotemporal brief-pulse ECT for 28 males to both determine how well seizure generalization is maintained along the course of electroconvulsive therapy (ECT) and examine correspondence between low-frequency EEG activity and other seizure durations. Durations of spike electroencephalographic (EEG) paroxysmal activity, heart rate elevation, and Ionic-clonic activity decreased about 30% along the course, p < 0.0001, yet correlated highly at both times, I = 0.69 to 0.88, p < 0.0005, as did their changes: these correlations demonstrate high-seizure generalization and its maintenance. EEG low-frequency persistence, the difference between total and spike EEG paroxysmal durations, doubled along the course (p = 0.041), but showed no association with any other seizure duration measure. This absence of association suggests that low-frequency activity and other seizure duration measures describe separate phenomena and should be expressed separately, rather than combined as the (traditional) total EEG paroxysmal duration.

Generalization of the effects of unilateral and bilateral ECT.

The correlation coefficients among four different measures of seizure duration (motor activity, EEG spikes, EEG total, tachycardia) were substantially lower with unilateral than bilateral ECT. This suggests that unilateral ECT is less well generalized through the brain than bilateral ECT.

Efficiency of the stimulus characteristics of ECT.

OBJECTIVE: Greater ECT stimulus efficiency allows for a lower stimulus dose and should diminish the side effects of ECT. METHOD: Four different ECT stimuli of identical charge (average mC=2.5 times age) with pulse widths of 0.5 msec and 1 msec and frequencies of 30 Hz and 60 Hz, respectively, were compared for efficiency. The stimuli were applied in a balanced order to each of 24 subjects. Asymmetric bilateral electrode placement was used. RESULTS: Peak heart rates were higher with the 0.5-msec pulse width than the 1-msec pulse width. Seizure induction was more successful with the 0. 5-msec pulse width than the 1-msec pulse width. Stimulus frequency had no effect on heart rate or seizure induction. CONCLUSIONS: The pulse width of 0.5 msec is more efficient than the 1-msec pulse width. The "half-age" dose for the first bilateral ECT treatment is usually successful for subsequent ECTs when the 0.5-msec pulse width is used.

Antidepressant effects of right versus left unilateral ECT and the lateralization theory of ECT action.

In a random-assignment, double-blind, controlled comparison of right versus left unilateral ECT in 30 melancholic men, the two methods were not significantly different in overall antidepressant potency, although there was a significantly faster rate of improvement with left unilateral ECT. These results imply that the antidepressant effects of ECT cannot be attributed primarily to right hemisphere mechanisms, as others have postulated.

Serum prolactin levels during extended cocaine abstinence.

Following a report indicating almost a 100% risk for hyperprolactinemia in cocaine users after 1 month of abstinence, the authors determined the serum prolactin concentrations of 23 male inpatients who had abstained from cocaine for 2-43 weeks. None showed high prolactin levels; this places the incidence below 12.3% with 95% confidence. These results imply that persistent hyperprolactinemia requires a medical explanation other than cocaine abstinence itself.

Differential effects of right unilateral and bilateral ECT on heart rate.

In a series of 11 melancholic patients who received both right unilateral and bilateral ECT during a single course of treatment, mean and minimum postictal heart rates were greater after bilateral ECT. Greater catecholamine release during bilateral ECT is the most likely explanation for these effects. These differences complement other evidence that bilateral ECT has a more pronounced physiological impact than unilateral ECT.

Cell surface oligosaccharide modulation during differentiation. II. Membrane mobility of oligosaccharide lectin conjugates.

The quantitative, population doubling level (PDL) dependent changes in cell surface oligosaccharides on IMR-90 cells, were investigated from the perspective of membrane mobility of the lectin-oligosaccharide conjugates. Concanavalin-A (CON-A), wheat germ agglutinin (WGA), Ricinus communis agglutinin (RCA-120), and Dolichos biflorus agglutinin (DBA) were all observed to cluster, cap, and endocytose in cultured human diploid fibroblasts (IMR-90). Quantitative photometry at 37 degrees C over defined periods of time indicated that as the IMR-90s approached cellular senescence a specific lectin-dependent inability to either endocytose or process the capped complex occurred. The development of a biotin/avidin/enzyme amplification assay permitted the assignment of the accumulating signal to the internal compartment. Kinetic data indicate that there are at least three separate (and separable) mechanisms for the PDL related changes in lectin binding. Data for the CON-A complex indicates that at least two classes of functional complexes are present. Regression analysis of the kinetic data for the RCA-120 complex indicates a similar membrane clearance for the IMR-90s at all population doubling levels (PDL), suggesting that the quantitative differences observed earlier were due to simple quantitative reductions in the RCA complexing molecules. Data for WGA mobility on the membrane indicates that they are both changes in the number and mobility status of the complexes. These results indicate that the quantitative changes in lectin binding observed previously as IMR-90 cells approach senescence are correlated with alterations in membrane mobility patterns of the lectin oligosaccharide conjugates.

Cell surface oligosaccharide modulation during differentiation: IV. Normal and transformed cell growth control.

In previous studies it was shown that cell surface oligosaccharide affinity class distributions and binding capacities were down-regulated as normal cells approach senescence. Using a sensitive, amplified, lectin/specific-ligand competition analysis three other growth regulation states were compared to that of cellular senescence. Non-senescent and senescent low-density and contact-induced growth inhibition was compared with neoplastic cell growth control. Non-senescent human fetal lung fibroblasts (IMR-90) down-regulated their mannosyl and galactosyl specificities in response to both low-density and contact-induced growth inhibition. Senescent IMR-90 down-regulate their mannosyl residues in response to contact conditions while they up-regulate their galactosyl residues under the same conditions. Growth-transformed transplantable canine glioma cells did not show density-dependent regulation of their cell surface oligosaccharide structures. Modulation of the CG cells with a specific alpha-mannosidase II inhibitor, Ricinus communis a galactosyl specific lectin, and pokeweed mitogen a cellular differentiating agent resulted in an altered growth phenotype and up-regulation of the mannosyl and galactosyl surface oligosaccharides. These data indicate a controller function for the cell surface oligosaccharides and a general influence on growth control.

Cell surface oligosaccharide modulation during differentiation: III. Lectin affinity class distributions.

In previous studies we showed that the onset of the morphological phenotype of cellular senescence (IMR-90) in vitro is preceded by complex cell surface changes. Using fluorescently conjugated lectins these studies showed: (1) quantitative PDL-dependent decreases in cell surface mannosyl, galactosyl, and N-acetyl-glucosamine residues; (2) these changes were correlated with changes in ligand/lectin membrane mobility, suggesting a functional relationship for the quantitative changes. To further investigate the biological significance of these observations we have developed a synthetic ligand competition assay to analyze the lectin binding event itself. The results of these analyses show that: (1) the number of binding affinity class distributions is highly restricted; (2) the PDL-dependent mannosyl change is due to the loss of a high-affinity class distribution without significant change in the low-affinity site; and (3) PDL-dependent changes in both galactosyl and N-acetyl glucosamine binding events are the result of changes in the affinity class distributions. These results are interpreted in terms of the potential available energy to act as the basis for signal transduction at the cell surface.

Kinetic modeling of hormone release: application to time-averaged met-enkephalin release.

The time course of hormone concentrations in response to a stimulus can be characterized with kinetic methods to express rates of hormone release and elimination, total amount of hormone release and expected best times for blood sampling. Routine application of kinetic methods should increase the sensitivity and applicability of hormonal challenge tests. Applications to the TRH test and to prolactin release measurements are reviewed. A new kinetic model for continuously collected samples is applied to measurements of met-enkephalin release in rats. Calculations indicated an initial concentration of 1876 pg/ml and a ventricular volume of distribution of 0.25 ml. After exposure of rats to nitrous oxide, the rate of release of met-enkephalin-like activity into the ventricles rose from 3.4 to 8.3 pg/min.

Correction of lithium levels for dose and blood sampling times.

Inconsistencies inherent in the clinical application of morning serum lithium levels can be eliminated by correcting the levels for variations in dosage schedule, rate of lithium elimination, and blood sampling time. In this report, graphs constructed from an accurate pharmacokinetic model of lithium elimination are used to convert the serum lithium level into the daily exposure of the body to lithium. This method facilitates safety and effectiveness in lithium treatment and enables outpatient blood samples for lithium levels to be conveniently drawn in the afternoon.

A learning aid for DSM-III: computerized prompting of diagnostic criteria.

To help overcome many of the difficulties of learning and using the new Diagnostic and Statistical Manual of Psychiatry, a system was developed for reviewing its contents as appropriate to individual clinical cases. It is faithful in format and contents to this Manual. This system is now being regularly used by medical students, residents, and psychiatrists on a voluntary basis, as a teaching aid. It also allows measurement of how the interpretation of DSM-III criteria differs among these groups. This system can be used on relatively inexpensive microcomputers.

Blood pressure reduction with ECT response.

A group of 48 male inpatients who responded to electroconvulsive therapy for major depression showed decreases in resting blood pressure along the course of treatment. Decreases occurred in both systolic (mean +/- SD = 8.0 +/- 17.3 mm Hg, p = .0025) and diastolic (7.4 +/- 13.2 mm Hg, p = .00030) pressures. Systolic pressure decreased by at least 20 mm Hg in 15 patients. These findings are consistent with reports that depressives show elevated plasma catecholamine levels, and that, with response to tricyclic antidepressants, their blood pressures decrease. Depression-associated blood pressure elevation might contribute to the excessive cardiac mortality of depressives; conversely, antidepressant treatment might control hypertension in some depressives.

Low serum testosterone and myocardial infarction in geriatric male inpatients.

A survey of serum testosterone levels and a range of medical and behavioral factors was conducted on 71 males aged 46 to 89 years in an extended care medical facility. Histories of myocardial infarction or heavy drinking were separately associated with diminished testosterone levels (P less than .002 and P less than .006, respectively). No other factor was associated with testosterone level, including age and mobility. A testosterone level of no more than 438 ng/dl best discriminated patients with myocardial infarction (P less than .005, sensitivity 86.2%, and selectivity 50%). Increased incidence of myocardial infarction appeared to be influenced by testosterone in a threshold manner, since the incidence did not rise further with lesser testosterone levels once the level was below 438 ng/dl. The incidence of myocardial infarction among patients with testosterone levels below this threshold was unaffected by their exposure to alcohol. Among the 21 formerly heavy drinkers, many (62%) showed testosterone levels less than or equal to 300 ng/dl. Formerly heavy drinkers should be routinely considered for serum testosterone determination.

Correction of blood drug levels for changes over the day.

A graph-based method is presented to compensate for the influence of variations in drug dosage schedules and blood sampling times upon the blood concentrations of drugs whose elimination half-life is between 7 and 48 hours. This method permits the clinician to interpret blood drug levels drawn at nonstandard times, and to correct blood drug levels for how the daily dose was divided. This method is expected to improve the convenience of monitoring blood drug levels.

Drug dose prediction with flexible test doses.

This article presents the first known practical method to apply one-compartment pharmacokinetic modeling to prediction of doses for drugs from one or more blood-drug concentrations, without requiring approximations or a computer. It should be useful for regulating doses of orally administered CNS drugs whose effects develop over a day or more, e.g., lithium, antidepressants, and anticonvulsants. Pharmacokinetic calculations for sequences of one, two, and three test doses are condensed into graphs that can be rapidly applied for clinical purposes. These graphs account for dose division, blood sampling time, and drug elimination rate; they show that the ratio of the steady-state day-mean drug level to the test-drug blood level is independent of the half-life if the test level is about a day after the last test dose. The calculations show the same value as experimental measurements for the ratio between steady-state serum lithium level and serum lithium level measured after a test dose. A rational strategy for drug-loading doses is discussed.