J. Mendels

Urinary free Cortisol excretion in depression

Urinary free cortisol (UFC) excretion was determined in 60 depressed inpatients and in 35 psychiatric inpatients with other disorders. The depressed patients had high daily UFC values, while the other patients excreted normal amounts. Over 40% of the depressed patients had UFC excretions in the range seen in Cushings disease, while only 6% of the other patients excreted such high amounts of cortisol. Age and sex differences did not account for the results. Among the depressed patients those with depressive neuroses excreted less than unipolar or bipolar depressives. Following treatment, more normal UFC excretion was found in depressed patients. The estimation of UFC and its clinical utility are discussed in detail. UFC determination is a simple and informative indicator of adrenal cortical activation and its application to psychoendocrine studies is recommended.

Cerebrospinal fluid and plasma free cortisol concentrations in depression

Cerebrospinal fluid (CSF) cortisol levels were examined in a total group of 65 patients. Those who were not depressed (ND), and those suffering from depressive neuroses (DN) had marginally elevated values. Patients with unipolar depression (UD) and bipolar depression (BD) had levels twice as high as the ND and DN patients. Psychotic UD and BD patients had the highest values, three to four times as high as the ND and DN subjects. A significant reduction of CSF cortisol levels was observed following treatment and recovery. Manic patients had moderately elevated CSF cortisol values. The CSF results were in good agreement with plasma total cortisol levels and with urinary free cortisol excretion. Age and sex effects were not responsible for the observed differences; similar results were found in patient subgroups studied in Australia and in the United States. Preliminary equilibrium dialysis data are presented for plasma and CSF cortisol binding. CSF cortisol was 20% bound and 80% free. Plasma free cortisol levels were in good agreement with CSF free cortisol values. Depressed patients have increased tissue and central nervous system (CNS) exposure to free, physiologically active glucocorticoids. The appearance of severe depressive symptoms which manifest a diurnal rhythm may be determined in part by excesssve CNS exposure to glucocorticoids.

The effect of psychoactive drugs on beta-adrenergic receptor binding sites in rat brain

Abstract The effect of a variety of psychotropic drugs, given to rats repeatedly over 16 days, on the number of beta-adrenergic receptor binding sites in cerebral cortex was measured. Labelled dihydroalprenolol, [ 3 H]-DHA, was used to measure beta-adrenergic binding sites. Both tricyclic antidepressants (amitriptyline, chlorimipramine, desmethylimipramine and nortriptyline) and monoamine oxidase inhibitors (nialamide and tranylcypromine) lowered [ 3 H]-DHA binding significantly. Repeated treatment of rats with the antidepressant. iprindole. produced the same effect as did treatment with bupropion. However, the experimental antidepressant mianserin did not reduce [ 3 H]-DHA binding nor did 11 other psychoactive compounds including chlorpromazine, diazepam, l -DOPA, tripelennamine and cocaine. The reduction in [ 3 H]-DHA binding produced by nialamide or iprindole treatment was due to a reduction in the maximum number of beta-adrenergic receptor binding sites. Drug treatment-induced lowering of [ 3 H]-DHA binding sites in cerebral cortex appears to have utility as a pre-clinical test for antidepressant drugs.

Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients.

A reduction in 5-hydroxyindoleacetic acid in cerebrospinal fluid was found in depressed and manic patients both while they were symptomatic and also after treatment. The concentration of homovanillic acid was initially reduced and then tended to increase after treatment.

Decrease in [3H]-serotonin binding in rat brain produced by the repeated administration of either monoamine oxidase inhibitors or centrally acting serotonin agonists

Abstract The effect of repeated administration of monoamine oxidase inhibitors or serotonin agonists on [ 3 H]-serotonin binding and serotonin concentrations in rat cerebral cortex was examined. Five days of clorgyline administration, which alone caused a significant reduction in [ 3 H]-serotonin binding, was unable to do this in animals pretreated with drugs that deplete brain serotonin. Pretreatment of rats with alpha-methyl- para tyrosine did not block the clorgyline-induced reduction in [ 3 H]-serotonin binding. Repeated treatment of rats with nialamide also lowered [ 3 H]-serotonin binding and the return of binding sites to control values was correlated temporally with the return of the serotonin concentration to control values. Repeated administration to rats of the serotonin agonists, quipazine or TFMPP, produced a decrease in [ 3 H]-serotonin binding. Both the clorgyline and serotonin agonist-induced reduction in [ 3 H]-serotonin binding were due to a significant reduction in the maximum specific binding capacity with no change in the apparent binding constant. The data presented here are consistent with the hypothesis that MAO inhibitors reduce [ 3 H]-serotonin binding indirectly, by increasing over time the exposure of serotonin receptors to the indolealkylamine.

Prediction of steady‐state imipramine and desmethylimipramine plasma concentrations from single‐dose data

Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dose of desmethylimipramine (DM1) or imipramine (IMl) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady‐state plasma levels. In patients receiving DM1 there was a correlation (r = 0.97, n = 10) between 24‐hr and steady‐state DM1 levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24‐hr and steady‐state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a “therapeutic” dosage regimen without delay.

A Study of Growth Hormone Release in Depression

Interest in biogenic amine function in affective disorders has stimulated a variety of research strategies including the measurement of hormonal response to a variety of stimuli as an indirect method of investigating the integrity of aminergic function in clinically depressed patients. Apomorphine and levodopa are known to stimulate growth hormone release via a dopaminergic pathway in median eminence. Administration of these agents to groups of depressed patients and age, sex-matched normal control subjects did not indicate any significant abnormality in this dopaminergic system.

Influence of Phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03‐mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03‐mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half‐life (t½) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t½ by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration‐time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding.

Prediction of the lithium ratio in man by means of an in vitro test

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium‐sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+‐loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.

Plasma and Erythrocyte Cations in Affective Illness

Plasma and erythrocyte cations (sodium and magnesium) were studied in groups of patients with an affective disorder and in normal subjects. Baseline determinations were obtained before initiation of treatment for mania or depression. In a subgroup of patients, sequential measurements of cations were made during treatment with lithium carbonate. No differences were found in intraerythrocyte sodium or magnesium among any of the patient groups and controls. Patients with a primary affective disorder had significantly higher plasma sodium than control subjects. Neither baseline cation concentrations nor changes in cation concentration during treatment with lithium correlated with treatment response. Gender was shown to be a significant variable affecting intraerythrocyte cation concentrations.