The possible clinical significance of the plasma protein binding of tricyclic antidepressants has been evaluated using imipramine (IMI), a typical tricyclic. Using equilibrium dialysis, the in vitro binding of IMI to plasma was compared to that of brain tissue. Cerebrospinal fluid (CSF) IMI was used as an independent measure of 'free' drug in the central nervous system. Intrinsic metabolic clearances were calculated on the basis of steady-state plasma IMI concentrations. There were three significant results: (1) variations in plasma binding are not great; (2) plasma protein binding does not limit the entry of IMI into the CSF; (3) variations in metabolism (intrinsic clearance) account for almost all variations in CSF concentrations of drug. It is concluded that measurement of free tricyclic antidepressant is not indicated in studies of clinical efficacy.

Animals↗

PubMed1979

Purinergic inhibition of diazepam binding to rat brain (in vitro).

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Animals↗

PubMed1979

A rapid and sensitive radioreceptor assay for benzodiazepine in plasma.

We describe a rapid and sensitive radioreceptor assay for measuring benzodiazepines in plasma. This method is based on the competition between tritiated diazepam and pharmacologically active benzodiazepines present in plasma, for binding sites on rat brain synaptosomal membranes. No interference is obtained with drug-free plasma or plasma samples containing high concentrations of other commonly used drugs. High correlations (r = 0.98; P less than .001) were obtained between the "diazepam equivalents" measured in plasma with the radioreceptor assay and the levels of diazepam and nordiazepam obtained by gas-liquid chromatography. The radioreceptor assay is rapid, sensitive, specific, and requires no sophisticated equipment or methods. It should therefore prove useful in monitoring blood benzodiazepine levels for both therapeutic and toxicologic purposes.

Animals↗

PubMed1979

Alcohol and central serotonin metabolism in man.

Animal studies and some of thephenomena associated with alcoholism in humans suggest that some central effects of alcohol may involve serotonergic systems. The CSF metabolites of serotonin and dopamine, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were studied in hospitalized alcoholics. There were no significant differences in HVA levels between groups. The level of 5HIAA of alcoholics in the abstinence phase, 28 to 63 days after their last drink, was significantly lower (21.8 +/- 1.9 ng/mL) than both a nonalcoholic comparison group (31.7 +/- 2.0 ng/mL) and alcoholics in the immediate postintoxication phase, within one to two days after their last drink (32.3 +/- 2.9 ng/mL).

Adult↗

PubMed1979

Rapid cycling in manic-depressives induced by tricyclic antidepressants.

Maintenance tricyclic antidepressants induced rapid cycling between mania and depression in five female bipolar (manic-depressive) patients. Lithium carbonate did not prevent the tricyclic-induced rapid cycling, although two patients subsequently responded well to lithium carbonate alone. In these patients, the action of tricyclics can be conceptualized as accelerating rather than counteracting the natural, cyclic course of the illness in all of its phases. In this respect, tricyclics are analogous to several other drugs that are capable of modulating the frequency of oscillatory biological processes.

Adolescent↗

PubMed1979

Novel antidepressants and the biogenic amine hypothesis of depression. The case for iprindole and mianserin.

The introduction of two tricyclic compounds (iprindole and mianserin) that are reported to have antidepressant properties but to be relatively devoid of effects on central amine neurotransmitter systems has raised questions about the amine hypothesis of depression and about the mechanism of action of tricyclics in general. In view of the importance of these questions, a critical review of both the clinical and pharmacological profiles of iprindole and mianserin was undertaken. Iprindole is a relatively weak inhibitor of both norepinephrine (NE) and serotonin, whereas mianserin possesses at least modest potency as an inhibitor of NE uptake. However, the evidence is as yet insufficient to prove the superiority of iprindole over placebo in the treatment of those depressions characterized by endogenous symptoms. In considering the pharmacological profiles of these two drugs together with their clinical profiles, the data are not inconsistent with the hypothesized role of biogenic amines in major depression.

Adjustment Disorders↗

PubMed1979

CNS benzodiazepine receptors: physiological studies and putative endogenous ligands.

The recent demonstration of benzodiazepine receptors in the mammalian CNS has provided new information on the mechanism of action of this important class of drugs. In addition, the presence of these receptors has prompted studies on their physiological significance, including attempts at isolating an endogenous ligand. The isolation of a number of substances from bovine brain that competitively inhibit (3H)-diazepam binding to synaptosomal membrane suggests the presence of an endogenous ligand. Two of these substances have been identified as the purines inosine and hypoxanthine. Pharmacological studies of these purines suggest that they may have diazepam-like effect in vivo. The possibility that the brain may contain its own benzodiazepine-like compound is currently being studied.

Animals↗

PubMed1979

Comparative pharmacokinetics of zimelidine and desipramine in man following acute and chronic administration.

Single dose and steady-state pharmacokinetics of zimelidine and desipramine were compared in eight depressed patients who were subjects in a double-blind crossover study. Within the same patient, there was no relationship between the pharmacokinetics of desipramine (pharmacokinetically similar to all other tricyclic antidepressants) and those of zimelidin, a bicyclic antidepressant. The weight-corrected dose of zimelidine gives a reasonable index of the concentration of its active metabolite norzimelidine, which predominates over zimelidine by a ratio of approximately 3 to 1. The variation in steady-state concentration of norzimelidine for a given dose of zimelidine in adults is about twofold and can be reduced by correcting for weight.

Adolescent↗

PubMed1979

Dopamine-mediated behavior produced by the enkephalin analogue FK 33-824.

Intraperitoneal injection of FK 33-824 produced apomorphine-like stereotyped behavior in rats. Antagonism of this stereotypy by naloxone and neuroleptics suggests that FK 33-824 can activate opiate and dopamine receptors in the brain. Because increased dopaminergic neuronal activity is thought to be involved in schizophrenia and dopamine-mediated stereotypy has been used as an animal model for this illness, these results are consistent with an involvement of endogenous opiate-like peptides in schizophrenia. This involvement provides a possible mechanism for the reported improvement in schizophrenic psychosis produced by naloxone.

Animals↗

PubMed1979

Tricyclic-induced mania and MHPG excretion.

In order to evaluate the presumed involvement of altered noradrenergic receptor sensitivity in the switch process from depression into mania, we explored the relationship between pretreatment 3-methoxy-4-hydroxy-phenylglycol (MHPG) and tricyclic-induced mania or hypomania in bipolar depressed patients. Within the group of patients developing mania or hypomania on tricyclics, there was a strong positive correlation between pretreatment 24-hour urinary MHPG and the latency of onset of the episode. This finding is consistent with both the reported differences in MHPG excretion between unipolar and bipolar patients and the postulated noradrenergic involvement in the switch process.

Affective Disorders, Psychotic↗

PubMed1979

Aggression in humans correlates with cerebrospinal fluid amine metabolites.

Cerebrospinal fluid of the major central metabolites of serotonin (5HT), norepinephrine (NE), and dopamine (DA)--5-hydroxyindoleacetic acid (5HIAA), 3-methoxy-4-hydroxy=phenylglycol (MHPG), and homovanillic acid (HVA), respectively--were studied in a group of 26 age-similar military men with no history of major psychiatric illness, but with various personality disorders and difficulties adjusting to military life. Independently scored history of aggressive behavior showed a significant negative correlation with 5HIAA (r = -0.78) and a significant positive correlation with MHPG (r = 0.64).

Adult↗

PubMed1979

Changes in lymphocyte beta-adrenergic receptors in depression and mania.

The beta-adrenergic receptors were studied in vitro in lymphocytes obtained from patients with major affective disorders and controls. Specific L-[3H]-dihydroalprenolol binding was decreased in both depressed and manic patients compared to controls and euthymic patients. Isoproterenol-stimulated, but not prostaglandin El-stimulated, cyclic adenosine-3',5'-monophosphate production was decreased in manic and depressed patients. These results suggest decreased lymphocyte beta-receptor functioning in depression and mania. This decrease may be an index of changes in brain beta-receptors in mania and depression, or may simply reflect homeostatic regulation of peripheral beta-receptors in response to stress-induced increases in circulating catecholamines.

Adult↗

PubMed1979

Effect of moderate exercise on urinary MHPG in depressed patients.

This study attempted to clarify sources of artefact in biochemical studies with affective disorders in which 3-methoxy-4-hydroxy phenylglycol (MHPG) is used as a measurement of change in central nervous system norepinephrine (NE) turnover. Substantial increases in urinary MHPG excretion occurred in ten of the 11 patients when they increased their level of physical activity (0.5 +/- .14 mg/12 hrs versus 1.54 +/- .49 mg/12 hrs). Increases were also observed in NE (19.2 +/- 5.1 microgram/12 hrs versus 25.2 +/- 3.7 microgram/12 hrs). In four patients in whom cerebrospinal fluid MHPG levels were obtained a consistent increase of MHPG levels was observed during the activity period. Elevation of these metabolites were not correlated with changes in depression as reflected by psychiatric observation and rating scales. These data reveal a considerable amount of lability in urinary and CSF MHPG levels in the face of an unchanging affective state. They ask for careful controls for activity and stress in psychiatric patients when urinary MHPG is used as an index of central NE turnover.

Depression↗