Depressed Patients Have Decreased Binding of Tritiated Imipramine to Platelet Serotonin 'Transporter'
01 Dec 1981-Archives of General Psychiatry (American Medical Association)-Vol. 38, Iss: 12, pp 1315-1317
TL;DR: These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression.
Abstract: The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake sites for serotonin. Since there is an excellent correlation between the relative potencies of a series of antidepressants in displacing 3H-imipramine from binding sites in human brain and platelet, we have examined the binding of 3H-imipramine to platelets from 14 depressed patients and 28 age- and sex-matched controls. A highly significant decrease in the number of 3H-imipramine binding sites, with no significant change in the apparent affinity constants, was observed in platelets from the depressed patients compared with the controls. These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression.
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TL;DR: Treatment of depression in patients with CVD improves their dysphoria and other signs and symptoms of depression, improves quality of life, and perhaps even increases longevity.
Abstract: This article reviews the burgeoning literature on the relationship of mood disorders and heart disease. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with cardiovascular disease (CVD). This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction. This review of the extant literature is derived from MEDLINE searches (1966-1997) using the search terms "major depression," "psychiatry," "cardiovascular disease," and "pathophysiology." Studies investigating pathophysiological alterations related to CVD in depressed patients are reviewed. The few studies on treatment of depression in patients with CVD are also described. Treatment of depression in patients with CVD improves their dysphoria and other signs and symptoms of depression, improves quality of life, and perhaps even increases longevity. Recommendations for future research are proposed.
1,567 citations
TL;DR: A large family of related gene products expressed in rodent brain is identified from two highly conserved regions of the transporters for noradrenaline and γ-aminobutyric acid, and one of these products hybridizes to a single 3.7-kilobase RNA restricted to rat midbrain and brainstem, where it is highly enriched within the serotonergic raphe complex.
Abstract: SELECTIVE antagonism of serotonin (5-hydroxytryptamine, 5HT) and noradrenaline transport by antidepressants is a key element in the 'amine' hypothesis of affective disorders1. Uptake2,3 and/or transport sites4,5 of 5HT have been reported to be reduced in platelets of patients suffering from depression and in post-mortem brain samples of depressed patients6 and suicide victims7. To date there has been little molecular information available on the structure and regulation of 5HT transporters. Using the polymerase chain reaction8with degenerate oligonucleotides9 derived from two highly conserved regions of the transporters for noradrenaline10 and γ-aminobutyric acid11(GABA), we have identified a large family of related gene products expressed in rodent brain. One of these products hybridizes to a single 3.7-kilobase RNA restricted to rat midbrain and brainstem, where it is highly enriched within the serotonergic raphe complex. Transfection with a single 2.3-kilobase brainstem complementary DNA clone is sufficient to confer expression of a Na+-dependent 5HT transporter upon non-neural cells, with transport selectively and potently antagonized by 5HT uptake-specific antidepressants, including paroxetine, citalopram and fluoxetine.
829 citations
TL;DR: The characterization of 5-HTT gene will aid to advance molecular pharmacologic studies of5-HT uptake regulation and facilitate investigations of its role in psychiatric disorders.
Abstract: The gene encoding the human serotonin transporter (5-HTT) has been isolated and characterized. The human 5-HTT gene is composed of 14 exons spanning approximately 31 kb. The sequence of all exons including adjacent intronic sequences and a tandem repeat DNA polymorphism (VNTR) has been determined and deposited in the EMBL/GenBank data base with the accession numbers X76753 to X76762. The characterization of 5-HTT gene will aid to advance molecular pharmacologic studies of 5-HT uptake regulation and facilitate investigations of its role in psychiatric disorders.
625 citations
TL;DR: Understanding of the role of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain.
510 citations
Cites background from "Depressed Patients Have Decreased B..."
...Alterations in [3H]imipramine binding to the 5-HT reuptake site on human platelets have been associated with depressed states (Briley et al. 1980; Paul et al. 1981); however, Ellis et al....
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...Alterations in [3H]imipramine binding to the 5-HT reuptake site on human platelets have been associated with depressed states (Briley et al. 1980; Paul et al. 1981); however, Ellis et al. (1992) were unable to find a clear relationship between recovery from depression and [3H]imipramine platelet…...
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TL;DR: The combined findings of both studies support the decreased use of serotonin in suicide victims and may also throw light on the mechanism of action of antidepressant drugs.
500 citations
References
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Journal Article•
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
289,852 citations
TL;DR: The development and initial reliability studies of a set of specific diagnostic criteria for a selected group of functional psychiatric disorders, the Research Diagnostic Criteria (RDC), indicate high reliability for diagnostic judgments made using these criteria.
Abstract: • A crucial problem in psychiatry, affecting clinical work as well as research, is the generally low reliability of current psychiatric diagnostic procedures. This article describes the development and initial reliability studies of a set of specific diagnostic criteria for a selected group of functional psychiatric disorders, the Research Diagnostic Criteria (RDC). The RDC are being widely used to study a variety of research issues, particularly those related to genetics, psychobiology of selected mental disorders, and treatment outcome. The data presented here indicate high reliability for diagnostic judgments made using these criteria.
6,238 citations
TL;DR: Results suggest that binding of tritiated imipramine in human platelets may represent a biochemical index of depression, possibly reflecting similar changes in the brain.
Abstract: The high-affinity binding of triatiated imipramine to platelet membranes was compared in samples from 16 untreated depressed women and 21 age-matched controls of the same sex. The maximal binding in the depressed group was significantly lower than that of the controls, although the affinity constants were similar. These results suggest that binding of tritiated imipramine in human platelets may represent a biochemical index of depression, possibly reflecting similar changes in the brain.
429 citations
TL;DR: A population of specific high-affinity binding sites for 3H-imipramine on brain membranes which may be responsible for the antidepressant effects of these drugs are demonstrated.
Abstract: The discovery of high-affinity binding sites for psychoactive drugs such as benzodiazepines1,2, opiates3 and neuroleptics4 has opened up new approaches to the study of these drugs and their mechanisms of action. Although most tricyclic antidepressants inhibit neuronal uptake of noradrenaline and serotonin5, their mechanism of action remains unclear. Changes in the sensitivity of the β-receptor after chronic tricyclic antidepressant treatment6,7 suggest that they modulate noradrenergic neuro-transmission. Tricyclic antidepressants also act directly on cholinergic8, histaminergic9, α-adrenergic10 and serotonergic11 receptors. It is not clear, however, which, if any, of these effects are related to the primary antidepressant effect or whether they are simply responsible for some of the side effects. We have thus investigated the possibility that specific binding sites for tricyclic antidepressants exist in the central nervous system. So far, binding studies using 3H-labelled tricyclic antidepressant drugs have only detected binding to histaminergic H2 and cholinergic muscarinic receptors12 and low-affinity binding13. We demonstrate here a population of specific high-affinity binding sites for 3H-imipramine on brain membranes which may be responsible for the antidepressant effects of these drugs.
266 citations
TL;DR: This report indicates that in the platelets of depressed patients the uptake of 5-HT is clearly decreased, and both the uptake kinetics in platelets and the inhibitory potencies of antidepressant drugs were recently shown to correlate well with those found in synaptosomes.
Abstract: THE search for biological aberrations in affective disorders has been intensified within the last few years1. Special attention has been given to the changes in the metabolites of 5-hydroxytryptamine (5-HT) and of catecholamines in the cerebrospinal fluid2. In this laboratory3 as well as in several others4,5 the blood platelet has been used as an easily obtainable model of 5-HT neurones. Studies on the storage, metabolism and uptake of 5-HT in various neurological and mental illnesses have been largely negative1,6,7 except in Down's syndrome8–10. Neither in schizophrenia6 nor in affective illness7 have any changes been found. By using low substrate concentrations and measuring the initial uptake rate, both the uptake kinetics in platelets and the inhibitory potencies of antidepressant drugs were recently shown to correlate well with those found in synaptosomes11. It was therefore of considerable interest to examine the kinetics of 5-HT uptake anew, in the platelets of certain psychiatric patients, notably those with manic-depressive illness. This report indicates that in the platelets of depressed patients the uptake of 5-HT is clearly decreased.
254 citations