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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Depression, a chronic disease and a leading cause of disability worldwide, will generate increasing needs in terms of public health in the coming years. Many antidepressants are now available. However, these molecules present real limitations and disadvantages. Thus there are great expectations on the part of the clinicians for more efficient drugs that are better tolerated. How can we satisfy such hopes and innovate in this domain today? One original and most promising strategy for developing new antidepressants that are more efficient and better tolerated involves antagonizing both alpha 2-noradrenergic and 5HT2 and 5HT3 serotonergic receptors, without blocking 5HT1A serotonergic receptors. The technology now available in pharmacological research allows the development of such molecules.
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PMID:[Pharmacological approach to failures of antidepressant treatment]. 994 41

This study sought to determine whether depressive symptoms and/or platelet serotonin receptor (5HT2A) density are associated with increased platelet activation (PA) found among smokers. Flow cytometric detection of PA was used to study 36 smokers and 16 nonsmokers, aged 18 to 48 years. Subjects were tested at baseline and after either smoking 2 cigarettes (smokers) or a similar resting interval (nonsmokers). Assessment of PA included both platelet secretion and fibrinogen receptor (GPIIb/IIIa) binding. Platelet 5HT2A receptor binding and saturation were tested using [3H]LSD, and depressive symptoms were measured using the Beck Depression Inventory. Platelet 5HT2A receptor density was increased among smokers versus nonsmokers (82.7+/-67.7 versus 40.0+/-20.2 fmol/mg protein; P<0.005), and there was a dose-dependent relationship between receptor density and packs/d among smokers. Baseline wound-induced GPIIb/IIIa binding at 1 minute and GPIIb/IIIa binding in response to collagen stimulation in vitro was increased among smokers (P<0.05); there were no changes in PA among smokers after smoking, and platelet secretion was not elevated among smokers. Depressive symptoms were associated with 5HT2A receptor density among nonsmokers (P<0.005), but no such relationship was evident among smokers; PA was unrelated to 5HT2A receptor density in either group. The findings indicate that smoking is associated with increased platelet serotonin receptor density and with increased GPIIb/IIIa receptor binding, although these 2 factors are not related to each other or to depressive symptoms among smokers. Serotonergic dysfunction may be an important factor in the development of cardiovascular disease among smokers.
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PMID:Increased serotonin receptor density and platelet GPIIb/IIIa activation among smokers. 1007 84

In epilepsy research, there is a growing interest in the role of the piriform cortex (PC) in the development and maintenance of limbic kindling and other types of limbic epileptogenesis leading to complex partial seizures. Neurophysiological studies on PC or amygdala-PC slice preparations from kindled rats showed that kindling of the amygdala induces long-lasting changes in synaptic efficacy in the ipsilateral PC, including spontaneous discharges and enhanced susceptibility of PC neurons to evoked burst responses. These long-lasting electrophysiological changes in the PC during kindling appear to be due, at least in part, to impaired function of gamma-aminobutyric acid (GABA)ergic interneurons. The aim of the present study was to develop an anesthetic protocol allowing electrophysiological single-unit recordings from inhibitory, presumably GABAergic PC interneurons in vivo. In addition to recording of spontaneously active PC neurons, microiontophoretic application of glutamate was used to activate silent neurons. Anesthesia of rats with ketamine/xylazine was not suited for single-unit recordings in the PC because of marked cardiovascular depression. Anesthesia with chloral hydrate allowed recording of spontaneous or glutamate-driven single-unit activity in approximately 40% of all animals. A similar percentage was obtained when recordings were done with the narcotic opioid fentanyl (plus gallamine), after all surgical preparations were performed under anesthesia with repeated administration of the barbiturate methohexital. To avoid brain accumulation of methohexital by repeated applications, we modified the anesthetic protocol in that methohexital was only injected once for initiation of surgical anesthesia, followed by the short-acting anesthetic propofol which does not accumulate upon repeated application. Again, after surgical preparation, electrophysiological recordings were done under fentanyl (plus gallamine). By this procedure, spontaneous or glutamate-driven single-unit activity could be measured in all rats in either layer II or III of the PC. Based on shape and frequency of action potentials, two types of neurons were recorded. The predominant type was similar in its firing characteristics to GABAergic neurons in other brain regions, was mainly located in layer III, and could be suppressed by the serotonin2A receptor antagonist MDL 100,907, suggesting that this type of PC neuron represents inhibitory, putative GABAergic interneurons. This new in vivo preparation may be useful for evaluation of PC neurons in kindled rats.
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PMID:Extracellular single-unit recordings of piriform cortex neurons in rats: influence of different types of anesthesia and characterization of neurons by pharmacological manipulation of serotonin receptors. 1008 83

We report on the successful treatment of two female patients with psychotic depression with the new atypical neuroleptic drug olanzapine. A 75-year-old female inpatient suffering from recurrent endogenous depression with tactile hallucinations and coenesthesia was refractory to a systematic sequential antidepressant treatment strategy during a 39-week period. After addition of the new atypical neuroleptic olanzapine to the SSRI citalopram, she showed immediate and ongoing symptom relief. In the second case of a 57-year-old female inpatient suffering from delusional depression, we observed marked symptom relief and correction of the delusions of impoverishment. Olanzapine is discussed with regard to its receptor-binding profile (antagonism to 5-HT2A- and D1-D4 receptors) as a potential neuroleptic drug in the treatment of affective disorders with psychotic symptoms.
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PMID:[Olanzapine in the treatment of depressive disorders with psychotic symptoms]. 1008 20

Serotonin (5-HT) plays a central role in the neurochemistry of the learned helplessness animal model of depression. Using quantitative autoradiography, we measured the density of 5-HT1A and 5-HT2A receptors and of 5-HT transport sites in medial prefrontal cortex, dorsal hippocampus, septum, hypothalamus, and amygdala in learned helpless rats, and in rats that were nonhelpless after inescapable stress, as well as in shuttlebox-tested and nonhandled controls. We found no changes in 5-HT1A receptor density among the groups in any region studied. In dorsal hippocampus, 5-HT2A receptor density was decreased in nonhelpless rats, while in amygdala 5-HT2A receptor density was decreased in both groups of stressed rats, whether helpless or nonhelpless. In the hypothalamus 5-HT2A receptor density, was decreased in helpless rats as compared to controls. In medial prefrontal cortex, the serotonin transport sites showed decreased density in helpless rats as compared to controls but not to nonhelpless rats. These findings further highlight the complexity of regional 5-HT effects in the learned helplessness animal model.
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PMID:Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT2A receptors and the serotonin transport site in rat brain. 1009 35

Exogenous delivery of the neurotrophic factors, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), promotes the function, sprouting and regrowth of 5-HT-containing neurones in the brains of adult rats. Similar infusions of BDNF into the dorsal raphe nucleus produce an antidepressant effect, as evaluated by several 'learned helplessness' paradigms. Environmental stressors such as immobilization induce depression and decrease BDNF mRNA. Antidepressants increase BDNF mRNA in the brain, via 5-HT2A and beta-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA. In this article, Tony Altar discusses how existing treatments of depression might work by increasing endogenous brain levels of BDNF or NT-3, which in turn could promote monoamine-containing neurone growth and function. Drugs that selectively stimulate the production of neurotrophins could represent a new generation of antidepressants.
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PMID:Neurotrophins and depression. 1010 65

The aims of this study were to examine whether pindolol, a serotonin (5-hydroxytryptamine [5-HT])-1A receptor antagonist, and mianserin, a 5-HT2A/C and alpha2-adrenoceptor (alpha2-AR) antagonist, may augment the clinical efficacy of fluoxetine, a selective serotonin reuptake inhibitor, and shorten the latency of onset of antidepressive activity in the treatment of major and treatment-resistant depression (TRD). Ten days after admission to the hospital, 31 major depressed patients were randomly assigned using a double-blind, controlled design to receive fluoxetine 20 mg daily, fluoxetine 20 mg daily plus pindolol 7.5 mg daily, or fluoxetine 20 mg plus mianserin 30 mg daily for 5 weeks. The 17-item Hamilton Rating Scale for Depression (HAM-D) score was the primary outcome measure. Analysis of efficacy was conducted according to the intent-to-treat analysis principle considering the change from baseline to endpoint. It was found that fluoxetine plus pindolol and fluoxetine plus mianserin were significantly more effective than fluoxetine alone. Using an outcome measure of 50% reduction in the HAM-D, a 60% response rate was found in patients treated with either fluoxetine plus pindolol or fluoxetine plus mianserin compared with a 9% response rate in patients treated with fluoxetine alone. The HAM-D score 1 week after starting fluoxetine plus mianserin decreased more than 4 points and was significantly greater than that obtained by fluoxetine alone. The results suggest that pindolol and mianserin augment the efficacy of fluoxetine in the treatment of TRD and that mianserin, but not pindolol, may significantly shorten the latency of onset of antidepressive action when combined with fluoxetine.
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PMID:Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients, including those with treatment resistance. 1021 20

LB50016 was characterized as a selective and potent 5-HT1A receptor agonist and evaluate its anxiolytic and antidepressant activities. It shows high affinity for 5-HT1A receptor, moderate affinity for alpha 2 adrenergic and 5-HT2A receptors and no significant affinity for other receptors tested. Hypothermia and increased serum corticosterone level were observed in LB50016-treated rats, which are mediated mostly by post synaptic 5-HT1A receptor activation. In the mouse forced swim model for depression, LB50016-elicited dose-dependent reductions in immobility time, showing ED50 of approximately 3 mg/kg i.p., which was blocked by pretreatment of NAN-190, 5-HT1A antagonist. In face-to-face test for anxiolytic activity in mice, estimated ED50 was 2 mg/kg, i.p. In isolation-induced aggression test with mice, fifty-fold increases in latency to attack were observed at 30 min and last up to 4 h after LB50016 treatment (3 mg/kg, i.p.). Taken together, LB50016-induced pharmacological activities are mediated by activation of 5-HT1A receptors, offering an effective therapeutic candidate in the management of anxiety and depression in humans.
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PMID:Pharmacological characterization of LB50016, N-(4-amino)butyl 3-phenylpyrrolidine derivative, as a new 5-HT1A receptor agonist. 1023 May 6

To further investigate the possible function of the serotonergic system in the pathophysiology of attention deficit hyperactivity disorder (ADHD), platelet serotonin 5-HT2A receptors were characterized for 19 ADHD children and 17 age-matched control subjects. Subjects were evaluated using the Diagnostic Interview for Children and Adolescents (DICA-R-C)-DSM IV and the Children's Depression Inventory. An aggressive subgroup was also determined by the presence of two or more positive aggressive symptoms on either subjects' or parents' reports. Platelets were isolated from venous blood and 5-HT2A receptor number, and affinity was determined using 125I-LSD binding. There was no difference in platelet 5-HT2A receptor binding characteristics between the two groups. The results from this pilot study suggest a limited function of 5-HT2A receptors in the pathophysiology of ADHD and extend the findings of other previous negative studies of the peripheral serotonergic system in ADHD.
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PMID:No difference between platelet serotonin--5-HT(2A) receptors from children with and without ADHD. 1035 15

Electroconvulsive therapy (ECT) is used to treat drug-resistant depressive disorders. The results of studies on the mechanism underlying the effectiveness of ECT on depression are still controversial. ECT stimulus is usually larger than the threshold of induction of seizures and activation of whole-brain is believed to be necessary to produce therapeutic effects. A single ECT session induces alterations of the electroencephalogram (EEG) including initial epileptic discharges, then slow waves, and finally flattened EEG. Repeated ECT results in an increasing number of slower waves in the EEG for as long as a month. ECT-induced changes in various neurotransmitter systems have also been reported. Serotonin (5-hydroxytryptamine, 5-HT) is one of the most important neurotransmitters involved in depressive illness, and ECT alters several 5-HT-receptor subtypes in the central nervous system. 5-HT1A receptors in post-synaptic neurons are sensitized by repeated ECT, but those in pre-synaptic neurons (auto-receptors) are not changed. In addition, our electrophysiological studies have shown that ECT increases sensitivity to 5-HT of 5-HT3 receptors in the hippocampus, resulting in an increase in release of neurotransmitters such as glutamate and gamma-aminobutyric acid. In contrast, ECT decreases the auto-receptor functions in noradrenergic and dopaminergic neurons in the locus coeruleus and substantia nigra, respectively, resulting in an increase in release of noradrenaline and dopamine. In conclusion, 5-HT1A-receptor sensitization may be important for explaining the effectiveness of ECT, as this change induces a decrease in the number of 5-HT2A receptors that are elevated in depressive patients. Facilitation of neurotransmitter releases due to 5-HT3-receptor sensitization by ECT may also play an important role in effective treatment of depressive patients refractory to therapeutic drugs.
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PMID:Mechanism underlying the therapeutic effects of electroconvulsive therapy (ECT) on depression. 1046 62


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