Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this chapter we review trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5-HT). Central catecholamine neurons seem to play a critical role in level of alertness, vigilance, orienting, selective attention, memory, fear conditioning, and cardiovascular responses to life-threatening stimuli. Evidence of catecholamine dysregulation in post-traumatic stress disorder (PTSD) includes exaggerated increases in heart rate and blood pressure when exposed to visual and auditory reminders of trauma, elevated 24-hour urine catecholamine excretion, decreased platelet alpha-2 adrenergic receptor number, exaggerated behavioral, cardiovascular, and biochemical responses to IY yohimbine, decreased cortical brain metabolism secondary to IV yohimbine, and clinical efficacy of adrenergic blocking agents. Serotonin seems to play numerous roles in the central nervous system, including regulation of sleep, aggression, appetite, cardiovascular and respiratory activity, motor output, anxiety, mood, neuroendocrine secretion, and analgesia. Evidence of serotonergic dysregulation in PTSD includes frequent symptoms of aggression, impulsivity, depression and suicidality, decreased platelet paroxetine binding, blunted prolactin response to fenfluramine, exaggerated reactivity to m-chloro-phenyl-piperazine, and clinical efficacy of serotonin reuptake inhibitors. It has been suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, intrusive memories, depressed mood, and suicidality.
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PMID:Neurotransmitter alterations in PTSD: catecholamines and serotonin. 1055 29

Serotonin-1A (5-HT(1A)) receptors are implicated in neurochemical mechanisms underlying anxiety and depression and their treatment. Animal studies have suggested that 4-(2'-methoxyphenyl)-1-[2'-[ N-(2"-pyridinyl)- p-[(18)F]fluorobenzamido] ethyl] piperazine ( p-MPPF) may be a suitable positron emission tomography (PET) tracer of 5-HT(1A) receptors. To test p-MPPF in humans, we performed 60-min dynamic PET scans in 13 healthy volunteers after single bolus injection. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 25% of the total radioactivity in plasma corresponded to p-MPPF. Radioactivity concentration was highest in hippocampus, intermediate in neocortex and lowest in basal ganglia and cerebellum. The interactions between p-MPPF and 5-HT(1A) receptors were described using linear compartmental models with plasma input and reference tissue approaches. The two quantification methods provided similar results which are in agreement with previous reports on 5-HT(1A) receptor brain distribution. In conclusion, our results show that p-MPPF is a suitable PET radioligand for 5-HT(1A) receptor human studies.
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PMID:Quantification of 5-HT(1A) receptors in human brain using p-MPPF kinetic modelling and PET. 1180 10

The present study examined the effects of meta-chlorophenyl piperazine (mCPP) and mianserin on the sleep-wake cycle of the clomipramine-induced behaviorally screened depressed rats. Six-hour polygraphic recordings were made between 06:00 and 12:00 h, after a single injection of either saline or mianserin or mCPP into the lateral cerebral ventricle (i.c.v.) of both the depressed (n=12) and control rats (n=12). The injection of mCPP in the depressed rats caused a significant reduction in the total duration and number of rapid eye movement (REM) sleep episodes while it increased the REM sleep onset latency compared to the control saline injections. The injection of mianserin in the depressed rats also caused a significant reduction in the total duration and number of REM sleep episodes without changing the REM sleep latency. These results demonstrate for the first time that the central administration of mCPP and mianserin could act as an antidepressant in the clomipramine-induced rat model of depression.
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PMID:Sleep-wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat. 1243 92

We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.
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PMID:Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor. 1253 38

Dopamine neurons of the substantia nigra pars compacta receive a prominent serotonin (5-HT) projection from the dorsal raphe nucleus and important functional interactions between the serotonergic and the dopaminergic system have been postulated. In the present report we examined the role of 5-HT in the modulation of the metabotropic glutamate receptor-mediated inhibitory postsynaptic current (mGluR-IPSC) in midbrain dopamine neurons, and we found a reversible depression of this synaptic response at concentrations of 5-HT ranging from 100 nm to 30 microm (EC50 1.06 microm). This resulted in a shift towards excitation of the overall dopamine neuron response to glutamatergic synaptic input. This effect was not because of a direct modulation of the Ca2+-sensitive K+ conductances underlying the mGluR-IPSC, but was associated with a decrease in the intracellular calcium signal triggered by mGluR stimulation. Similar results were obtained with alpha-methyl-5-hydroxytryptamine and 5-methoxytryptamine, but not with 5-carboxamidotryptamine or 1-(3-chlorophenyl) piperazine. No significant depression of the mGluR-IPSC by 5-HT was observed in the presence of the 5-HT2 antagonist cinanserin or the 5-HT4 receptor antagonist RS 23597-190, whereas the 5-HT2C antagonist RS 102221 was ineffective. Our results demonstrate a powerful inhibition of the mGluR-IPSC by 5-HT in midbrain dopamine neurons, most probably through stimulation of 5-HT2A and 5-HT4 receptors.
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PMID:Depression of mGluR-mediated IPSCs by 5-HT in dopamine neurons of the rat substantia nigra pars compacta. 1465 23

Three new 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines, 1-(3-chlorophenyl)-4-[2-(4-fluorophenoxy)-2-phenylethyl]-piperazine 7, 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(2-methoxyphenyl)-piperazine 8, and 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-piperazine 9, modeled after the potent antidepressant fluoxetine and coupled with several functionalized piperazines, have been prepared by chemical synthesis as selective serotonin reuptake inhibitors (SSRIs) with a potentially improved adverse reaction profile. Typical SSRIs, although very effective in the treatment of depression, still face the troublesome side effect of sexual dysfunction. A number of pharmacological agents-notably, drugs in the piperazine class-have been used to reverse SSRI-induced sexual dysfunction, and evidence for developing an improved SSRI by coupling a fluoxetine congener with the pharmacophore of a reversal agent holds promise. Preliminary data indicates that the hydrochloride (HCl) salts 10, 11, and 12 each exhibit single-site binding at the site of the serotonin reuptake transporter (SERT). However, each of the three compounds are much less potent than typical SSRIs, showing micromolar (microM) affinity for the SERT with IC(50) values of 1.45 microM, 3.27 microM, and 9.56 microM, respectively. Further biological evaluation of compounds 10, 11, and 12 is needed before definitive conclusions can be made with regard to each compound's potential for use as an SSRI-type candidate which is devoid of sexual side effects. Nevertheless, the initial findings are quite encouraging, thus lending credence to the idea of hybridizing an SSRI congener with that of the pharmacophore of an agent known to reverse or treat SSRI-induced sexual dysfunction.
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PMID:Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile. 1501 22

A number of newer antianginal agents, including nicorandil, trimetazidine, and ivabradine, have been synthesized in recent years, but ranolazine, a piperazine derivative that partially inhibits fatty acid oxidation and the late INa current in animal models, is of particular interest mechanistically. Earlier clinical trials with immediate-release ranolazine led to the current sustained-release version tested in the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) (n = 193) and Combination Assessment of Ranolazine In Stable Angina (CARISA) trials (n = 823) of patients with chronic angina and severe limitation of exercise capacity (ie, < 5 metabolic equivalents). MARISA was a placebo-controlled, randomized trial that compared ranolazine monotherapy (500 mg, 1000 mg, and 1500 mg, twice daily) to placebo. CARISA was a placebo-controlled trial that randomized patients on background beta-blocker or calcium antagonist therapy to placebo or ranolazine (750 mg or 1000 mg, twice daily). Both studies showed a significant increase in total exercise duration, time to angina onset, and time to 1 mm ST segment depression. The average magnitude of increase in exercise duration over placebo was 29 to 56 seconds at peak and 24 to 46 seconds at trough with the 3 doses tested in MARISA, and 24 to 34 seconds greater than placebo with the 2 doses used in CARISA. The beneficial effect was achieved without clinically important changes in rest or exercise heart rate or blood pressure. Weekly angina attack frequency and nitroglycerin usage were significantly reduced in a dose-dependent manner in the 12-week CARISA trial. Reported adverse effects were similar in MARISA and CARISA and consisted of asthenia, nausea, constipation, and dizziness. Syncope, reported in 8 patients at doses of 1000 mg twice daily or more may be related to attenuation of alpha-1 receptor activity. The mean QTc interval increased with dose and was less than 10 msec on ranolazine at 1000 mg twice daily. The mortality rates at 1 and 2 years in MARISA and CARISA open-label run-on studies were 2% and less than 5%, acceptable for this high-risk population with limited exercise capacity. In conclusion, clinical trial evidence with ranolazine to date is consistent with its proposed mechanism of action and demonstrates an effective antianginal profile that may benefit patients with severe chronic angina.
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PMID:Efficacy and safety of a metabolic modulator drug in chronic stable angina: review of evidence from clinical trials. 1537 31

Trazodone is an antidepressant agent used in Spain since 1975. There are few documented reports of fatalities solely attributed to trazodone and none in which the main metabolite is analyzed. A fatal case of self-poisoning following oral ingestion is reported along with a description of the validated analytical methods involved, a discussion of poisoning characteristics, and a review of reports describing trazodone overdose cases with analytical results. The deceased was an 86-year-old man with cancer, who suffered depression. He went to see his doctor in a primary health care unit and told him he had just taken an unknown amount of tablets of Deprax to commit suicide. The doctor induced emesis as a first emergency measure. His death occurred before arriving to the hospital, and he left a suicide note nearby. Systematic toxicological analysis of postmortem blood used routinely in our laboratory revealed the presence of trazodone 4.9 mg/L and m-chlorophenyl-piperazine (m-CPP) 0.6 mg/L, its active and major metabolite. In addition, metamizol 19.6 mg/L and 4-methyl-amino-antipyrine (4-MAA) 40.7 mg/L, its active metabolite, were also found in blood. All drugs and metabolites involved in the case were detected using gas chromatography-nitrogen-phosphorus detection (GC-NPD) and confirmed using gas chromatography-mass spectrometry (GC-MS) mode total ion chromatogram. An additional high-performance liquid chromatography-diode array detection (HPLC-DAD) screening also obtained the same results. Quantitation of trazodone together with its metabolite in blood was carried out using GC-NPD, while quantitation of metamizol was performed using HPLC-DAD. Limits of detection for trazodone and m-CPP were 33 and 11 microg/L, respectively, absolute recoveries were more than 86% and 75%, respectively, intra-assay precisions less than 4%, interassay precisions less than 5%, and linearity up to 2.0 mg/L. Limit of detection for metamizol was 1117 microg/L, absolute recovery more than 84%, intra-assay precision less than 8%, interassay precision less than 12%, and linearity up to 48 mg/L. Based on the autopsy findings, patient history, toxicology results, and previously reported trazodone intoxications, the forensic pathologists ruled that the cause of death was due to an overdose of trazodone, and the manner of death was listed as suicide.
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PMID:Investigation of a fatality due to trazodone poisoning: case report and literature review. 1597 58

Cinnarizine, a piperazine derivative, is a widely prescribed medication for the treatment of vestibular disorders and motion sickness. Cinnarizine has antihistaminic, antiserotoninergic, antidopaminergic, and calcium channel-blocking properties. We present the first report in the English literature of cinnarizine poisoning and toxicokinetics. A 30-month-old toddler ingested 225 mg of cinnarizine, 18 times the recommended dose for older children. Four hours later, she became jittery with a wide-based gait and vomited 3 times. She was examined by her family physician, who reported stupor and twitching in both hands. On admission to the hospital, 6 hours after the ingestion, she was stuporous and had 3 short, generalized tonic-clonic convulsions that were controlled with a single dose of midazolam. Full clinical recovery was seen 10 hours after ingestion. Serum cinnarizine levels were 7407, 2629, and 711 ng/mL on admission and at 4 and 12 hours thereafter, respectively, 26.9 times higher than the therapeutic levels in adults. Elimination rate constant, calculated by linear regression of the ln concentrations of the 3 data points, was 0.19. Half-life, calculated from the equation t(1/2) = 0.693/kel, where kel is the elimination rate constant, was 3.65 hours. The manufacturing company revealed that their database contains 23 reports of cinnarizine overdose (adult and children), received between 1972 and 2004. Clinically, these cases reflect mainly symptoms of alterations in consciousness ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, and hypotonia. In a small number of young children, convulsions developed; recovery was uneventful in 4 cases and not reported in 1. The neurologic complication may be explained by the antihistaminic effect of cinnarizine because central nervous system depression and convulsions are known complications of antihistaminic overdose. It is hypothesized that cinnarizine-induced convulsions also are related to the antidopaminergic effect of the drug. Apart from the convulsions, no other adverse effects related to calcium channel-blocking properties, such as bradycardia or hemodynamic instability, were observed. Pediatric patients with cinnarizine overdose need to be observed in a health care facility for potential neurologic complications and be treated symptomatically. The delay to onset of clinical effect should be considered in the observation period.
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PMID:Pediatric cinnarizine overdose and toxicokinetics. 1663 15

EPIX Pharmaceuticals Inc (formerly Predix Pharmaceuticals Inc) is developing PRX-00023, an oral aryl piperazine 5-HT1A agonist, for the potential treatment of depression. While initially in development for generalized anxiety disorder, EPIX is now only focusing on the development of PRX-00023 for depression. In November 2006, EPIX reported that it planned to initiate a phase II trial in patients with depression in the first half of 2007.
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PMID:Drug evaluation: PRX-00023, a selective 5-HT1A receptor agonist for depression. 1726 89


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